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Multiple Sclerosis References: 2003

(826 References)

Aarli, J. A. (2003). "Role of cytokines in neurological disorders." Curr Med Chem 10(19): 1931-7.

            The balance between cytokines with pro- and anti-inflammatory effects contributes to the course of the Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. TNFalpha seems to be an important factor in the cascade of events leading to demyelination and even axonal damage. During the acute phase, the serum concentrations of TNFalpha and IL-6 are elevated while anti-inflammatory cytokines are up-regulated in the recovery phase. Cytokines also have a key role in the pathogenesis of multiple sclerosis and most data suggest that this effect is mediated by myelin-specific CD4 T lymphocytes secreting Th type 1 cytokines. However, several different immune cells including B lymphocytes, CD8 T lymphocytes and NK T lymphocytes are also involved in the pathogenesis. Both Th1 and Th2 lymphocytes and cytokines probably participate in the development of myasthenia gravis (MG). The IFNalpha production is probably related to the severity of the disease, with clinical improvement associated with decreased production. The serum levels of IL-18 are significantly elevated in MG, with highest concentrations in patients with generalized disease. The immune system may be involved in the pathogenesis of AD by the effect of microglia, which can induce microglial activation with subsequent release of pro-inflammatory cytokines. In parkinsonism, there is evidence of chronic inflammation in the substantia nigra and striatum. Activated microglia, producing proinflammatory cytokines, surround the degenerating dopaminergic neurons and may contribute to the dopaminergic neuron loss. Studies of patients with epilepsy and animals with experimentally induced seizures indicate that cytokines may also influence the electrophysiological properties of neurons.


Aboul-Enein, F., H. Rauschka, et al. (2003). "Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases." J Neuropathol Exp Neurol 62(1): 25-33.

            Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.


Acar, G., F. Idiman, et al. (2003). "Nitric oxide as an activity marker in multiple sclerosis." J Neurol 250(5): 588-92.

            Nitric oxide (NO) molecules have one of the most important roles in the pathogenesis of multiple sclerosis (MS). It has been stated that a continuous and high concentration of NO metabolites in CSF and in the serum of MS patients in relapse may cause toxic damage to myelin and oligodendroglia. The aim of this study was to investigate whether NO is a marker of disease activity and is correlated with other disease activity markers such as active lesions on brain magnetic resonance imaging (MRI) and increased immunoglobulin G (IgG) index.Cerebrospinal fluid (CSF) and peripheral serum (PS) samples were taken from patients with definite MS (n = 24) during relapse and remission and from control subjects (n = 18). The Griess reaction was used to measure the NO metabolites, nitrite and nitrate in CSF and PS. Cranial MRI was carried out with triple dose (0,3 mmol/kg) gadolinium and the IgG index was determined.Nitrite and nitrate concentrations (NNCs) of CSF were 11.16 +/- 8.60 micromol/ml in relapse and 6.72 +/- 3.50 micromol/ml in remission, whereas in PS they were 12.89 +/- 7.62 micromol/ml during relapse and 12.35 +/- 6.62 micromol/ml during remission. In control subjects NNCs in CSF and PS were 7.42 +/- 2.81 micromol/ml and 4.37 +/- 1.63 micromol/ml respectively. NNCs in CSF during relapse period were significantly higher than those of both remission phase and control subjects (p = 0.000). Although serum NNCs did not differ in relapse and remission, they were still higher than normal controls. Validity analysis revealed that NNC measurement in CSF was 71 % specific and 66 % sensitive to disease activity. The most important result was the significant correlation of increased NNCs with the existence of active lesion in cranial MRI and an increase in IgG index (p < 0.05).In conclusion, these results add background data to assist in further outlining the possible role of NO in the pathogenesis of MS. Together with the other markers it may be used as an activity marker in relapses of MS.


Achiron, A., Y. Barak, et al. (2003). "Alfacalcidol treatment in multiple sclerosis." Clin Neuropharmacol 26(2): 53.


Achiron, A. and Y. Barak (2003). "Cognitive impairment in probable multiple sclerosis." J Neurol Neurosurg Psychiatry 74(4): 443-6.

            OBJECTIVES: To evaluate and characterise cognitive impairment in the very early stage of multiple sclerosis (MS), in which patients are still diagnosed as suffering from probable MS. METHODS: The Brief Repeatable Battery-Neuropsychological (BRB-N) that has been validated for MS patients was used. Abnormal performance was defined as one standard deviation below the mean reported for healthy age matched subjects. Neurological disability and brain magnetic resonance imaging (MRI) were performed for all patients. Correlation coefficients were calculated between disease burden variables and performance on the BRB-N. RESULTS: Sixty seven patients with probable MS were evaluated within a mean of one month of the onset of new neurological symptoms. Evidence for the presence of cognitive impairment was shown in 53.7% of patients. Verbal abilities and attention span were most frequently affected. Impairment was not correlated with neurological disability or MRI disease burden. CONCLUSION: Prevalent cognitive impairment already exists at onset of MS.


Ackerman, K. D., A. Stover, et al. (2003). "Relationship of cardiovascular reactivity, stressful life events, and multiple sclerosis disease activity." Brain Behav Immun 17(3): 141-51.

            Previous studies of stress in multiple sclerosis patients have suggested that life events may alter the onset and development of MS. However, results have been inconsistent because of infrequent monitoring and reporting bias. We followed fifty female MS patients for 1 year to determine characteristics of life events associated with MS exacerbations, and examine the influence of cardiovascular activity. Subjects completed weekly life-event checklists. The short- and long-term threat of each event was determined using the Life Events and Difficulties Schedule. Neurologic symptoms were also monitored weekly. MS exacerbations were confirmed by a neurologist blinded to psychosocial events. Cardiovascular reactivity to an acute psychological stressor was determined at study onset, and resting heart rate and blood pressure were monitored monthly. Forty-two percent of life events were associated with exacerbations in the subsequent 6 weeks. Logistic regression confirmed that exacerbations were more likely during at-risk periods following life events and were relatively independent of the threat level and type of stressor. Participants with higher cardiovascular reactivity to acute stress and higher baseline heart rate demonstrated a greater number of exacerbations and proportion of weeks ill. Using multiple regression, we found that disability level, medication usage, cardiovascular reactivity, baseline heart rate, and life event density explained approximately 30% of the variance in the proportion of weeks ill. These results are consistent with the hypothesis that stress is a potential trigger of MS disease activity and suggest that autonomic tone and stress reactivity may play a role in the development of stress-related exacerbations.


Adam, P., O. Sobek, et al. (2003). "CSF and serum orosomucoid (alpha-1-acid glycoprotein) in patients with multiple sclerosis: a comparison among particular subgroups of MS patients." Clin Chim Acta 334(1-2): 107-10.

            INTRODUCTION: To compare cerebrospinal fluid (CSF) and serum orosomucoid (alpha-1-acid glycoprotein-AAG) concentrations in various subgroups of patients with multiple sclerosis (MS). MATERIALS AND METHODS: CSF and serum AAG concentrations, AAG quotient (i.e., CSF AAG/serum AAGx10(3)) and index were determined in a group of 59 patients with clinically definite or probable MS. Patients were subdivided according to the disease form, disease severity according to an expanded disability status scale (EDSS), its treatment, disease duration and sex. RESULTS: CSF AAG was increased in 52.5% of the patients and AAG quotient even in 64.4%. An increase in the CSF AAG concentration, as well as in AAG quotient and index, appear only after several years of disease duration, while no significant correlation with age has been found. This suggests that CSF AAG changes in MS represent a secondary, unspecific phenomenon and that this protein is not relevant for the aethiopathogenesis of the disease. Nevertheless, the finding of subnormal CSF AAG levels in some MS patients in remission (never observed in those in the attack) implies the possibility that CSF AAG may be used as a "state marker" in MS. Serum AAG levels were significantly lower in secondary progressive form and in severely disabled patients. This observation suggest that serum AAG values determination might have some prognostic significance. Further studies are, however, needed. Serum AAG should be investigated in parallel with other CSF and serum protein fractions in order to establish a pannel of examinations enabling multiple statistical analyses. This approach may lead to the finding of a "complex state marker" enabling thus to evaluate more precisely disease course in individual patients and to accept appropriate therapeutic measures.


Adiga, G. U., L. Abebe, et al. (2003). "Partially successful treatment of a patient with chronic lymphocytic leukemia and Hodgkin's disease: case report and literature review." Am J Hematol 72(4): 267-73.

            Chronic lymphocytic leukemia (CLL) is rarely associated with Hodgkin's disease (HD). We report a case of nodular sclerosis HD in a patient previously diagnosed with CLL. Reed-Sternberg cells were CD15(+) and CD30(+). He was treated with dose-escalated CHOP and at relapse, mitoxantrone, vinblastine, and CCNU (MVC) with partial response to the former and complete response to the latter, although the patient died 15 months later. Data from 88 other similar cases published in the English language were analyzed. Based on the histological and clinical features at the time of transformation, these patients were divided into distinct categories for analysis. Prognosis was found to be poorer in patients with continued active CLL when compared with those with CLL in remission at the time of transformation to HD. It is suggested that these two presentations may derive from different pathogenic mechanisms.


Aggarwal, S., N. Ghilardi, et al. (2003). "Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17." J Biol Chem 278(3): 1910-4.

            Interleukin (IL)-17 is a pro-inflammatory cytokine that is produced by activated T cells. Despite increasing evidence that high levels of IL-17 are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis, and multiple sclerosis, the regulation of its expression is not well characterized. We observe that IL-17 production is increased in response to the recently described cytokine IL-23. We present evidence that murine IL-23, which is produced by activated dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion. IL-23 also induced expression of the related cytokine IL-17F. IL-23 is a heterodimeric cytokine and shares a subunit, p40, with IL-12. In contrast to IL-23, IL-12 had only marginal effects on IL-17 production. These data suggest that during a secondary immune response, IL-23 can promote an activation state with features distinct from the well characterized Th1 and Th2 profiles.


Akassoglou, K., E. Douni, et al. (2003). "Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice." Proc Natl Acad Sci U S A 100(2): 709-14.

            Tumor necrosis factor (TNF) is up-regulated in a variety of central nervous system (CNS) diseases with diverse etiology and pathologic manifestation. TNF mediates multiple biological activities through two membrane receptors, the p55 and p75 TNF receptors (TNFRs). We have shown previously that human transmembrane TNF (tmTNF)p55TNFR signaling in transgenic mice triggers oligodendrocyte apoptosis, endothelial cell activation, parenchymal inflammation, and primary demyelinating lesions similar to those of acute multiple sclerosis. To address the role of the p75TNFR in the CNS, we have generated "humanized" mice that express human tmTNF in astrocytes and a physiologically regulated human p75TNFR transgene, in the absence of the endogenous (murine) p55TNFR. Human tmTNFp75TNFR transgenic mice develop CNS vascular pathology, characterized by endothelial cell activation, meningeal inflammation, and vessel fibrosis. There is no evidence of oligodendrocyte apoptosis or primary demyelination in these mice. Late in disease, vasculitis can result in vessel occlusion and secondary, multifocal CNS ischemic injury. These results identify a proinflammatory role for the p75TNFR at the level of the CNS vascular endothelium, which correlates with the expression pattern of this receptor in the CNS, and indicate that the differential expression patterns of the two TNFRs within the CNS play a significant role in shaping the outcome of TNF signaling during neuroimmune interactions.


Aktas, O. and F. Zipp (2003). "Regulation of self-reactive T cells by human immunoglobulins--implications for multiple sclerosis therapy." Curr Pharm Des 9(3): 245-56.

            The intravenous administration of high doses of immunoglobulins pooled from the plasma of healthy donors (IVIg therapy) has beneficial effects in patients with a variety of autoimmune disorders. These clinical observations indicate that IVIg have potent antiinflammatory characteristics, and identification of the precise mode of action may open up perspectives for future therapeutic strategies. In certain tissue-specific autoimmune disorders like multiple sclerosis (MS), self-reactive T cells recognizing autoantigens play a significant role for disease pathogenesis, as these cells are able to initiate, maintain, and propagate the harmful immune attack in experimental animal models of disease. These findings render self-reactive T cells an important therapeutic target for autoimmune diseases. Here, we review the effects of IVIg on the homeostasis of T cells and discuss the possible therapeutic implications for multiple sclerosis. As supported by several experimental studies, IVIg regulate crucial steps of T cell-mediated immune responses. These effects involve the modulation of activation, proliferation, differentiation, apoptosis, and effector mechanisms of T cells. The pattern of IVIg-T cell interactions is complex, as IVIg may directly bind to regulatory structures on T cells, or modulate T cell functions indirectly via soluble or cellular components of the immune system.


Al-Shammari, S., R. F. Nelson, et al. (2003). "HHV-6 DNAaemia in patients with multiple sclerosis in Kuwait." Acta Neurol Scand 107(2): 122-4.

            OBJECTIVE: To study the presence of active human herpesvirus type-6 (HHV-6) infection indicated by the presence of HHV-6 DNA in serum (DNAaemia) in patients suffering from multiple sclerosis (MS) in Kuwait. MATERIAL AND METHODS: Sera from 24 patients with MS (18 relapsing-remitting, six secondary progressive disease), control sera from 13 patients suffering from other neurological diseases and sera from 20 healthy volunteers were examined for the presence of HHV-6 DNA by nested polymerase chain reaction (PCR) test. RESULTS: None of the MS patients, nor patient controls were positive for HHV-6 DNAaemia while, one of the normal healthy controls was positive for HHV-6 DNAaemia. CONCLUSION: HHV-6 DNAaemia, indicating active HHV-6 infection could not be demonstrated in a sample of Kuwaiti patients suffering from active clinically definite MS. There is no evidence to incriminate this virus in the pathogenesis of MS in Kuwait.


Albrecht, P. J., J. C. Murtie, et al. (2003). "Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production." Neurobiol Dis 13(2): 89-101.

            Multiple sclerosis is characterized by multiple lesions with selective loss of myelin and oligodendrocytes, leading to deficits of sensation and movement, as well as cognitive disabilities. Consequently, a major research endeavor is to identify strategies to enhance oligodendrocyte regeneration and remyelination. FGF-2 is a potent mitogen for OPCs, and it is induced in astrocytes in animal models of demyelinating diseases in conjunction with successful remyelination. However, the factors responsible for inducing FGF-2 after demyelination in astrocytes are unknown. Here we show that CNTF mRNA and protein increase coincident with spinal cord remyelination in mice recovering from MHV-induced demyelination. We identify CNTF within astrocytes surrounding and within remyelinating lesions, and show that CNTF increases FGF-2 ligand and receptor mRNAs in spinal cord after direct application. Furthermore, we show that CNTF increases FGF-2 mRNA approximately 2.5-fold in cultured mouse spinal cord astrocytes. Altogether, these results strongly implicate CNTF as an important cytokine in demyelinating disease and as an upstream regulator of FGF-2 production in astrocytes during early remyelination.


Alizadeh, M., M. C. Babron, et al. (2003). "Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients." Ann Neurol 54(1): 119-22.

            Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122


Alley, J., S. Khasabov, et al. (2003). "More severe neurologic deficits in SJL/J male than female mice following Theiler's virus-induced CNS demyelination." Exp Neurol 180(1): 14-24.

            Although multiple sclerosis (MS) is more prevalent in women than men, male MS patients develop more severe clinical symptoms and deteriorate faster than female patients. We investigated the differences in CNS demyelinating disease between SJL/J male and female mice following Theiler's murine encephalomyelitis virus (TMEV) infection. Infected female mice had consistently higher serum levels of virus-specific IgG at 14 and 21 days and and 7 months postinfection, which resulted in less infectious virus in CNS. All male mice infected for 6 to 7 months developed paralysis, with 50% displaying bilateral posterior limb paralysis, whereas 77% of age-matched female mice were paralyzed, all displaying unilateral posterior limb paralysis. Male mice infected for 6 to 7 months performed up to threefold fewer spontaneous horizontal and vertical movements (activity box test) compared to infected age-matched females. In addition, infected male mice performed the coordination and balance (Rotarod) test at 27 +/- 4% of the expected level (expressed as a percentage of that of uninfected age-matched mice), whereas infected female mice performed at 41 +/- 5% of the expected level. Male mice had a small increase in the extent of spinal cord white matter demyelination analyzed at both 45 days and between 6 and 7 months postinfection. For individual male and female mice, the extent of demyelination had a negative linear relationship with the neurologic performances. The emergence of a disease paradigm similar to MS supports using the TMEV model to investigate molecular and genetic factors responsible for the gender dimorphism in MS and other autoimmune diseases.


Alter, A., M. Duddy, et al. (2003). "Determinants of human B cell migration across brain endothelial cells." J Immunol 170(9): 4497-505.

            Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.


Alusi, S. H., S. Glickman, et al. (2003). "Target board test for the quantification of ataxia in tremulous patients." Clin Rehabil 17(2): 140-9.

            OBJECTIVE: The objective was to develop and assess the validity and reliability of a target board test (TBT) for quantifying ataxia and measuring dysmetria in the presence of tremor. DESIGN: Each subject was instructed to reach out and mark a target placed at arm's length with a pen (10 times with each hand). Ten patients performed the test twice. SETTING: A hospital-based multiple sclerosis (MS) unit. SUBJECTS: Fifty-three patients with MS and upper limb tremor/ataxia and 20 healthy control subjects. The MS patients were classified into four subgroups: MS control group (n = 13), MS tremor group (n = 9), MS dysmetria group (n = 6), MS mixed (tremor and dysmetria) group (n = 25). MAIN OUTCOME MEASURES: The main outcome measures were the average radial distance away from the target (mean R) and the mean directional error (mean V) of the 10 contact points from the target. From these a dysmetria tremor index (DTI) was calculated by dividing mean V by mean R. Also used were a dysmetria scale, a dysdiadochokinesia scale and a finger-tapping test. RESULTS: Mean R correlated significantly with dysmetria, dysdiadochokinesia, kinetic tremor and (inversely) with the finger-tapping test (all p < 0.005). The median difference between two measurements of mean R for all 10 contact points was 11.3% and 19.0% and for mean V48.3% and 63.4% and DTI 57.2% and 50.5% for the right- and left-hand sides respectively, indicating the considerable directional variability within ataxia. CONCLUSION: The TBT provides simple quantitative objective measurements of upper limb ataxia.


Alvarez-Linera, J., J. Escribano, et al. (2003). "[Hydrogen spectroscopy in neurology]." Neurologia 18(6): 324-40.

            for a long time to the research field despite its unquestionable diagnostic value. The availavility of programs able to automatically obtain a spectrum, and the current possibility of estimating easily the relationship among its different peaks, have approached this diagnostic technology to the current clinical situation. With hydrogen MRI spectroscopy (MRS) it is possible to obtain additional information which make it possible to distinguish among different neurological alterations with similar morphological appearance, such as cerebral tumors and pseudotumoral types of inflammatory processes, or tumor recurrence and radionecrosis. On other occasions, it makes it possible to detect alterations which are invisible by imaging study, such as medial temporal sclerosis, or multiple sclerosis. It is also very useful in following-up many alterations, either in their natural history, as in Alzheimers disease, or in order to monitor treatments on cerebral tumors or infectious processes. However, MRS does not often show pathognomonic patterns, so it is always recommended to consider it not just in the clinical context, but as inseparable part of an MR study, either structural or functional (diffusion, perfusion), since it is this is how it provides more useful information from a clinical point of view. Neurologia 2003;18(6):324-340


Amarenco, G., S. S. Ismael, et al. (2003). "Urodynamic effect of acute transcutaneous posterior tibial nerve stimulation in overactive bladder." J Urol 169(6): 2210-5.

            PURPOSE: Of the various treatments proposed for urge incontinence, frequency and urgency electrostimulation has been widely tested. Different techniques have been used with the necessity of surgical implantation (S3 neuromodulation or sacral root stimulation) or without requiring surgery (perineal transcutaneous electrostimulation). Recently peripheral electrical stimulation of the posterior tibial nerve was proposed for irritative symptoms in first intention or for intractable incontinence. Clinical studies have demonstrated good results and urodynamic parameters were improved after chronic treatment. However, to our knowledge no data concerning acute stimulation and immediate cystometry modifications have been reported. We verified urodynamic changes during acute posterior tibial nerve stimulation. MATERIALS AND METHODS: A total of 44 consecutive patients with urge incontinence, frequency and urgency secondary to overactive bladder were studied. There were 29 women and 15 men with a mean age +/-SD of 53.3 +/- 18.2 years. Of the patients 37 had detrusor hyperreflexia due to multiple sclerosis (13), spinal cord injury (15) or Parkinson's disease (9), and 7 had idiopathic detrusor instability. Routine cystometry at 50 ml. per minute was done to select the patients with involuntary detrusor contractions appearing before 400 ml. maximum filling volume. Repeat cystometry was performed immediately after the first study during left posterior tibial nerve stimulation using a surface self-adhesive electrode on the ankle skin behind the internal malleolus with shocks in continuous mode at 10 Hz. frequency and 200 milliseconds wide. Volume comparison was done at the first involuntary detrusor contraction and at maximum cystometric capacity. The test was considered positive if volume at the first involuntary detrusor contraction and/or at maximum cystometric capacity increased 100 ml. or 50% during stimulation in compared with standard cystometry volumes. RESULTS: Mean first involuntary detrusor contraction volume on standard cystometry was 162.9 +/- 96.4 ml. and it was 232.1 +/- 115.3 ml. during posterior tibial nerve stimulation. Mean maximum cystometric capacity on standard cystometry was 221 +/- 129.5 ml. and it was 277.4 +/- 117.9 ml. during stimulation. Posterior tibial nerve stimulation was associated with significant improvement in first involuntary detrusor contraction volume (p <0.0001) and significant improvement in maximum cystometric capacity (p <0.0001). The test was considered positive in 22 of the 44 patients. CONCLUSIONS: These results suggest an objective acute effect of posterior tibial nerve stimulation on urodynamic parameters. Improved bladder overactivity is an encouraging argument to propose posterior tibial nerve stimulation as a noninvasive treatment modality in clinical practice.


Anane, R., M. Geffard, et al. (2003). "Effects of GSM-900 microwaves on the experimental allergic encephalomyelitis (EAE) rat model of multiple sclerosis." Bioelectromagnetics 24(3): 211-3.

            The effects of acute exposure to GSM-900 microwaves (900 MHz, 217 Hz pulse modulation) on the clinical parameters of the acute experimental allergic encephalomyelitis (EAE) model in rats were investigated in two independent experiments: rats were either habituated or nonhabituated to the exposure restrainers. EAE was induced with a mixture of myelin basic protein and Mycobacterium tuberculosis. Female Lewis rats were divided into cage control, sham exposed, and two groups exposed either at 1.5 or 6.0 W/kg local specific absorption rate (SAR averaged over the brain) using a loop antenna placed over their heads. There was no effect of a 21 day exposure (2 h/day) on the onset, duration, and termination of the EAE crisis.


Ando, Y., Y. Liang, et al. (2003). "Caspase-1 and -3 mRNAs are differentially upregulated in motor neurons and glial cells in mutant SOD1 transgenic mouse spinal cord: a study using laser microdissection and real-time RT-PCR." Neurochem Res 28(6): 839-46.

            Amyotrophic lateral sclerosis is characterized by selective motor neuron degeneration. An apoptotic pathway is thought to be involved. It is difficult, however, to analyze the molecular pathogenic mechanism in single motor neurons because of complexity in the neural tissue, which consists of multiple lineages of cells neighboring motor neurons. We quantified the caspase-1 and -3 mRNA in single motor neurons and neighboring glial cells isolated from the spinal ventral horn of mutant SOD1 transgenic (Tg) mice and littermates. Motor neurons and neighboring glial cells were isolated from spinal sections by laser microdissection, and the mRNAs were quantified by RT-PCR. In the Tg mice, caspase-1 mRNA was first upregulated in motor neurons and second in glial cells. The caspase-3 mRNA was increased in motor neurons following the caspase-1 mRNA. These results indicated that caspase-1 and -3 mRNAs are differentially upregulated in motor neurons and glial cells of the Tg mice, and that mRNAs in isolated cells can be accurately assessed using our procedures.


Angelov, D. N., S. Waibel, et al. (2003). "Therapeutic vaccine for acute and chronic motor neuron diseases: implications for amyotrophic lateral sclerosis." Proc Natl Acad Sci U S A 100(8): 4790-5.

            Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu/Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 +/- 7 days (n = 15) to 263 +/- 8 days (n = 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.


Anlar, O., M. Kisli, et al. (2003). "Visual evoked potentials in multiple sclerosis before and after two years of interferon therapy." Int J Neurosci 113(4): 483-9.

            Magnetic resonance imaging (MRI) is important in the diagnosis of and follow-up for the treatment of multiple sclerosis (MS); evoked potentials may be important if MRI is normal or cannot be performed. We assessed serial visual evoked potentials (VEPs) and cranial MRI in a group of clinically relapsing-remitting multiple sclerosis (N = 15) treated with interferon beta-lb (INFB-1b) and in normal subjects (N = 15). The investigations were done 1 week before INFB-lb therapy, 1 year later (N = 15), and 2 years later (N = 10). VEPs were abnormal in most of the patients; MRIs were abnormal in all patients. We used P100 latency as an electrophysiological index for the progress of illness. There were significant differences in VEPs between the beginning and ending of the interferon treatment. We concluded that VEPs would be a reliable index for following up the progress of MS under interferon therapy.


Anlar, B. (2003). "Infection and multiple sclerosis." J Neurol Neurosurg Psychiatry 74(5): 692-3.


Antel, J. P. and A. Bar-Or (2003). "Do myelin-directed antibodies predict multiple sclerosis?" N Engl J Med 349(2): 107-9.


Antonijevic, I. A. and A. Steiger (2003). "Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis." Psychoneuroendocrinology 28(6): 780-95.

            Acute exacerbations of multiple sclerosis (MS) are commonly treated with high doses of corticosteroids that can influence sleep regulation and hypothalamo-pituitary-adrenal (HPA) activity. We examined the sleep-EEG (including conventional and spectral EEG analysis) in 9 female patients with relapsing-remitting MS (and no psychiatric disorder) just prior to and on days 2 and 10 of high dose corticosteroid treatment (500 mg/day methylprednisolone given IV for 5 days, then PO taper down) and age-matched healthy female controls.Before treatment with corticosteroids, MS patients compared to controls showed few changes of the sleep EEG, namely a significant increase in slow wave sleep (SWS) and a decrease in stage 2 sleep. In contrast, on day 10, but not day 2 of treatment, MS patients showed a number of sleep-EEG changes typically observed in patients with depression, including a reduction in REM latency, an increase in REM density, a decrease in the SWS and delta sleep ratio and a decrease in sigma EEG activity. However, no concomitant effect of treatment on mood was noted.In summary, unlike acute treatment with methylprednisolone, prolonged treatment induces several changes of the sleep-EEG in MS patients, that are also observed in patients with an acute depressive episode. Further prospective studies with longer-term follow-up are needed to examine the clinical relevance of our preliminary data.


Arai, T., K. Nakahara, et al. (2003). "Age-related mitochondrial DNA deletion in human heart: its relationship with cardiovascular diseases." Aging Clin Exp Res 15(1): 1-5.

            BACKGROUND AND AIMS: Accumulation of damage to mitochondrial DNA (mtDNA) occurs in myocardial tissue with advancing age. However, despite higher incidence of cardiac diseases in the elderly, little attempt has been made to detect deletions of mtDNA in the myocardial tissue of aged individuals. The aim of the present study was to clarify the relationship between aging, mtDNA deletion and cardiovascular (CV) diseases. METHODS: We examined 163 autopsy cases, aged 60 years or older, using two different kinds of polymerase chain reaction (PCR): highly sensitive PCR to detect a common 4977-bp deletion and long-PCR for multiple deletions, which could be detected in case that deleted mtDNA accounted for more than several percents in total mtDNA. RESULTS: The common 4977-bp deletion was detected in 156 cases (95.7%), showing no significant difference among these age groups and no relation to CV diseases. By long-PCR, multiple deletions in cardiac mtDNA were found in 33 (20.2%) of 163 cases. The proportion of the mtDNA deletion in the nineties (46.2%) was significantly higher than those in the younger (15.3%, p < 0.05). Female predominance was significantly found in the group with the mtDNA deletion (p < 0.05). Multiple deletions of mtDNA were not significantly related to ischemic change, valvular diseases, left ventricular hypertrophy, congestive heart failure, coronary sclerosis, or heart weight except for right ventricular hypertrophy. CONCLUSIONS: These findings suggest that there is a close relationship between aging and deletion of mtDNA, and that the ratio of deleted mtDNA to total mtDNA increases with advancing age. Age-related deletion of mtDNA may have little influence on CV diseases except for right ventricular hypertrophy.


Araki, I., M. Matsui, et al. (2003). "Relationship of bladder dysfunction to lesion site in multiple sclerosis." J Urol 169(4): 1384-7.

            PURPOSE: We investigated the relationship of voiding dysfunction type and the lesion site in patients with multiple sclerosis. MATERIALS AND METHODS: Voiding dysfunction was evaluated in 32 patients with multiple sclerosis using the International Prostate Symptom Score and urodynamic tests. Lesion sites were determined by combined neurological examination and magnetic resonance imaging findings. RESULTS: Compared with reports from Western countries the ratio of emptying-to-filling symptoms was high in Japan. Of urinary symptoms only filling correlated with disability status and disease duration. Urinary symptoms were not related to lesion sites. Urodynamic evaluation revealed detrusor hyperreflexia in 14 of 32 patients, hyporeflexia or areflexia in 12, detrusor hyperreflexia with impaired contractile function in 4, a low compliance bladder in 1 and normal function in 1. Of 14 patients with hyperreflexia 13 had overactive sphincter concurrently. Incompetent sphincter was identified in 2 patients who had detrusor hyperreflexia with impaired contractility and in 1 with a low compliance bladder. A significant correlation was noted for a pontine lesion and detrusor hyporeflexia, and for a cervical cord lesion and detrusor-sphincter dyssynergia. CONCLUSIONS: Detrusor hyporeflexia and detrusor-sphincter dyssynergia are indicative of a pontine and cervical spinal cord lesion, respectively. Thus, the lesion site in the central nervous system may be a major determinant of the type of bladder and urethral sphincter dysfunction. The high prevalence of emptying symptoms in Japanese patients may reflect the prevalence of detrusor hyporeflexia and detrusor-sphincter dyssynergia.


Araki, M., T. Kondo, et al. (2003). "Th2 bias of CD4+ NKT cells derived from multiple sclerosis in remission." Int Immunol 15(2): 279-88.

            Although CD1d-restricted NKT cells have been implicated as a participant in the regulatory mechanism of autoimmune diseases, it remains unclear how they would regulate human autoimmune diseases such as multiple sclerosis (MS). Furthermore, although the NKT cells comprise CD4(+) and CD4(-) populations, prior studies have often represented them as simply a CD4(-) population. Given that CD4(+) and CD4(-) NKT cells may represent functionally distinct populations, it appears crucial to examine the individual NKT subset in autoimmune diseases. Here we studied the frequency and cytokine phenotypes of the CD4(+) and CD4(-) NKT cells in fresh peripheral blood mononuclear cells, and of alpha-galactosylceramide-stimulated short-term cell lines obtained during the remission or relapse phase of MS as compared with from healthy subjects (HS). Here we report that CD4(+) NKT line cells expanded from MS in remission (MS-rem) would produce a larger amount of IL-4 than those from HS or from MS in relapse (MS-rel). They were significantly biased for T(h)2 as judged by the IL-4/IFN-gamma balance. However, there was no functional bias toward T(h)1 or T(h)2 in CD4(-) NKT line cells from MS-rem due to the defects in both IFN-gamma and IL-4 production, compared with HS. Of note, although double-negative NKT cells in the periphery were greatly reduced, the reduction of CD4(+) NKT cells was only marginal, if any, in MS-rem compared with HS. The T(h)2 bias of CD4(+) NKT line cells from MS-rem may support an immunoregulatory role for the CD4(+) NKT cells in vivo.


Aranapakam, V., G. T. Grosu, et al. (2003). "Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis." J Med Chem 46(12): 2361-75.

            The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.


Arbour, N., A. Holz, et al. (2003). "A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis." J Neuroimmunol 137(1-2): 197-209.

            We used a flow cytometry assay to measure proliferation and cytokine production of self-antigen-specific T cells in individual patients during the clinical course of multiple sclerosis (MS). Myelin-associated oligodendrocytic basic protein (MOBP) was selected for proof of principles in the assay, along with myelin basic protein (MBP) to assess specific activated T cells in 10 MS patients over an 18-month period, in parallel with brain magnetic resonance imaging (MRI) scans and clinical rating scale. A positive correlation occurred between antigen-specific T cell proliferation and interferon-gamma production with clinical relapses and MRI lesion activity that was absent when the same patients were in remission.


Arevalo-Martin, A., J. M. Vela, et al. (2003). "Therapeutic action of cannabinoids in a murine model of multiple sclerosis." J Neurosci 23(7): 2511-6.

            Theiler's virus infection of the CNS induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids may act as immunosuppressive compounds that have shown therapeutic potential in chronic inflammatory disorders. Using the Theiler's murine encephalomyelitis virus model, we report here that treatment with the synthetic cannabinoids WIN 55,212-2, ACEA, and JWH-015 during established disease significantly improved the neurological deficits in a long-lasting way. At a histological level, cannabinoids reduced microglial activation, abrogated major histocompatibility complex class II antigen expression, and decreased the number of CD4+ infiltrating T cells in the spinal cord. Both recovery of motor function and diminution of inflammation paralleled extensive remyelination. Overall, the data presented may have potential therapeutic implications in demyelinating pathologies such as MS; in particular, the possible involvement of cannabinoid receptor CB2 would enable nonpsychoactive therapy suitable for long-term use.


Armutlu, K., A. Meric, et al. (2003). "The effect of transcutaneous electrical nerve stimulation on spasticity in multiple sclerosis patients: a pilot study." Neurorehabil Neural Repair 17(2): 79-82.

            The aim of this study was to examine the effects of transcutaneous electrical nerve stimulation on spasticity in patients with multiple sclerosis. The study was carried out in the Hacettepe University School of Physical Therapy and Rehabilitation. The subjects in the study were 10 clinically definite, primary and secondary progressive type multiple sclerosis outpatients with mild to moderate spasticity in the plantar flexor muscles of the ankle. Stimuli of frequency 100 Hz and pulse width 0.3 msec were used 20 minutes per day for 4 weeks. Patients were assessed by electromyography, Modified Ashworth Scale, and Ambulation Index. Electromyography was performed before and after the daily treatment of spastic muscles with transcutaneous electrical nerve stimulation in order to assess the effect on muscle relaxation. The Modified Ashworth Scale and Ambulation Index were used before and after 4 weeks' treatment. After 4 weeks of treatment, there were statistically significant reductions in spasticity of both extremities as assessed by myoelectric activity and the Modified Ashworth Scale (P < 0.05). Ambulation Index level was not improved significantly (P > 0.05).


Aronica, E., D. Troost, et al. (2003). "Expression and regulation of voltage-gated sodium channel beta1 subunit protein in human gliosis-associated pathologies." Acta Neuropathol (Berl) 105(5): 515-23.

            Auxiliary beta1 subunits of voltage-gated sodium channels (NaChs) critically regulate channel activity and may also act as cell adhesion molecules (CAMs). In a recent study we have shown that the expression of beta1 NaCh protein is increased in reactive astrocytes in a rat epilepsy model of mesial temporal lobe epilepsy. The present study was undertaken to examine whether changes of NaCh beta1 subunit protein expression are also associated with structural changes occurring in human reactive astrocytes under different pathological conditions in vivo, as well as in response to changing environmental conditions in vitro. Strong beta1 astroglial immunoreactivity was present in human brain tissue from patients with astrogliosis. The over-expression of beta1 protein in reactive glia was observed in both epilepsy-associated brain pathologies (temporal lobe epilepsy, cortical dysplasia), as well as non-epileptic (cerebral infarction, multiple sclerosis, amyotrophic lateral sclerosis, meningo-encephalitis) disorders. The up-regulation of beta1 subunit protein in astrocytes can be reproduced in vitro. beta1 protein is highly expressed in human astrocytes cultured in the presence of trophic factors, under conditions in which they show morphology similar to the morphology of cells undergoing reactive gliosis. The growth factor-induced overexpression of beta1 protein was abrogated by PD98059, which inhibits the mitogen-activated protein kinase pathway. These findings demonstrate that the expression of NaCh beta1 subunit protein in astrocytes is plastic, and indicate a novel mechanism for modulation of glial function in gliosis-associated pathologies.


Aruoma, O. I. (2003). "Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods." Mutat Res 523-524: 9-20.

            The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, Downs syndrome) and aging challenges continue to emerge from difficulties associated with methods used in evaluating antioxidant actions in vivo. Our interest presently is focused on development of neurodegeneration models based on the integrity of neuronal cells in the central nervous system and how they are protected by antioxidants when challenged by neurotoxins as well as Fenton chemistry models based on the profile of polyunsaturated fatty acids (PUFAs) for the assessment of antioxidant actions in vivo. Use continues to be made of several in vitro analytical tools to characterise the antioxidant propensity of bioactive compounds in plant foods and supplements. For example, the oxygen radical absorbance capacity (ORAC), ferric reducing antioxidant power (FRAP), total oxidant scavenging capacity (TOSC), the deoxyribose assay, assays involving oxidative DNA damage, assays involving reactive nitrogen intermediates (e.g. ONOO(-)), Trolox equivalent antioxidant capacity (TEAC) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. There is need to agree governance on in vitro antioxidant methods based on an understanding of the mechanisms involved. Because some of the assays are done in non-physiological pH values, it is impossible to extrapolate the results to physiological environment. The consensus of opinion is that a mix of these tools should be used in assessing the antioxidant activities in vitro. The proof of bio-efficacy must emanate from application of reliable in vivo models where markers of baseline oxidative damage are examined from the standpoint of how they are affected by changes in diet or by antioxidant supplements.


Ashjazadeh, N., A. Borhani Haghighi, et al. (2003). "Neuro-Behcet's disease: a masquerader of multiple sclerosis. A prospective study of neurologic manifestations of Behcet's disease in 96 Iranian patients." Exp Mol Pathol 74(1): 17-22.

            Behcet's disease is a multisystem vasculitis. Its neurologic complications include different syndromes. The purpose of this investigation was to study the prevalence of neurologic manifestations among patients with Behcet's disease and to determine the frequency of different symptoms, signs, and syndromes in neuro-Behcet's disease. Ninety-six consecutive patients who were referred to the Behcet's Disease Clinic in Shiraz (southern Iran) were interviewed and thoroughly examined. Psychiatric evaluation, CSF analysis, electroencephalography, electrodiagnostic studies, and neuroradiologic imaging (preferably MRI) were performed in appropriate cases. Six patients (6.3%) had definite neuro-Behcet's disease. They were 4 males and 2 females (mean age 37.5 years). In 2 patients Behcet's disease had not been diagnosed before. The most frequent symptoms of neuro-Behcet's disease were headache (83.3%), paresthesia (83.3%), unsteadiness (66.7%), diplopia (66.7%), and weakness (50%). The most frequent signs were gait abnormalities (66.7%), sensory abnormalities (66.7%), ophthalmoplegia (50%), cerebellar ataxia (50%), and hemiplegia (50%). The most common syndrome was brain-stem+ type (50%). Subacute onset and relapsing-remitting course were the most common temporal patterns. Neurological manifestation is a relatively less frequent complication of Behcet's disease but it produces severe disabilities. It must be considered in differential diagnosis of multiple sclerosis.


Ashton, E. A., C. Takahashi, et al. (2003). "Accuracy and reproducibility of manual and semiautomated quantification of MS lesions by MRI." J Magn Reson Imaging 17(3): 300-8.

            PURPOSE: To evaluate the accuracy, reproducibility, and speed of two semiautomated methods for quantifying total white matter lesion burden in multiple sclerosis (MS) patients with respect to manual tracing and to other methods presented in recent literature. MATERIALS AND METHODS: Two methods involving the use of MRI for semiautomated quantification of total lesion burden in MS patients were examined. The first method, geometrically constrained region growth (GEORG), requires user specification of lesion location. The second technique, directed multispectral segmentation (DMSS), requires only the location of a single exemplar lesion. Test data sets included both clinical MS data and MS brain phantoms. RESULTS: The mean processing times were 60 minutes for manual tracing, 10 minutes for region growth, and 3 minutes for directed segmentation. Intra- and interoperator coefficients of variation (CVs) were 5.1% and 16.5% for manual tracing, 1.4% and 2.3% for region growth, and 1.5% and 5.2% for directed segmentation. The average deviations from manual tracing were 9% for region growth and 5.7% for directed segmentation. CONCLUSION: Both semiautomated methods were shown to have a significant advantage over manual tracing in terms of speed and precision. The accuracy of both methods was acceptable, given the high variability of the manual results. J. Magn. Reson. Imaging 2003;17:300-308.


Aune, T. M., K. Maas, et al. (2003). "Gene expression profiles in human autoimmune disease." Curr Pharm Des 9(23): 1905-17.

            To acquire a functional view of human autoimmunity, we compared differences in gene expression (>4000 genes) in the peripheral blood mononuclear cells of normal individuals following immunization to those in individuals with four different autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, insulin dependent diabetes mellitus, and multiple sclerosis). Each individual from all disease groups displayed a similar pattern of gene expression that was highly distinct from the gene expression pattern of the immunized group. These findings indicate that the expression pattern accompanying autoimmunity is not simply a recapitulation of the immune response to non-self. Of note, expression levels of genes that encode key proteins in several distinct apoptosis pathways were markedly reduced in all autoimmune disease groups. Taken together, these data indicate that the pattern of gene expression describes a molecular portrait of autoimmunity that is constant among individuals with autoimmune disease but is independent of the specific autoimmune disease and the clinical parameters associated with any individual autoimmune disease.


Avasarala, J. R., A. H. Cross, et al. (2003). "Comparative assessment of Yale Single Question and Beck Depression Inventory Scale in screening for depression in multiple sclerosis." Mult Scler 9(3): 307-10.

            OBJECTIVES: To examine if depression in multiple sclerosis (MS) can be accurately recognized using the Yale Single Question (YSQ) screen as compared with the Beck Depression Inventory (BDI), a 21-item self-report rating scale for depression. In addition, we sought to assess the sensitivity, specificity the positive predictive value (PPV) and the negative predictive value (NPV) of the YSQ. BACKGROUND: Depression associated with MS is a major contributor to morbidity. Screening for depression in patients with MS currently includes the BDI, which measures characteristic attitudes and symptoms of depression. However, in a busy outpatient clinic, the BDI might not be the most appropriate instrument, particularly if depression screening can be assessed accurately using simpler techniques that are easy to administer and consume less time. We compared the accuracy of the YSQ screen response against the BDI to screen for depression in MS patients, in an outpatient setting. METHODS: This is a comparative outcome study of two 'instruments' used for screening depression in MS patients in an academic outpatient setting. All patients were initially screened for depression by asking patients the YSQ--'Do you frequently feel sad or depressed?', followed by BDI administration. Depression was defined as a score of > or = 13 on the BDI. One hundred and twenty successive patients who presented to the MS clinic at Washington University School of Medicine and met the criteria for diagnosis of MS were screened for depression. All patients diagnosed as having MS, regardless of type, were included in the study. RESULTS: Of the 120 patients studied, a total of 49 of 120 were clinically depressed as defined by a BDI cut-off of > or = 13; 71 of 120 were not. The sensitivity of the YSQ was 32 of 49 = 65.3% with a 95% confidence interval (0.50, 0.78), specificity was 62 of 71 = 87.3% (0.77, 0.94), PPV was 32 of 41 = 78.0% (0.62, 0.89) and NPV was 62 of 79 = 78.5% (0.68, 0.87). Of the 49 patients depressed by BDI criteria, 17 responded 'no' to the YSQ, yielding a false-negative rate of 34.7% (0.22, 0.50). The Wilcoxon-Mann-Whitney test for difference in age among those on antidepressants compared with those who were not showed no statistical difference (P = 0.35). For patients on antidepressants, the mean BDI score was 16.0+/-8.9 (mean+/-SD) and 9.5+/-8.7 for those not on antidepressants. Differences in BDI scores among patients on antidepressants versus those who were not were statistically significant (P < 0.0001). Patients on antidepressants had significantly higher BDI scores. CONCLUSIONS: Our results show that the YSQ cannot replace the BDI as a screening instrument for depression in MS. The YSQ could not identify 34.7% of patients who were depressed by BDI criteria. However, as reported in a published study, BDI missed 30% of cases with early depression in MS when a cut-off of > or = 13 was used. The YSQ appears to be specific in ruling out depression when a patient is not depressed. MS is a chronic disease and since prevalence of depression varies, it is important to screen patients repeatedly over time so as not to miss the diagnosis. That BDI scores were higher among those taking antidepressants underscores the fact that this subset of patients need to be on medication, but the higher scores could also represent a sampling error since the duration of antidepressant use was not studied.


Avasarala, J. R., A. H. Cross, et al. (2003). "Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis." Mult Scler 9(1): 59-62.

            Mitoxantrone is a recently approved drug for patients with secondary progressive multiple sclerosis (SPMS). However, cardiac side effects limit Mitoxantrone use in SPMS and its lifetime cumulative dose should not exceed 140 mg/m2. Additionally, Mitoxantrone is contraindicated for use in SPMS patients with a baseline left ventricular ejection fraction (LVEF) of < or = 50%. The goal of this study was to monitor LVEF more frequently than ordinarily recommended since experience with Mitoxantrone use in SPMS patients is limited. An unexpected decline in LVEF in one of the SPMS patients being treated with Mitoxantrone prompted further investigation into this finding. In our clinic, 47 patients on Mitoxantrone were followed prospectively; 28 of 47 patients had received a minimum of three doses and underwent a repeat LVEF evaluation prior to their fourth dose of Mitoxantrone. Of these 28 patients, five of 28 (17.8%) had a significant decline in LVEF from baseline. It is suggested that more stringent cardiac monitoring guidelines than current Food and Drug Administration (FDA) recommendations be used to avert potential cardiac complications in SPMS patients on Mitoxantrone.


Avolio, C., M. Ruggieri, et al. (2003). "Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes." J Neuroimmunol 136(1-2): 46-53.

            In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9 predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may participate in the remodeling of the extracellular matrix (ECM) such as in chronic disease and is inhibited by TIMP-2. These differences may be reflected in serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP-9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of different types of the disease, as this information was not previously clearly stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than short disease duration (SDD) relapsing-remitting (RR) MS, but not different from the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed higher (p=0.04) values in SDD RR MS than PP but also in active patients, evaluated either clinically (p=0.006) or from the magnetic resonance imaging (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not differ between MS subtypes, suggesting systemic rather CNS-restricted changes. These results show that an increase in MMP-2/TIMP-2 ratio marks chronic progression in MS, but it is as high as in HC, and also confirm that high MMP-9 activity characterizes short duration relapsing and active forms of the disease.


Babcock, A. and T. Owens (2003). "Chemokines in experimental autoimmune encephalomyelitis and multiple sclerosis." Adv Exp Med Biol 520: 120-32.


Back, T., R. Mockel, et al. (2003). "Combined MR measurements of magnetization transfer, tissue diffusion and proton spectroscopy. A feasibility study with neurological cases." Neurol Res 25(3): 292-300.

            Magnetic resonance imaging (MRI) of diffusion and magnetization transfer was combined with 1H-spectroscopic imaging (CSI) to evaluate the clinical potential of in-vivo profiles of various brain pathologies. Ten patients (multiple sclerosis, cerebrovascular disease, leukodystrophy, Alzheimer dementia) and five healthy volunteers were investigated with diffusion-weighted MRI, magnetization transfer imaging, and CSI. Proton spectra were analyzed as ratios of NAA/Cr and Cho/Cr calculated from the peak areas of N-acetylaspartate (NAA), (phospho)-creatine (Cr) and choline (Cho). The apparent diffusion coefficient (ADC) and the magnetization transfer ratio (MTR) were determined in identical voxels to ensure identical partial volume effects compared to CSI. Compared to MTR and ADC assessments, the lower spatial resolution of CSI clearly indicates a hindrance at 1.5 T. In most demyelinating lesions, NAA/Cr reduction paralleled attenuated MTRs and elevated ADCs. By contrast, in acute stroke and some acute MS lesions the ADC was reduced, while MTR and NAA/Cr were also decreased. In Alzheimer's dementia, ADC was increased, MTR unchanged and Cho/Cr increased. In a case of leukodystrophy, ADC was pronouncedly increased, MTR and NAA/Cr both reduced, and Cho/Cr normal. Combined measurements of ADC, MTR and CSI are feasible and provide differential in-vivo information on various brain pathologies.


Bagaeva, L. V., L. P. Williams, et al. (2003). "IL-12 dependent/IFN gamma independent expression of CCR5 by myelin-reactive T cells correlates with encephalitogenicity." J Neuroimmunol 137(1-2): 109-16.

            Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease with similarities to multiple sclerosis (MS). It is induced in mice by the transfer of myelin-reactive T cells. Here we demonstrate that IL-12 stimulates myelin-reactive T cells to up-regulate the beta-chemokine receptor, CCR5, in correlation with the acquisition of central nervous system-infiltrating and encephalitogenic properties. These effects of IL-12 are IFN gamma-independent. The CCR5 ligands, RANTES and MIP-1 alpha, are expressed in the spinal cords of mice at EAE onset. Our results suggest that reagents that block CCR5/beta-chemokine interactions and/or antagonize IL-12 might be useful for treatment of autoimmune demyelination.


Bagnato, F. and C. Pozzilli (2003). "Pharmacological methods to overcome IFN-beta antibody formation in the treatment of multiple sclerosis." Expert Opin Investig Drugs 12(7): 1153-63.

            Diminished efficacy in terms of clinical relapses and lesion load on magnetic resonance images for patients developing neutralising antibodies (NAbs) to recombinant IFN-beta may be found in multiple sclerosis. NAbs become detectable over the first few years of therapy, disappearing during the treatment course in some patients and persisting longer in some others. Therefore, the administration of concomitant therapies to recombinant IFNbeta to prevent the formation of NAbs could be indicated mainly in the latter group of patients at the early stage of the treatment. Among those therapies, steroids meet the best criteria in terms of either safety or impact on the development of NAbs, at the present time.


Bagnato, F., N. Jeffries, et al. (2003). "Evolution of T1 black holes in patients with multiple sclerosis imaged monthly for 4 years." Brain 126(Pt 8): 1782-9.

            T1 black holes (BHs) on MRIs may represent either areas of oedema or axonal loss in patients with multiple sclerosis. BHs begin as contrast enhancing lesions (CELs) and evolve differently from patient to patient, and within the same patient over time. We analysed BHs formation over a 4-year period. Forty-eight monthly MRIs of nine non-treated multiple sclerosis patients were evaluated for numbers of CELs and BHs. A BH was defined as a hypointense lesion on a T1 pre-constrast image that coincided with a region of high signal intensity on the T2-weighted images. A BH was considered as acute (ABH) when it occurred coincidently with the presence of enhancement and as persisting (PBH) when present after the cessation of enhancement. The present study aimed to analyse: (i) the incidence of CELs and new PBHs, and the accumulation of PBHs; (ii) the relationship between the quantity of the CELs in a given month and the likelihood of accumulating PBHs in the subsequent month; and (iii) the relationship between the duration of CELs and PBHs. Pitman's correlation test evaluated the effect of time on either the increase of CELs and new PBHs or the accumulation of PBHs, while a multiple logistic regression analysis evaluated the relationship between progression of time and CELs, and the increase of PBHs in a multivariate model. The relationship between the enhancing lesions duration and the PBHs duration, or the time to revert back to an isointense lesion was analysed using Kaplan-Meier survival models. PBHs accumulated (P < 0.001) in all patients, but the formation of new PBHs increased in four patients (P </= 0.007) in conjunction with an increase in either the quantity of CELs (P < 0.001, for two patients) or the proportion of CELs turning into PBHs (P </= 0.02, for two patients). Logistic regression analysis showed that neither progression of time nor the number of CELs in a given month were able to predict the probability of increasing the number of PBHs in the subsequent month in any patient. Out of 397 ABHs, 55.7% evolved to a PBH. The duration of PBHs correlated with the duration of enhancement. PBHs preceded by CELs observable on a single MRI persisted for a shorter time (P < 0.002) than those preceded by CELs visible on >/=2 monthly MRIs. The formation of a new PBH was found to be related to CELs activity; however, duration of PBHs is most likely a consequence of the duration of the enhancement.


Bagnato, F. and J. A. Frank (2003). "The role of nonconventional magnetic resonance imaging techniques in demyelinating disorders." Curr Neurol Neurosci Rep 3(3): 238-45.

            The use of nonconventional magnetic resonance imaging techniques (eg, magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging) allows for an accurate characterization of lesions as compared with conventional or standard approaches in demyelinating diseases. Magnetization transfer, magnetic resonance spectroscopy, and diffusion weighted imaging have revolutionized our understanding of demyelinating diseases because these techniques have been used to identify pathologic changes of normal-appearing brain tissue and characterize the differences in lesions. Metrics derived from these methods correlate with clinical disability and provide more accurate tools for monitoring disease activity and treatment effect over time. Quantitative T1 and T2 relaxation time maps provide additional information on demyelinating diseases, allowing for the evaluation of myelin water and distribution of water within tissues. Finally, the measurement of central nervous system atrophy has become a valuable element in determining the course of multiple sclerosis.


Baker, D., P. Adamson, et al. (2003). "Potential of statins for the treatment of multiple sclerosis." Lancet Neurol 2(1): 9-10.


Baker, D., G. Pryce, et al. (2003). "The therapeutic potential of cannabis." Lancet Neurol 2(5): 291-8.

            Research of the cannabinoid system has many similarities with that of the opioid system. In both instances, studies into drug-producing plants led to the discovery of an endogenous control system with a central role in neurobiology. Few compounds have had as much positive press from patients as those of the cannabinoid system. While these claims are investigated in disorders such as multiple sclerosis spasticity and pain, basic research is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection. Large randomised clinical trials of the better known compounds are in progress. Even if the results of these studies are not as positive as many expect them to be, that we are only just beginning to appreciate the huge therapeutic potential of this family of compounds is clear.


Baker, D. and D. J. Hankey (2003). "Gene therapy in autoimmune, demyelinating disease of the central nervous system." Gene Ther 10(10): 844-53.

            Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), where suspected autoimmune attack causes nerve demyelination and progressive neurodegeneration and should benefit from both anti-inflammatory and neuroprotective strategies. Although neuroprotection strategies are relatively unexplored in MS, systemic delivery of anti-inflammatory agents to people with MS has so far been relatively disappointing. This is most probably because of the limited capacity of these molecules to enter the target tissue, because of exclusion by the blood-brain barrier. The complex natural history of MS also means that any therapeutic agents will have to be administered long-term. Gene therapy offers the possibility of site-directed, long-term expression, and is currently being preclinically investigated in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. While some immune effects may be targeted in the periphery using DNA vaccination, strategies both viral and nonviral are being developed to target agents into the CNS either via direct delivery or using the trafficking properties of cell-carrier systems. Targeting of leucocyte activation, cytokines and nerve growth factors have shown some promising benefit in animal EAE systems, the challenge will be their application in clinical use.


Baker, D. and G. Pryce (2003). "The therapeutic potential of cannabis in multiple sclerosis." Expert Opin Investig Drugs 12(4): 561-7.

            There has been renewed interest in the therapeutic applications of cannabis, and people, particularly those with multiple sclerosis, claim that it may offer benefit in symptom control. Cannabis exerts many of its effects because it taps into an endogenous cannabinoid system. Recent advances have begun to shine light on the biology of this system and may support some of the anecdotal medical claims. The problem with cannabis as a drug is that both the positive and negative aspects are largely the work of the same receptor. However, it may be possible to avoid these through modulation of the endogenous system. Cannabinoids provide a novel therapeutic target, not only for controlling symptoms, but also slowing disease progression through inhibition of neurodegeneration, which is the cause of accumulating irreversible disability.


Bakshi, R. (2003). "Fatigue associated with multiple sclerosis: diagnosis, impact and management." Mult Scler 9(3): 219-27.

            In patients with multiple sclerosis (MS) fatigue is the most common symptom and one of the most disabling features. As many as 40% have described it as the single most disabling symptom--a higher percentage than weakness, spasticity, motor problems, or bowel or bladder problems. The etiology and pathophysiology of MS-related fatigue remain unknown. Studies have failed to demonstrate an association between MS-related fatigue and the level of disability, clinical disease subtype, or gender, although recent data show an association between MS-related fatigue and depression and quality of life. Imaging studies using positron emission tomography suggest that fatigue in MS is related to hypometabolism of specific brain areas, including the frontal and subcortical circuits. The impact of fatigue on patient functioning and quality of life clearly warrants intervention. In addition to nonpharmacologic measures, such as exercise and energy conservation strategies, several pharmacologic agents have been evaluated for their ability to reduce MS-related fatigue, including amantadine, central nervous system stimulants (pemoline), and the novel wake-promoting agent modafinil.


Barca, O., S. Ferre, et al. (2003). "Interferon beta promotes survival in primary astrocytes through phosphatidylinositol 3-kinase." J Neuroimmunol 139(1-2): 155-9.

            Although interferon-beta (IFN-beta) has been demonstrated to be effective in the treatment of multiple sclerosis (MS) patients, the mechanism(s) underlying its beneficial effects has not been uncovered yet. Until now, most of the effort in the study of the relevant mechanisms of IFN-beta has dealt with its ability to modulate the immune response. Only recently, it has been proposed that the beneficial effects of IFN-beta in MS patients could depend on its ability to modulate astrocyte function. In the present work, we have found that IFN-beta treatment promotes the survival of astrocytes through stimulation of the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway. We propose that the beneficial effects of IFN-beta in MS therapy may depend, at least in part, on its capacity to protect astrocytes against the apoptotic cell death that occurs in the early steps of the pathogenesis of MS.


Barcellos, L. F., J. R. Oksenberg, et al. (2003). "HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course." Am J Hum Genet 72(3): 710-6.

            Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the HLA-DRB1*1501 allele and its associated haplotype (DRB1*1501-DQB1*0602 or DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data.


Barkhof, F., M. Rocca, et al. (2003). "Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a." Ann Neurol 53(6): 718-24.

            In the recently proposed diagnostic criteria for multiple sclerosis (MS) by McDonald, the modified magnetic resonance imaging (MRI) Barkhof criteria have been incorporated. We examined the validity of this implementation in the Early Treatment of MS study, a randomized, double-blind, placebo-controlled study of 22 microg interferon beta1a given subcutaneously once weekly in 309 patients with a first episode consistent with demyelinating disease (and abnormal MRI). Conversion to clinically definite MS (CDMS) within 2 years of follow-up, as evidenced by a new clinical episode, occurred in 41% of patients (independent of treatment) with gadolinium enhancement or nine or more T2 lesions versus 11% of those without either finding (p = 0.017); similarly, proportions converting were 44% versus 31% for infratentorial lesions (p = 0.026), 40% versus 35% for juxtacortical lesions (p = 0.413), and 41% versus 17% for three or more periventricular lesions (p = 0.034). The rate of conversion to CDMS based on the number of modified Barkhof criteria was 22% for two or fewer positive criteria, increasing to 47% with four positive criteria. For a cutoff of three positive criteria, the hazard ratio for time to CDMS was 2.3 (95% confidence interval, 1.17-4.55; p = 0.016). Treatment effect seemed more evident as the number of positive criteria increased, and the number of patients needed to avoid one patient converting to CDMS decreased from 50 in patients with one or two positive criteria to 5.6 in patients with four positive criteria. However, the study was not powered to detect statistically significant treatment by variable interaction, and this remains an important issue for further study.


Barnes, M. P., R. M. Kent, et al. (2003). "Spasticity in multiple sclerosis." Neurorehabil Neural Repair 17(1): 66-70.

            The objective of this article is to establish the prevalence of spasticity in a random selection of people with multiple sclerosis (MS) in the city of Newcastle upon Tyne in the Northeast of England. A secondary aim was to assess the adequacy of current pharmacological intervention for spasticity and assess the relationship between spasticity and overall disability. The study design was a simple comparison that examined differences in functional independence in 2 random groups of people with MS subdivided by the presence of clinically significant spasticity. A total of 68 adults with a diagnosis of clinically definite MS were included in the study. Their level of functional independence was assessed using the Newcastle Independence Assessment Form (NIAF), the Functional Independence Measure (FIM), and the Kurtzke Extended Disability Status Scale (EDSS). Spasticity was assessed using the Modified Ashworth Scale. A subjective analysis was made of the appropriateness of oral antispastic medication by a rehabilitation physician. Thirty-two people (47%) had clinically significant spasticity (Modified Ashworth Score of 2, 3, or 4). Seventy-eight percent of the population were receiving some oral antispastic medication, but 50% were deemed to require some drug adjustment or additional treatment. Individuals with spasticity were found to have significantly higher levels of disability than those who had no spasticity or clinically insignificant spasticity. This study has confirmed that spasticity is highly prevalent in the MS population and is significantly associated with a reduced level of functional independence. Treatment of spasticity is suboptimal in a large proportion of the population, and the need for further information and education to health professionals and to people with MS is highlighted.


Barnett, M. H., D. B. Williams, et al. (2003). "Progressive increase in incidence and prevalence of multiple sclerosis in Newcastle, Australia: a 35-year study." J Neurol Sci 213(1-2): 1-6.

            The prevalence of multiple sclerosis (MS) in Newcastle, Australia increased significantly between 1961 and 1981 and the incidence of the disease also increased between the decades 1950-1959 and 1971-1981. The present study sought to determine whether there has been a further increase in the frequency of MS in the subsequent 15 years, and to examine the potential factors underlying this change. The incidence, prevalence and clinical profile of multiple sclerosis were therefore re-examined in Newcastle, Australia in 1996 using comparable diagnostic criteria and methods to those employed in studies in the same region in 1961 and 1981. There has been a significant progressive increase in prevalence from 19.6 to 59.1 per 100,000 population and a significant increase in incidence from 1.2 to 2.4 per 100,000 population from 1961 to 1996. The most pronounced increase in prevalence was in females and in the age-group over 60 years, and there was also an increased incidence in females aged 20-29 years. There was little change in the age of disease onset, but duration of disease in females had increased substantially. The significant increase in prevalence is attributed to increased incidence, particularly in females; and to increased survival. Although such trends in prevalence have been observed in the Northern Hemisphere, this is the first such study in the Southern Hemisphere to show a longitudinal increase in prevalence and incidence over a period of this duration.


Bashir, K. and R. A. Kaslow (2003). "Chlamydia pneumoniae and multiple sclerosis: the latest etiologic candidate." Epidemiology 14(2): 133-4.


Bates, I. R., J. M. Boggs, et al. (2003). "Membrane anchoring and charge effects in the interaction of myelin basic protein (MBP) with lipid bilayers studied by site-directed spin labeling." J Biol Chem.

            Myelin basic protein (MBP) maintains the compaction of the myelin sheath in the central nervous system by anchoring the cytoplasmic face of the two apposing bilayers, and may also play a role in signal transduction. Site-directed spin labeling was done at 8 matching sites in each of two recombinant murine MBPs, qC1 (charge +19) and qC8 charge (+13), which respectively emulate the native form of the protein (C1) and a post-translationally modified form (C8) that is increased in multiple sclerosis (MS). When interacting with large unilamellar vesicles, most spin-labeled sites in qC8 were more mobile than those in qC1. Depth measurement via continuous wave power saturation indicated that the N-terminal and C-terminal sites in qC1 were located below the plane of the phospholipid headgroups. In qC8, the C-terminal domain dissociated from the membrane, suggesting a means by which the exposure of natural C8 to cytosolic enzymes and ligands might increase in vivo in MS. The importance of two FF pairs in MBP to its interactions with lipids was investigated by separately mutating each pair to AA. The mobility at F42A-F43A and especially F86A-F87A increased significantly. Depth measurements and helical wheel analysis indicated that the F86-F87 region could form a surface-seeking amphipathic alpha-helix.


Batocchi, A. P., M. Rotondi, et al. (2003). "Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta." J Neuroimmunol 139(1-2): 150-4.

            The role of leptin was investigated in relapsing-remitting multiple sclerosis (MS). Control and MS patients showed comparable baseline serum leptin levels. During the first year of IFNbeta-1a treatment, leptin significantly decreased since 2 months after starting therapy in 11 patients who had no relapses. A significant decrease in IL12/IL10 ratio was observed in this group of patients only after 1 year of treatment. An increase of leptin was observed before the first clinical exacerbation in 13 relapsing patients. Leptin may play a pathogenic role in MS and can be a useful marker of disease activity and response to therapy.


Battistini, L., L. Piccio, et al. (2003). "CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1." Blood 101(12): 4775-82.

            Multiple sclerosis (MS) is considered an autoimmune inflammatory disease of the central nervous system. Under physiologic conditions, we compared the adhesiveness of CD4+ and CD8+ lymphocytes from nontreated patients with acute, relapsing-remitting multiple sclerosis (RRMS) and from healthy donors. We show that in patients with RRMS CD8+, but not with RRMS CD4+, T cells display increased rolling and arrest in inflamed murine brain venules. Moreover, CD8+, but not CD4+, lymphocytes from MS patients show increased rolling on P-selectin in vitro. Anti-P-selectin glycoprotein ligand-1 (PSGL-1) antibodies dramatically block the recruitment of CD8+ cells in brain vessels of patients with MS, suggesting that PSGL-1 represents a novel pharmaceutical target that may be exploited to block the selective entrance of CD8+ cells during early inflammation. Vascular cell adhesion molecule-1 (VCAM-1), but not PSGL-1, is critical for the adhesion of CD4+ cells in MS patients, highlighting a fundamental dichotomy in the mechanisms governing the recruitment of lymphocyte subsets in RRMS. Importantly, 7-color fluorescence-activated cell sorter (FACS) analysis, together with functional data, indicates that a large fraction of CD8+ cells from MS patients display the characteristics of memory-effector phenotype. In conclusion, our results show that CD8+, but not CD4+, T cells from patients with RRMS in the acute phase of the disease display increased ability to be recruited in inflamed brain venules.


Baumhackl, U., C. Franta, et al. (2003). "A controlled trial of tick-borne encephalitis vaccination in patients with multiple sclerosis." Vaccine 21 Suppl 1: S56-61.

            The aim of this study was to investigate a possible link between a single vaccination against tick-borne encephalitis (TBE) and the appearance of one or more new cerebral lesions in magnetic resonance imaging (MRI) and/or a clinical relapse of MS. Fifteen MS patients with documented history of MS relapses living in a TBE endemic area were matched with 15 patients selected from a patient database containing 500 cases of MS. Three patients in each group were unvaccinated while all others had basic immunisation and regular booster vaccinations. Patients of the vaccination group received a single dose (3.3 microg) of a TBE vaccine. TBE antibodies were detected by ELISA and confirmed by neutralisation test. MRI was used as marker for disease activity and progression in addition to the clinical neurological examination. No association was seen between TBE vaccination and MRI detected disease activity, clinical relapse or disease progression of MS.


Bazzi, C., C. Petrini, et al. (2003). "Fractional excretion of IgG predicts renal outcome and response to therapy in primary focal segmental glomerulosclerosis: a pilot study." Am J Kidney Dis 41(2): 328-35.

            BACKGROUND: Prolonged treatment with steroids and/or cyclophosphamide improves the prognosis of primary focal segmental glomerulosclerosis (FSGS). In nephrotic patients, no clinical or histological feature predicts responsiveness to therapy. METHODS: In 50 patients with FSGS, fractional excretion (FE) of immunoglobulin G (IgG), albumin, transferrin, and alpha(1)-microglobulin (alpha(1)m) was calculated. The aim of the study is to assess whether FE IgG and FE alpha(1)m: (1) correlate with histological lesions, (2) predict outcome, and (3) may be useful to guide therapy. RESULTS: The association of FE IgG with percentage of glomeruli with segmental sclerosis was at the limit of significance (P = 0.01). FE alpha(1)m was associated with extent of tubulointerstitial damage (P = 0.008). By multiple regression analysis, FE alpha(1)m was dependent on FE IgG (R(2) = 0.76; P = 0.000). The predictive value of proteinuric variables on outcome was evaluated in 29 patients with nephrotic syndrome and baseline normal renal function (serum creatinine level, 1.04 +/- 0.22 mg/dL [92 +/- 19 micromol/L]; follow-up, 50 +/- 33 months); remission rates were 91% and 0% in patients with FE IgG less than versus greater than 0.140 (P = 0.0009). By multiple logistic regression analysis, only FE IgG was associated with remission (P = 0.043). Proteinuria less than versus greater than 7.5 g/d of protein predicted end-stage renal failure (0% versus 36%; P = 0.004); the predictive value of FE IgG less than versus greater than 0.140 was higher (0% versus 71%; P = 0.0000). Patients with FE IgG less than 0.025 were responsive to steroids alone (70%) or steroids and cyclophosphamide (20%); patients with FE IgG greater than 0.025 and less than 0.140 were responsive to steroids alone (20%) or steroids and cyclophosphamide (80%); and 100% of patients with FE IgG greater than 0.140 were unresponsive to therapy (P = 0.000). CONCLUSION: In FSGS, FE IgG is at the limit of statistically significant association with segmental sclerosis, and FE alpha(1)m is associated with extent of tubulointerstitial damage. FE IgG shows the best predictive value for remission, progression, and response to therapy and may be useful to guide treatment. Am J Kidney Dis 41:328-335.


Beatty, W. W., D. M. Orbelo, et al. (2003). "Comprehension of affective prosody in multiple sclerosis." Mult Scler 9(2): 148-53.

            Deficits in cognition have been repeatedly documented in patients with multiple sclerosis (MS), but their ability to comprehend emotional information has received little study. Forty-seven patients with MS and 19 demographic controls received the comprehension portion of the Aprosodia Battery, which is known to be sensitive to the impairments of patients with strokes and other neurological conditions. Patients also received tests of hearing, verbal comprehension and naming, a short cognitive battery, and the Beck Depression Inventory. Patients with MS were impaired in identifying emotional states from prosodic cues. The magnitude of the deficits was greatest for patients with severe physical disability and under test conditions of limited prosodic information. Correlational analyses suggested that the patients' difficulties in comprehending affective prosodic information were not secondary to hearing loss, aphasic deficits, cognitive impairment, or depression. For some patients with MS, deficits in comprehending emotional information may contribute to their difficulties in maintaining effective social interactions.


Becanovic, K., E. Wallstrom, et al. (2003). "New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis." J Immunol 170(2): 1062-9.

            Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4, 10, 15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 x PVG.1AV1) male/female F(2) population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1(av1) MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae16 on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.


Beck, R., H. Wiendl, et al. (2003). "Human herpesvirus 6 in serum and spinal fluid of patients with multiple sclerosis?" Arch Neurol 60(4): 639; author reply 639-40.


Becker, H., F. Chochon, et al. (2003). "[Report of the 55th meeting of the American Academy of Neurology. Honolulu, March 29-April 6, 2003]." Rev Neurol (Paris) 159(4): 470-86.


Bedinghaus, J. M. (2003). "A piece of my mind. Family history." Jama 289(2): 142.


Bee, Y. S., M. C. Lin, et al. (2003). "Optic neuritis: clinical analysis of 27 cases." Kaohsiung J Med Sci 19(3): 105-12.

            We retrospectively reviewed 27 cases diagnosed as idiopathic optic neuritis between 1992 and 2001 at Kaohsiung Veterans General Hospital to assess the clinical features, visual prognosis, neuroimaging, laboratory studies, and development of multiple sclerosis in Chinese patients with optic neuritis. Patient age ranged from 13 to 54 years (mean, 35.8 +/- 11.3 years). Five cases presented as bilateral optic neuritis and 22 as unilateral. Visual function improved gradually from 2 weeks after treatment. Twelve (44.4%) cases showed disc swelling and ocular pain was also noted in 44.4% of patients. All cases that underwent visual field and visual evoked potential tests showed abnormality in lesion eyes. Of the 23 cases that underwent neuroimaging studies, including computerized tomography (17 patients) and magnetic resonance imaging (6 patients), 10 revealed optic nerve thickening. Four cases (14.8%) developed multiple sclerosis during follow-up (mean, 4.3 years). The incidence of disc swelling was higher than that reported by the Optic Neuritis Treatment Trial, but the incidence of initial ocular pain, the presence of periventricular plaques, and the development of multiple sclerosis were lower in our study. The unilateral group had significantly better visual outcome than the bilateral group.


Beeton, C., H. Wulff, et al. (2003). "A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes." J Biol Chem 278(11): 9928-37.

            T lymphocytes with unusually high expression of the voltage-gated Kv1.3 channel (Kv1.3(high) cells) have been implicated in the pathogenesis of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. We have developed a fluoresceinated analog of ShK (ShK-F6CA), the most potent known inhibitor of Kv1.3, for detection of Kv1.3(high) cells by flow cytometry. ShK-F6CA blocked Kv1.3 at picomolar concentrations with a Hill coefficient of 1 and exhibited >80-fold specificity for Kv1.3 over Kv1.1 and other K(V) channels. In flow cytometry experiments, ShK-F6CA specifically stained Kv1.3-expressing cells with a detection limit of approximately 600 channels per cell. Rat and human T cells that had been repeatedly stimulated 7-10 times with antigen were readily distinguished on the basis of their high levels of Kv1.3 channels (>600 channels/cell) and ShK-F6CA staining from resting T cells or cells that had undergone 1-3 rounds of activation. Functional Kv1.3 expression levels increased substantially in a myelin-specific rat T cell line following myelin antigen stimulation, peaking at 15-20 h and then declining to baseline over the next 7 days, in parallel with the acquisition and loss of encephalitogenicity. Both calcium- and protein kinase C-dependent pathways were required for the antigen-induced Kv1.3 up-regulation. ShK-F6CA might be useful for rapid and quantitative detection of Kv1.3(high) expressing cells in normal and diseased tissues, and to visualize the distribution of functional channels in intact cells.


Ben-Hur, T., O. Einstein, et al. (2003). "Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis." Glia 41(1): 73-80.

            Transplanted neural precursor cells remyelinate efficiently acutely demyelinated focal lesions. However, the clinical value of cell transplantation in a chronic, multifocal disease like multiple sclerosis will depend on the ability of transplanted cells to migrate to the multiple disease foci in the brain. Here, we expanded newborn rat neural precursor cells in spheres and transplanted them intracerebroventricularly or intrathecally in rats. The cells were labeled by the nuclear fluorescent dye Hoechst or by incubation with BrdU to enable their identification at 2 days and 2 weeks after transplantation, respectively. Spheres consisted of PSA-NCAM(+), nestin(+), NG2(-) undifferentiated precursor cells that differentiated in vitro into astrocytes, oligodendrocytes, and neurons. Spheres that were transplanted into intact rats remained mostly in the ventricles or in the spinal subarachnoid space. Following transplantation at peak of experimental autoimmune encephalomyelitis, cells migrated into the brain or spinal cord parenchyma, exclusively into inflamed white matter but not into adjacent gray matter regions. After 2 weeks, many transplanted cells had migrated into distant white matter tracts and acquired specific markers of the astroglial and oligodendroglial lineages. Thus, the inflammatory process may attract targeted migration of transplanted precursor cells into the brain parenchyma.


Benatru, I., P. Terraux, et al. (2003). "[Gustatory disorders during multiple sclerosis relapse]." Rev Neurol (Paris) 159(3): 287-92.

            Gustatory dysfunction is a known but uncommon element in the course of multiple sclerosis. Gustatory dysfunction has been described during the chronic progressive phase and during the relapse phase. We report five patients with clinically definite multiple sclerosis who developed transient gustatory disorders during the relapse phase of their disease. Agueusia occurred as one of the first symptoms in three patients, revealing the disease. Symptoms generally improved with remission or corticosteroid administration. These disorders are due to demyelinating lesions of the gustatory pathways in the thalamus or brainstem. MRI studies were not performed during the relapse phase and no clinical neuroimaging correlations could be established. Agueusia may be accompanied by olfactory dysfunction which is due to plaque demyelinization of the olfactory pathways, particularly in the temporal and inferior frontal lobes. Taste anomalies can also be observed in other diseases, including systemic diseases such as sarcoidosis or Sjogren's syndrome. Drug-induced gustatory disorders are also reported.


Benedict, R. H., F. Munschauer, et al. (2003). "Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire." Mult Scler 9(1): 95-101.

            Since there is a need for cost-effective screening techniques to identify neuropsychological impairment in multiple sclerosis (MS) patients, and because existing methods require cognitive testing with subsequent interpretation by a neuropsychologist, a brief self-report procedure was developed to screen for neuropsychological impairment in MS. In the first phase of the study, a pool of 80 items was generated based on a literature review and consultation with healthcare professionals. The set was reduced to 15 via Rasch analysis. Using these items, a brief (five minute) MS Neuropsychological Screening Questionnaire (MSNQ), including patient- and informant-report forms, was composed. In phase II, 50 MS patients and their caregivers completed the MSNQ. A comprehensive neuropsychological test battery was also administered. Analyses covered the reliability of the MSNQ and correlations between both patient- and informant-report scores and objective neuropsychological testing. Cronbach's alpha coefficients were 0.93 and 0.94 for the patient- and informant-report forms, respectively, and both forms of the test were strongly correlated with a more general cognitive complaints questionnaire. The patient MSNQ form correlated significantly with measures of depression but not with objective tests of cognitive function. In contrast, the informant form was correlated with patient cognitive performance but not depression. A cut-off score of 27 on the informant form of the MSNQ optimally separated patients based on a neuropsychological summary score encompassing measures of processing speed and memory. There were two false-negatives and one false-positive, giving the test a sensitivity of 0.83 and a specificity of 0.97. It is concluded, therefore, that this self-administered neuropsychological screening test is reliable and predicts neuropsychological impairment in MS patients with a reasonable degree of accuracy.


Benito-Leon, J. and P. Martinez-Martin (2003). "[Health-related quality of life in multiple sclerosis]." Neurologia 18(4): 210-7.

            The clinical scales used to assess disease severity in multiple sclerosis (MS) patients share a common feature: assessment is made and interpreted by neurologists, and, therefore, someone other than the patient. Furthermore, these scales do not assess the health factors that are important components of patient's experienced quality of life. Health-related quality of life (HRQoL) instruments include several domains, which are regarded by patients as being more important determinants of their overall health states. In fact, HRQoL measurements in MS are becoming important in assessing the effect of treatment and progression of the disease. This article will provide a review of the most significant studies on HRQoL in MS. Neurologia 2003;18(4):210-217


Benjamins, J. A., L. Nedelkoska, et al. (2003). "Protection of mature oligodendrocytes by inhibitors of caspases and calpains." Neurochem Res 28(1): 143-52.

            Mature mouse oligodendrocytes (OLs) are susceptible to death in demyelinating diseases such as multiple sclerosis and in brain injury following neurotrauma, ischemia, or stroke. To understand mechanisms leading to death of mature OLs and develop strategies for protection, we utilized cultures of mature mouse OLs to investigate the role of caspases and calpains in OL cell death mediated by different mechanisms. The agents used were (i) staurosporine, which induces apoptotic death via inhibition of protein kinases; (ii) kainate, which activates non-NMDA glutamate receptors; (iii) thapsigargin, which releases intracellular calcium stores; and (iv) SNAP, which releases active NO species and causes necrotic cell death. Inhibitors blocking primary effector caspases (including caspase 3), the FAS (death receptor)-mediated initiator caspases (including caspase 8), and stress-induced caspases (including caspase 9), were tested for their protective effects. Inhibition of caspases 3, 8, and 9 each robustly protected OLs following insult with staurosporine, thapsigargin, or kainate when added at optimal times. The time of addition of the inhibitors for maximal protection varied with the agent, from 1 h of preincubation before addition of staurosporine to 6 h after addition of kainate. Much less protection was seen for the NO generator SNAP under any condition. The role of calcium in OL death in each model was investigated by chelating extracellular Ca++ with EGTA, and by inhibiting the Ca++-activated calpain proteases. Calcium chelation did not protect against staurosporine, but decreased OL death initiated by kainate, thapsigargin, or NO. The calpain inhibitors PD150606 and calpain inhibitor I protected from cell death initiated by staurosporine, kainate, and thapsigargin, but not from cell death initiated by the NO donor SNAP.


Benz, M. S., J. S. Glaser, et al. (2003). "Progressive outer retinal necrosis in immunocompetent patients treated initially for optic neuropathy with systemic corticosteroids." Am J Ophthalmol 135(4): 551-3.

            PURPOSE: To report two cases of progressive outer retinal necrosis occurring in immunocompetent individuals after treatment with corticosteroids for presumed optic neuropathy. DESIGN: Observational case report. SETTING: University-based tertiary eye hospital. METHODS: Retrospective review of existing clinical records. RESULTS: Two patients were treated empirically with systemic corticosteroids for suspected inflammatory papillopathy. Subsequently, both were diagnosed with necrotizing herpetic retinitis with features of progressive outer retinal necrosis. Anterior chamber paracentesis confirmed varicella-zoster infection. Both patients were human immunodeficiency virus negative; one patient with rheumatoid arthritis was taking etanercept. Both became completely blind in one eye despite intensive treatment with antiviral medication intravenously and intravitreally. CONCLUSIONS: Progressive outer retinal necrosis is not confined to patients with underlying severe immunodeficiency, such as acquired immune deficiency syndrome. Initial treatment of acute, unexplained vision loss with systemic corticosteroids may lead to catastrophic visual loss in patients with evolving necrotizing herpetic retinopathy.


Berger, T., P. Rubner, et al. (2003). "Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event." N Engl J Med 349(2): 139-45.

            BACKGROUND: Most patients with multiple sclerosis initially present with a clinically isolated syndrome. Despite the fact that clinically definite multiple sclerosis will develop in up to 80 percent of these patients, the course of the disease is unpredictable at its onset and requires long-term observation or repeated magnetic resonance imaging (MRI). We investigated whether the presence of serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome predicts the interval to conversion to clinically definite multiple sclerosis. METHODS: A total of 103 patients with a clinically isolated syndrome, positive findings on cerebral MRI, and oligoclonal bands in the cerebrospinal fluid were studied. At base line, serum samples were collected to test for anti-MOG and anti-MBP antibodies with Western blot analysis, and the lesions detected by cerebral MRI were quantified. Neurologic examinations for relapse or disease progression (defined as conversion to clinically definite multiple sclerosis) were performed at base line and subsequently every three months. RESULTS: Patients with anti-MOG and anti-MBP antibodies had relapses more often and earlier than patients without these antibodies. Only 9 of 39 antibody-seronegative patients (23 percent) had a relapse, and the mean (+/-SD) time to relapse was 45.1+/-13.7 months. In contrast, 21 of 22 patients (95 percent) with antibodies against both MOG and MBP had a relapse within a mean of 7.5+/-4.4 months, and 35 of 42 patients (83 percent) with only anti-MOG antibodies had a relapse within 14.6+/-9.6 months (P<0.001 for both comparisons with antibody-seronegative patients). The adjusted hazard ratio for the development of clinically definite multiple sclerosis was 76.5 (95 percent confidence interval, 20.6 to 284.6) among the patients who were seropositive for both antibodies and 31.6 (95 percent confidence interval, 9.5 to 104.5) among the patients who were seropositive only for anti-MOG antibodies, as compared with the seronegative patients. CONCLUSIONS: Analysis of antibodies against MOG and MBP in patients with a clinically isolated syndrome is a rapid, inexpensive, and precise method for the prediction of early conversion to clinically definite multiple sclerosis. This finding may be important for the counseling and care of patients with a first demyelinating event suggestive of multiple sclerosis.


Bermel, R. A., J. Sharma, et al. (2003). "A semiautomated measure of whole-brain atrophy in multiple sclerosis." J Neurol Sci 208(1-2): 57-65.

            Brain atrophy is a proposed MRI marker of irreversible pathologic damage in multiple sclerosis (MS). The brain parenchymal fraction (BPF) is the ratio of brain parenchymal volume to the total volume within the surface contour. We developed a semiautomated measure of BPF using commercially available edge-finding and thresholding software (30-min analysis time per patient). We measured BPF in 78 patients with MS and 17 healthy controls. BPF was lower in a cohort of patients with MS (n=50) (0.843+/-0.042, range 0.743-0.906) age-matched to controls (0.877+/-0.020, range 0.835-0.901) (p<0.001). BPF correlated inversely with third ventricular width (r=-0.785, p<0.001), and total T1 hypointense lesion volume (r=-0.347, p=0.011), but not with total T2 hyperintense lesion volume (r=-0.213, p=0.13). BPF correlated negatively with expanded disability status scale (EDSS) score (r=-0.391, p=0.0006) and disease duration (r=-0.281, p=0.01). Stepwise regression compared the relative abilities of MRI variables to predict clinical data. By regression of age, BPF, third ventricular width, T2 lesions, and T1 lesions, BPF was the best predictor of disability score (R(2)=0.204, p<0.001). Third ventricular width was the best predictor of disease duration (R(2)=0.316, p<0.001). None of the MRI variables differed between relapsing-remitting (RR) (n=60) and secondary progressive (SP) (n=18) disease course (p>0.05). The intrarater, interrater, and scan-rescan BPF variability (COV) was 0.31%, 0.34%, and 0.41% and the accuracy against a phantom was 99.1%. We conclude that whole-brain atrophy in MS can be reliably and readily quantified by a semiautomated approach. Longitudinal studies are warranted to determine if this method provides a sensitive biologic marker of the MS disease process.


Bermel, R. A., M. D. Innus, et al. (2003). "Selective caudate atrophy in multiple sclerosis: a 3D MRI parcellation study." Neuroreport 14(3): 335-9.

            Deep gray matter damage may be an important component of the multiple sclerosis (MS) disease process. We tested whether caudate atrophy occurs in MS, and whether it correlates with conventional MRI or clinical markers of disease progression. Caudate nuclei of 24 MS patients and 10 age-matched healthy controls were traced, normalized, reconstructed and visualized from MRI scans. Normalized bicaudate volume was 19% lower in MS controls ( p< 0.001), an effect that persisted after adjusting for whole-brain atrophy ( p< 0.008). Caudate volume did not correlate with disease duration, physical disability score, whole-brain atrophy, or total T2 hyperintense or T1 hypointense lesion load (all p > 0.05). We conclude that selective caudate atrophy is associated with MS and may occur through direct mechanisms.


Besler, H. T. and S. Comoglu (2003). "Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis." Nutr Neurosci 6(3): 189-96.

            Free radical-mediated peroxidation of biological molecules, especially of lipids, is implicated in the pathogenesis of a number of diseases like multiple sclerosis. Low concentration of antioxidant vitamins: beta carotene, retinol, alpha tocopherol and ascorbic acid have been observed in serum or cerebrospinal fluid of multiple sclerosis patients. On the basis of these observations, we studied the potential lipoprotein oxidation and total antioxidant capacity in the pathogenesis of multiple sclerosis. Lipoprotein oxidizability for plasma in vitro, serum levels of autoantibodies against oxidized low-density lipoproteins, plasma total homocysteine levels with vitamin B12 and folate, and plasma total antioxidant capacity were measured in twenty four patients with multiple sclerosis and twenty four healthy sex- and age-matched person as control. In multiple sclerosis patients during an attack, a significant increase in both in vitro lipid oxidizability for plasma and in the levels of autoantibodies against oxidized low-density lipoproteins, and a strong decrease in plasma total antioxidant capacity were detected. Plasma total homocysteine levels were significantly higher in multiple sclerosis patients whose plasma vitamin B12 and folate levels were lower but not statistically significant, than controls. The present study indicates that lipoprotein oxidation may be important factor in the course of multiple sclerosis and in vitro measurements of plasma oxidation kinetics as an indication for lipoprotein oxidation might be useful as an additional tool for the clinical diagnosis of multiple sclerosis.


Bettelli, E., M. Pagany, et al. (2003). "Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis." J Exp Med 197(9): 1073-81.

            Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.


Bilinska, M., I. Frydecka, et al. (2003). "Fas expression on T cells and sFas in relapsing-remitting multiple sclerosis." Acta Neurol Scand 107(6): 387-93.

            OBJECTIVES: To investigate the proportions of peripheral blood CD4+/Fas+ and CD8+/Fas+ cells and serum sFas levels in relapsing-remitting multiple sclerosis (RRMS) patients with relapses (active RRMS), those without relapses (stable RRMS), and controls over 1 year. MATERIAL AND METHODS: Sixteen RRMS patients and 10 controls were tested monthly. Cells were analyzed by dual immunofluorescence and the sFas levels by ELISA. There were 14 relapses which occurred 1223 days after the last control visits. The measurements performed at these visits in the active RRMS patients were considered as relapse-related, while the rest were regarded as relapse-unrelated. RESULTS: In active RRMS patients the median of CD4+ Fas+ to total CD4+ and CD8+ Fas+ to total CD8+ from relapse-related measurements were higher than the median from relapse-unrelated measurements (P=0.003, 0.004, respectively). The median of CD4+ Fas+ to total CD4+ from relapse-unrelated measurements in active RRMS was higher compared with stable RRMS (P = 0.005) and controls (P = 0.004). The sFas level from relapse-unrelated measurements was also higher in active RRMS than in stable RRMS (P = 0.04) and in controls (P = 0.004). CONCLUSIONS: We suggest that increased expression of Fas antigen on CD4+ subset and increased serum sFas level are valuable markers of clinical activity in MS.


Bingham, S. C. and P. W. Beatty (2003). "Rates of access to assistive equipment and medical rehabilitation services among people with disabilities." Disabil Rehabil 25(9): 487-90.

            PURPOSE: To determine rates of access to assistive equipment and medical rehabilitation services among people with disabilities in the US, and to determine whether health plan type is associated with rates of access to these health services. METHOD: Results were derived from a nationwide US survey sample of people with cerebral palsy, multiple sclerosis or spinal cord injury. Analyses were restricted to working-age adults (n=500). Need for, and receipt of (1) assistive equipment in the last 12 months, and (2) rehabilitative services in the last 3 months, was determined. RESULTS: Over half of the sample indicated a need for assistive equipment in the last 12 months. Nearly a third of those who indicated a need did not receive assistive equipment every time it was needed. Forty per cent of the sample indicated a need for rehabilitative services in the last 3 months, and over half of those indicating a need did not receive rehabilitative services every time they were needed. Access rates did not differ appreciably between respondents covered by managed care and fee-for-service health plans. CONCLUSION: Emphasis in healthcare for people with disabilities should shift from traditional acute healthcare models that focus on functional restoration, to preventive services, and maintenance of function, health and independence.


Birnboim, S. (2003). "The automatic and controlled information-processing dissociation: is it still relevant?" Neuropsychol Rev 13(1): 19-31.

            The purpose of this paper is to examine the "dual-process" information-processing model of Schneider and Shiffrin (Schneider, W., and Shiffrin, R. M., Psychol. Rev. 84: 1-66, 1977; see also Shiffrin, R. M., and Schneider, W., Psychol. Rev. 84: 127-190, 1977) in light of the research data that have accumulated since the model was introduced more than 20 years ago. First, a brief introduction of the basic model of automatic and controlled information processing will be given. Second, some alternatives to the basic model that were developed over the last two decades will be reviewed. Third, data from neuropsychology and cognitive neuroscience that have a bearing upon this framework will be considered. Finally, some comments on the current usefulness of the dual-process framework for neuropsychological research will be offered.


Bjartmar, C. and B. D. Trapp (2003). "Axonal degeneration and progressive neurologic disability in multiple sclerosis." Neurotox Res 5(1-2): 157-64.

            Accumulating data support axonal degeneration as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). The extent of axonal injury correlates with the degree of inflammation in active MS lesions and occurs at early stages of disease, indicating that inflammatory demyelination is an important factor behind axon pathology at the relapsing-remitting stage of MS. Axonal loss from disease onset can remain clinically silent for many years, and permanent neurological disability develops when a threshold of axonal loss is reached and the CNS compensatory resources are exhausted. Lack of myelin-derived trophic support due to long term demyelination may cause continuous axonal degeneration in chronic inactive lesions at the secondary-progressive stage of MS. Axonal pathology is not limited to demyelinated lesions, but also extends into normal appearing white matter. The concept of MS as a neurodegenerative disorder has important clinical implications: First, proactive anti-inflammatory and immunomodulatory treatment should prevent or delay chronic disability since inflammation influences axonal injury. Second, the pathophysiological mechanisms underlying axonal degeneration in MS need to be clarified in order to develop novel neuroprotective therapeutics. Finally, surrogate markers of axonal pathology, such as N-acetyl aspartate, can be used to monitor axonal dysfunction, axonal loss and treatment efficiency in patients with MS.


Bjartmar, C., J. R. Wujek, et al. (2003). "Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease." J Neurol Sci 206(2): 165-71.

            Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing-remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted. Experimental support for this view-the axonal hypothesis-is provided by data from various animal models with primary myelin or axonal pathology, and from pathological or magnetic resonance studies on MS patients. In mice with experimental autoimmune encephalomyelitis (EAE), 15-30% of spinal cord axons can be lost before permanent ambulatory impairment occurs. During secondary progressive MS (SP-MS), chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support. In addition, we hypothesize that reduced trophic support from damaged targets or degeneration of efferent fibers may trigger preprogrammed neurodegenerative mechanisms. The concept of MS as an inflammatory neurodegenerative disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of neuroprotective treatment strategies.


Blanco, Y., J. Yague, et al. (2003). "No association of inducible nitric oxide synthase gene ( NOS2A) to multiple sclerosis." J Neurol 250(5): 598-600.

            Nitric oxide (NO) is a nonspecific inflammatory mediator that has been involved in the pathogenesis of multiple sclerosis (MS). The influence of the promoter polymorphism of inducible NO synthase gene ( NOS2A) on susceptibility and outcome was studied in 140 MS Spanish patients and 147 healthy controls matched for sex, age, and ethnicity. No association was found between MS susceptibility, course or outcome of the disease, and NOS2A polymorphisms.


Blom, T., A. Franzen, et al. (2003). "Comment on "The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease"." Science 299(5614): 1845; author reply 1845.


Bobholz, J. A. and S. M. Rao (2003). "Cognitive dysfunction in multiple sclerosis: a review of recent developments." Curr Opin Neurol 16(3): 283-8.

            PURPOSE OF REVIEW: Nearly half of all patients diagnosed with multiple sclerosis will develop cognitive dysfunction, a symptom associated with significant decline in activities of daily living. The purpose of this review is to discuss recent literature investigating issues related to cognitive dysfunction in multiple sclerosis. RECENT FINDINGS: Recent studies, examined in this review, have provided increased understanding regarding specific cognitive processes affected in multiple sclerosis, as well as a characterization of its natural history. Studies have also continued to emphasize the extent to which cognitive deficits in the condition are associated with decline in daily living skills. Recent concerns regarding driving performance have been documented among cognitively impaired individuals. Studies have also examined correlates of cognitive dysfunction, with particular emphasis on neuroimaging techniques reflecting disease activity or lesion burden. With increased understanding of neurobiological correlates of cognitive deficits, investigators have begun to examine potential treatments for managing cognitive dysfunction. SUMMARY: This area of research has suggested that disease modifying medications can have an impact on magnetic resonance imaging disease activity by altering the cerebral demyelinating process resulting in a slower decline in cognitive functions over time and improved activities of daily living for patients with multiple sclerosis.


Bode, R. K., J. S. Lai, et al. (2003). "Issues in the development of an item bank." Arch Phys Med Rehabil 84(4 Suppl 2): S52-60.

            OBJECTIVE: To describe and illustrate 2 issues involved in the development of an item bank that can be used to improve measurement across settings and over time. DESIGN: Secondary (psychometric) analysis of data collected on existing quality of life (QOL) instruments. SETTING: Five cancer clinics in hospital settings in various parts of the United States; 523 solo or group practices in 3 major US cities; and an inpatient rehabilitation hospital in a large metropolitan area. PARTICIPANTS: Illustration 1: 399 persons being treated for or having a history of cancer, 170 persons being treated for human immunodeficiency virus (HIV), 328 persons with stroke assessed during and after acute rehabilitation, and 433 persons being treated for multiple sclerosis. Illustration 2: 1714 persons with cancer and/or HIV participating in a large-scale multisite study, 3429 persons with prevalent treatable chronic health conditions, and 125 persons with stage IV metastatic breast cancer. INTERVENTIONS: Not applicable. Main Outcomes Measures: QOL as measured by 10 different instruments. RESULTS: The illustrations show that (1). core items, which functioned similarly across 4 diagnostic groups, can be identified and used to construct instruments measuring physical function that are tailored to each of these groups, and (2). items from 3 separate datasets can be linked to create a dataset that can serve as an initial pain item bank. CONCLUSION: The methodology exists to develop item banks to develop better measures of QOL.


Boeije, H. R., M. S. Duijnstee, et al. (2003). "Continuation of caregiving among partners who give total care to spouses with multiple sclerosis." Health Soc Care Community 11(3): 242-52.

            As is expressed in the term 'caregiving career', caregiving is a dynamic phenomenon. The present study addresses the total care phase in which spouses give direct and ongoing personal care to their partners with multiple sclerosis (MS). The dyadic nature of caregiving is stressed by examining the roles which both spouses play in establishing a commitment that results in the continuation of caregiving. For this purpose, 17 couples facing MS were selected in the Netherlands and Belgium. Ten females and seven males were disabled, and all were living with partners who provided a full range of care. Both partners were interviewed separately about their motivation to give care, dependency on help, the continuation of caregiving and their relationship. The analysis consisted of fragmenting and connecting the data, and involved close reading and constant comparison. The present findings support those previous studies, i.e. that continuation of caregiving is the result of an interchange between the partners. The commitment that is established can be expressed in terms of inevitability, shared misfortune, reciprocity and the desire to prevent admission to a nursing home. Three aspects appear to contribute to the creation of commitment and the ensuing continuation of caregiving: namely, marital loyalty, and the arbitrariness of the disease and its serious nature. For community care, it is important to consider the negotiations between partners and the impact of caregiving on their relationship.


Bolviken, B., E. G. Celius, et al. (2003). "Radon: a possible risk factor in multiple sclerosis." Neuroepidemiology 22(1): 87-94.

            Ecological studies in Norway, using a method for spatially moving bivariate correlation analysis, show that south of 65 degrees N, there are significant positive correlations (p < 0.01) for rates of multiple sclerosis (MS) versus contents of radon (Rn) in indoor air, and significant negative correlations for MS rates versus fallout of magnesium (Mg) and amounts of precipitation. Based on these data, we propose the hypothesis that the content of Rn in inhaled air is a risk factor in MS. The release of harmful Rn levels to the air may be influenced by (1) the levels of exchangeable Mg in soil, which may affect the soil content of the Rn precursor radium (Ra), and (2) the amounts of precipitation through its effects on soil moisture, which is one of the factors controlling Rn emanation from the soil. This hypothesis agrees with several of the known epidemiological characteristics of MS.


Borchmann, P. and M. Reiser (2003). "Pixantrone (Novuspharma)." IDrugs 6(5): 486-90.

            Novuspharma is developing pixantrone, a second-generation, well-tolerated anthracenedione analog, for the potential treatment of lymphoma and multiple sclerosis.


Bosch, X. (2003). "Spanish centre for rehabilitation of multiple sclerosis to be built." Lancet Neurol 2(7): 391.


Boven, L. A., N. Vergnolle, et al. (2003). "Up-regulation of proteinase-activated receptor 1 expression in astrocytes during HIV encephalitis." J Immunol 170(5): 2638-46.

            Proteinase-activated receptor 1 (PAR-1) is a G protein-coupled receptor that is activated by thrombin and is implicated in the pathogenesis of inflammation. Although PAR-1 is expressed on immunocompetent cells within the brain such as astrocytes, little is known about its role in the pathogenesis of inflammatory brain diseases. Herein, we investigated PAR-1 regulation of brain inflammation by stimulating human astrocytic cells with thrombin or the selective PAR-1-activating peptide. Activated cells expressed significantly increased levels of IL-1 beta, inducible NO synthase, and PAR-1 mRNA. Moreover, supernatants of these same cells were neurotoxic, which was inhibited by an N-methyl-D-aspartate receptor antagonist. Striatal implantation of the PAR-1-activating peptide significantly induced brain inflammation and neurobehavioral deficits in mice compared with mice implanted with the control peptide or saline. Since HIV-related neurological disease is predicated on brain inflammation and neuronal injury, the expression of PAR-1 in HIV encephalitis (HIVE) was investigated. Immunohistochemical analysis revealed that PAR-1 and (pro)-thrombin protein expression was low in control brains, but intense immunoreactivity was observed on astrocytes in HIVE brains. Similarly, PAR-1 and thrombin mRNA levels were significantly increased in HIVE brains compared with control and multiple sclerosis brains. These data indicated that activation and up-regulation of PAR-1 probably contribute to brain inflammation and neuronal damage during HIV-1 infection, thus providing new therapeutic targets for the treatment of HIV-related neurodegeneration.


Bowen, J. D., K. Maravilla, et al. (2003). "Open-label study of pirfenidone in patients with progressive forms of multiple sclerosis." Mult Scler 9(3): 280-3.

            BACKGROUND: Pirfenidone is an oral medication with a number of actions affecting the immune system. It has been proposed as a possible treatment for multiple sclerosis (MS). METHODS: An early-phase study of progressive forms of MS was conducted. Pirfenidone was slowly titrated to 2400 mg/day. Safety, clinical, quality-of-life, and magnetic resonance image (MRI) outcomes were measured. RESULTS: Twenty people were enrolled (13 with secondary progressive and seven with primary progressive MS). The mean age was 47.7 years; the mean Expanded Disability Status Scale (EDSS) was 5.15; 75% were female. Eighteen patients achieved the full dose, although five additional patients eventually had to decrease the dose, primarily because of nausea. The Neurologic Rating Scale showed a slight worsening, from 69.8+/-8.4 at baseline to 71.8+/-8.9 at one year (P = 0.03). Other clinical outcomes remained stable, including the EDSS, ambulation index, and nine-hole peg test. The Short-Form Health Survey (SF-36) quality-of-life measure remained unchanged. Comparisons of MRI scans at baseline and one year found that 715 plaques were unchanged, six were better, and 10 were worse. Three patients had plaques that improved and two patients had plaques that were worse. There were eight gadolinium-enhancing lesions on the baseline scans and 14 on the one-year scans. CONCLUSIONS: Pirfenidone was well tolerated in patients with MS. Patients with primary progressive or secondary progressive MS tolerated the medication and remained clinically stable during the one year of follow up. Placebo-controlled blinded studies are needed to determine clinical effectiveness.


Bowling, A. C. and T. M. Stewart (2003). "Current Complementary and Alternative Therapies for Multiple Sclerosis." Curr Treat Options Neurol 5(1): 55-68.

            The use of complementary and alternative medicine (CAM) appears to be high in the general population and in patients with multiple sclerosis (MS). There are no diets or dietary supplements that are definitely effective in altering the disease course in MS. However, diets and dietary supplements that increase the intake of polyunsaturated fatty acids may produce mildly beneficial effects. Because these approaches are not definitely effective, they may be of limited interest to physicians and other conventional health providers. In contrast, for patients with MS, these interventions may be of considerable interest, because they may be mildly effective and are inexpensive and relatively safe. Vitamin D, ginkgo biloba, cannabinoids, and Padma 28 produce immunomodulatory actions and therapeutic effects in experimental autoimmune encephalomyelitis. However, for these compounds, there are not enough clinical trial data or safety information to support their use as disease-modifying therapies. The role of antioxidant compounds in MS is unclear. There is no evidence that vitamin B(12) supplementation or gluten-free diets are effective MS therapies. Conventional health providers can play an important role in the care of MS patients by being open to discuss CAM therapies and by providing objective MS-relevant CAM information.


Boyd, J. G., V. Skihar, et al. (2003). "Olfactory ensheathing cells: Historical perspective and therapeutic potential." Anat Rec 271B(1): 49-60.

            Olfactory ensheathing cells (OECs) are the glial cells that ensheath the axons of the first cranial nerve. They are attracting increasing attention from neuroscientists as potential therapeutic agents for use in the repair of spinal cord injury and as a source of myelinating glia for use in remyelinating axons in demyelinating diseases such as multiple sclerosis. This review mainly addresses the cell biological aspects of OECs pertinent to addressing two questions. Namely, where do OECs fit into the groupings of central nervous system (CNS)/peripheral nervous system (PNS) glial cells and should OECs be viewed as a clinically relevant alternative to Schwann cells in the treatment of spinal cord injury? The evidence indicates that OECs are indeed a clinically relevant alternative to Schwann cells. However, much more work needs to be done before we can even come close to answering the first question as to the lineage and functional relationship of OECs to the other types of CNS and PNS glial cells. Anat Rec (Part B: New Anat) 271B:49-60, 2003. Copyright 2003 Wiley-Liss, Inc.


Bozzao, A., R. Floris, et al. (2003). "Cerebrospinal fluid changes after intravenous injection of gadolinium chelate: assessment by FLAIR MR imaging." Eur Radiol 13(3): 592-7.

            Fluid-attenuated inversion recovery (FLAIR) sequence is currently used in clinical practice. Some reports emphasize the possibility that, in pathologic conditions, intravenous injection of gadolinium chelates may lead to an increased signal inside the cerebrospinal fluid (CSF). The aim of this study was to evaluate the presence of CSF signal changes in pathologic conditions causing blood-brain barrier disruption or neovascularization when imaging is performed after intravenous injection of gadolinium. We obtained FLAIR sequences after gadolinium injection from 33 patients affected by different intracranial pathologies and 10 control subjects. Patients were affected by ischemic stroke in the subacute phase, from 2 to 7 days from onset of symptoms (12 patients), meningiomas (8 patients), high-grade gliomas (5 patients), previous surgical procedures for intra-axial neoplasms (5 patients), and multiple sclerosis with active plaques (3 patients). Magnetic resonance imaging was performed in patients and controls using a 1.5-T magnet, using T2- and T1-weighted FLAIR sequences. The FLAIR sequence was acquired before and 1-3 h after injection of a standard dose of gadolinium. In those patients affected by ischemic lesions, FLAIR sequences were repeated the next days and 3-4 days later. The CSF signal was visually evaluated by two readers and scored from 0 to 3 depending by the degree of enhancement. The location of CSF signal changes (close to the lesion, hemispheric, or diffuse) was also considered. The CSF signal was markedly increased after 3 h from intravenous injection of gadolinium in all the patients with stroke, in those with previous surgery, and in those with high-grade gliomas whose neoplasm's surface was in contact with the subarachnoid spaces (SAS) or ventricles; a strong enhancement was also evident inside the necrotic component of the tumor. The CSF changes were more evident close to the pathology and/or in the hemisphere involved by the pathology. Moderate CSF enhancement was observed in the SAS close to meningiomas. No signal changes were evident in all the others. In those patients with stroke imaged in the following days, CSF signal showed to be diffuse to both hemispheres the next day and returned to normal values within 2 days. In patients affected by pathologies with blood-brain barrier breakdown or neovascularization close the SAS or the ventricles, CSF changes, related to gadolinium leakage, are likely when FLAIR sequences are acquired 2-24 h after i.v. injection of the contrast. This pattern should be known in order to differentiate it from that of subarachnoid hemorrhage.


Bradbury, J. (2003). "Wrong cytokine backed in multiple-sclerosis model." Lancet Neurol 2(4): 203.


Breij, E. C., W. L. van der Pol, et al. (2003). "No association of FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb polymorphisms with MS." J Neuroimmunol 140(1-2): 210-5.

            Anti-myelin IgGs occur in the cerebrospinal fluid (CSF) and serum of multiple sclerosis (MS) patients, and can induce inflammatory effector functions in leukocytes by crosslinking IgG receptors (FcgammaR). The efficiency of FcgammaR-mediated inflammatory processes is affected by functional polymorphisms of three Fcgamma receptors (FcgammaRIIa, FcgammaRIIIa, FcgammaRIIIb).The relevance of FcgammaR polymorphisms in MS was evaluated by studying the distribution of FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb genotypes in 432 MS patients and 515 healthy controls. No significant differences were found between MS patients and controls, or between subgroups of patients. We conclude that Fcgamma receptor polymorphisms influence neither susceptibility nor clinical disease course of MS.


Breithaupt, C., A. Schubart, et al. (2003). "Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein." Proc Natl Acad Sci U S A.

            Multiple sclerosis is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal loss. The immunopathogenesis of demyelination in multiple sclerosis involves an autoantibody response to myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the surface of CNS myelin. Here we present the crystal structures of the extracellular domain of MOG (MOG(Igd)) at 1.45-A resolution and the complex of MOG(Igd) with the antigen-binding fragment (Fab) of the MOG-specific demyelinating monoclonal antibody 8-18C5 at 3.0-A resolution. MOG(Igd) adopts an IgV like fold with the A'GFCC'C" sheet harboring a cavity similar to the one used by the costimulatory molecule B7-2 to bind its ligand CTLA4. The antibody 8-18C5 binds to three loops located at the membrane-distal side of MOG with a surprisingly dominant contribution made by MOG residues 101-108 containing a strained loop that forms the upper edge of the putative ligand binding site. The sequence R(101)DHSYQEE(108) is unique for MOG, whereas large parts of the remaining sequence are conserved in potentially tolerogenic MOG homologues expressed outside the immuno-privileged environment of the CNS. Strikingly, the only sequence identical to DHSYQEE was found in a Chlamydia trachomatis protein of unknown function, raising the possibility that Chlamydia infections may play a role in the MOG-specific autoimmune response in man. Our data provide the structural basis for the development of diagnostic and therapeutic strategies targeting the pathogenic autoantibody response to MOG.


Brooke, H. (2003). "How I coped with....nursing and MS. Interview by David Crouch." Nurs Times 99(17): 38-9.


Brostrom, S., J. L. Frederiksen, et al. (2003). "Motor evoked potentials from the pelvic floor in patients with multiple sclerosis." J Neurol Neurosurg Psychiatry 74(4): 498-500.

            The use of motor evoked potentials (MEPs) to study the integrity of pelvic floor motor innervation is poorly described in the literature. This study evaluated the clinical use of pelvic floor MEPs in 16 women with multiple sclerosis. Lower urinary tract dysfunction was assessed with urodynamic investigations. Transcutaneous magnetic stimulation was applied over the motor cortex and spinal roots, and MEPs were recorded from the puborectalis, the external urethral sphincter, and the abductor hallucis muscles. In many patients, responses from the pelvic floor muscles could not be evoked, and central motor conduction times for the puborectalis motor pathways could only be calculated in 56%. There was a poor correlation of abnormal conduction to lower urinary tract dysfunction. It is concluded, that unevokable responses from pelvic floor muscles in a patient with multiple sclerosis should be interpreted with care, and that pelvic floor MEPs have a limited clinical value in the investigation of suspected demyelinating disease.


Brown, J. S. (2003). "Correlation of mollicutes and their viruses with multiple sclerosis and other demyelinating diseases." Med Hypotheses 60(2): 298-303.

            To identify infectious diseases likely involved in MS, the author previously correlated the geographical distribution of MS with the global distribution of tick-borne diseases. Tick-borne infectious agents include mollicutes or mycoplasmas. The current paper reviews evidence that mollicutes, especially spiroplasmas, or their viruses could be the initial exposure that causes MS. Mollicute infections, including the effects of their toxins, can be treated or prevented with gold salts or tetracyclines. If further research recommended by this review finds a role of mycoplasmas in MS, treatment of MS with gold with tetracycline should be evaluated.


Bruck, W., T. Kuhlmann, et al. (2003). "Remyelination in multiple sclerosis." J Neurol Sci 206(2): 181-5.

            Remyelination in multiple sclerosis (MS) lesions has been described in several studies. It depends on the presence of myelinating oligodendrocytes and a functional interaction between these myelinating cells and axons. The imaging signal of remyelination in magnetic resonance imaging or spectroscopy is not yet defined. The present review will focus on the morphological appearance of remyelinating MS lesions, their correlation with oligodendrocyte pathology, and possible markers for remyelination in imaging.


Buchanan, R. J., S. Wang, et al. (2003). "Gender analyses of nursing home residents with multiple sclerosis." J Gend Specif Med 6(2): 35-46.

            OBJECTIVE: To present gender comparisons of residents with multiple sclerosis (MS) at admission to nursing facilities, including demographic characteristics, health measures, and treatments. METHODS: We analyzed 13,998 admission assessments in the Minimum Data Set for residents with MS recorded between June 23, 1998 and December 31, 2000. RESULTS: Although both male and female residents with MS tended to have severe disability, there were significant gender differences in measures of activities of daily living (ADL) dependency and disability, with males slightly more likely to exhibit total ADL dependence and greater loss of voluntary movement. Females with MS tended to have significantly better cognitive performance and better communication abilities than males with MS. There were significant gender differences in pain symptoms among residents, with one-third of females and one-fifth of males experiencing daily pain. Depression was the most common comorbidity among residents with MS, with females significantly more likely to have this diagnosis. Although females with MS were slightly more likely to have depression or anxiety disorder, males with MS were slightly more likely to receive mental health services. CONCLUSIONS: These analyses demonstrate that many nursing facilities need to improve pain management and mental health care provided to residents with MS, especially to females.


Buchanan, R. J., S. Wang, et al. (2003). "Analyses of nursing home residents with multiple sclerosis and depression using the Minimum Data Set." Mult Scler 9(2): 171-88.

            Depression is the most common psychiatric condition among people with multiple sclerosis (MS). A total of 14009 people with MS at admission to a nursing facility were analyzed using the Minimum Data Set and 36% also had depression. This study developed profiles of nursing home residents with MS who also had depression and compared them with other residents with MS. MS residents with depression were significantly more likely to be female and younger than other MS residents, with significant racial differences as well. MS residents with depression were significantly more likely than other MS residents to have a history of mental health conditions, exhibit mood indicators, and have unsettled relationships. Both groups of MS residents had high levels of physical disability, although MS residents with depression tended to be slightly less disabled. MS residents with depression were more likely than other MS residents to experience daily pain and more likely to have the diseases common to all residents with MS. This research found that most MS residents with depression did not receive mental health services, demonstrating that nursing facilities must improve the mental healthcare provided to residents with MS with depression.


Bunin, A. and A. A. Iakovlev (2003). "[Pathology of the lateral geniculate body and visual function]." Vestn Oftalmol 119(1): 46-9.


Burt, R. K., B. A. Cohen, et al. (2003). "Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of intense immune suppression to prevent disease progression in patients with high disability scores." Blood.

            Twenty-one patients with rapidly progressive multiple sclerosis (MS) were treated on a phase I/II study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no one year mortality. Following transplant, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pre transplant EDSS </= 6.0. In 8 of 12 patients with high pre transplant disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1 point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. Two patients with a pre-transplant EDSS of 7.0 and 8.0 died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression and hematopoietic stem cell transplantation (HSCT) is not effective for patients with progressive disease and high pre-transplant disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. In specific, more patients and longer follow-up would be required in patients with an EDSS </= 6.0 before drawing conclusions on this subgroup.


Burton, C. and R. Kaczmarski (2003). "Oxidative haemolysis secondary to high-dose vitamins in a woman with glucose-6-phosphate dehydrogenase deficiency." Br J Haematol 121(2): 201.


Busche, K. D., J. D. Fisk, et al. (2003). "Short term predictors of unemployment in multiple sclerosis patients." Can J Neurol Sci 30(2): 137-42.

            BACKGROUND: Unemployment is common in people with multiple sclerosis (MS) and is associated with loss of income and impaired health related quality of life. This study determined variables associated with unemployment and risk factors for the development of unemployment in people with MS. METHODS: Ninety-six patients who were under age 65 and participated in two previous studies to measure economic costs and health related quality of life in MS were included. The baseline employment rate and variables associated with unemployment at baseline were determined. The ability of these variables to predict unemployment over the next two and a half years was then evaluated. RESULTS: At baseline 50.1% (50/96) of participants were employed. Two and a half years later only 40.6% (39/96) remained employed. This represents loss of employment for 22.0% (11/50) of those originally employed. Factors associated with unemployment at baseline included greater disability, progressive disease course, longer disease duration, and older age. Risk factors for loss of employment over the next 2.5 years included greater disability and older age. CONCLUSIONS: This study confirms the low employment rate among people with MS and confirms the association of several previously-reported factors with greater risk of unemployment. It is also the first study to confirm that some of these factors also increase the risk of future unemployment. People with MS who are over age 39 or have moderate disability and are still employed can now be identified as at risk for becoming unemployed over the next 2.5 years. They should be considered for interventions to maintain employment or to lessen the impact of unemployment.


Butterfield, R. J., R. J. Roper, et al. (2003). "Sex-Specific Quantitative Trait Loci Govern Susceptibility to Theiler's Murine Encephalomyelitis Virus-Induced Demyelination." Genetics 163(3): 1041-6.

            Susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination (TMEVD), a mouse model for multiple sclerosis (MS), is genetically controlled. Through a mouse-human comparative mapping approach, identification of candidate susceptibility loci for MS based on the location of TMEVD susceptibility loci may be possible. Composite interval mapping (CIM) identified quantitative trait loci (QTL) controlling TMEVD severity in male and female backcross populations derived from susceptible DBA/2J and resistant BALBc/ByJ mice. We report QTL on chromosomes 1, 5, 15, and 16 affecting male mice. In addition, we identified two QTL in female mice located on chromosome 1. Our results support the existence of three linked sex-specific QTL on chromosome 1 with opposing effects on the severity of the clinical signs of TMEV-induced disease in male and female mice.


Caillier, S., L. F. Barcellos, et al. (2003). "Osteopontin polymorphisms and disease course in multiple sclerosis." Genes Immun 4(4): 312-5.

            Osteopontin (OPN), also known as early T-cell activating gene (Eta-1), has been recently shown to be a critical factor in the progression of experimental autoimmune encephalomyelitis, and perhaps multiple sclerosis (MS). Here we investigated whether the 327T/C, 795C/T, 1128A/G or 1284A/C single-nucleotide polymorphisms in the OPN gene were correlated with susceptibility or any of the several clinical end points in a cohort of 821 MS patients. Overall, we observed no evidence of genetic association between the OPN polymorphisms and MS. Although not reaching statistical significance, a modest trend for association with disease course was detected in patients carrying at least one wild-type 1284A allele, suggesting an effect on disease course. Patients with this genotype were less likely to have a mild disease course and were at increased risk for a secondary-progressive clinical type.Genes and Immunity (2003) 4, 312-315. doi:10.1038/sj.gene.6363952


Cannella, B., S. Gaupp, et al. (2003). "Differential efficacy of a synthetic antagonist of VLA-4 during the course of chronic relapsing experimental autoimmune encephalomyelitis." J Neurosci Res 71(3): 407-16.

            The integrin VLA-4 has been shown to play a key role in the entry of antigen-specific T cells into the CNS during autoimmune demyelination. Treatment of animals with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, with antibodies to VLA-4 is known to suppress acute disease. In the present study, a synthetic antagonist of VLA-4 (TBC 3486) was injected subcutaneously into mice adoptively sensitized for chronic relapsing EAE. TBC 3486 was administered daily for 14 days at early (before acute signs) and late time points (during chronic disease). Early treatment led to marked delay in disease onset and reduction in clinical severity and demyelination. After termination of treatment, clinical severity remained lower than in controls for more than 1 week. TBC 3486-treated animals showing no clinical signs (at the height of disease in controls) displayed moderate levels of inflammation but little damage to myelin. Late administration of TBC 3486 to animals with chronic EAE had no effect clinically. Immunocytochemistry and Western blotting of CNS tissue from acutely treated animals supported a moderate shift toward a Th2-type cytokine profile after treatment. Thus, TBC 3486 effectively delayed and reduced the acute (but not chronic) phase of EAE, and this amelioration correlated with changes in the inflammatory molecule profile.


Cao, M. D. and B. G. Xiao (2003). "Influence of gamma irradiation on phenotype and function of human dendritic cells in vitro." Zhongguo Shi Yan Xue Ye Xue Za Zhi 11(3): 282-6.

            To determine whether gamma irradiation influences phenotype and function of human dendritic cells (DC) in vitro, dendritic cells were induced from the peripheral blood mononuclear cells of multiple sclerosis patients with RPMI 1640 medium containing recombinant human GM-CSF (rhGM-CSF, 800 U/ml) and recombinant human IL-4 (rhIL-4, 500 U/ml). Phenotypic changes were monitored by light microscopy. Lipopolysaccharide at a concentration of 5 micro g/ml was added into the cultures after 6 days of growth for DC complete maturation, and the cells were cultured for another 24 hours. The harvested DC on day 7 were divided equally into several parts. One part was used as non-irradiated DC (naive DC) while the other parts were irradiated by gamma ray at a dose of 25 Gy and 30 Gy respectively. Cell surface molecules were analyzed by flow cytometry. The capability of DC to stimulated autologous T cell proliferation were determined. The results showed that gamma irradiation reduced expression of CD86, CD80 and HLA-DR molecules on dendritic cells, especially CD86 molecules. Dendritic cells effectively stimulated autologous T cells proliferation while irradiated DC in all groups showed profound decrease of capability to promote T cells proliferation. It is concluded that gamma irradiation of dendritic cells not only influenced phenotype of DC but also altered their function as stimulator cells in mixed lymphocyte reaction.


Caon, C., M. Zvartau-Hind, et al. (2003). "Intercaudate nucleus ratio as a linear measure of brain atrophy in multiple sclerosis." Neurology 60(2): 323-5.

            Intercaudate nucleus ratio (ICR) is a linear measure of brain atrophy that does not require software application and is independent of image acquisition techniques. The authors examined the relationship between ICR and disability in 190 patients with MS. The results show that ICR correlates with Expanded Disability Status Scale score (r = 0.67; p = 0.0001) and disease duration (r = 0.32; p < 0.01). Intercaudate ratio appears to be a reliable and reproducible linear measure of brain atrophy and correlates with disability and disease duration in MS.


Carreras, E., A. Saiz, et al. (2003). "CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients." Haematologica 88(3): 306-14.

            BACKGROUND AND OBJECTIVES: Autologous stem cell transplantation (ASCT) is currently being evaluated as a therapy for patients with multiple sclerosis (MS). We report the results of a phase II trial to evaluate feasibility and toxicity of CD34+ selected ASCT (CD34+/ASCT) and treatment results at one year of follow-up. DESIGN AND METHODS: Patients with advanced secondary progressive (SP) or relapsing-remitting (RR) MS and confirmed worsening of the extended disability status scale (EDSS) in the previous year despite interferon or other immunotherapies were included. Peripheral blood stem cells were obtained by leukaphereses after mobilization with cyclophosphamide (Cy) and granulocyte colony-stimulating factor (G-CSF). CD34+ selection was performed by means of an Isolex 300 or CliniMACS device. BCNU, Cy and antithymocyte globulin (ATG) were administered as conditioning regimen. RESULTS: Fifteen patients (9 SPMS and 6 RRMS) with a median EDSS of 6.0 (4.5-6.5) and a median of 3 (1-7) relapses in the previous year were included. Mobilization was unsuccessful in one patient. During mobilization, one patient had a transient neurologic deterioration. The main complication during ASCT were engraftment syndrome, which developed in three patients, CMV reactivation in one, and neurologic deterioration in two patients coinciding with high-fever related to ATG. Hematologic recovery was fast and complete in all cases. At 12 months, the EDSS had improved in three patients, worsened in two and remained stable in nine. Despite withdrawal of all immunosuppressive therapy only two patients had relapses. Magnetic resonance imaging showed disappearance of enhanced T1 lesions but oligoclonal bands persisted in the cerebrospinal fluid of all evaluated cases. INTERPRETATION AND CONCLUSIONS: CD34+/ASCT using BCNU, Cy and ATG as conditioning regimen has an acceptable toxicity and clearly reduces the progression of MS. Further follow-up is necessary to establish the real impact of this procedure on the long-term evolution of the disease.


Casanova, B., M. C. Martinez-Bisbal, et al. (2003). "Evidence of Wallerian degeneration in normal appearing white matter in the early stages of relapsing-remitting multiple sclerosis: a HMRS study." J Neurol 250(1): 22-8.

            OBJECTIVE: Wallerian degeneration in normal appearing white matter in early relapsing-remitting multiple sclerosis (RRMS), and its correlation with the number of relapses and disease duration. Background Recent pathological studies have demonstrated Wallerian degeneration in normal appearing white matter (NAWM) in multiple sclerosis (MS), in established RRMS, and in chronic MS. However, the presence of Wallerian degeneration early in the disease and its correlation with relapse and with disease duration has not been studied. METHODS: We performed proton magnetic resonance spectroscopic imaging in 21 MS patients, and 4 healthy controls, age and gender matched, aged under 45 years, with a maximum of 4 years since first bout, and an EDSS score of less than 3.0. N-acetyl-aspartate (NAA) (an index of axonal integrity) was measured in the NAWM from the pons and the cerebellar peduncles. RESULTS: We observed that the NAA levels were abnormally low in the NAWM in the early RRMS patients (p = 0.04, Student's t-test). The decrease in the NAA concentration correlated with disease duration in the two areas studied (p = 0.03 for pons and p = 0.04 for cerebellar peduncle); and with the number of previous relapses (Pearson's correlation = -0.582, p < 0.002). CONCLUSION: Wallerian degeneration measured by the NAA concentration at pons and cerebellar peduncles is present early in the disease and correlates with the number of relapses and disease duration.


Castriota-Scanderbeg, A., F. Fasano, et al. (2003). "Coefficient D(av) is more sensitive than fractional anisotropy in monitoring progression of irreversible tissue damage in focal nonactive multiple sclerosis lesions." AJNR Am J Neuroradiol 24(4): 663-70.

            BACKGROUND AND PURPOSE: Persistently hypointense lesions on T1-weighted MR images have been shown to correlate with the amount of axonal damage and clinical disability in multiple sclerosis (MS) patients. The purpose of this study was to investigate whether diffusion coefficient D(av) and fractional anisotropy (FA) are able to detect quantifiable differences among three groups of focal nonactive multiple sclerosis (MS) lesions that appear qualitatively different on T1-weighted images. METHODS: Conventional and diffusion tensor MR images of the brain were obtained in 18 patients with relapsing remitting (n = 10) or secondary progressive (n=8) MS and in 18 healthy volunteers. Focal nonactive MS lesions were classified as T1 isointense, T1 mildly hypointense, and T1 severely hypointense on unenhanced T1-weighted images. Differences among groups were assessed with one-way analysis of variance using the T1 lesion appearance as the grouping factor and either FA or coefficient D(av) as the dependent measure. RESULTS: FA was lowest and coefficient D(av) was highest in T1 severely hypointense lesions, and then, in ascending and descending order, respectively, T1 mildly hypointense lesions and T1 isointense lesions. A significant difference in the values of FA was detected only between T1 isointense lesions and T1 severely hypointense lesions (P <.01), whereas no difference was found between T1 mildly hypointense lesions and either one of these two groups. A significant difference was found in the values of coefficient D(av) among all investigated lesion groups. Coefficient D(av) was found to correlate inversely with the T1-weighted contrast ratio (r=-0.58, P <.0001), whereas FA and deltaFA (percentage of FA variation in the lesion, a relative FA measure that minimizes the effect of FA spatial dependence) were not. CONCLUSION: Coefficient D(av) is more sensitive than FA to variations in the degree of T1 hypointensity and, thus, in the amount of the permanent brain tissue damage in patients with MS.


Cattaneo, C., C. Almici, et al. (2003). "A case of acute promyelocytic leukaemia following mitoxantrone treatment of multiple sclerosis." Leukemia 17(5): 985-6.


Cazzato, G. and M. Zorzon (2003). "[Clinical surveillance of patients with multiple sclerosis]." Recenti Prog Med 94(4): 173-6.

            Clinical management of people with multiple sclerosis (MS) is based not only on the control of side-effects of disease-modifying drugs but also on the recognition and treatment of disease exacerbations, on the evaluation of disease progression and on the management of the wide range of MS symptoms. A multidisciplinary approach is essential to achieve the best results and improve the quality of life of MS patients.


Cazzullo, C. L., D. Trabattoni, et al. (2003). "Research on psychoimmunology." World J Biol Psychiatry 4(3): 119-23.

            Several lines of evidence suggest a role for the immune system in the multifactorial pathogenesis of schizophrenia and other psychiatric and neurodegenerative disease. Later, the role of immune mediators like cytokines became a source of main interest related to the process on inflammation in the CSM. In this article we report the results of our research on cytokines in a different groups of psychiatric patients following their clinical symptomatology and the course of diseases. In particular, we observed a prevalent type 1 cytokine profile in acute multiple sclerosis patients, while IL-10 production predominated in stable multiple sclerosis individuals. The modifications of cytokine profiles observed in schizophrenic patients suggests that clinical improvement is associated with a reduction in the inflammatory-like situation present in those not currently under treatment. Our data on Alzheimer's disease (AD) support the role of the inflammatory process in the pathogenesis of AD and reinforce the hypothesis that the neurodegenerative processes in the AD patients are associated with an abnormal antigen-specific immune response. The activation of immune system mechanisms observed in obsessive compulsive disorders could be due to the combination of endogenous (hormonal alterations associated to the modifications in the hypothalamic-pituitary-adrenal axis) and exogenous (viral or bacterial infections) factors.


Cermelli, C., R. Berti, et al. (2003). "High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection." J Infect Dis 187(9): 1377-87.

            The frequency of human herpesvirus 6 (HHV-6) DNA was assessed in autopsy material from multiple sclerosis (MS) plaques and normal-appearing white matter (NAWM) from brains of persons with MS, healthy brains, and brains of persons with other neurologic diseases. Specific areas from formalin-fixed, paraffin-embedded brain tissue samples were isolated by laser microscope. DNA was extracted from laser microdissected brain material, and HHV-6 genomic sequences were amplified by nested polymerase chain reaction. We analyzed 44 NAWM samples and 64 MS plaques from 13 patients with MS, 46 samples from 13 patients with non-MS neurologic disorders, and 41 samples from 12 healthy control brains. Of the 44 NAWM samples, 7 (15.9%) were positive for HHV-6 DNA sequences, versus 37 (57.8%) of 64 MS plaques (P<.0005). HHV-6 DNA was detected in 10 (21.7%) of 46 samples from patients with non-MS neurologic disorders and in 11 (26.8%) of 41 samples from patients without known neurologic disease. Although the frequency of HHV-6 DNA did not differ significantly by sample type, HHV-6 DNA was significantly more common in MS plaques, suggesting that HHV-6 may play a role in MS pathogenesis.


Cetta, F. (2003). "[Gastro-enteropathic neuroendocrine tumors in diverse hereditary multiple tumor syndromes of multiple endocrine neoplasms (MEN)]." G Chir 24(1-2): 5-10.


Chadwick, D. and R. Gray (2003). "Shared scheme for assessing drugs for multiple sclerosis: dealing with uncertainties about cost effectiveness of treatments is difficult problem." Bmj 326(7400): 1212-3.


Chancellor, A. M., M. Addidle, et al. (2003). "Multiple sclerosis is more prevalent in northern New Zealand than previously reported." Intern Med J 33(3): 79-83.

            BACKGROUND: There have been no studies of multiple sclerosis (MS) prevalence from New Zealand (NZ) in the past two decades, and only one in a northern NZ district. Our impression was that the local prevalence of MS was higher than previously published data would suggest. There is limited access to new treatments for MS in NZ. AIMS: The present paper aims to: (i). measure the prevalence of definite and probable MS in the Bay of Plenty (BOP), a North Island province, (ii). compare this with previous NZ studies, (iii). study the profile of disability in this population-based group and (iv). determine the proportion of MS patients who receive government funding for modern drug treatment (beta-interferons). METHODS: Patients were identified from a geographically and demographically defined area of the North Island of NZ, using multiple sources of case ascertainment and modern diagnostic criteria. All clinical records were reviewed and data were supported by a telephone interview. All patients' eligibility for -government-funded treatment with beta-interferon was considered. RESULTS: Eighty-six patients were identified as residents in BOP, NZ, on 15 January 2001. Excluding 'possible' cases, this represented a prevalence of 50/105 (95% confidence interval 40-62/105). Half of the population-based cohort had a disability defined as 'moderate to severe' (i.e. aids needed to walk, unable to take more than a few steps, or worse). Eleven patients (13%) had a primarily progressive form of MS. Eleven patients (13%) had the relapsing--remitting form of the disease and qualified for -government-funded treatment with beta-interferon. CONCLUSION: The prevalence of MS in the defined region was twice as high as that reported from an adjacent area, the Waikato, 20 years previous. Our data will help to update NZ prevalence statistics and are of direct relevance to current funding issues for modern treatments which, in NZ, are presently limited to a proportion of patients with relapsing- remitting disease.


Chang, C. H., D. L. Nyenhuis, et al. (2003). "Psychometric evaluation of the Chicago Multiscale Depression Inventory in multiple sclerosis patients." Mult Scler 9(2): 160-70.

            OBJECTIVE: The Chicago Multiscale Depression Inventory (CMDI), a comprehensive self-report measure of depression, has proven useful in the assessment of patients with chronic medical conditions. The objective of this study was to determine the validity of the CMDI in multiple sclerosis (MS) patients and explore the nature of depressive symptoms reported by people with MS. METHOD: Using a combined classical and modern psychometric approach, the factor structure of responses in MS patients was compared with that of a normative sample to confirm meaningful subtypes of depression in MS (mood, depressive cognition, and vegetative symptoms). Patient groups also were compared by disease severity to evaluate differences in depression associated with differences in disease severity. RESULTS: The results supported the factor structures of the measure, which was internally consistent, reliable, and factorially valid. Some items function differently in MS patients when compared with depressed patients and normals, offering a further opportunity to understand the unique clinical aspects of depression in people with MS compared with those without a concurrent physical illness. CONCLUSIONS: Use of the CMDI to assess separate dimensions of depression may help to clarify the complex interrelationships among aspects of depression and health-related behavior.


Chapenko, S., A. Millers, et al. (2003). "Correlation between HHV-6 reactivation and multiple sclerosis disease activity." J Med Virol 69(1): 111-7.

            This study examined the association between HHV-6 infection and multiple sclerosis (MS) and the relationship between HHV-6 reactivation and disease activity. The frequency of HHV-6 genomic sequences in peripheral blood mononuclear cells (PBMCs), the incidence of plasma viremia (nPCR), the transcription of viral mRNA in PBMCs (RT-PCR), the presence of antiviral IgM and IgG class antibodies in the plasma (IFA) of 16 relapsing/remitting and secondary progressive MS patients were studied in comparison with clinical manifestations of the disease, magnetic resonance imaging (MRI) of brain, and serum interleukin (IL)-12 concentrations (ELISA). The prevalence of HHV-6 infection was significantly higher in patients with MS (16/26) than in patients with other neurological diseases (6/21) and in blood donors (43/150). HHV-6 reactivation was found during periods of disease activity with Gadolinium-enhancing lesions on MRI in both relapsing/remitting and secondary progressive MS (10/13; 76.9%). In patients with active MS disease, serum concentrations of IL-12 were significantly higher in those patients with active HHV-6 infection than in patients with latent infection. The data confirm an association between HHV-6 infection and MS and show a correlation between HHV-6 reactivation and disease activity in relapsing/remitting and secondary progressive MS. The risk of an exacerbation of MS was significantly higher (P < 0.005) in patients with active HHV-6 infection than in patients with latent infection. A clear correlation between HHV-6 reactivation and serum IL-12 concentrations during disease activity has been demonstrated. The results suggest that HHV-6 reactivation is implicated in exacerbation of MS, possibly through modulation of IL-12 synthesis.


Chaudhuri, A. and P. O. Behan (2003). "Shared scheme for assessing drugs for multiple sclerosis: why are eyes tightly shut to considering causes other than autoimmunity?" Bmj 326(7400): 1213.


Chaudhuri, A. and P. O. Behan (2003). "Natalizumab for relapsing multiple sclerosis." N Engl J Med 348(16): 1598-9; author reply 1598-9.


Chaudhuri, A. and P. O. Behan (2003). "Mitoxantrone trial in multiple sclerosis." Lancet 361(9363): 1133-4; author reply 1134.


Cheema, J. I., L. E. Grissom, et al. (2003). "Radiographic characteristics of lower-extremity bowing in children." Radiographics 23(4): 871-80.

            Lower-extremity bowing is common in infants and children and can result from a variety of conditions. At radiography, developmental bowing shows varus angulation centered at the knee, "metaphyseal beaking," thickening of the medial tibial cortices, and tilted ankle joints. Tibia vara (Blount disease) demonstrates genu varum and depression of the proximal tibia medially. Congenital bowing manifests as posteromedial bowing with cortical thickening along the concavity of the curvature and, in some cases, diaphyseal broadening. In rickets, radiographic changes occur primarily at sites of rapid growth and are predominantly metaphyseal, with widening of the zone of provisional calcification. Achondroplasia is characterized by shortening and thickening of the long bones with metaphyseal flaring and cupping. In neurofibromatosis, there may be anterolateral bowing of the tibia, and there is often focal narrowing and intramedullary sclerosis or cystic change at the apex of the angulation. The tibia is typically involved at the junction of the middle and distal thirds. Osteogenesis imperfecta demonstrates bowing from softening due to osteoporosis and multiple fractures and typically involves the entire skeleton. In camptomelic dysplasia, lower-extremity bowing is associated with a short trunk, short limbs, and deficiencies in pelvic bone development. Recognition of these pathologic conditions is important for differentiating those that will resolve spontaneously from those that require surgery or other treatment.


Cheknev, S. B. (2003). "[Endogenous biological retranslation in current clinical and biological studies]." Vestn Ross Akad Med Nauk(4): 28-34.

            The paper generalizes the results of research implemented within the framework of the methodological concept of the Endogenous Biological Retranslation (EBR) for the purpose of finding new data about the immune pathogenesis of multiple sclerosis (MS), whose mechanisms are related with violations of the EBR processes in the body. A possibility is considered to use the priming of interferon (INF) production, as an EBR variant, for evaluating the functioning of the INF system. The thus obtained materials prove convincingly that the experimental approaches, based on priming the blood cells to the IFN production, can be clinically used in the diagnosis and therapy of MS. A new effective combined IFN-therapy scheme for the disease in question was demonstrated. A set of criteria, which makes it possible to prescribe the INF preparations for MS patients with regard for an evaluated response degree of patients' blood cells to them and with regard for a prognosticated efficacy of an assumed treatment is offered. Possibilities of an individualized comprehensive therapy for MS by using the offered experimental approaches are discussed.


Chiaravalloti, N. D., H. Demaree, et al. (2003). "Can the repetition effect maximize learning in multiple sclerosis?" Clin Rehabil 17(1): 58-68.

            OBJECTIVE: The 'repetition effect' stipulates that recall ability improves as the number of learning trials that a person receives increases. While the repetition effect has been supported through many empirical investigations in healthy individuals, it has not yet been applied to clinical populations. The present study tested the hypothesis that an increased number of learning trials improves recall ability in persons with a neurological disorder, namely multiple sclerosis (MS). DESIGN: Prospective between-group design with 30-minute, 90-minute and one-week assessments. SETTING: Private, nonprofit, research facility. SUBJECTS: Sixty-four MS subjects; 20 healthy control subjects (HC). INTERVENTIONS: Subjects were given a modified Selective Reminding Test (SRT), a list of 10 words to remember in a selective reminding format. To control for the amount of information initially learned, the learning trials were repeated until the subject recalled all 10 words on two consecutive trials. MAIN OUTCOME MEASURES: SRT word recall and recognition was tested 30 minutes, 90 minutes and one week subsequent to initial acquisition. RESULTS: Interestingly, the antithesis of our hypothesis was found. That is, persons with MS who required more learning trials to reach the perfect learning criterion performed significantly worse on the recall trials. However, this was not the case in a sample of healthy individuals undergoing the same protocol. CONCLUSIONS: These results indicate that individuals with MS may not benefit from repetition in isolation, but rather require the use of more intensive cognitive rehabilitation strategies (i.e., increased organization) to help improve their depth of encoding of new information.


Chilcott, J., C. McCabe, et al. (2003). "Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Commentary: evaluating disease modifying treatments in multiple sclerosis." Bmj 326(7388): 522; discussion 522.

            OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from pound 42,000 (66,469 dollars; 61,630 euro) to pound 98,000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than pound 20,000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments.


Chitnis, T. and S. J. Khoury (2003). "20. Immunologic neuromuscular disorders." J Allergy Clin Immunol 111(2 Suppl): S659-68.

            Immune-mediated disorders of each of the structural subdivisions of the nervous and neuromuscular system have been described. Despite the immune privilege of the central nervous system, and to a lesser extent the peripheral nervous system, immune dysregulation is not uncommon. Environmental, genetic, and immunologic factors have been postulated to be involved in the development of these disorders. Major immune-mediated neurologic diseases of the central nervous system include multiple sclerosis and acute disseminated encephalomyelitis. Immune-mediated diseases of the peripheral nervous system include myasthenia gravis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, idiopathic polymyositis, dermatomyositis, and inclusion body myositis. Some of these disorders, such as myasthenia gravis and certain forms of acute inflammatory demyelinating polyneuropathy, are clearly autoimmune in nature, whereas the immune system plays an important role in pathogenesis in others. Understanding the immune mechanisms of disease and uncovering potential therapeutic targets are essential for the design of new treatments. The epidemiology, pathogenesis, diagnostic criteria, and current therapeutic approaches to the major neuroimmunologic diseases are reviewed.


Choyke, P. L., G. M. Glenn, et al. (2003). "Hereditary renal cancers." Radiology 226(1): 33-46.

            Hereditary renal cancer syndromes can lead to multiple bilateral kidney tumors that occur at a younger age than do nonhereditary renal cancers. Imaging plays an important role in the diagnosis and management of these syndromes. During the past decade, several new hereditary renal syndromes have been discovered but are not yet widely known. Whereas previously, the list of hereditary renal cancers in adults included von Hippel-Lindau disease and a rare form of chromosomal translocation, the list now includes the following syndromes: tuberous sclerosis, hereditary papillary renal cancer, Birt-Hogg-Dube syndrome, hereditary leiomyoma renal cell carcinoma, familial renal oncocytoma, hereditary nonpolyposis colon cancer, and medullary carcinoma of the kidney. In addition, a number of newly described but poorly understood syndromes are under investigation. Even at this early stage, it is clear that elucidation of the underlying genetic mutations that cause hereditary renal cancer syndromes will have profound implications for understanding the origins of nonhereditary renal tumors. These studies will likely culminate in a better understanding of the causes of renal cancer, its prevention, and, ultimately, its cure.


Christensen, T., P. D. Sorensen, et al. (2003). "Antibodies against a human endogenous retrovirus and the preponderance of env splice variants in multiple sclerosis patients." Mult Scler 9(1): 6-15.

            The human endogenous retrovirus HERV-H is associated with multiple sclerosis (MS). Previously performed reverse transcriptase-polymerase chain reactions (RT-PCR) on virion-RNA demonstrated sequence variants of the HERV-H family located in the particulate fraction of MS patient plasma samples and not in controls. In this study a significantly elevated level of antibodies towards peptides derived from HERV-H/RGH-2 DNA sequences in serum and cerebrospinal fluid (CSF) from MS patients is demonstrated. Further, Wistar rats immunized with purified virions develop a specific serologic response, indicating that some virion proteins are encoded by HERV-H-related sequences. Also shown is that in RNA from blood cells, a HERV-H protease-env splice variant can be found together with an env splice variant in about 40% of MS patients but only in 10% of controls. The results substantiate the association between activated HERV-H and MS, but a causal relationship is yet to be demonstrated. HERV-H could represent a causal factor either by eliciting an autoimmune response or through the pathogenic potential of the retrovirus itself.


Christensen, T. and A. Moller-Larsen (2003). "[Human endogenous retroviruses and disease?]." Ugeskr Laeger 165(6): 556-61.

            Endogenous retroviruses represent sequences descended from ancient virus infections integrated in the host genome. They participate in processes, such as speciation, recombination, ontogenesis, and regulation of tissue specificity and gene expression. It has been suggested in recent years that human endogenous retroviruses may play a role in certain types of cancer and autoimmune diseases. Human endogenous retroviruses represent both putative susceptibility genes and putative pathogenic viruses in diseases like systemic lupus erythematosus, Sjogren's disease, rheumatoid arthritis, and possibly type 1 diabetes. Multiple sclerosis is specifically associated with expression of human endogenous retroviruses as virions. It is not yet known if the human endogenous retroviruses also represent causal factors, but several pathogenic mechanisms are possible.


Chutorian, A. M. (2003). "[Acute loss of vision in children]." Rev Neurol 36(1): 264-71.

            The differential diagnosis of acute loss of vision in children includes acute loss of vision due to retinal or optic nerve disease, and cortical blindness. The retinal disorders which may be mis diagnosed as optic neuritis include Leber neuroretinitis, Leber hereditary optic neuropathy, and Stargardt macular dystrophy. Retinal changes which evolve in neuroretinitis, and the pseudopapilledema in Leber heredity optic neuropathy are helpful in differentiating these disorders from optic neuritis. Stargardt macular dystrophy, a disorder associated with a variety of mutations, may be mis diagnosed as psychogenic visual loss due to the early normal appearance of the retina, and the loss of vision over a period of weeks. The differentiation of optic neuritis from anterior ischemic optic neuropathy (AION), depends upon the initial appearance of the optic disc (in AION either hyperemia due to reperfusion, or swelling and pallor if total infarction has occurred). The authors have described children with abrupt loss of vision during renal dialysis, whose risk factors for AION included systemic hypotension and intra ocular hypertension. Children with vigorous treatment of accelerated hypertension, and children with migraine and pro thrombotic disorders have also incurred AION. Thus, AION should be suspected when acute loss of vision occurs in association with certain ocular and systemic risk factors. In children capable of cooperating for visual field examination, the typical change in AION is an altitudinal defect, while optic neuritis it is a central scotoma. The association of optic neuritis with multiple sclerosis, DeVic disease, and with acute demyelinating1 encephalomyelitis require special consideration in regard to treatment and prognosis. Acute loss of vision due to cerebral cortical insults involves a large differential diagnosis which includes vascular, metabolic and infective disease; as well as disorders causing transitory blindness such as seizures and migraine


Ciccarelli, O., D. J. Werring, et al. (2003). "A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging--evidence of Wallerian degeneration." J Neurol 250(3): 287-92.

            Diffusion tensor imaging (DTI) investigates brain tissue microstructure in vivo. In multiple sclerosis (MS) Wallerian degeneration of axons traversing focal lesions is a potential mechanism of damage in normal-appearing white matter. In vivo evidence for this hypothesis is limited. The present study investigated the relationship between DTI-derived indices in the normal-appearing corpus callosum (CC) and the lesion loads (LLs) in connected cerebral regions. DTI was performed in 39 MS patients and in 21 age-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in the genu, body and splenium of CC. Patients showed lower FA and higher MD in the CC than controls and both correlated with the total LL (r = -0.56 and r = 0.54, p < 0.0001). The LL of individual cerebral lobes correlated with both FA and MD in the corresponding callosal regions, with the body showing the strongest correlations with frontal and parietal LL (p < 0.0001). The strong correlations between DTI indices in the CC and the extent of lesions in connected brain regions support the hypothesis that Wallerian degeneration of axons transected by remote, but connected focal lesions, is an important pathogenic mechanism of damage in MS.


Cid, C., J. C. Alvarez-Cermeno, et al. (2003). "Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients." J Neuroimmunol 136(1-2): 119-24.

            Neuronal apoptosis has recently been implicated in multiple sclerosis (MS). Apoptotic cell death of neurons is induced in cultures exposed to cerebrospinal fluid (CSF) from MS patients. Since caspases are essential in the regulation of apoptosis, direct evidence was sought linking caspases to CSF-induced neuronal death. Caspase activity was measured in cell extracts from MS CSF-treated cultured neurons by the cleavage of caspase-1 and caspase-3 substrates. Caspase-3 activity, but not caspase-1, was induced in neuronal cultures in response to MS CSF treatment. This caspase-3 activity was inhibited in vitro by Ac-YVAD-cmk and Ac-DEVD-cmk caspase inhibitors. Treatment of MS CSF-incubated neuronal cells with these caspase inhibitors completely preserved neuronal survival and largely attenuated DNA fragmentation detected in situ. These findings show that neuronal cells are rescued from MS CSF-induced death by caspase inhibitors and suggest ways to treat MS.


Cimini, A., A. Bernardo, et al. (2003). "TNFalpha downregulates PPARdelta expression in oligodendrocyte progenitor cells: implications for demyelinating diseases." Glia 41(1): 3-14.

            TNFalpha has been implicated in several demyelinating disorders, including multiple sclerosis (MS) and X-adrenoleukodystrophy (X-ALD). TNFalpha abundance is greatly increased in the areas surrounding damaged regions of the central nervous system of patients with MS and X-ALD, but its role in the observed demyelination remains to be elucidated. A class of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs), has been implicated in several physiological and pathological processes. In particular, PPARdelta has been shown to promote oligodendrocyte (OL) survival and differentiation and PPARgamma has been implicated in inflammation. In the present study, we investigate on the effects of TNFalpha on OLs during differentiation in vitro. The results obtained show that TNFalpha treatment impairs PPARdelta expression with concomitant decrease of lignocerolyl-CoA synthase and very-long-chain fatty acid beta-oxidation as well as plasmalogen biosynthesis. We propose a hypothetical model possibly explaining the perturbation effects of proinflammatory cytokines on myelin synthesis, maturation, and turnover.


Cipriani, B., L. Chen, et al. (2003). "Upregulation of group 1 CD1 antigen presenting molecules in guinea pigs with experimental autoimmune encephalomyelitis: an immunohistochemical study." Brain Pathol 13(1): 1-9.

            In humans, group 1 CD1 glycoproteins present foreign and self lipid and glycolipid antigens to T-cells. Homologues of these molecules are not found in mice or rats but are present in guinea pigs (GPs). We examined CD1 and MHC class II expression in the central nervous system (CNS) of GPs sensitized for experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In normal GPs and the uninflamed CNS, low-level MHC class II (MHC II) immunoreactivity occurred on vascular elements, meningeal macrophages and parenchymal microglial cells, whereas immunoreactivity for CD1 was absent. In the inflamed CNS, the majority of infiltrating cells were MHC II+ and microglia showed increased expression. CD1 immunoreactivity was detected on astrocytes and subsets of inflammatory cells Including B cells and macrophages. Minimal CD1 and MHC II co-expression was noted on inflammatory cells or glia. We conclude that group 1 CD1 molecules are strongly upregulated in the inflamed CNS on subsets of cells distinct from the majority of MHC II bearing cells. The expression of CD1 proteins in such lesions broadens the potential repertoire of antigens recognized at these sites and highlights the value of the GP as a model for studies of the relevance of CD1 molecules in host defense and autoimmune diseases.


Clanet, M., E. Cassol, et al. (2003). "Clinical-MRI correlations in the secondary progressive phase of MS: lessons from the treatment trials." J Neurol Sci 206(2): 139-44.

            Conventional MRI techniques are sensitive to detect MS lesions and their change overtime. In relapsing-remitting MS correlations with clinical measures are weak suggesting a pathological heterogeneity of these lesions. There are less data available in secondary progressive phase of the disease. The best source for clinical MRI correlations analysis is the placebo arm of the published interferon beta trials. This review presents the main clinical-MRI findings from these trials then focuses on recent promising observations obtained with non conventional MRI techniques in SP MS patients.


Clement, P., C. Conessa, et al. (2003). "[Susac syndrome or microangiopathy of the cochlea, brain and retina]." Ann Otolaryngol Chir Cervicofac 120(1): 49-53.

            OBJECTIVES: Susac syndrome, also called SICRET syndrome (small infarction of cochlear, retinal, and encephalic tissue) is a rare condition difficult to diagnose. Sudden deafness may be the inaugural sign. MATERIAL AND METHODS: A female patient developed subacute encephalopathy, bilateral sensorineural hearing loss, and ischemic retinopathy. The patient was given cyclophosphamid and methylprednisolone for six months, followed by prednisone for eight months. RESULTS: Signs of encephalopathy had totally regressed by month 14 and retinal arteries were free of obstruction. Deafness remained unchanged. CONCLUSION: Diagnosis of this microangiopathy involving the inner ear, the brain, and the retina is suggested by the clinical triad and established on the basis of tonal audiometry, fundus examination, fluorescein angiography, examination of the cerebrospinal fluid, magnetic resonance imaging. Multiple sclerosis is the main differential diagnosis. The pathogenesis remains unknown. We observed transient-evoked otoacoustic emissions. There is no consensus concerning treatment. Many advocate combining corticosteroids and immunosuppressors. Otolaryngologists should be aware that an ophthalmological examination is required for patients with central or visual disorders associated with hearing loss.


Clowse, M. E. and F. M. Wigley (2003). "Digital necrosis related to carboplatin and gemcitabine therapy in systemic sclerosis." J Rheumatol 30(6): 1341-3.

            We present a woman with scleroderma who developed multiple ischemic digits after chemotherapy for lung cancer. The ischemia started during treatment with carboplatin and gemcitabine and required amputation of the affected digits. A review of the literature shows that thrombotic episodes coinciding with chemotherapy are not uncommon, though venous thrombosis occurs more frequently than arterial. Scleroderma patients are at particular risk for digital infarction because of their underlying vascular disease and associated Raynaud's phenomenon. This case illustrates the risk of severe digital ischemia and digital loss in patients with scleroderma during chemotherapy with carboplatin and gemcitabine.


Cohen, Y., A. Polliack, et al. (2003). "Treatment of refractory autoimmune diseases with ablative immunotherapy using monoclonal antibodies and/or high dose chemotherapy with hematopoietic stem cell support." Curr Pharm Des 9(3): 279-88.

            Immunological manipulations are the basis for modern treatments of autoimmune diseases (AID). Targeted immune suppression with lymphopenic based chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral part of the conditioning for stem cell transplantation (SCT). Immune manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab (RI), with or without stem cell support are the basis for emerging therapeutic modalities aiming to eradicate the autoreactive clone in various autoimmune disorders. Couple of hundreds of SCTs have been recently performed in various autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA). Preliminary results are encouraging. Better selection of patients and earlier treatment, before irreversible organ failure develops will probably improve results. Current ongoing multicenter studies are evaluating the role of SCT in MS, RA, SLE, and PSS.


Colman, D., C. Lubetzki, et al. (2003). "Multiple paths towards repair in multiple sclerosis." Trends Neurosci 26(2): 59-61.

            Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, affecting approximately 1/1000 individuals in the Western world. Available treatments limit CNS inflammation and strategies to repair damage in the CNS offer the potential of recovery of both tissue and function. With further fundamental knowledge developing, this area is ripe for 'translation' to clinical application.


Columba-Cabezas, S., B. Serafini, et al. (2003). "Lymphoid chemokines CCL19 and CCL21 are expressed in the central nervous system during experimental autoimmune encephalomyelitis: implications for the maintenance of chronic neuroinflammation." Brain Pathol 13(1): 38-51.

            The simultaneous presence of dendritic, T- and B-cells in the central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, suggests that interactions among these cell types might be instrumental in the local induction and maintenance of autoimmune reactions. In this study, we explored the possibility that such aberrant leukocyte recruitment in the CNS could be sustained by "lymphoid" chemokines which orchestrate dendritic cell and lymphocyte homing to lymphoid organs. Transcripts for CCL19 and CCL21 and their common receptor CCR7 were induced in the CNS of mice undergoing relapsing-remitting and chronic-relapsing EAE. While CCL21 immunoreactivity was confined to the endothelium of some inflamed blood vessels, CCL19 was expressed by many infiltrating leukocytes and some astrocytes and microglia in the CNS parenchyma. CCR7+ cells accumulated in inflammatory lesions during EAE progression, when abundant infiltration of the CNS by mature dendritic cells, B-cells and cells expressing naive T-cell markers also occurred. These findings suggest that CCL19 and CCL21 produced in the EAE-affected CNS may be critical for the homing of antigen presenting cells and lymphocytes, resulting in continuous local antigenic stimulation and maintenance of chronic neuroinflammation.


Confavreux, C., S. Vukusic, et al. (2003). "Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process." Brain 126(Pt 4): 770-82.

            Prognosis of multiple sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset of irreversible disability. Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached. We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound). We used Kaplan-Meier analyses and Cox regression models to determine the influence of the clinical variables on the time to disability onset. Median times from onset of multiple sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by gender, age, symptoms and course (relapsing-remitting or progressive) at onset of the disease, degree of recovery from the first relapse, time to a second neurological episode, and the number of relapses in the first 5 years of the disease. Similarly, times from onset of multiple sclerosis to a score of 6 and 7 were influenced by time to a score of 4. In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7. Early assessable clinical variables significantly influence the time from the onset of multiple sclerosis to the assignment of a disability score of 4, but not the subsequent progression of irreversible disability.


Cooper, G. S. and B. C. Stroehla (2003). "The epidemiology of autoimmune diseases." Autoimmun Rev 2(3): 119-25.

            Autoimmune diseases are among the leading causes of death among young and middle-aged women in the United States. Incidence rates vary among the autoimmune diseases, with estimates ranging from less than one newly-diagnosed case of systemic sclerosis to more than 20 cases of adult-onset rheumatoid arthritis per 100000 person-years. Prevalence rates range from less than 5 per 100000 (e.g. chronic active hepatitis, uveitis) to more than 500 per 100000 (Grave disease, rheumatoid arthritis, thyroiditis). At least 85% of thyroiditis, systemic sclerosis, systemic lupus erythematosus, and Sjogren disease patients are female. Although most diseases can occur at any age, some diseases primarily occur in childhood and adolescence (e.g. type 1 diabetes), in the mid-adult years (e.g. myasthenia gravis, multiple sclerosis), or among older adults (e.g. rheumatoid arthritis, primary systemic vasculitis). Ethnic and geographic differences in incidence of specific autoimmune diseases have been documented, but specific groups may be at higher risk for some diseases and lower risk for other diseases. The incidence of type 1 diabetes increased but the rates of rheumatoid arthritis declined over the past 40 years. Thus although there are commonalities, there are also important demographic differences between diseases. Disease-specific research, as well as studies that focus on potentially related diseases, needs to be conducted.


Corboy, J. R., D. S. Goodin, et al. (2003). "Disease-modifying Therapies for Multiple Sclerosis." Curr Treat Options Neurol 5(1): 35-54.

            Multiple sclerosis (MS) is likely an autoimmune disorder, although this remains unproven. Immunotherapeutic treatments have been shown to be helpful, especially in relapsing forms of the illness, but the treatments are incomplete, and many patients continue to worsen over time, even with standard therapy. Immunotherapies presently available appear to have their greatest effect when used early in the course of the illness. In relapsing-remitting multiple sclerosis (RRMS), there is overwhelming Class I data from large clinical trials that supports the use of interferon-beta-1a (IFNbeta-1a), interferon-beta-1b (IFNbeta-1b), and glatiramer acetate. Comparative data are limited, and results published in different trials support the idea that treatment outcomes with the various drugs are more similar than different. Decisions about treatment choice should be tailored to the needs of the individual patient. With the exception of a small number of patients with benign MS, all RRMS patients should be treated with one of the interferons or glatiramer acetate. There are Class I data consistent with the idea that higher dose or more frequent administration of interferon-beta (IFNbeta) is associated with better clinical outcome and reduced progression of changes on brain MRI scans. The duration of this effect is not clear, and higher dose with more frequent administration is associated with higher cost, more side effects, and greater production of interferon antibodies. Interferon antibodies possibly reduce efficacy of IFNbeta in RRMS and secondary progressive multiple sclerosis (SPMS). Clinically isolated syndromes (CIS) of demyelination in the central nervous system can be reliably diagnosed, and the risk of further episodes of demyelination is consistent with the diagnosis of RRMS stratified by use of brain MRI scans. Patients at high risk of developing RRMS after CIS achieve significant benefit after treatment with IFNbeta-1a, and initiation of therapy after CIS should be given strong consideration. There are no similar data for IFNbeta-1b or glatiramer acetate, but logic would dictate a similar response with these agents. In SPMS, there are Class I data that treatment with IFNbeta-1a or IFNbeta-1b has a significant effect on progression of brain MRI lesions, but clinical outcomes are less clearly affected. It is justifiable to treat SPMS patients with IFNbeta. Mitoxantrone may be effective in slowing progression of SPMS, and its risks are moderate. It should be used in patients with SPMS, but potential long-term risks must be discussed with the patient in detail. Results of treatment of SPMS in advanced cases (Extended Disability Status Score greater than 6.5, or restricted to wheelchair) is mostly unknown. These patients are at high risk of developing infections, especially if they use indwelling catheters, and the use of agents that induce immunosuppression may be risky. There are no effective therapies for primary progressive multiple sclerosis (PPMS). Although PPMS patients are frequently treated with one or more therapeutic agents, there is no medical justification for this now.


Correale, J. and M. de los Milagros Bassani Molinas (2003). "Time course of T-cell responses to MOG and MBP in patients with clinically isolated syndromes." J Neuroimmunol 136(1-2): 162-71.

            CD4(+) T-cell lines (TCLs) from patients with clinically isolated syndromes (CIS) were selected with purified human myelin basic protein (MBP) and recombinant human myelin oligodendrocyte glycoprotein (rhMOG), at onset of neurological symptoms and when patients developed clinically definite multiple sclerosis (CDMS). The epitope specificity of each TCL was mapped with overlapping synthetic peptides. TCLs were assessed for their ability to secrete IFN-gamma, IL-4, and IL-6. Diverse patterns of epitope recognition were observed: (a) recognition of a broad spectrum of MBP peptide epitopes with evidence of shifts over time; (b) an initial T-cell response focused to a restricted segment of the MBP molecule (83-102) that broadened over the course of disease; and (c) persistence of a focused anti-MOG T-cell response. CIS patients who failed to develop CDMS maintained a focused epitope response against two to six MBP epitopes. Most MBP peptide-specific TCLs secreted considerable amounts of IFN-gamma and low amounts of IL-4 and IL-6, whereas anti rhMOG(Igd) peptide-specific TCLs secreted preferentially IL-4 and IL-6. These data raise important issues for the pathogenesis and treatment of multiple sclerosis (MS).


Costello, K. and C. Harris (2003). "Differential diagnosis and management of fatigue in multiple sclerosis: considerations for the nurse." J Neurosci Nurs 35(3): 139-48.

            Fatigue is one of the most disabling aspects of multiple sclerosis (MS), affecting an estimated 70%-90% of patients. Yet, despite its prevalence, it is also one of the most difficult MS symptoms to accurately diagnose and effectively treat. This is because of numerous factors, including the subjective and nonspecific nature of fatigue; its variable manifestations; its similarity to psychological, motor, cognitive, respiratory, and non-MS-related disturbances and conditions; and a lack of understanding of its precise etiology. In contrast to fatigue experienced by people without MS, MS fatigue is characterized by its persistence and sensitivity to core and ambient temperatures. Differential diagnosis of MS fatigue is largely dependent on delineating chronic versus acute onset and determining whether fatigue is a symptom in and of itself (primary MS fatigue) or an aspect of an MS-related or non-MS-related etiology (secondary MS fatigue). Once the presence of fatigue is established, a through medical history, physical examination, and fatigue assessments can guide effective management, which includes education, self-care strategies, and pharmacological treatment. As patient advocates and gatekeepers, MS nurses are in an optimal position to establish and evaluate fatigue as a symptom in and of itself and effectively guide this process.


Craner, M. J., A. C. Lo, et al. (2003). "Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination." Brain 126(Pt 7): 1552-61.

            Myelinated fibres are characterized by the aggregation of Nav1.6 sodium channels within the axon membrane at nodes of Ranvier, where their presence supports saltatory conduction. In this study, we used immunocytochemical methods to study the organization of sodium channels along axons in experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis. We studied axons within the optic nerve, a CNS tract commonly affected in multiple sclerosis, and their cell bodies of origin (retinal ganglion cells), using subtype-specific antibodies generated against sodium channel subtypes Nav1.1, Nav1.2, Nav1.3 and Nav1.6, which previously have been shown to be expressed by retinal ganglion cells. We demonstrate a significant switch from Nav1.6 to Nav1.2 expression in the optic nerve in EAE; there was a reduction in frequency of Nav1.6-positive nodes (84.5% Nav1.6-immunopositive nodes in control versus 32.9% in EAE) and increased frequency of Nav1.2-positive nodes (11.8% Nav1.2 immunopositive nodes in control versus 74.9% in EAE). Moreover, we observed a significant increase in the number of linear (presumably demyelinated) axonal profiles demonstrating extended diffuse immunostaining for Nav1.2 in EAE versus control optic nerves. These changes within the optic nerve are paralleled by decreased levels of Nav1.6 and increased Nav1.2 protein, together with increased levels of Nav1.2 mRNA, within retinal ganglion cells in EAE. Our findings of a loss of Nav1.6 and increased expression of Nav1.2 suggest that electrogenesis in EAE may revert to a stage similar to that observed in immature retinal ganglion cells in which Nav1.2 channels support conduction of action potentials along axons.


Craner, M. J., A. C. Lo, et al. (2003). "Annexin II/p11 is up-regulated in Purkinje cells in EAE and MS." Neuroreport 14(4): 555-8.

            The sensory neuron specific sodium channel Na(v)1.8 is normally detectable at only very low levels within cerebellar Purkinje cells. Annexin II light chain (p11) binds to the amino terminus of Na(v)1.8 and facilitates its functional expression within the cell membrane. We previously demonstrated that expression of Na(v)1.8 is up-regulated in cerebellar Purkinje cells in experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS). In this study we demonstrate that expression of p11 is significantly up-regulated in Purkinje cells in EAE (71 +/- 9.0% vs 21.3 +/- 4.9% in controls) and in MS(65.5 +/- 1.6% vs 21.8 +/- 6.2% in controls). We also demonstrate a high degree of co-expression of p11 and Na(v)1.8 (84.8 +/- 8.9%). Together with earlier results which show that experimental expression of Na(v)1.8 within Purkinje cells perturbs the temporal pattern of impulse generation in these cells, our results extend the evidence for an acquired channelopathy which interferes with cerebellar function in MS.


Croxford, J. L. and S. D. Miller (2003). "Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212." J Clin Invest 111(8): 1231-40.

            Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R+WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-gamma production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-alpha, IL1-beta, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.


Croxford, J. L. (2003). "Therapeutic potential of cannabinoids in CNS disease." CNS Drugs 17(3): 179-202.

            The major psychoactive constituent of Cannabis sativa, delta(9)-tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as anandamide, signal through G-protein-coupled cannabinoid receptors localised to regions of the brain associated with important neurological processes. Signalling is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents in CNS disease where inhibition of neurotransmitter release would be beneficial. Anecdotal evidence suggests that patients with disorders such as multiple sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can alleviate tremor and spasticity in animal models of multiple sclerosis, and clinical trials of the use of these compounds for these symptoms are in progress. The cannabinoid nabilone is currently licensed for use as an antiemetic agent in chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a synthetic cannabinoid, is currently being assessed in clinical trials for traumatic brain injury and stroke. Animal models of mechanical, thermal and noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in clinical trials of postoperative and cancer pain and pain associated with spinal cord injury, cannabinoids have proven more effective than placebo but may be less effective than existing therapies. Dronabinol, a commercially available form of delta(9)-THC, has been used successfully for increasing appetite in patients with HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity. Acute adverse effects following cannabis usage include sedation and anxiety. These effects are usually transient and may be less severe than those that occur with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive effects from potential therapeutic benefits. The existence of other cannabinoid receptors may provide novel therapeutic targets that are independent of CB(1) receptors (at which most currently available cannabinoids act) and the development of compounds that are not associated with CB(1) receptor-mediated adverse effects. Further understanding of the most appropriate route of delivery and the pharmacokinetics of agents that act via the endocannabinoid system may also reduce adverse effects and increase the efficacy of cannabinoid treatment. This review highlights recent advances in understanding of the endocannabinoid system and indicates CNS disorders that may benefit from the therapeutic effects of cannabinoid treatment. Where applicable, reference is made to ongoing clinical trials of cannabinoids to alleviate symptoms of these disorders.


Cushman, K. E., M. Maqbool, et al. (2003). "Variation of podophyllotoxin in leaves of Eastern Red Cedar (Juniperus virginiana)." Planta Med 69(5): 477-8.

            Leaves of Eastern red cedar (Juniperus virginiana L. Cupressaceae) have been reported to contain podophyllotoxin, a pharmaceutical compound used to manufacture drugs for treatment of cancer, rheumatoid arthritis, genital warts, psoriasis, and multiple sclerosis. Podophyllotoxin content of leaves of immature, mature male, and mature female plants (approximately 1.45 mg x g -1) was significantly higher than that of leaves of juvenile plants (0.60 mg x g -1). Sampling date also affected podophyllotoxin content. Leaves harvested in January and April exhibited higher podophyllotoxin contents (1.56 and 1.45 mg x g -1, respectively) than leaves harvested in February and June (1.06 and 1.08 mg x g -1, respectively). There was no obvious pattern or trend in the data due to sampling date. There was no significant interaction between plant type and sampling date. These results indicate that foliage of mature Eastern red cedar, a waste product of the lumber industry, could be a low-yielding, but relatively stable, source of podophyllotoxin.


Cwiklinska, H., M. P. Mycko, et al. (2003). "Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains." Int Immunol 15(2): 241-9.

            Heat shock proteins (hsp) are known to facilitate the generation of specific immune responses by chaperoning proteins and peptides involved in T cell activation. Hsp have been shown to be strikingly elevated in multiple sclerosis (MS) lesions. The unique chaperonin properties of hsp70 have allowed identification of immunogenic proteins bound to it by the ex vivo demonstration of hsp associations with proteins implicated in the immune response. We have investigated the association of hsp70 with myelin basic protein (MBP), myelin proteolipid protein (PLP) and myelin oligodendrocyte protein (MOG) in MS and control brain tissue. In co-immunoprecipitation experiments, in all samples of MS brains examined (n = 3), but not control brain tissue (n = 3), direct association of MBP with hsp70, but not with hsp90, was found. In some MS brain samples, association between PLP and hsp70 was also seen. In similar co-immunoprecipitation experiments on brain tissue obtained from mice with experimental autoimmune encephalomyelitis (n = 5) induced by immunization with PLP peptide, specific association of hsp70 with PLP and MBP was found. Using surface plasmon resonance we demonstrated specific binding of hsp70 with MBP in vitro. Analysis of the amounts of MBP bound to hsp70 yielded a molecular ratio of MBP binding to hsp70 at 6.5:1. MBP complexed with hsp70 was taken up at significantly higher rates by antigen-presenting cells than MBP alone and enhanced MBP-specific immune responses. These results indicate that hsp70 specifically associates with MBP in MS brain tissue. This association might be relevant to the enhanced immune recognition of MBP in MS.


Cymet, T. C. (2003). "A practical approach to fibromyalgia." J Natl Med Assoc 95(4): 278-85.

            Fibromyalgia is the name given to a collection of symptoms with no clear physiologic cause, The constellation of symptoms are clearly recognizable as a distinct pathologic entity. The diagnosis is made through clinical observations made by the examiner. Differential diagnosis must include other somatic syndromes as well as disease entities like hepatitis, hypothyroidism, diabetes mellitus, electrolyte imbalance, multiple sclerosis, and cancer. Diagnostic criteria are given as guidelines for the diagnosis, not as absolute requirements. Treatment of this condition remains individualized and relies heavily on having a therapeutic relationship with a provider. Treatment of this syndrome needs to be looked at as an ongoing process. Goal oriented treatment aimed at maintaining specific functions can be directed at helping a patient get restorative sleep, alleviating the somatic pains that ail the patient, keeping a person productive, regulating schedules or through goal oriented agreements made with the patient. Since this syndrome is chronic and may effect all areas of a persons functioning the family and social support system of the person being treated need to be evaluated. Patients often seek alternative medical treatments for this problem including diet therapy, acupuncture, and herbal therapy. Treatment must involve more than just the symptoms presented and the patient can only be treated successfully if they are willing to work at changing their own perceptions, and ways of relating to stressors in their world.


D'Agati, V. (2003). "Pathologic classification of focal segmental glomerulosclerosis." Semin Nephrol 23(2): 117-34.

            Focal segmental glomerulosclerosis (FSGS) is defined as a clinical-pathologic syndrome manifesting proteinuria and focal and segmental glomerular sclerosis with foot process effacement. The pathologic approach to the classification of FSGS is complicated by the existence of primary (idiopathic) forms and multiple subcategories with etiologic associations, including human immunodeficiency virus (HIV)-associated nephropathy, heroin nephropathy, familial forms, drug toxicities, and a large group of secondary FSGS mediated by structural-functional adaptations to glomerular hyperfiltration. A number of morphologic variants of primary and secondary focal sclerosis are now recognized, including FSGS not otherwise specified (NOS), perihilar, cellular, tip, and collapsing variants. The defining features of these morphologic variants and of the major subcategories of FSGS are discussed with emphasis on distinguishing light microscopic patterns and clinical-pathologic correlations.


D'Ambrosio, D., P. Panina-Bordignon, et al. (2003). "Chemokine receptors in inflammation: an overview." J Immunol Methods 273(1-2): 3-13.

            Chemokine receptors play a key role in directing the migration of inflammatory cells into various injured or infected organs. However, migration of inflammatory cells into tissues can in itself be a cause and amplifier of tissue damage and disease, particularly in chronic autoimmune or allergic disorders. On this basis, much effort is currently devoted at the identification of molecular signals regulating the recruitment of inflammatory cells into tissues and at developing novel strategies to inhibit discrete pathways in this process. Great progress has recently been made in identification of a number of chemokine receptors involved in the process of leukocyte migration. The challenge is now to elucidate the specific contribution and involvement of the different receptors in distinct inflammatory processes and diseases and to prove that interference with any of these pathways may lead to development of novel therapeutics.


Dalton, C. M., P. A. Brex, et al. (2003). "New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes." Ann Neurol 53(5): 673-6.

            In clinically isolated syndromes, the new McDonald criteria for multiple sclerosis diagnosis require new gadolinium-enhancing lesions for dissemination in time at a 3-month follow-up magnetic resonance imaging scan. In a cohort of 56 patients, these criteria were specific (95%) but less sensitive (58%) for clinically definite multiple sclerosis at 3 years. If new T2 lesions were allowed as an alternative for dissemination in time, sensitivity increased (74%) with maintained specificity (92%), enabling an accurate diagnosis of multiple sclerosis in more patients.


Dalton, C. C. and L. N. Gottlieb (2003). "The concept of readiness to change." J Adv Nurs 42(2): 108-17.

            AIM: Readiness is associated with change, yet there is little understanding of this construct. The purpose of this study was to examine readiness; its referents, associated factors and the resulting consequences. METHODS: In the course of nursing five clients living with multiple sclerosis over a 7-month period using a Reflective Practice Model, data were systematically gathered using open-ended and then more focused questioning. Data collected during 42 client encounters (28 face-to-face encounters; 14 telephone contacts) were analysed using Chinn and Kramer's concept analysis technique. Findings. The concept of readiness was inductively derived. Readiness is both a state and a process. Before clients can create change they need to become ready to change. A number of factors trigger readiness. These include when: (a) clients perceive that a health concern is not going to resolve, (b) a change in a client's physical condition takes on new significance, (c) clients feel better able to manage their stress, (d) clients have sufficient energy, (e) clients perceive that they have adequate support in undertaking change. When one or more of these factors is present clients become ready to consider change. The process of readiness involves recognizing the need to change, weighing the costs and benefits and, when benefits outweigh costs, planning for change. The desire to change and to take action determines clients' degree of readiness. When they experience a high degree of readiness they report less anger, less depression, and view their condition in a more positive light. In contrast, when they experience a low degree of readiness they report feeling depressed, afraid and vulnerable in the face of change. CONCLUSION: Nursing has an important role to play in creating conditions to support change. To fulfil this role, nurses need to be able to assess readiness for change and the factors that enable it and then to intervene in ways that facilitate readiness.


Daly, C. and B. J. Rollins (2003). "Monocyte Chemoattractant Protein-1 (CCL2) in Inflammatory Disease and Adaptive Immunity: Therapeutic Opportunities and Controversies." Microcirculation 10(3-4): 247-57.

            Monocyte chemoattractant protein (MCP)-1 (CCL2) specifically attracts monocytes and memory T cells. Its expression occurs in a variety of diseases characterized by mononuclear cell infiltration, and there is substantial biological and genetic evidence for its essential role in atherosclerosis and multiple sclerosis. Despite intensive screening, there are as yet no small-molecule antagonists of the receptor of MCP-1/CCL2, CCR2. However, biological agents, including antibodies and inhibitory peptides, have been developed and may be useful for these indications. Recent evidence from genetically modified mice indicates that MCP-1 and CCR2 have unanticipated effects on T helper (Th) cell development. However, unlike the identical phenotypes of MCP-1/CCL2(-/-) and CCR2(-/-) mice in inflammatory diseases, the phenotypes of these mice are disparate in adaptive immunity: MCP-1 stimulates Th2 polarization, whereas CCR2 activation stimulates Th1 polarization. This presents both a challenge and an opportunity for targeting the MCP-1/CCL2/CCR2 axis in disease.Microcirculation (2003) 10, 247-257. doi:10.1038/sj.mn.7800190


Danilov, A. I., M. Andersson, et al. (2003). "Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis." J Neuroimmunol 136(1-2): 112-8.

            Nitric oxide (NO) is formed as a consequence of induction of the iNOS enzyme during inflammatory disorders. To investigate NO production in multiple sclerosis (MS), we determined the concentrations of its oxidation products (NOx) in the cerebrospinal fluid (CSF) and plasma of 61 MS patients. The patients were divided into three groups on the basis of their clinical disease activity. The total levels of NOx in CSF were significantly increased in all MS groups as compared to healthy controls and tension headache patients. CSF nitrite correlated with clinical disease activity. At exacerbation, the CSF nitrite levels exceed the plasma level. This suggests that clinical disease activity is due to a CNS inflammatory response, which is more intense and qualitatively different from that during clinical stable phases. This study supports NO involvement in the pathogenesis of MS and determination of nitrite levels may be useful a surrogate marker for disease activity.


Das, U. N. (2003). "Is there a role for saturated and long-chain fatty acids in multiple sclerosis?" Nutrition 19(2): 163-6.


Dasgupta, S., M. Jana, et al. (2003). "Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells." J Biol Chem 278(25): 22424-31.

            The presence of neuroantigen-primed T cells recognizing self-myelin antigens within the CNS is necessary for the development of demyelinating autoimmune disease like multiple sclerosis. This study was undertaken to investigate the role of myelin basic protein (MBP)-primed T cells in the expression of proinflammatory cytokines in microglial cells. MBP-primed T cells alone induced specifically the microglial expression of interleukin (IL)-1beta, IL-1alpha tumor necrosis factor alpha, and IL-6, proinflammatory cytokines that are primarily involved in the pathogenesis of MS. This induction was primarily dependent on the contact between MBP-primed T cells and microglia. The activation of microglial NF-kappaB and CCAAT/enhancer-binding protein beta (C/EBPbeta) by MBP-primed T cell contact and inhibition of contact-mediated microglial expression of proinflammatory cytokines by dominant-negative mutants of p65 and C/EBPbeta suggest that MBP-primed T cells induce microglial expression of cytokines through the activation of NF-kappaB and C/EBPbeta. In addition, we show that MBP-primed T cells express very late antigen-4 (VLA-4), and functional blocking antibodies to alpha4 chain of VLA-4 (CD49d) inhibited the ability of MBP-primed T cells to induce microglial proinflammatory cytokines. Interestingly, the blocking of VLA-4 impaired the ability of MBP-primed T cells to induce microglial activation of only C/EBPbeta but not that of NF-kappaB. This study illustrates a novel role of VLA-4 in regulating neuroantigen-primed T cell-induced activation of microglia through C/EBPbeta


Dasgupta, S., Y. Zhou, et al. (2003). "Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps." J Immunol 170(7): 3874-82.

            Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-kappaB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-kappaB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-kappaB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.


DasGupta, R. and C. J. Fowler (2003). "Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies." Drugs 63(2): 153-66.

            Although patients with multiple sclerosis (MS) are likely to have problems with bladder, bowel and sexual function, these problems have often been neglected in the past. Bladder dysfunction produces symptoms of urgency, frequency and urge incontinence (due to bladder overactivity and incomplete emptying), and is found in up to 75% of patients with MS. The mainstay of drug treatment for neurogenic bladder overactivity is anticholinergic medication, although intravesical treatments have also been proposed, such as the vanilloids and botulinum toxin, as well as sublingual cannibanoids. There has been much progress with pro-erectile agents in recent years, notably the use of sildenafil citrate, which has been shown to be particularly efficacious in these patients. Other agents include apomorphine hydrochloride and newer phosphodiesterase 5 inhibitors; however, the efficacy of these drugs in patients with MS remains to be proven. Research in female sexual dysfunction is also progressing, although this aspect of patient well being has only recently been addressed; the reported development of a classification system for the condition is likely to help categorise future treatments. Unlike bladder and sexual dysfunction, there have been rather limited advances in the treatment of faecal incontinence and constipation specifically for patients with MS, despite a prevalence of up to 50%. This review highlights the strategies for these types dysfunction commonly seen in patients with MS, with report of recent pharmacological developments.


Davies, G. R., A. Ramani, et al. (2003). "Preliminary magnetic resonance study of the macromolecular proton fraction in white matter: a potential marker of myelin?" Mult Scler 9(3): 246-9.

            We report on a new quantitative magnetization transfer (MT) technique that allows for the in vivo estimation of the macromolecular proton fraction (f) and the bound pool T2 relaxation time (T2b), whilst permitting whole brain coverage. In this pilot study, five subjects with multiple sclerosis (MS) and five healthy controls were studied. Both f and T2b were significantly different between MS lesions and normal control white matter (WM). Relationships between f and T1 relaxation time [Spearmans rank correlation coefficient (r(s)) = -0.97, P < 0.001] and f and the magnetization transfer ratio (MTR; r(s) = 0.80, P < 0.001) were observed. Compared with MTR, f and T2b have the potential advantage of relative independence from MT acquisition protocol while offering more pathologically specific information. In particular, f may provide a more direct indication of myelin content in WM.


Davies, G., G. Keir, et al. (2003). "The clinical significance of an intrathecal monoclonal immunoglobulin band: a follow-up study." Neurology 60(7): 1163-6.

            BACKGROUND: Intrathecal oligoclonal band synthesis occurs in 95% of patients with clinically definite MS but may also occur in the context of CNS infection and other inflammatory conditions. By contrast, the significance of an intrathecal synthesis of a monoclonal band remains uncertain. Previously, an association between a single intrathecal band and CNS lymphoma has been reported but a relationship has also been shown with diagnoses more usually associated with an oligoclonal pattern. At present, it is not known whether a single band will convert to an oligoclonal response with time. METHODS: Data were obtained from patients who had CSF and serum analyzed by isoelectric focusing (IEF) at the authors' institutions over a 6-year period. Clinical details were acquired for those who underwent repeat lumbar puncture after an initial CSF examination revealed an intrathecal monoclonal immunoglobulin G band. RESULTS: Of the 31 patients identified as having an initial intrathecal monoclonal band, clinical details were available for 27. Of those, 9 were found on subsequent lumbar puncture to have developed an intrathecal oligoclonal response. CONCLUSIONS: Among those subjects who developed oligoclonal bands, there was a propensity for either a diagnosis of MS or clinically isolated syndromes due to demyelination. In the 18 subjects who either reverted to having normal CSF IEF or continued to exhibit only the monoclonal band, no cases of MS were encountered. Importantly, one of these had cerebral lymphoma.


Davis, D. P. and A. Marino (2003). "Acute cerebellar ataxia in a toddler: case report and literature review." J Emerg Med 24(3): 281-4.

            Acute cerebellar ataxia (ACA) is an inflammatory CNS disease that is characterized by rapid onset of ataxia in a child under 6 years of age. Symptoms typically occur in association with a relatively benign viral illness and have been reported after vaccination as well. Immunological studies suggest that both involve autoimmune destruction of axon tracts, with pathological and radiographic evidence of a link with multiple sclerosis. The emergency approach should be focused on excluding more significant illnesses, such as meningitis or an intracranial mass lesion. Here we present a case of a young girl with ACA and review the relevant literature.


Dawson, J., W. Miltz, et al. (2003). "Targeting monocyte chemoattractant protein-1 signalling in disease." Expert Opin Ther Targets 7(1): 35-48.

            Monocyte chemoattractant protein-1 (MCP-1) has been implicated in many inflammatory and autoimmune diseases. The G-protein-coupled receptor CCR-2B is probably the most important MCP-1 receptor in vivo, and loss of MCP-1 effector function alone is sufficient to impair monocytic trafficking in inflammation models. MCP-1 signalling appears to be a relevant target, especially in rheumatoid arthritis (RA). In RA patients, MCP-1 is produced by synovial cells and infiltrating monocytes, plasma MCP-1 concentrations correlate with swollen joint count, and elevated serum MCP-1 concentrations were found in juvenile RA in patients with active disease. Modulation of MCP-1 signalling in experimental RA showed beneficial effects on inflammation and joint destruction. With respect to chronic neuroinflammation, a critical role for MCP-1 has been established in animal models for multiple sclerosis. In acute neuroinflammation, experimental evidence for a detrimental role of MCP-1 in stroke and excitotoxic injury has been found. Several selective small molecular weight CCR-2B antagonists and MCP-1-blocking antibodies have been described. The proof for the validity of targeting MCP-1 signalling in disease, however, has yet to be established in clinical trials.


De Andres, C. (2003). "[The interest of multiple sclerosis attacks. Physiopathology and therapy]." Rev Neurol 36(11): 1058-64.

            AIMS. To review the clinical concept of an attack, the physiopathological mechanisms underlying the symptoms of the attack, in the recovery phase, and those corresponding to the progressive or degenerative phase of the disease. DEVELOPMENT. Although they do not explain the exact mechanisms responsible for the onset of the attack or the processes that account for the clinical and pathological heterogeneity, most research studies suggest that the lesions produced in multiple sclerosis are the consequence of complex immunological interactions that take place mostly in the white matter of the central nervous system. These lesions affect, to variable extents, the myelin and the axon. We survey how these events are reflected in the images obtained by magnetic resonance. Clinical observations have shown that, in some patients, infections and hormones can exert an influence on the activity of the disease. Recovery, in the initial stages at least, would be produced by the action of poorly understood mechanisms that limit inflammation, and by local or cortical neuroplasticity or repair processes. Finally, we discuss the mechanisms behind the action of corticoids that justify their use when treating these attacks. CONCLUSION. A more thorough understanding of these events opens up the way to providing better therapy in the future.


De Keyser, J., E. Zeinstra, et al. (2003). "Are astrocytes central players in the pathophysiology of multiple sclerosis?" Arch Neurol 60(1): 132-6.

            An interaction between antimyelin T cells and antigen-presenting glial cells is a crucial step in the cascade of immune events that lead to the inflammatory lesions in multiple sclerosis (MS). One of the most debated and controversial issues is whether microglial cells or astrocytes are the key players in initiating the (auto)immune reactions in the central nervous system in MS. Many investigators consider microglia to be the responsible intrinsic immunoeffector cells. In this review, we speculate that in MS astrocytes may serve as primary (facultative) antigen-presenting cells due to a failure of noradrenergic suppression of class II major histocompatibility complex molecules, which is caused by a loss of beta(2)-adrenergic receptors. If this hypothesis is correct, pharmacologic suppression of the antigen-presenting capacities of astrocytes may be a potential therapy for MS.


De Stefano, N., P. M. Matthews, et al. (2003). "Evidence of early cortical atrophy in MS: relevance to white matter changes and disability." Neurology 60(7): 1157-62.

            OBJECTIVE: To assess cortical gray matter (GM) changes in MS and establish their relevance to clinical disability and to inflammatory changes of white matter (WM) in patients with the relapsing-remitting (RR) and primary progressive (PP) forms of the disease. METHODS: Conventional MRI examinations were obtained in patients with definite MS who had either the RR or the PP form of the disease. An automated analysis tool was used with conventional T1-weighted MR images to obtain total and cortical brain volumes normalized for head size. Total brain lesion load was estimated on conventional proton density and T2-weighted MR images. The relationship between volumetric MR measures and scores of clinical disability was assessed. RESULTS: Normalized cortical volumes (NCV) were lower for both RR and PP MS patients than for normal control subjects (p < 0.001) but were similar between the two patient groups (p > 0.5). NCV decreases in both patients groups were detected even in those patients with short disease duration (<5 years; p < 0.001 in RR MS and p < 0.05 in PP MS) and minimal brain lesion volume (<5 mL; p < 0.0001 in RR MS and p < 0.005 in PP MS). Measures of NCV in individual patients were negatively correlated with T2-weighted lesion volume (r = -0.47, p < 0.001) and disease duration (r = -0.25, p < 0.05) only in the patients with RR MS. NCV correlated with Expanded Disability Status Scale scores across all of the patients, but the strength of the correlation was stronger (p < 0.05) for PP (r = -0.64, p < 0.0001) than for RR (r = -0.27, p = 0.04) MS patients. CONCLUSIONS: These data confirm substantial neocortical volume loss in MS patients and suggest that neocortical GM pathology may occur early in the course of the disease in both RR and PP MS patients and contribute significantly to neurologic impairment. Although a proportion of this neocortical pathology may be secondary to WM inflammation, the extent of the changes suggests that, especially in patients with PP MS, an independent neurodegenerative process also is active.


Debruyne, J. C., J. Versijpt, et al. (2003). "PET visualization of microglia in multiple sclerosis patients using [11C]PK11195." Eur J Neurol 10(3): 257-64.

            Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.


Dedrick, R. L., S. Bodary, et al. (2003). "Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection." Expert Opin Biol Ther 3(1): 85-95.

            Inflammatory disorders such as autoimmune diseases and graft rejection are mediated by activated leukocytes, particularly T lymphocytes, which penetrate the inflamed tissue and perpetuate or amplify the immune reaction. In an unstimulated state, leukocytes do not readily adhere to the vascular endothelium. However, inflammatory signals induce the expression of proteins on the endothelial cell surface that promote the adhesion and extravasation of activated immune cells from the circulation into the underlying tissues. Key among these molecules are P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the endothelial cells, and their respective counter receptors, P-selectin glycoprotein ligand-1 (PSGL-1), leukocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4), on the leukocytes. In vitro blockade of these molecules inhibits the adhesion of leukocytes. In many cases there is attenuation of leukocyte activation as well. Adhesion blockade in animal models prevents or ameliorates graft rejection and disease severity in autoimmune models. Clinical studies with humanised monoclonal antibodies which interfere with LFA-1/ICAM-1 or VLA-4/VCAM-1 interactions have shown significant efficacy and good safety profiles in autoimmune disease, including psoriasis, multiple sclerosis and inflammatory bowel disease. Thus, adhesion blockade is emerging as a useful therapeutic strategy in several inflammatory settings.


Dehmeshki, J., D. T. Chard, et al. (2003). "The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study." J Neurol 250(1): 67-74.

            BACKGROUND: In 10-15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. METHODS: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75% probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). RESULTS: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = -0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = -0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. CONCLUSIONS: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted.


Delgado, M., C. Abad, et al. (2003). "PACAP in immunity and inflammation." Ann N Y Acad Sci 992: 141-57.

            The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the VIP/secretin/glucagon family of peptides, produced by the lymphoid cells, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, PACAP has been clearly identified as a potent anti-inflammatory factor that exerts its function by regulating the production of both anti- and proinflammatory mediators. In this sense, PACAP prevents death by septic shock, an acute inflammatory disease with a high mortality. In addition, PACAP regulates the expression of costimulatory molecules, inasmuch as this related to the modulation in the shift from Th1 towards Th2 differentiation. We recently reported that PACAP prevents the deleterious effects of arthritis by downregulating both inflammatory and autoimmune components of the disease. Therefore, PACAP and analogs have been proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, arthritis, multiple sclerosis, Crohn's disease, or autoimmune diabetes.


Denkinger, C. M., M. Denkinger, et al. (2003). "In vivo blockade of macrophage migration inhibitory factor ameliorates acute experimental autoimmune encephalomyelitis by impairing the homing of encephalitogenic T cells to the central nervous system." J Immunol 170(3): 1274-82.

            Macrophage migration inhibitory factor (MIF) is a cytokine that plays a critical role in the regulation of macrophage effector functions and T cell activation. However, its role in the pathogenesis of T cell-mediated autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), has remained unresolved. In this study, we report that anti-MIF Ab treatment of SJL mice with acute EAE improved the disease severity and accelerated the recovery. Furthermore, the anti-MIF treatment impaired the homing of neuroantigen-reactive pathogenic T cells to the CNS in a VCAM-1-dependent fashion. Interestingly, MIF blockade also decreased the clonal size of the neuroantigen-specific Th1 cells and increased their activation threshold. Taken together, the results demonstrate an important role for MIF in the pathogenesis of EAE/multiple sclerosis and suggest that MIF blockade may be a promising new strategy for the treatment of multiple sclerosis.


Derk, C. T. and S. A. Jimenez (2003). "Systemic sclerosis: current views of its pathogenesis." Autoimmun Rev 2(4): 181-91.

            Systemic sclerosis (SSc) is an autoimmune disorder of unknown etiology characterized by severe and often progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immune abnormalities. Clinically, SSc is very heterogeneous, encompassing a spectrum ranging from mild limited forms of skin sclerosis with minimal internal organ involvement to severe skin and multiple internal organ fibrosis. Mortality and morbidity in SSc are very high and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to better target and design effective therapy in the future.


DeStefano, F., T. Verstraeten, et al. (2003). "Vaccinations and risk of central nervous system demyelinating diseases in adults." Arch Neurol 60(4): 504-9.

            BACKGROUND: Several case reports of the onset or exacerbation of multiple sclerosis or other demyelinating conditions shortly after vaccination have suggested that vaccines may increase the risk of demyelinating diseases. OBJECTIVE: To evaluate the association between vaccination and onset of multiple sclerosis or optic neuritis. DESIGN: Case-control study involving cases of multiple sclerosis or optic neuritis among adults 18 to 49 years of age. Data on vaccinations and other risk factors were obtained from computerized and paper medical records and from telephone interviews. SETTING: Three health maintenance organizations. PARTICIPANTS: Four hundred forty case subjects and 950 control subjects matched on health maintenance organization, sex, and date of birth. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Onset of first symptoms of demyelinating disease at any time after vaccination and during specified intervals after vaccination (<1 year, 1-5 years, and >5 years). RESULTS: Cases and controls had similar vaccination histories. The odds ratios (95% confidence intervals), adjusted for potential confounding variables, of the associations between ever having been vaccinated and risk of demyelinating disease (multiple sclerosis and optic neuritis combined) were 0.9 (0.6-1.5) for hepatitis B vaccine; 0.6 (0.4-0.8) for tetanus vaccination; 0.8 (0.6-1.2) for influenza vaccine; 0.8 (0.5-1.5) for measles, mumps, rubella vaccine; 0.9 (0.5-1.4) for measles vaccine; and 0.7 (0.4-1.0) for rubella vaccine. The results were similar when multiple sclerosis and optic neuritis were analyzed separately. There was no increased risk according to timing of vaccination. CONCLUSION: Vaccination against hepatitis B, influenza, tetanus, measles, or rubella is not associated with an increased risk of multiple sclerosis or optic neuritis.


Devendra, D. and G. S. Eisenbarth (2003). "17. Immunologic endocrine disorders." J Allergy Clin Immunol 111(2 Suppl): S624-36.

            Immune-mediated tissue destruction or disregulation is the cause of multiple common, as well as rare, endocrine disorders including type 1 diabetes, Graves' disease, Hashimoto thyroiditis, and Addison's disease. Each of these disorders can be divided into a series of stages beginning with genetic susceptibility, environmental triggering events, and active autoimmunity, followed by metabolic abnormalities with overt disease. Common genetic susceptibility is suggested by the clustering of a series of disorders in the same individual and his or her family. A major portion of the genetic susceptibility lies in the HLA region, but for several disorders, mutation of transcription factors underlies disease susceptibility (eg, X-linked polyendocrinopathy, immune deficiency and diarrhea, and autoimmune polyendocrine syndrome type 1). With improving immunogenetic and pathogenic understanding, type 1A diabetes is now predictable, and excellent autoantibody screening assays are available. This knowledge, combined with studies in animal models, has led to trials for the prevention of diabetes. In addition, aberrant immunologic reactions (eg, insulin autoantibodies after insulin therapy, Graves' disease after monoclonal anti-T-cell therapy in multiple sclerosis) can complicate standard and experimental therapies. We therefore believe that an understanding of the immunogenetics and immunopathogenesis of endocrine disorders can aid in the prevention of morbidity and mortality for these related diseases.


Devlin, N., J. Appleby, et al. (2003). "Patients' views of explicit rationing: what are the implications for health service decision-making?" J Health Serv Res Policy 8(3): 183-6.

            Patient groups in England and Wales have expressed concerns about the decision-making processes of the National Institute for Clinical Excellence (NICE), the body responsible for explicit rationing. Five key issues were identified by the Multiple Sclerosis Society regarding NICE appraisals and guidance: they focus too narrowly on costs to the National Health Service; quality-adjusted life-years are an inadequate measure of health gain, particularly for long-term conditions; NICE takes too conservative a view of long-term benefits; NICE's cost-effectiveness threshold is inappropriate; and NICE evaluations fail to capture patients' personal experiences of their condition and treatments. We question the veracity of some of these arguments and, where appropriate, suggest ways in which NICE's processes might be strengthened.


Dharmasaroja, P. (2003). "Specificity of autoantibodies to epitopes of myelin proteins in multiple sclerosis." J Neurol Sci 206(1): 7-16.

            An autoimmune response to one or more myelin-protein components is thought to be part of the pathogenesis of multiple sclerosis (MS). The immunodominant-autoantibody epitope may be localized on a linear peptide segment, on a conformation-sensitive epitope, or on an epitope resulting from post-translational modifications. Primary, secondary, and tertiary structures of myelin proteins may determine the specific site for binding of autoantibodies. A myelin protein-specific autoantibody can bind to either a linear or conformational epitope, whereas all of the T cell epitopes are linear. At present, the conformational epitopes of myelin proteins have not been identified; most of the methods used to identify the myelin-protein epitopes corresponding to the pathogenesis of multiple sclerosis are involved in the linear epitope mapping. Polymorphism or mutations may cause inappropriate expression of the myelin proteins with alterations to their linear and/or conformational epitopes, and make them susceptible to autoantibody binding, especially if these changes occur at the surface of the protein. This review focuses on the specificity of autoantibodies to the epitopes of myelin proteins and correlates this to the structures of proteins. Factors that influence the expression of myelin-protein epitopes such as the alpha-helical or beta-sheet structure of the protein, the tri-proline site, and the post-translational modifications as well as physicochemical properties of amino acid changed are included.


Dhib-Jalbut, S., M. Chen, et al. (2003). "Glatiramer acetate-reactive peripheral blood mononuclear cells respond to multiple myelin antigens with a Th2-biased phenotype." J Neuroimmunol 140(1-2): 163-71.

            One favored mechanism of action of glatiramer acetate (GA) in multiple sclerosis (MS) involves the induction of GA-reactive Th2 cells that are believed to enter the central nervous system and mediate bystander suppression in response to cross-reactive myelin antigens. To test this hypothesis, we examined the proliferative response and cytokine release from peripheral blood mononuclear cells (PBMCs) of 12 MS patients treated with GA, in response to 16 myelin peptides that were previously described as immunodominant or encephalitogenic and a tetanus peptide as a control antigen. Interferon-gamma (IFN-gamma) and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by enzyme-linked immunosorbent assay (ELISA). GA-stimulated PBMCs from 9 of 12 patients (75%) proliferated to one or more myelin peptides. Among the 16 peptides tested, GA-stimulated PBMCs from the majority of the patients proliferated in response to MOG(21-44). PBMCs from two thirds of the patients produced IL-5 in response to myelin peptides, while half of them produced IFN-gamma. Th1/Th0/Th2 cytokine phenotypes demonstrated that responses from 10 of 12 patients were either Th0- or Th2-biased. Responses from two patients were Th1-biased. Conversely, some myelin-specific T-cell lines (TCLs) responded to GA by proliferation (3 of 21 TCLs), IL-5 release (11 of 21 TCLs), and IFN-gamma release (3 of 21 TCLs). These results indicate that GA-reactive TCLs can respond to a spectrum of myelin peptides in a Th2-biased fashion, which is consistent with the concept of bystander suppression. Furthermore, some myelin-specific TCLs are able to recognize GA, with a tendency to produce more IL-5 than IFN-gamma, which would suggest a systemic modulatory effect of the drug.


Dhib-Jalbut, S. (2003). "Glatiramer acetate (Copaxone(R)) therapy for multiple sclerosis." Pharmacol Ther 98(2): 245-55.

            Glatiramer acetate (GA) (Copaxone(R)) is a worldwide-approved drug for the treatment of relapsing multiple sclerosis (MS), an autoimmune disease of the CNS. The drug is a synthetic copolymer with an amino acid composition based on the structure of myelin basic protein, one of the autoantigens implicated in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE). Developed initially as a "tool" to study EAE, the drug unexpectedly inhibited disease and was subsequently developed for the treatment of MS. The drug has been shown in controlled clinical trials to significantly reduce relapse rate and progression of disability in MS with long-term efficacy, remarkable safety, and tolerability. Efficacy as measured by magnetic resonance imaging parallels its clinical benefits as manifested by a reduction in gadolinium-enhancing lesions and brain atrophy. The mechanism of action of the drug in humans is believed to involve the induction of glatiramer-reactive regulatory cells, including CD4+ and CD8+ T-cells. Glatiramer-reactive Th2 cells are believed to enter the brain and, through cross-reactivity with myelin antigens, produce bystander suppression, antiinflammatory effects, and neuroprotection.


Di Legge, S., M. C. Piattella, et al. (2003). "Longitudinal evaluation of depression and anxiety in patients with clinically isolated syndrome at high risk of developing early multiple sclerosis." Mult Scler 9(3): 302-6.

            We investigated the relationship between emotional changes, brain lesion burden and development of multiple sclerosis (MS). Thirty-seven consecutive patients with clinically isolated syndrome (CIS) were prospectively assessed with the Expanded Disability Status Scale (EDSS), the 21-item Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI) and gadolinium enhanced (Gd+) MRI scans. BDI and STAI were also administered to 36 age-matched controls. Conversion to MS was defined as the occurrence of a clinical relapse. CIS patients were more likely to endorse symptoms of anxiety and depression than controls. Baseline scores for depression and anxiety did not correlate with the total lesion load (i.e., volume of Gd+, T2 and T1 lesions) and the number of Gd+ lesions during the first six months of follow-up. A positive correlation was found between severity of depressive scores and the lesion load in the right temporal region (P = 0.005). After 33+/-6 months of the study entry, patients who had a clinical relapse were more frequently depressed (P = 0.001) than those relapse free. Emotional disturbances are frequently observed in CIS patients and show a tendency towards a normalization in relapse-free patients. The increased rate of depressive symptoms observed in patients who developed MS seems to result from a combination of psychological and organic features. The lesion load in the right temporal region is confirmed as a key area for developing depressive symptoms, even in the early phase of the disease.


Dianzani, U., A. Chiocchetti, et al. (2003). "Role of inherited defects decreasing Fas function in autoimmunity." Life Sci 72(25): 2803-24.

            Fas is a death receptor belonging to the TNFR superfamily and induces cell apoptosis by both activating a caspase cascade and altering mitochondria. In the immune system, Fas is involved in the switching-off of the immune responses and cell mediated cytotoxicity. In humans, genetic defects decreasing Fas function cause the Autoimmune Lymphoproliferative Syndrome (ALPS) where autoimmunities are associated with accumulation of polyclonal lymphocytes in the secondary lymphoid tissues and expansion of T cells lacking both CD4 and CD8 (DN cells). Expansion of DN cells is absent in an ALPS variant, named Dianzani's Autoimmune Lymphoproliferative Disease (DALD). The observation that DALD patients' families display increased frequency of autoimmune diseases different from ALPS suggests that defects of Fas function may also play a role in development of "common" autoimmune diseases. This possibility is supported by detection of defective Fas function in substantial proportions of patients with the multiple autoimmune syndrome or aggressive forms of type 1 diabetes or multiple sclerosis. This article reviews data suggesting that development of autoimmune/lymphoproliferative patterns may involve several alterations hitting the Fas system, but might also involve alterations in other systems contributing to the switching-off or proliferation of lymphocytes.


Diaz-Arrastia, R., Y. Gong, et al. (2003). "Increased risk of late posttraumatic seizures associated with inheritance of APOE epsilon4 allele." Arch Neurol 60(6): 818-22.

            BACKGROUND: Late posttraumatic seizures are a common complication of moderate and severe traumatic brain injury. Inheritance of the apolipoprotein E (APOE) epsilon4 allele is associated with increased risk of Alzheimer disease, progression to disability in multiple sclerosis, and poor outcome after traumatic brain injury. OBJECTIVE: To determine whether inheritance of APOE epsilon4 is associated with increased risk of developing late posttraumatic seizures. DESIGN: Prospective study. SETTING: Neurosurgical service at an urban level I trauma center.Patients Patients admitted with a diagnosis of moderate and severe traumatic brain injury were enrolled. METHODS: Six months after injury, patients were contacted to determine functional outcome (according to the Glasgow Outcome Scale-Expanded [GOS-E]) and the presence of late posttraumatic seizures. Genotype at the APOE locus was determined by restriction fragment length polymorphism analysis. RESULTS: DNA and outcome information was obtained from 106 subjects. Six months after injury, 31 (29%) had a poor outcome (GOS-E score, 1-4), 47 (44%) had an intermediate outcome (GOS-E score, 5-6), and 28 (26%) had a favorable outcome (GOS-E score, 7-8). Twenty-one patients (20%) had at least 1 late posttraumatic seizure. The relative risk of late posttraumatic seizures for patients with the epsilon4 allele was 2.41 (95% confidence interval, 1.15-5.07; P =.03). In this cohort, inheritance of APOE epsilon4 was not associated with an unfavorable GOS-E score 6 (P =.47). CONCLUSIONS: Inheritance of the APOE epsilon4 allele is associated with increased risk of late posttraumatic seizures. In this cohort, this risk appears to be independent of an effect of epsilon4 on functional outcome. A better understanding of the molecular role of APOE in neurodegenerative diseases may be helpful in developing antiepileptogenic therapies.


Dieckmann, K., R. Potter, et al. (2003). "Does bulky disease at diagnosis influence outcome in childhood Hodgkin's disease and require higher radiation doses? Results from the German-Austrian Pediatric Multicenter Trial DAL-HD-90." Int J Radiat Oncol Biol Phys 56(3): 644-52.

            PURPOSE: The identification of risk factors is required for risk-adapted treatment strategies in the treatment of Hodgkin's disease. To assess the influence of bulky disease at diagnosis as compared with other risk factors on event-free survival (EFS) in pediatric Hodgkin's disease such as stage, B-symptoms, number of involved lymph node regions, histology, and remission status after chemotherapy, we analyzed the outcome of 552 patients treated with a risk-adapted treatment strategy consisting of OPPA(OEPA)/COPP (vincristine, procarbazine, etoposide, prednisone, adriamycin, cyclophosphamide) and involved-field radiotherapy. METHODS AND MATERIALS: Between 1990 and 1995, 578 patients with primary Hodgkin's disease (HD) were enrolled in the German/Austrian Pediatric Hodgkin's Disease Study Group (DAL) Multicenter Study (HD-90). Patients were stratified into three treatment groups (TGs) for early, intermediate, and advanced stage. All patients received induction chemotherapy (CT) with two cycles of OEPA for boys and two cycles of OPPA for girls. Patients in TG2 and TG3 received another two or four cycles, respectively, of COPP. Chemotherapy was followed by involved-field radiotherapy. The radiation field, which was prescribed by the study center, was treated with a dose of 25 Gy/25 Gy/20 Gy (TG1/TG2/TG3), and in case of insufficient remission with a local boost of 5 Gy to 10 Gy. The following prognostic factors were analyzed with regard to their impact on EFS: bulky disease, mediastinal tumor, number of involved lymph node regions, histology, treatment group, B-symptoms, sex, age, and remission status after chemotherapy. RESULTS: Significant univariate predictive factors for the EES were: nodular sclerosis type 2 (NS2) histology (relative risk [RR] 3.43; p = 0.0002), presence of B-symptoms (RR 2.70; p = 0.0014), number of involved regions (1.55; p = 0.019), and treatment groups (RR 1.33; p = 0.017). There was a higher risk (RR 1.92; p = 0.040) for patients with bulky compared with nonbulky disease (5-year EFS 89.6%/94.6%). In the multiple regression model, only NS2 and B-symptoms remained strong predictive factors. The remission status after chemotherapy did not correlate with EFS (p = 0.66). CONCLUSION: Treatment strategies in Hodgkin's disease have an impact on different risk factors. In the risk-adapted treatment strategy of the HD-90 study, tumor burden indicated as bulky disease or as number of involved lymph nodes loses its importance, whereas NS2 histology and B-symptoms have a major impact on treatment outcome. Bulky disease at diagnosis might require higher radiation doses only in case of insufficient remission.


Diem, R., A. Tschirne, et al. (2003). "Decreased amplitudes in multiple sclerosis patients with normal visual acuity: a VEP study." J Clin Neurosci 10(1): 67-70.

            Primary demyelination with relative preservation of axons is considered to be one pathological hallmark of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. However, imaging and pathomorphological studies have stimulated a recent re-emergence of interest in the axonal, neurodegenerative aspect of MS pathology. Axonal injury appears to be a key factor of disability and permanent neurological deficit in MS patients. In the present electrophysiological study, visual potentials evoked by pattern reversal (VEPs) were recorded in 25 MS patients with normal visual acuity and unimpaired visual functions. Compared to a control population, VEP amplitudes for two different spatial frequencies were significantly decreased. From this observation, we conclude that an underlying pathological process threatening axonal integrity may not be reliably reflected by clinical parameters due to the distinct ability of the visual system to compensate for axonal loss. Pattern VEP may thus serve as an objective tool to diagnose and to monitor axonal pathology in MS. Focal conduction block due to demyelination as a cause for reduced VEP amplitudes can not be fully excluded, but would appear less likely since latency prolongation in the MS group was moderate compared to controls.


Dilorenzo, T., J. Halper, et al. (2003). "Reliability and validity of the multiple sclerosis quality of life inventory in older individuals." Disabil Rehabil 25(16): 891-7.

            PURPOSE: Despite the increasing number of older individuals with multiple sclerosis (MS), there is a paucity of research on this subpopulation. Health-related quality of life (HRQOL) has received extensive attention in MS; however samples tend to be young. The present study assesses the internal consistency reliability and construct validity of the MS Quality of Life Inventory (MSQLI), a widely employed measure of HRQOL, in older individuals. METHOD: Select subscales of the MSQLI and other measures of mental health and physical functioning were administered by telephone to 30 randomly selected older ( >or= 60) individuals and a gender-matched sample of younger ( < 60) individuals. Reliability estimates were calculated separately for each group. Construct (convergent) validity was assessed by examining the pattern of correlations between MSQLI subscales and measures of related constructs in the two groups. RESULTS: Reliability estimates were similar in the two groups. With few exceptions, the correlations measuring convergent validity were in the expected direction, and of considerable magnitude, in both groups. CONCLUSIONS: Results provide preliminary evidence that the MSQLI is a reliable and valid instrument for use with older individuals. The slightly different pattern of results observed in the validity analysis might be explained by an adjustment hypothesis. Future research on HRQOL in this subpopulation is encouraged.


Dimayuga, F. O., Q. Ding, et al. (2003). "The neuregulin GGF2 attenuates free radical release from activated microglial cells." J Neuroimmunol 136(1-2): 67-74.

            The neuregulin glial growth factor 2 (GGF2) is a neural growth factor that is best known for its ability to promote the survival and proliferation of oligodendrocytes and Schwann cells. While it has been shown in recent years that GGF2 is effective in the treatment of autoimmune models of brain injury, it is not known if the beneficial effects of GGF2 are based in part on modulation of brain inflammation. In this report, we document the anti-inflammatory effects of recombinant human GGF2 (rhGGF2) on microglial free radical production in vitro. The presence of the neuregulin receptors ErbB2, 3, and 4 was confirmed in N9 microglial cells by Western blot analysis. Pretreatment of N9 cells with 10-100 ng/ml rhGGF2 24 h before either phorbol 12-myristate 3-acetate (PMA) or interferon gamma (IFNgamma) caused dose-dependent decreases in oxidative burst activity and nitrite release, respectively, with 50 and 100 ng/ml causing significant effects. When cells were co-treated with increasing doses of rhGGF2 and PMA or IFNgamma, only concentrations of 50 ng/ml, but not 10 or 100 ng/ml, were able to decrease oxidative burst activity and nitrite release. Finally, when microglial cell viability following treatment of cells with IFNgamma with or without rhGGF2 was evaluated, it was observed that 50 and 100 ng/ml rhGGF2 conferred significant protection against IFNgamma-induced cell death in microglial cells. Overall, these results indicate that the neuregulin rhGGF2 may have anti-inflammatory and antioxidant properties in the brain, and may also provide trophic support for brain-resident microglial cells.


Doggrell, S. A. (2003). "Is natalizumab a breakthrough in the treatment of multiple sclerosis?" Expert Opin Pharmacother 4(6): 999-1001.

            In patients with either relapsing-remitting or secondary-progressive multiple sclerosis, there were fewer new lesions/patient with natalizumab (0.7 and 1.1 with natalizumab 3 and 6 mg/kg every 28 days, respectively) than in the placebo group (9.6 new lesions/patient) over 6 months. There were also fewer relapses in the natalizumab groups than the placebo group. However, there were no changes in the Expanded Disability Status Scale scores in any of the groups. Natalizumab was well-tolerated. Thus, the initial results with natalizumab treatment over 6 months in multiple sclerosis are encouraging.


Dogusan, Z., N. Martens, et al. (2003). "Effects of prolactin on cloned human T-lymphocytes." Endocrine 20(1-2): 171-6.

            To evaluate the possible role of prolactin (PRL) in T-lymphocytes, we monitored gene induction in one cytotoxic T-lymphocyte (CTL) clone derived from a patient with hemochromatosis and in several T-helper clones generated from a normal donor and a patient with multiple sclerosis. The CTL clone expressed conventional PRL receptor (PRLR), and PRL induced the expression of suppressor of cytokine signaling-3 (SOCS-3) and increased the expression of SOCS-2 and cytokine-inducible src homology-2 containing protein (CIS, another member of the SOCS family). As is the case in granulocytes, expression of a conventional receptor for PRL could not be shown by polymerase chain reaction analysis on three helper clones. In addition, as in granulocytes, PRL modulated the expression of genes such as the interferon-regulatory factor-1, inducible nitric oxide synthase, CIS, and SOCS-2. These effects were also elicited with ovine PRL and could be prevented by anti-PRL antibodies. Thus, the use of clones allowed the detection of direct effects of PRL on T-cells, even when these have few or no detectable PRLR, confirming that human T-lymphocytes are targets for PRL.


Dohi, N., S. Ishikawa, et al. (2003). "Multiple sclerosis with open-ring enhancement in the cerebrum and spinal cord." Intern Med 42(3): 273-6.

            A 67-year-old woman presented with open-ring enhancement on MR images in the thoracic spinal cord. Steroid therapy improved the patient's paraplegia, but six months later she developed left hemiparesis and a new open-ring enhancement appeared in the right cerebrum. Despite high-dose methylprednisolone therapy and plasmapheresis, another lesion appeared at the middle portion of the left centrum semiovale. Stereotaxic brain biopsy demonstrated active demyelination characteristics of multiple sclerosis (MS). This case indicates that openring enhancement can help differentiate MS from nondemyelinating disease, and that MS showing ring enhancement may contribute to disease severity and need more intensive immunomodulatory therapies.


Drulovic, J., D. Popadic, et al. (2003). "Decreased frequency of the tumor necrosis factor alpha -308 allele in Serbian patients with multiple sclerosis." Eur Neurol 50(1): 25-9.

            Tumor necrosis factor (TNF) alpha has been considered the prototypic cytopathogenic cytokine in multiple sclerosis (MS), but recently this cytokine has been shown to possess significant anti-inflammatory and neuroprotective effects in demyelinating diseases. It has been reported that the TNFalpha -308 polymorphism influences levels of TNFalpha production, and that the rare allele, TNF2, is associated with high TNFalpha production. We investigated the TNFalpha -308 polymorphism in 143 unrelated Serbian patients with MS and 123 ethnically matched, healthy individuals using the allele-specific restriction fragment length polymorphism polymerase chain reaction technique. The frequency of the TNF2 allele was significantly decreased in MS patients (14%) in comparison with controls (24%; p = 0.044). The TNF2 allele had no influence on disease behavior, since it was not associated with the course and severity of MS in this group of patients. The result suggests that in the Serbian population polymorphism at position -308 of TNFalpha or at an adjacent locus might have a role in MS susceptibility.


Dubois, B. D., E. Keenan, et al. (2003). "Interferon beta in multiple sclerosis: experience in a British specialist multiple sclerosis centre." J Neurol Neurosurg Psychiatry 74(7): 946-9.

            BACKGROUND: The efficacy of interferon beta (IFN beta) is well established in relapsing-remitting multiple sclerosis (MS). However, the use of this drug in clinical practice is complex, especially because it is only partially effective, its long term efficacy and side effects are unknown, its efficacy may be abrogated by the development of neutralising antibodies, compliance is variable, and its cost effectiveness is controversial. Objectives and Methods: Analysis of a prospectively followed up series of 101 MS patients treated with IFN beta was undertaken to: (1) monitor the outcome of IFN beta treatment in clinical practice; (2) compare the immunogenicity of the three commercial IFN beta preparations available; (3) assess the proportion of patients fulfilling the current guidelines of the Association of British Neurologists for stopping IFN beta therapy. RESULTS: During a median treatment period of 26 months (range 2-85), the relapse rate decreased by 41%. Although the reduction in the relapse rate was similar for all three commercial products, none of the Avonex treated patients were relapse free, compared with 19% of the Betaferon treated and 27% of the Rebif treated patients (p=0.02). Neutralising antibodies were not detected in Avonex treated patients (0 of 18), compared with 12 of 32 (38%) Betaferon treated and 10 of 23 (44%) Rebif treated patients (p=0.02). Forty of 101 (40%) patients satisfied the current (2001) Association of British Neurologists criteria for stopping IFN beta treatment at some stage during their treatment. CONCLUSION: IFN beta is effective in reducing the relapse rate in patients with relapsing-remitting MS in routine clinical practice. However, after a median treatment duration of 26 months, 40% of initially relapsing-remitting MS patients seem to have ongoing disease activity, presenting as disabling relapses or insidious progression.


Durelli, L., E. Verdun, et al. (2003). "Re: Vartanian T. An examination of the results of the EVIDENCE, INCOMIN, and phase III studies of interferon beta products in the treatment of multiple sclerosis. Clin Ther. 2003;25:105-118." Clin Ther 25(6): 1890-3.


Duvanel, C. B., P. Honegger, et al. (2003). "Inhibition of glial cell proinflammatory activities by peroxisome proliferator-activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro." J Neurosci Res 71(2): 246-55.

            Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a member of the nuclear hormone superfamily originally characterized as a regulator of adipocyte differentiation and lipid metabolism. In addition, PPAR-gamma has important immunomodulatory functions. If the effect of PPAR-gamma's activation in T-cell-mediated demyelination has been recently demonstrated, nothing is known about the role of PPAR-gamma in antibody-induced demyelination in the absence of T-cell interactions and monocyte/macrophage activation. Therefore, we investigated PPAR-gamma's involvement by using an in vitro model of inflammatory demyelination in three-dimensional aggregating rat brain cell cultures. We found that PPAR-gamma was not constitutively expressed in these cultures but was strongly up-regulated following demyelination mediated by antibodies directed against myelin oligodendrocyte glycoprotein (MOG) in the presence of complement. Pioglitazone, a selective PPAR-gamma agonist, partially protected aggregates from anti-MOG demyelination. Heat shock responses and the expression of the proinflammatory cytokine tumor necrosis factor-alpha were diminished by pioglitazone treatment. Therefore, pioglitazone protection seems to be linked to an inhibition of glial cell proinflammatory activities following anti-MOG induced demyelination. We show that PPAR-gamma agonists act not only on T cells but also on antibody-mediated demyelination. This may represent a significant benefit in treating multiple sclerosis patients.


Egner, A., V. L. Phillips, et al. (2003). "Depression, fatigue, and health-related quality of life among people with advanced multiple sclerosis: Results from an exploratory telerehabilitation study." NeuroRehabilitation 18(2): 125-33.

            This study reports on secondary data, depression, fatigue and health-related quality of life (HRQOL), collected on people with advanced multiple sclerosis (MS) as part of a larger study of the impact of a telerehabilitation intervention on people with severe mobility impairment. People with spinal cord injuries (SCIs) (n=111) and the prevention of pressure sores were the primary group of interest of the project. The focus here is on data collected from people with advanced MS (n=27), who were included as an exploratory cohort, as they experience increased risk of pressure ulcer development as their level of mobility declines. The study consisted of a nine-week intervention with three randomized groups: video, telephone, and standard care. Aside from information on pressure sores, data were also collected on fatigue, depression, and HRQOL for a two-year follow-up period. For the video group HRQOL scores trended higher and fatigue and depression scores lower for 24 months. Fatigue scores were significantly lower for the video group at month six, 12, and 18. In the sample overall, fatigue symptoms were far more prominent than depressive symptoms and affected 100% higher rates of depression than women. At baseline, controlling for Extended Disability Status Score (EDSS), depression and fatigue were correlated. However, contrary to indications from previous cross-sectional studies, no consistent relationship was observed over time between the two. Telerehabilitation interventions for people with advanced MS warrant further investigation. Findings here suggest that such interventions may be beneficial, although the results need affirmation through larger samples. In addition, the higher prevalence of male depression merits serious attention.


Ehde, D. M., M. P. Jensen, et al. (2003). "Chronic pain secondary to disability: a review." Clin J Pain 19(1): 3-17.

            BACKGROUND: Until recently, very little has been written regarding chronic pain as a secondary problem in persons who already have a physical disability, despite the potential for pain to increase the negative impact of what may already be a very disabling condition. The purpose of this review is to summarize what is currently known concerning the nature and scope of chronic pain as a secondary condition to disability, specifically spinal cord injury, acquired amputations, cerebral palsy, multiple sclerosis, neuromuscular disease, and postpolio syndrome. METHOD: What is known concerning the frequency, severity, impact, and treatment of pain in these specific conditions is reviewed, as are the factors that contribute to, or are associated with, adjustment to chronic pain in these disability groups. The authors conclude with several research questions that emerge from this knowledge, the answers to which will contribute to the long-term goal of the reduction of pain and suffering in persons with disabilities. CONCLUSIONS: The existing literature clearly documents that many persons with disabilities experience chronic pain. Many questions remain unanswered regarding the scope, severity, and treatment of chronic pain in these groups.


Eikelenboom, M. J., A. Petzold, et al. (2003). "Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy." Neurology 60(2): 219-23.

            OBJECTIVE: To evaluate markers of axonal damage in CSF and serum of patients with different subtypes of MS in relation to measures of disease progression on MRI. METHODS: In 51 patients with MS (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and -NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions). RESULTS: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r = -0.51, p < 0.001), T2 lesion load (r = 0.41, p < 0.05), ventricular fraction (r = 0.37, p < 0.05), and T1 lesion load (r = 0.37, p < 0.05). For the anti-NfH index, a correlation was found with the PF (r = -0.39, p < 0.05). No correlations were found between the IgG index and MRI measures. CONCLUSIONS: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.


Einarsson, U., K. Gottberg, et al. (2003). "Multiple sclerosis in Stockholm County. A pilot study exploring the feasibility of assessment of impairment, disability and handicap by home visits." Clin Rehabil 17(3): 294-303.

            OBJECTIVE: A pilot study performed within Stockholm County to evaluate the feasibility of collecting data using a comprehensive evaluation package administered in the home environment to assess impairment, disability and handicap in order to explore the consequences of multiple sclerosis (MS). DESIGN: Home visits to 26 purposefully selected MS patients with different levels of disability, in both ordinary and sheltered living. The comprehensive evaluation package included: biographical data, Mini-Mental State Examination, Free Recall and Recognition of 12 Random Words Test, Symbol Digit Modalities Test, Beck Depression Index, Lindmark Motor Capacity Assessment, time to walk 10 metres, Nine-hole Peg Test, Barthel ADL Index, Katz Extended ADL Index, Frenchay Activities Index, Sickness Impact Profile and frequency of falls and injurious falls. RESULTS: This pilot study demonstrates that the proposed methods can be used to evaluate MS patients differing in levels of disability and forms of living. The data collection method, based on home visits, was well accepted by the patients, their spouses and salaried personal assistants and could be performed within 2-2 1/2 hours. CONCLUSIONS: The evaluation package used in this pilot study is suitable for use in population-based studies and it should provide comprehensive information on the impact and consequences of MS on patients, and should contribute to the identification of areas in which the provision of rehabilitation and health care services needs to be improved.


Elliott, P. J., T. M. Zollner, et al. (2003). "Proteasome inhibition: a new anti-inflammatory strategy." J Mol Med 81(4): 235-45.

            The ubiquitin-proteasome pathway has a central role in the selective degradation of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. Consequently proteasome inhibition is a potential treatment option for cancer and inflammatory conditions. Thus far, proof of principle has been obtained from studies in numerous animal models for a variety of human diseases including cancer, reperfusion injury, and inflammatory conditions such as rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis. Two proteasome inhibitors, each representing a unique chemical class, are currently under clinical evaluation. Velcade (PS-341) is currently being evaluated in multiple phase II clinical trials for several solid tumor indications and has just entered a phase III trial for multiple myeloma. PS-519, representing another class of inhibitors, focuses on the inflammatory events following ischemia and reperfusion injury. Since proteasome inhibitors exhibit anti-inflammatory and antiproliferative effects, diseases characterized by both of these processes simultaneously, as is the case in rheumatoid arthritis or psoriasis, might also represent clinical opportunities for such drugs.


Embrey, N. and C. Lowndes (2003). "Benchmarking best practice in relapse management of multiple sclerosis." Nurs Stand 17(22): 38-42.

            The Midlands multiple sclerosis (MS) nurse group developed a benchmark for relapse management in MS, using the framework outlined in the DoH document Essence of Care (DoH 2001). The authors discuss the benchmarking process and demonstrate how specialist nurses can collaboratively establish best practice and influence the quality of care. The potential benefits of applying the benchmarking process to relapse management are discussed. Good practice for management of patients with relapsing MS has been developed.


Enzinger, C., S. Ropele, et al. (2003). "Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele." Arch Neurol 60(1): 65-70.

            BACKGROUND: In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging. OBJECTIVE: To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4. DESIGN: A 2-year clinical and (1)H-MRS follow-up cohort study. SETTING: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. PATIENTS: We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months. MAIN OUTCOME MEASURE: Levels of N-acetylaspartate as measured by (1)H-MRS. RESULTS: Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19). CONCLUSIONS: The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.


Eriksen, E., R. Haugstad, et al. (2003). "Interferon-beta Treatment in Multiple Sclerosis; Patients' Experience in the First 100 Patients." Acta Neurol Scand 107(6): 429-30.


Eriksson, M., O. Andersen, et al. (2003). "Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis." Mult Scler 9(3): 260-74.

            This paper extends on previous data on prognosis in multiple sclerosis (MS), to encompass the entire course of the disease. The first episode suggestive of MS [the clinically isolated syndrome (CIS)] was included as a starting point, and the speed of secondary progression as an end point. Primary progressive MS was not included. Unique preconditions, with one neurological service covering the Goteborg district, allowed for establishing a strictly population-based, essentially untreated 15-year incidence cohort of 308 MS patients who were followed for 25 years. Survival analysis was performed as Kaplan-Meyer graphs, and independent predictors were ascertained by Cox regression analysis. A matrix of several predictors and end points was created. From CIS, a higher risk of developing clinically definite MS (CDMS), secondary progressive course and Disability Status Scale 7 (DSS7) was predicted by efferent tract lesions. However, less than 25% had reached DSS7 25 years after CIS with pure afferent lesions or other favorable predictors. During the first five years, higher relapse frequency, as well as incomplete remission of early bouts, predicted higher risks of secondary progressive course and DSS7 during follow-up to 25 years. However, these early predictors were unable to predict the rate of progression, which seems to contain an element of the disease process unassociated with its early events. Only late predictors, such as a shorter time from onset to secondary progression (1-10 years) and a higher number of functional systems involved at onset of progression predicted a faster progression rate. Predictors from this study could be used to refine historically controlled trials.


Evans, J. P., M. H. Brown, et al. (2003). "Revising the troublesome stoma: combined abdominal wall recontouring and revision of stomas." Dis Colon Rectum 46(1): 122-6.

            PURPOSE: Despite preoperative siting and maturation of stomas, some patients may have poor stoma function because of redundant pannus, scars, creases, and parastomal or incisional hernias. In these patients, a combined abdominoplasty and stoma revision may be helpful. The object of this manuscript is to report our preliminary results. METHODS: Eight patients (mean age, 48 years; female/male ratio, 7/1) undergoing this procedure are reported. Five patients had inflammatory bowel disease, two had malignancies, and one had multiple sclerosis with bladder and bowel involvement. Patients were contacted at two months to two years follow-up to assess functional outcome and satisfaction with the procedure. RESULTS: Indications for surgery were difficulty maintaining an appliance (n = 7), frequent stool leakage (n = 6), and skin irritation (n = 4). Multiple surgeries (n = 4), skin creases (n = 3), scarring (n = 2), large weight loss (n = 4), and hernias (n = 5) were contributing factors. At surgery five patients had hernias repaired (3 parastomal, 2 incisional), three had stomas resited, and three underwent resections for Crohn's disease. One patient developed a seroma postoperatively. At follow-up six patients were able to maintain an appliance for at least four days, whereas one changed the appliance every three days because of personal preference. None experience stool leakage. All reported a dramatic improvement in body image. CONCLUSION: Combined stoma revision and abdominoplasty can be performed safely and leads to improved functional results and outcome.


Fagius, J. (2003). "[Disease-modifying treatment of MS--progress with complications]." Lakartidningen 100(13): 1164, 1167-8.


Fassas, A. (2003). "Intense immunosuppression and autologous hematopoietic stem cell transplantation for multiple sclerosis." Haematologica 88(3): 244-5.


Fazakerley, J. K. and R. Walker (2003). "Virus demyelination." J Neurovirol 9(2): 148-64.

            A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.


Feindel, W. (2003). "Osler and the "medico-chirurgical neurologists": Horsley, Cushing, and Penfield." J Neurosurg 99(1): 188-99.

            Sir Victor Horsley's lecture "On the Technique of Operations on the Central Nervous System," delivered in Toronto in 1906, set the stage for an appraisal of Sir William Osler as a protagonist for the emerging specialty of neurosurgery. During his time at McGill University from 1871 to 1884, Osler performed more than 1000 autopsies. Hispathological reports covered the topics of cerebral aneurysm, apoplectic hemorrhage, vascular infarction, subdural hematoma, meningitis, multiple sclerosis, cerebral abscess, and brain tumor. He wrote about cerebral localization and anatomy and the relationships between the morphological characteristics of the brain and intelligence and criminality. During his continuing career at Philadelphia and Baltimore, Osler published widely on problems in clinical neurology, including monographs on cerebral palsies and chorea as well as chapters on disorders of the nervous system in the first five editions of his popular textbook, The Principles and Practice of Medicine. He became familiar with many of the outstanding figures in medical neurology of his time. Regarding neurosurgery, Osler commended the pioneer operation for a brain tumor in 1884 by Rickman Godlee and the surgery for epilepsy in 1886 by Horsley. In 1907, in discussing the state of brain surgery as reviewed by Horsley, William Macewen, and others, Osler made a plea for "medico-chirurgical neurologists, properly trained in the anatomical, physiological, clinical and surgical aspects of the subject." He played a significant role as a referring physician, mentor, and friend to his young colleague Harvey Cushing (later to become Osler's Boswell), who was breaking new ground in neurosurgery at Johns Hopkins Hospital. Beyond that Osler became an inspiring hero figure for his Oxford student Wilder Penfield, who a few decades later would establish a neurological institute at McGill University where medico-chirurgical neurology would flourish.


Feinstein, D. L. (2003). "Therapeutic potential of peroxisome proliferator-activated receptor agonists for neurological disease." Diabetes Technol Ther 5(1): 67-73.

            Activation of peroxisome proliferator-activated receptors (PPARs) mediates the insulin-sensitizing effects of thiazolidinediones used for treatment of type 2 diabetes, owing to changes in the transcription and expression of genes influencing carbohydrate and lipid metabolism. However, PPAR activation can have additional effects upon cellular physiology, including anti-proliferative and anti-inflammatory. These effects are observed in many cell types, including brain glial cells and blood lymphocytes, cells whose activation contributes to the initiation and progression of damage occurring in neurological diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS). In view of the need for development of additional therapeutic options, several recent studies have tested the possibility that PPAR agonists would be neuroprotective in these diseases. This paper will summarize data from cell culture experiments and from studies in animal models, demonstrating that PPARgamma agonists can exert neuroprotective effects, thereby providing the basis for the design of clinical trials to test the safety and efficacy of thiazolidinediones in neuroinflammatory conditions such as AD and MS.


Feki, I., F. Belahsen, et al. (2003). "[Subacute myelitis revealed by human immunodeficiency virus infection]." Rev Neurol (Paris) 159(5 Pt 1): 577-80.

            A 35 year-old heterosexual man had a six months history of cervical myelitis with progressive paraplegia, leg weakness and paresthesia of the four extremities. Spinal cord MRI showed a high T2 signal intramedullary lesion wide from the bulbo-medullary junction to D4. Post gadolinium T1 sequence revealed an enhancement in front of C3-C4 vertebrae. VIH serology was positive. Corticosteroid treatment achieved a marked improvement. In addition to vacuolar myelopathy, well-known at the advanced stages of the HIV infection (AIDS), myelitis and clinical pictures simulating multiple sclerosis were described during early stages of the infection. These inflammatory lesions of the central nervous system and sometimes of the peripheral nervous system seems to be related to the immune response dysfunction induced by the VIH.


Fernandez, O., T. Arbizu, et al. (2003). "Clinical benefits of interferon beta-1a in relapsing-remitting MS: a phase IV study." Acta Neurol Scand 107(1): 7-11.

            OBJECTIVE: To evaluate the efficacy and safety of IFNbeta-1a (Avonex, Biogen, Inc., Cambridge, MA, USA) in patients with relapsing-remitting multiple sclerosis (MS). METHODS: In this multicenter, open-label, prospective clinical trial, 96 patients with relapsing-remitting MS received IFNbeta-1a 30 mcg intramuscularly once weekly for 2 years. Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2. RESULTS: IFNbeta-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2. Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFNbeta-1a treatment was well tolerated. CONCLUSION: This study confirms and extends the beneficial clinical profile for IFNbeta-1a in relapsing MS.


Ferrari, R. (2003). "Acute cervical hyperextension-hyperflexion injury may precipitate and/or exacerbate symptomatic multiple sclerosis." Eur J Neurol 10(1): 109-10.


Feve, A. (2003). "[Spasticity and botulinum toxin in 2003. An update]." Neurochirurgie 49(2-3 Pt 2): 265-70.

            After the spastic foot in cerebral palsy, there are now wider indications for botulinum toxin injections in spasticity. Post stroke upper limb spasticity has been usefully treated by botulinum toxin in several studies, including double blind placebo-controlled studies. Two serotypes and one serotype B are marketed, with various properties. Botulinum toxin has been studied in multiple etiologies of spasticity. In multiple sclerosis, few studies revealed an efficacy in angulations and comfort. In spinal cord injuries, gait and sphincter disorders can be improved. In post stroke spasticity, lower limb angulations are improved, but gait remained difficult to evaluate. In upper limb spasticity, angulation, function and quality of life were improved in double blind, placebo controlled studies. Comparisons of costs and efficacy are made between botulinum toxin and the other antispastic methods.


Feys, P., W. F. Helsen, et al. (2003). "Intention tremor during manual aiming: a study of eye and hand movements." Mult Scler 9(1): 44-54.

            Accurate goal-directed movements toward a visual target require a precise coordination of both the oculomotor and limb motor systems. Intention tremor and eye movement deficits are frequently observed in multiple sclerosis (MS). The goal of this study was to examine the characteristics of intention tremor and simultaneously produced eye movements during rapid goal-directed movements. Eye and hand movements were synchronously measured in 16 MS patients with intention tremor and 16 control subjects. Manual performances of the patient group were characterized by a delayed onset, slower execution and aiming inaccuracies. In line with the clinically defined picture of intention tremor differences between patients and control subjects were most pronounced toward the end of the movement. Dependent variables were obviously greater in MS patients compared with control subjects, and correlated well with clinical outcome measures. The application of an inertial load to the limb did not show any effect on intention tremor. In addition to impaired limb coordination, evidence has been found that eye movements, too, were abnormal in patients compared with control subjects. Moreover, eye and hand movement deficits seemed to be closely related, suggesting a common underlying command structure. Inaccurate eye movements were likely to hamper an accurate motor performance of the hand.


Feys, P. G., A. Davies-Smith, et al. (2003). "Intention tremor rated according to different finger-to-nose test protocols: a survey." Arch Phys Med Rehabil 84(1): 79-82.

            OBJECTIVES: To investigate the dependence of intention tremor rating scores on different finger-to-nose test (FNT) protocols, varying in arm position and the time the finger has to be kept on the nose, and to examine their relevance to function. DESIGN: Observational survey. Video recordings were made while patients performed the FNTs and functional tasks such as pouring water. SETTING: Three European rehabilitation centers in Belgium, Finland, and England. PARTICIPANTS: Twenty-six multiple sclerosis patients with intention tremor (avg age, 44.1y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Six examiners rated the degree of intention tremor by using the Fahn Tremor Rating Scale. RESULTS: Interrater reliability for rating intention tremor during the FNTs was high (kappa=.65-.74). Both the required arm position and time constraints affected the magnitude of intention tremor rating scores (mean rank, 2.27-2.95) and their functional relevance (rho=.70-.84). Intention tremor was scored the highest when the arm was lifted to 90 degrees of abduction at the shoulder and the subject was required to stabilize the finger on the nose. However, its functional relevance was lower compared with a more "functionally" executed FNT. CONCLUSIONS: The rating of intention tremor during the FNT depends on test instructions. A standardized protocol is needed.


Filion, L. G., D. Matusevicius, et al. (2003). "Monocyte-derived IL12, CD86 (B7-2) and CD40L expression in relapsing and progressive multiple sclerosis." Clin Immunol 106(2): 127-38.

            Multiple sclerosis has been postulated to be an autoimmune disease in which Th1 immune responses predominate. This response is associated with an increased production of IFNgamma and IL12 produced by T cells and by cells of the monocyte (MO) lineage, respectively. An increased expression of costimulatory molecules by T cells and antigen-presenting cells is also observed. We hypothesized that in relapsing-remitting MS (RRMS) (with or without of IFNbeta treatment) and in secondary progressive patients (SPMS) IL12 and costimulatory molecules (CD80 [B7-1], CD86 [B7-2], CD28, CD40, CD40L) would be differentially produced or expressed by MO or T cells. We performed cross-sectional and longitudinal flow cytometric studies (at monthly intervals) on peripheral blood mononuclear cells (PBMC) or on MO from SPMS or untreated and IFNbeta-treated patients with RRMS. We determined that CD86 and CD40L expression was highest on MO derived from SPMS patients compared to those from RRMS or from healthy controls (HC). In vitro culture of PBMC with recombinant human IL10, a cytokine that may be increased in response to treatment with IFNbeta and that down-regulates CD86 expression, reduced the expression of CD86 on MO derived from RRMS patients to a much higher degree compared to cells derived from SPMS or HC. In vitro secreted IL12 levels from freshly isolated MO from SPMS patients were more than 10-fold higher than either the treated or the untreated RRMS or HC. RRMS patients treated with IFNbeta demonstrated slightly lower levels of MO IL12 secretion. Our data suggest that a key mechanism in the pathogenesis of MS is the increased expression of CD86 and CD40L and the increased production of IL12 during disease progression. Part of the mechanism of action of IFNbeta may be to reduce MO CD86 and CD40L expression and IL12 secretion; failure to do so might signify either a lack of response or a transition to a more progressive phase of illness.


Filion, L. G., G. Graziani-Bowering, et al. (2003). "Monocyte-derived cytokines in multiple sclerosis." Clin Exp Immunol 131(2): 324-34.

            MS is an inflammatory, presumably autoimmune, disease mediated by the activation of T cells, B cells and monocytes (MO). Inflammation is thought to occur early during the relapsing-remitting phase of MS (RRMS), whereas in the later phases of MS such as secondary progressive MS (SPMS), inflammation tends to diminish. Our objective was to compare the types and amounts of proinflammatory and regulatory cytokines produced by MO from relapsing-remitting patients with or without treatment with IFN-beta (RRMS+ therapy, RRMS- therapy), respectively, from secondary progressive patients (SPMS) and from healthy controls (HC). MO were isolated by a density-gradient technique and three different techniques (RNase protection assay, ELISA and intracellular cytokine staining) were used to assess cytokine levels. An increase in IL6, IL12 and TNF-alpha was observed by all three methods for RRMS- therapy and for SPMS patients compared to HC and RRMS+ therapy patients. We conclude that proinflammatory and regulatory monokines can be derived from MO of MS patients and that these levels are modulated by IFN-beta therapy. Although it is believed that inflammation tends to diminish in SPMS patients, our data show that inflammatory cytokines continue to be released at high levels, suggesting that IFN-beta or IL10 treatment may be beneficial for this group.


Filippi, M. and M. A. Rocca (2003). "Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging." Curr Opin Neurol 16(3): 275-82.

            PURPOSE OF REVIEW: This review is intended to provide an up-to-date summary of the main functional magnetic resonance imaging studies conducted in patients with multiple sclerosis, and to show how such studies are changing our views on the ability of the multiple sclerosis brain to limit the clinical consequences of irreversible structural tissue damage. RECENT FINDINGS: Brain cortical reorganization is a common phenomenon occurring in patients with multiple sclerosis, independent of disease duration and clinical phenotype, which can be elicited by macroscopic lesions, as well as by the presence of 'occult' multiple sclerosis-related damage of the brain and cervical cord. An increased recruitment of the cerebral networks involved in the performance of given tasks might represent a first step in cortical reorganization with the potential to maintain a normal level of function in the course of multiple sclerosis. The progressive failure of these mechanisms, because of accumulating tissue damage, might, on the one hand, result in the activation of previously silent 'second-order' compensatory areas, and, on the other, contribute to the accumulation of irreversible disability. SUMMARY: Functional magnetic resonance imaging has the potential to provide important information about cortical reorganization following multiple sclerosis-related tissue damage, which should improve our understanding of the factors associated with the accumulation of irreversible disability in this disease. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for multiple sclerosis.


Filippi, M., M. A. Rocca, et al. (2003). "The use of quantitative magnetic-resonance-based techniques to monitor the evolution of multiple sclerosis." Lancet Neurol 2(6): 337-46.

            Conventional MRI can improve accuracy in the diagnosis of multiple sclerosis (MS) and monitor the efficacy of experimental treatments. However, conventional MRI provides only gross estimates of the extent and nature of tissue damage associated with this disease. Other quantitative magnetic-resonance-based techniques have the potential to overcome the limitations of conventional MRI and, as a consequence, to improve our understanding of the natural history of MS. Magnetisation-transfer, diffusion-weighted, and functional MRI-as well as proton magnetic-resonance spectroscopy-are helping us to elucidate the mechanisms that underlie injury, repair, and functional adaptation in patients with MS. These techniques are substantially changing our understanding of how MS causes irreversible disability and should be used more extensively in clinical trials and in studies of disease progression.


Filippi, M. (2003). "MRI-clinical correlations in the primary progressive course of MS: new insights into the disease pathophysiology from the application of magnetization transfer, diffusion tensor, and functional MRI." J Neurol Sci 206(2): 157-64.

            Despite patients with primary progressive multiple sclerosis (PPMS) experience a progressive disease course from onset, the burden and activity of lesions on conventional magnetic resonance imaging (MRI) scans of the brain are lower than in all other main clinical phenotypes of MS. This review outlines the major contributions given by magnetization transfer MRI, diffusion tensor MRI and functional MRI to the understanding of the pathophysiology of PPMS and provides evidence that, at least, three factors might explain this clinical/MRI discrepancy: (a) the presence of a diffuse tissue damage at a microscopic level; (b) a prevalent involvement of the cervical cord, and (c) an impairment of the adaptive capacity of the cortex to limit the functional consequences of subcortical structural damage.


Filippi, M., M. Bozzali, et al. (2003). "Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis." Brain 126(Pt 2): 433-7.

            Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.


Filippi, M. (2003). "Magnetization transfer MRI in multiple sclerosis and other central nervous system disorders." Eur J Neurol 10(1): 3-10.

            The present review summarizes the major contributions given by magnetization transfer-magnetic resonance imaging to provide an accurate in vivo picture of the heterogeneity of central nervous system pathology and, ultimately, to improve our ability to monitor the evolution of various neurological conditions.


Filippini, G., L. Munari, et al. (2003). "Interferons in relapsing remitting multiple sclerosis: a systematic review." Lancet 361(9357): 545-52.

            BACKGROUND: Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs. METHODS: With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo. FINDINGS: The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life. INTERPRETATION: Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.


Filippovich, A. N. (2003). "[Diagnosis of multiple sclerosis in the initial stage of the disease]." Zh Nevrol Psikhiatr Im S S Korsakova 103(2): 49-50.


Finesilver, C. (2003). "Multiple sclerosis." Rn 66(4): 36-43; quiz 44.


Firouzi, R., A. Rolland, et al. (2003). "Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model." J Neurovirol 9(1): 79-93.

            A retroviral element (multiple sclerosis-associated retrovirus, MSRV) defining a family of genetically inherited endogenous retroviruses (human endogenous retrovirus type W, HERV-W) has been characterized in cell cultures from patients with multiple sclerosis. Recently, MSRV retroviral particles or the envelope recombinant protein were shown to display superantigen activity in vitro, but no animal model has yet been set up for studying the pathogenicity of this retrovirus. In the present study, the pathogenicity of different sources of MSRV retroviral particles has been evaluated in a hybrid animal model: severe combined immunodeficiency (SCID) mice grafted with human lymphocytes and injected intraperitoneally with MSRV virion or mock controls. MSRV-injected mice presented with acute neurological symptoms and died within 5 to 10 days post injection. Necropsy revealed disseminated and major brain hemorrhages, whereas control animals did not show abnormalities (P <.001). In ill animals, reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed circulating MSRV RNA in serum, whereas overexpression of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma was evidenced in spleen RNA. Neuropathological examination confirmed that hemorrhages occurred prior to death in multifocal areas of brain parenchyma and meninges. Further series addressed the question of immune-mediated pathogenicity, by inoculating virion to SCID mice grafted with total and T lymphocyte-depleted cells in parallel: dramatic and statistically significant reduction in the number of affected mice was observed in T-depleted series (P <.001). This in vivo study suggests that MSRV retroviral particles from MS cultures have potent immunopathogenic properties mediated by T cells compatible with the previously reported superantigen activity in vitro, which appear to be mediated by an overexpression of proinflammatory cytokines.


FitzGerald, U. F., T. Gilbey, et al. (2003). "Transcription factor expression and cellular redox in immature oligodendrocyte cell death: effect of Bcl-2." Mol Cell Neurosci 22(4): 516-29.

            Multiple sclerosis (MS) is characterized by the progressive damage or loss of oligodendrocytes. In an effort to better understand the causes of oligodendrocyte destruction in MS plaques, we treated immature oligodendrocytes with glucose oxidase, ceramide, or brefeldin A. These treatments model the different mechanisms by which oligodendrocytes are thought to die. We report that the AP-1 and Egr-1 transcription factors are induced within an hour of treatment. Of the AP-1 proteins studied, c-Jun was expressed at the highest level, followed by JunD, c-Fos, and Fra-2, although different treatments induced slightly different levels of expression. Bcl-2 overexpression protects against all treatments, to differing degrees. Although Bcl-2 did not have a dramatic effect on AP-1 or Egr-1 induction within the first 3 h, it caused a lowering of steady-state redox levels with a concomitant increase in cellular glutathione. We propose that the lowering of cellular redox and the upregulation of glutathione are responsible in part for the protective properties of Bcl-2.


Flodin, U., A. M. Landtblom, et al. (2003). "Multiple sclerosis in nurse anaesthetists." Occup Environ Med 60(1): 66-8.

            BACKGROUND: Volatile anaesthetics are chemically related to organic solvents used in industry. Exposure to industrial solvents may increase the incidence of multiple sclerosis (MS). AIM: To examine the risk among nurse anaesthetists of contracting MS. METHODS: Nurses with MS were identified by an appeal in the monthly magazine of the Swedish Nurse Union and a magazine of the Neurological Patients Association in Sweden. Ninety nurses with MS responded and contacted our clinic. They were given a questionnaire, which was filled in by 85 subjects; 13 of these were nurse anaesthetists. The questionnaire requested information about work tasks, exposure, diagnosis, symptoms, and year. The number of active nurse anaesthetists was estimated based on information from the National Board of Health and Welfare and The Nurse Union. Incidence data for women in the region of Gothenburg and Denmark were used as the reference to estimate the risk by calculation of the standardised incidence ratio (SIR). RESULTS: Eleven of the 13 nurse anaesthetists were exposed to anaesthetic gases before onset of MS. Mean duration of exposure before diagnosis was 14.4 years (range 4-27 years). Ten cases were diagnosed in the study period 1980-99, resulting in significantly increased SIRs of 2.9 and 2.8 with the Gothenburg and the Danish reference data, respectively. CONCLUSION: Although based on crude data and a somewhat approximate analysis, this study provides preliminary evidence for an excess risk of MS in nurse anaesthetists. The risk may be even greater than observed, as the case ascertainment might have been incomplete because of the crude method applied. Further studies in this respect are clearly required to more definitely assess the risk.


Flores, N., C. Duran, et al. (2003). "NFkappaB and AP-1 DNA binding activity in patients with multiple sclerosis." J Neuroimmunol 135(1-2): 141-7.

            Current evidence suggests that multiple sclerosis (MS) results from an autoimmune response mediated by T lymphocytes, which would be activated in the peripheral blood and migrate into the central nervous system. NFkappaB and AP-1 are two main transcription factors involved in T-cell activation. To investigate possible alterations in the activity of these factors in MS individuals, we have assayed NFkappaB and AP-1 DNA binding activity in peripheral blood mononuclear cells (PBMC). Binding activity was analyzed by gel mobility shift assay in MS patients compared with controls. No significant differences were found between the two groups, indicating no evidence of abnormalities associated with MS in NFkappaB or AP-1 binding activities in PBMC, both basally and after PMA+anti-CD3 antibody induction.


Folgar, S., E. M. Gatto, et al. (2003). "Parkinsonism as a manifestation of multiple sclerosis." Mov Disord 18(1): 108-10.

            We describe a 48-year-old patient, with a diagnosis of relapsing-remitting multiple sclerosis, who presented to our service with a parkinsonian syndrome that markedly improved after corticosteroid treatment. To the best of our knowledge, only 12 cases of parkinsonism have been reported from 1970 to the present, of which only 8 seemed secondary to MS, i.e., those presenting conclusive imaging evidence or unequivocal response to corticosteroids.


Forbes, A., A. While, et al. (2003). "Impact of clinical nurse specialists in multiple sclerosis--synthesis of the evidence." J Adv Nurs 42(5): 442-62.

            BACKGROUND: Multiple sclerosis is a chronic neurological condition demanding a broad range of interventions and support. Multiple sclerosis nurse specialists are emerging as a leading force in providing care to this group of patients. AIM: This review aimed to identify and synthesize the evidence on the role of clinical nurse specialists in meeting the care needs of people with multiple sclerosis. METHODS: A systematic review of the literature addressing the role of the multiple sclerosis nurse specialist was undertaken. The review examined both the appropriateness and effectiveness of the multiple sclerosis nurse specialist role. The content of each item identified in the review was analysed, examining the structure, process and outcomes variables associated with the role. Materials containing an explicit methodology were critically appraised using established schedules and graded as strong, moderate or weak. The data were then synthesized in tables, thematically and using a quasi-judicial approach called the 'System of Reasoning'. FINDINGS: Fifty-five items were examined and most (53%; n = 18) were descriptive in nature. There was insufficient evidence to demonstrate that the multiple sclerosis nurse role makes a difference to care. However, evidence was found to support current descriptions of the role - meaning? and there appeared to be a good fit between the role and the care needs of people with multiple sclerosis. CONCLUSION: A systematic overview of the attributes of the multiple sclerosis nurse role is provided which should help service providers, nurses and other professionals consider how multiple sclerosis nurse specialists roles can contribute to the care of people with this condition. While there is little current evidence of effectiveness for the multiple sclerosis nurse specialist role, there is evidence for its appropriateness, although more rigorous primary research is required to test this.


Foster, S. C., C. Daniels, et al. (2003). "Dysregulation of the hypothalamic-pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis." J Neuroimmunol 140(1-2): 78-87.

            The ability of sex hormones to regulate cytokine production is well established, but the ability of cytokines to regulate sex hormone production has only begun to be investigated. We measured sex hormones in mice with passive experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS) patients with sexual dysfunction. Abnormally low serum testosterone levels were found in male mice with EAE and in male MS patients, while serum estrogen levels in female mice with EAE were normal. An inverse relationship between cytokine and testosterone levels in male mice with EAE, coupled with an increase in serum luteinizing hormone (LH) levels, suggests that inflammatory cytokines suppress testosterone production by a direct effect on testicular Leydig cells. Gender differences in the sensitivity of the hypothalamic-pituitary-gonadal (HPG) axis to inflammation may be an important factor regulating the duration and severity of central nervous system (CNS) autoimmunity.


Foxman, B. (2003). "Epidemiology of urinary tract infections: incidence, morbidity, and economic costs." Dis Mon 49(2): 53-70.

            Urinary tract infections (UTIs) are considered to be the most common bacterial infection. According to the 1997 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, UTI accounted for nearly 7 million office visits and 1 million emergency department visits, resulting in 100,000 hospitalizations. Nevertheless, it is difficult to accurately assess the incidence of UTIs, because they are not reportable diseases in the United States. This situation is further complicated by the fact that accurate diagnosis depends on both the presence of symptoms and a positive urine culture, although in most outpatient settings this diagnosis is made without the benefit of culture.Women are significantly more likely to experience UTI than men. Nearly 1 in 3 women will have had at least 1 episode of UTI requiring antimicrobial therapy by the age of 24 years. Almost half of all women will experience 1 UTI during their lifetime. Specific subpopulations at increased risk of UTI include infants, pregnant women, the elderly, patients with spinal cord injuries and/or catheters, patients with diabetes or multiple sclerosis, patients with acquired immunodeficiency disease syndrome/human immunodeficiency virus, and patients with underlying urologic abnormalities. Catheter-associated UTI is the most common nosocomial infection, accounting for >1 million cases in hospitals and nursing homes. The risk of UTI increases with increasing duration of catheterization. In noninstitutionalized elderly populations, UTIs are the second most common form of infection, accounting for nearly 25% of all infections.There are important medical and financial implications associated with UTIs. In the nonobstructed, nonpregnant female adult, acute uncomplicated UTI is believed to be a benign illness with no long-term medical consequences. However, UTI elevates the risk of pyelonephritis, premature delivery, and fetal mortality among pregnant women, and is associated with impaired renal function and end-stage renal disease among pediatric patients. Financially, the estimated annual cost of community-acquired UTI is significant, at approximately $1.6 billion.


Franciotta, D., E. Zardini, et al. (2003). "Interferon gamma and interleukin 4 producing T cells in peripheral blood of multiple sclerosis patients undergoing immunomodulatory treatment." J Neurol Neurosurg Psychiatry 74(1): 123-6.

            Intracellular cytokine flow cytometry was used to analyse the percentages of interferon (IFN) gamma and interleukin (IL)-4 producing T cells in the peripheral blood of multiple sclerosis patients, before and after immunomodulatory treatment, and of healthy controls. After six months of treatment, different doses of IFN beta1a (Avonex or Rebif) decreased CD4(+) (Th1, Th2) and CD8(+) (Tc1) cells to a similar extent, without affecting the Th1/Th2 ratio. These T cell subsets were unmodified after nine months of glatiramer acetate (Copaxone) treatment, and after six day courses of high dose 6-methylprednisolone. The data suggest that IFN beta1a produces sustained downmodulation of IFN gamma and IL-4 producing T cells in vivo, which may contribute to its therapeutic efficacy; that glatiramer acetate possibly acts without altering non-specific cellular immunity; and that glucocorticoid induced lymphocytopenia does not affect the percentages of Th1, Th2, and Tc1 cells; at least in the periphery, none of the treatments caused a Th1 to Th2 shift that could account for their respective therapeutic effects.


Francis, G., H. Panitich, et al. (2003). "Re: Vartanian T. An examination of the results of the EVIDENCE, INCOMIN, and phase III studies of interferon beta products in the treatment of multiple sclerosis. Clin Ther. 2003;25:105-118." Clin Ther 25(6): 1888-90.


Franklin, R. J. (2003). "Remyelination by transplanted olfactory ensheathing cells." Anat Rec 271B(1): 71-6.

            The olfactory ensheathing cells (OECs) of the peripheral olfactory system associate with the axons of the first cranial nerve. These axons are not myelinated by OECs because of their very small diameter. However, when OECs are transplanted into areas where they encounter larger-diameter axons, such as in a model of primary demyelination, these cells assume a myelinating phenotype. Myelinating OECs very closely resemble myelinating Schwann cells by all criteria currently examined, including morphology, ultrastructure, biochemistry, and transcriptional regulation. Indeed, it is currently impossible to reliably distinguish myelinating OECs and myelinating Schwann cells that have been transplanted into experimental models of CNS demyelination. This article describes recent studies on the myelinating properties of transplanted OECs, focusing on their intrinsic myelinating potential and how this can be augmented by the presence of meningeal cells. The relative merits of OECs compared with Schwann cells when transplanted into astrocyte-containing lesions in the CNS are discussed together with their potential role in transplanted-mediated repair of demyelinating disease such as multiple sclerosis. Anat Rec (Part B: New Anat) 271BB:71-76, 2003. Copyright 2003 Wiley-Liss, Inc.


Fraser, C., O. Hadjimichael, et al. (2003). "Predictors of adherence to glatiramer acetate therapy in individuals with self-reported progressive forms of multiple sclerosis." J Neurosci Nurs 35(3): 163-70.

            The purpose of this study was to evaluate psychological, biophysical, and sociodemographic variables as predictors of adherence to glatiramer acetate (Copaxone) therapy in individuals with self-reported progressive forms of multiple sclerosis (MS). The literature lends support for self-efficacy, self-esteem, hope, and disability to be predictors of adherence. Therefore the hypotheses for this study were (a) higher self-efficacy will be a significant predictor of adherence, (b) higher self-esteem will be a significant predictor of adherence, (c) higher hope will be a significant predictor of adherence, and (d) a lower level of disability will be a significant predictor of adherence. The MS Self-Efficacy Scale (MSSE), Rosenberg Self-Esteem Scale, Herth Hope Index, and Performance Scales; a sociodemographic questionnaire; and an information sheet regarding consent to participate in the study were mailed to 1,200 potential participants. A total of 594 individuals responded, and for the evaluation of predictors of adherence in individuals with self-reported progressive forms of MS, 199 met the criteria. Logistic regression analysis revealed four significant predictors of adherence: the MSSE Control subscale, MSSE Function subscale, perceived support of the physician, and perceived support of the spouse. The higher the score on the MSSE Control subscale, the more likely the individual will adhere to glatiramer acetate therapy. The higher the score on the MSSE Function subscale, the more likely the individual will adhere to glatiramer acetate therapy. The MSSE Control and Function subscales show promise of being useful to predict adherence.


Fredrikson, S., Q. Cheng, et al. (2003). "Elevated suicide risk among patients with multiple sclerosis in Sweden." Neuroepidemiology 22(2): 146-52.

            Results from previous studies of suicide risk among patients with multiple sclerosis (MS) are inconsistent. This may be explained partly by differences in methodology and study populations. The purpose of our study was to investigate suicide risk among hospital patients with MS in Sweden. During the period 1969-1996, 12,834 cases were recorded in the Swedish Hospital Inpatient Register, with 77,377 hospital admissions, in which MS was a primary or secondary diagnosis at discharge. The mean follow-up time for the whole cohort was 9.9 (SD 7.3) years. When the data for these MS patients were linked to the Swedish Causes of Death Register for the same period, 5,052 (39.4%) were found to have died. Among the 5,052 deaths, suicide was an underlying cause of death in 90 cases (1.8%). The mean period between the initial admission date with an MS diagnosis at discharge and the date of death for the 90 MS suicide cases was 5.8 (SD 5.1) years. This was significantly shorter (p = 0.002) than the mean of 7.9 (SD 6.4) years for MS cases who died due to other causes. Suicide risk, calculated as the standardized mortality ratio (SMR), was significantly elevated (SMR = 2.3) among both male and female MS cases compared with the general population. Suicide risk was particularly high in the first year after initial admission with an MS diagnosis, and among younger male MS cases. The mean age at the time of suicide was 44.5 (SD 12.4) years, and 58% of the suicides were committed within 5 years after the first admission with an MS diagnosis. The crude suicide rate among MS patients during the study period was 71 per 100,000 person-years. The rate was significantly higher (p < 0.001) in males (114) than in females (47), with an odds ratio of 2.4 (95% CI: 1.6-3.8). These findings have implications for suicide preventive measures in neurological practice.


Freedman, M., J. King, et al. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1822-3; author reply 1823-4.


Freire-Garabal, M., M. J. Nunez, et al. (2003). "Administration of the 5-hydroxytryptamine(1A) receptor antagonist WAY100635 suppresses acute experimental allergic encephalomyelitis in Lewis rats." Neurosci Lett 342(1-2): 33-6.

            Experimental allergic encephalomyelitis (EAE) is a T-cell inflammatory disease of the central nervous system (CNS) widely considered as an animal model of multiple sclerosis. In Lewis rats, myelin basic protein-complete Freund's adjuvant (MBP-CFA)-induced EAE is an acute monophasic disease from which animals recover fully. In our experiments, daily treatment (since day 1 after MBP-CFA inoculation) with the 5-hydroxytryptamine((1A)) (5-HT(1A)) receptor agonist (R)-(+)-8-hydroxy-2-(Dipropylamino)-tetralin (R(+)-8-OH-DPAT) resulted in a dose-related enhancement of neurological and histological signs in EAE-induced rats. This effect of R(+)-8-OH-DPAT was reduced by the co-administration of the 5-HT(1A) receptor antagonist (N-[2-(4-[2-mehoxyphenil]-1-piperazinyl)-ethyl]-N-2-pyridinylcyclohexaneca rboxamide (WAY100635) at the peak of the acute disease. Moreover, treatment with WAY100635 since inoculation resulted in a delayed onset of the first clinical signs, milder disease and earlier regression of neurological signs along with a decrease in inflammation in the CNS.


French, L. E. and J. Tschopp (2003). "Protein-based therapeutic approaches targeting death receptors." Cell Death Differ 10(1): 117-23.

            Death receptors (DRs) are a growing family of transmembrane proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Eight human DRs (Fas, TNF-R1, TRAMP, TRAIL-R1, TRAIL-R2, DR-6, EDA-R and NGF-R) have been identified. The best studied to date is Fas (CD95). Expression and signaling by Fas and its ligand (FasL, CD95L) is a tightly regulated process essential for key physiological functions in a variety of organs, including the maintenance of immune homeostasis. Recently, strong evidence has shown that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of tissue destructive diseases such as graft-versus-host disease, toxic epidermal necrolysis, multiple sclerosis and stroke. With these new developments, strategies for modulating the function of Fas signaling have emerged and provided novel protein-based therapeutic possibilities that will be discussed herein. Selective triggering of DR-mediated apoptosis in cancer cells is an emerging approach that is being intensely investigated as a mode of cancer therapy. Local administration of Fas agonists, and more promisingly, systemic use of soluble recombinant forms of TRAIL have shown efficacy in preclinical models of the disease. Developments in this field that may have important clinical implications for the treatment of cancer are reviewed.Cell Death and Differentiation (2003) 10, 117-123. doi:10.1038/sj.cdd.4401185


Frohman, E. M. (2003). "Multiple sclerosis." Med Clin North Am 87(4): 867-97, viii-ix.

            Multiple sclerosis (MS) is the most common disabling neurologic disease of young people affecting between 350 and 450,000 individuals in the United States. Substantial advances have been made in the diagnostic assessment and treatment interventions over the last 10 years such that we are now able effectively to treat both the disease process and the associated symptomatic complaints associated with MS. Most patients consult with their primary care physician at the time when the first clinical manifestations of MS emerge. These physicians play a central role in the early identification and treatment of patients with MS. This article emphasizes the expanding diagnostic and therapeutic capabilities evolving for the MS patient and the crucial role played by primary care physicians in collaboration with neurologists in the coordination of the initial diagnostic and treatment plan.


Frohman, E. M., P. D. Kramer, et al. (2003). "Benign paroxysmal positioning vertigo in multiple sclerosis: diagnosis, pathophysiology and therapeutic techniques." Mult Scler 9(3): 250-5.

            OBJECTIVE: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appropriate diagnostic techniques and treatment interventions. BACKGROUND: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessary treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. All patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appropriate for the specific diagnosis. CONCLUSIONS: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.


Frohman, E. M., P. O'Suilleabhain, et al. (2003). "A new measure of dysconjugacy in INO: the first-pass amplitude." J Neurol Sci 210(1-2): 65-71.

            BACKGROUND: The ratios of abducting to adducting eye movements (versional dysconjugacy index, VDI) for saccadic velocity and acceleration have been useful measures by which to objectively characterize internuclear ophthalmoparesis (INO). Amplitude measures of dysconjugacy have been less useful, given that many patients maintain the ability to ultimately reach a centrifugal fixation target and that traditional amplitude measures of VDI have focused on this 'final amplitude' (FA) position. METHODS: We utilized infrared oculography to define a new amplitude measure of dysconjugacy in 42 multiple sclerosis (MS) patients with INO. The first-pass amplitude (FPA)-VDI is the ratio of abduction/adduction eye movement amplitudes computed at the time when the abducting eye initially achieves the centrifugal horizontal fixation target. RESULTS: FPA-VDI values were significantly more sensitive and specific than FA-VDI values in demonstrating dysconjugacy in INO, and there was a 14-fold increase in dysconjugacy as measured by FPA-VDI Z-scores when compared to FA-VDI Z-scores. CONCLUSION: Consideration of velocity (pulse) and amplitude (step) components of dysconjugacy in patients with INO can provide a greater understanding of the dynamic aspects of this syndrome. We propose to characterize the relationship between the pathophysiology of INO and neuroradiologic measures of tissue injury in MS.


Frohman, E. M. and T. C. Frohman (2003). "Horizontal monocular saccadic failure: an unusual clinically isolated syndrome progressing to multiple sclerosis." Mult Scler 9(1): 55-8.

            This paper describes an unusual clinically isolated syndrome of inflammatory demyelination that was characterized by a right VI nerve palsy and right internuclear ophthalmoparesis (INO), along with an unusual form of dissociated nystagmus. Magnetic resonance imaging (MRI) revealed an isolated lesion within the right dorsomediolateral pontine tegmentum. Four years later, the subject developed a partial sensory transverse myelitis, confirming clinically definite multiple sclerosis (MS). This paper extends the range of isolated syndromes associated with MS.


Frost, E. E., J. A. Nielsen, et al. (2003). "PDGF and FGF2 regulate oligodendrocyte progenitor responses to demyelination." J Neurobiol 54(3): 457-72.

            Acute demyelination of adult CNS, resulting from trauma or disease, is initially followed by remyelination. However, chronic lesions with subsequent functional impairment result from eventual failure of the remyelination process, as seen in multiple sclerosis. Studies using animal models of successful remyelination delineate a progression of events facilitating remyelination. A universal feature of this repair process is extensive proliferation of oligodendrocyte progenitor cells (OPs) in response to demyelination. To investigate signals that regulate OP proliferation in response to demyelination we used murine hepatitis virus-A59 (MHV-A59) infection of adult mice to induce focal demyelination throughout the spinal cord followed by spontaneous remyelination. We cultured glial cells directly from demyelinating and remyelinating spinal cords using conditions that maintain the dramatically enhanced OP proliferative response prior to CNS remyelination. We identify PDGF and FGF2 as significant mitogens regulating this proliferative response. Furthermore, we demonstrate endogenous PDGF and FGF2 activity in these glial cultures isolated from demyelinated CNS tissue. These findings correlate well with our previous demonstration of increased in vivo expression of PDGF and FGF2 ligand and corresponding receptors in MHV-A59 lesions. Together these studies support the potential of these pathways to function in vivo as critical factors in regulating remyelination.


Fujino, M., N. Funeshima, et al. (2003). "Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment." J Pharmacol Exp Ther 305(1): 70-7.

            Experimental autoimmune encephalomyelitis (EAE) is a T-cell-dependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis (MS). We investigated the efficacy and mechanism of immunosuppression against EAE by administering 2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride (FTY720) in Lewis rats immunized with myelin basic protein together with complete Freund's adjuvant. FTY720 treatment almost completely protected the rats against disease. The protection by FTY720 was associated with a dramatic reduction in the number of lymphocytes staining for T-cell receptors in the spinal cord as examined by immunohistochemistry. The mRNA expression of Th1 cytokines interleukin (IL)-2, IL-6, and interferon-gamma in the spinal cord was also reduced dramatically as assessed by reverse-transcription polymerase chain reaction. Furthermore, lymphocytes isolated from the spleen of FTY720-treated rats were transferred into naive recipient rats against EAE manifestation by reducing both disease incidence and clinical score. These results suggested that the protective anti-inflammatory effect of treatment with FTY720 was, to a large extent, due to the inhibition of encephalitogenic T-cell responses and/or their migration into the central nervous system and may be a potential candidate for use in treating patients with MS.


Furlan, R., S. Pluchino, et al. (2003). "Gene therapy-mediated modulation of immune processes in the central nervous system." Curr Pharm Des 9(24): 2002-8.

            Selective interference with immune processes in the central nervous system (CNS) is a very difficult task because of the limitations associated with the delivery of immuno modulatory molecules across the blood brain barrier. Systemic administration of immune-mediators, either by conventional routes or by intramuscularly or intravenous gene therapy, is hampered by severe side effects and alters immune-system functions also in peripheral organs. To overcome these problems, different gene therapy strategies have been developed to deliver immuno modulatory molecules directly within the central nervous system. The use of engineered CNS antigen-specific circulating cells as selective delivery vehicles, the direct injection of gene vectors into the brain parenchyma, or also the ependymal route, have been proposed as possible alternative gene therapy protocols to selectively interfere with immuno-pathological processes in the CNS. We will review the use of these CNS-targeted gene therapy protocols for the treatment of experimental autoimmune encephalomyelitis (EAE), the prototypical experimental immune-mediated disease of the CNS, and therefore discuss the relevance of these results for the therapy of multiple sclerosis (MS) the most common, immune-mediated, demyelinating disease of the CNS in humans.


Furlan, R., S. Pluchino, et al. (2003). "The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system." Curr Opin Neurol 16(3): 385-92.

            PURPOSE OF REVIEW: Gene therapy protocols aimed to deliver therapeutic molecules into the central nervous system may represent an alternative therapeutic strategy in patients affected by inflammatory demyelinating diseases of the central nervous system where systemic therapies have shown limited therapeutic efficacy possibly owing to the blood-brain barrier, a major obstacle for the entry of therapeutic molecules into the central nervous system. RECENT FINDINGS: Among inflammatory demyelinating diseases of the central nervous system, gene therapy approaches have been so far developed almost exclusively for multiple sclerosis. However, the chronic/relapsing nature of the disease, the restriction to the central nervous system of the pathological process as well as the necessity to inhibit the ongoing inflammatory process but also to foster endogenous remyelinating pathways, have posed several questions which still need to be properly addressed for the development of a successful gene therapy strategy in multiple sclerosis patients. SUMMARY: The gene therapy approaches for multiple sclerosis have been so far developed and tested only in rodents and monkeys with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The results of these studies clearly indicate that the delivery of therapeutic genes within the central nervous system is superior to the peripheral delivery. In particular, the intracerebral delivery of genes coding for anti-inflammatory and/or neurotrophic molecules, using gene vectors derived from non-replicative viruses, showed to inhibit not only the detrimental function of blood-borne mononuclear effector cells but also to foster proliferation and differentiation of surviving oligodendrocytes within demyelinated areas. Here, we summarize the most recent findings of this novel area of research.


Furlan, R., A. Bergami, et al. (2003). "Activation of invariant NKT cells by alphaGalCer administration protects mice from MOG35-55-induced EAE: critical roles for administration route and IFN-gamma." Eur J Immunol 33(7): 1830-8.

            Invariant NKT (inv. NKT) cells co-express an invariant alpha beta T cell receptor and the NK receptor NK1.1 and, upon CD1d-restricted recognition of the glycosphingolipid antigen alpha-galactosyl ceramide (alphaGalCer), secrete large amounts of regulatory cytokines. We investigated whether alphaGalCer-dependent activation of inv. NKT cells protects from experimental autoimmune encephalomyelitis (EAE), an immune-mediated disease of the central nervous system mimicking multiple sclerosis, induced in C57BL/6 mice by the myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptide aa 35-55. alphaGalCer was administered at the time of immunization s.c., mixed with complete Freund's adjuvant and MOG35-55 peptide, or administered i.p., diluted in PBS. EAE onset was delayed and disease severity was decreased only when alphaGalCer was s.c. administered. The protective effect of s.c. administration of alphaGalCer was associated with a markedly enhanced IFN-gamma production by liver-confined inv. NKT cells which, in turn, suppressed Th1-cytokine production and fostered secretion of IL-10 from MOG35-55-specific T cells. In vivo neutralization of IFN-gamma, but notIL-4, reversed the protective effect induced by s.c. administration of alphaGalCer, further confirming the critical regulatory role exerted by IFN-gamma-producing inv. NKT cells. Our results indicate that alphaGalCer, properly administered, may elicit an inv. NKT-cell-mediated suppressive effect on the effector function of encephalitogenic T cells; this effect is able to ameliorate autoimmunedemyelination.


Gadoth, N. (2003). "Multiple sclerosis in children." Brain Dev 25(4): 229-32.

            Multiple sclerosis (MS) is traditionally the domain of adult neurologists due to its characteristic presentation during early adult life. Although descriptions of infants with MS appeared in the beginning of the last century and the first autopsy was described even earlier, it was not until 1980 that childhood onset MS was recognized and subsequently well characterized. In spite of this, the awareness of pediatricians and pediatric neurologists to the occurrence of MS especially in infants and young children is still unsatisfactory. It is not infrequent that a meticulous, time consuming and costly search for metabolic and degenerative disorders other that MS is initiated before the diagnosis of MS is considered. This leads to a significant diagnostic and therapeutic delay in many young patients. Moreover, when the presentation is acute and characterized by confusion, seizures, CSF pleocytosis following a viral infection, a diagnosis of meningoencephalitis will be frequently reached. In this review, updated data on frequency, epidemiology, some special clinical and radiological features of childhood onset MS, outcome and treatment will be briefly discussed with the purpose of alerting physicians to the possibility of the occurrence of MS even in infants and young children.


Gagliardi, B. A. (2003). "The experience of sexuality for individuals living with multiple sclerosis." J Clin Nurs 12(4): 571-8.

            Little is known of the experience of sexuality among people living with multiple sclerosis (MS). This Roy Adaptation Model-based study focused on identifying the experiences of sexuality reported by individuals living with MS. A qualitative, naturalistic case study method was employed. Five women and three men diagnosed with MS were interviewed by telephone three times over a period of 1 year. The telephone interview guide consisted of a series of structured questions. Analysis of the telephone interview transcripts revealed three themes. The theme, "How I Feel About My Appearance", reflected elements of the Roy model physiological, self-concept, role function and interdependence modes. The theme, "I Have Feelings About My Sexuality", reflected the self-concept and interdependence modes, and the theme, "Sexuality For Me Has Both Negative and Positive Emotions", reflected the self-concept and interdependence modes. The small sample size precludes generalization of the results to all individuals living with MS. Nurses and other health care providers need to recognize that sexuality is an important issue for individuals with MS. Researchers should continue to examine experiences of sexuality in a larger sample of individuals with MS and also should begin to examine the effects of nursing interventions, such as support groups and individual counselling, on feelings about sexuality in individuals with MS.


Galie, E., A. Pietrangeli, et al. (2003). "Demyelinating disease in monoclonal gammopathy of undetermined significance." J Exp Clin Cancer Res 22(2): 337-9.

            We describe herein the case of a 57 year old man who, over the last five years, has presented ataxic and spastic gait on the right side, a reduction in fine motor movement of the fingers mainly on the right side, superficial right side brachiocrural hypoesthesia and a marked dysarthria associated with internuclear ophthalmoplegia. The neurological picture, after an initial progressive worsening which lasted some months, remained relatively stable over the years. Repeated magnetic resonance imaging (MRI) of the brain and spinal cord documented the presence of demyelinating plaques spread in the white matter of the periventricular region and the semioval centres, and a right side paramedian plaque at the C4-C5 level, none of which were in the active phase. Oligoclonal bands were revealed in the cerebrospinal fluid (CSF). Monoclonal IgM/lambda gammopathy with anti-myelin and anti-nucleo reactivity, found with serum immunofixation, were confirmed several times in successive annual controls, not associated to myeloproliferative pathology. The lack of progression in the clinical picture would seem to contradict the diagnosis of late Multiple Sclerosis. The presence of antibody activity against the myelin might support the hypothesis of a pathogenetic role of the immunoglobulins at the onset of the demyelinating disease in this patient. However, in the end, there is the possibility of casual association with a poorly functioning immune system connected to age.


Gallus, J. and V. Mathiowetz (2003). "Test-retest reliability of the Purdue Pegboard for persons with multiple sclerosis." Am J Occup Ther 57(1): 108-11.

            OBJECTIVE: The Purdue Pegboard test often is used in clinical settings to evaluate changes in clients' fine motor dexterity. The purpose of this study was to determine the test-retest reliability and practice effects of the Purdue Pegboard for persons with multiple sclerosis. In addition, this study compared the reliability of one-trial administration to three-trial administration of the four subtests. METHOD: Thirty-two volunteers from a midwestern community-based maintenance rehabilitation center for persons with multiple sclerosis participated in this study. The participants were administered the four subtests of the Purdue Pegboard, three trials in a row. A second administration was completed 1 week later. Data from 25 participants were analyzed using paired t tests, Pearson product-moment correlations, and intraclass correlation coefficients. RESULTS: The test-retest reliability coefficients ranged from .85 to .90 for one-trial administration and from .92 to .96 for the sum of three trials. No significant practice effects existed except for the sum of three trials of both hands. CONCLUSION: This study suggests that the one-trial administration of the Purdue Pegboard is a sufficiently reliable assessment to use with persons with multiple sclerosis. Findings further suggest that for a person with multiple sclerosis, any changes in Purdue Pegboard scores using one-trial administration may reflect actual change in that person's dexterity, as no practice effect was demonstrated in this study.


Gambetti, P., P. Parchi, et al. (2003). "Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia." Clin Lab Med 23(1): 43-64.

            Studies on hereditary CJD and FFI have contributed greatly to the understanding of all forms of prion disease. Most importantly, they have provided strong support for the prion hypothesis [2]. The linkage of pathogenic PRNP mutations to human prion disease strengthens the notion that a change in PrP conformation is a key event that triggers the development of the disease. Although hereditary CJD and FFI account for only 10% of all cases of human prion disease, they provide a unique opportunity for studying disease pathogenesis initiated by perturbation in the PrP structure. An understanding of the events that accompany a change in PrP conformation has far-reaching implications for sCJD (the most common form of the disease) and for sporadic fatal insomnia. A wealth of available evidence indicates that a common pathway in disease pathogenesis may be shared by both the sporadic and the hereditary forms of prion disease, except that the initiating events are stochastic in the former, rather than predetermined by the presence of a germ-line mutation. In addition, investigations of hereditary CJD and FFI have provided plausible mechanisms of phenotypic heterogeneity in prion disease, a phenomenon analogous to the "prion strain" diversity in animal prion disease. Although many other neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's chorea are fairly homogeneous in disease phenotype, prion disease includes many clinically and pathologically distinct disease entities. In hereditary prion disease, the disease phenotype is likely to be determined by the combined effect of pathogenic mutations, codon 129 polymorphism, and the type of PrPSc. The pathogenic mutations include point mutations that are located mostly in the central and C-terminal region of PrP, and deletion and insertion mutations that are located in the N-terminal region. It is conceivable that these distinct types of mutations may result in differential changes in conformation or stability of PrP. The codon 129 polymorphism plays a twofold role in modulating the disease outcome. On the mutant allele, it determines the basic features of the disease phenotype--as in the case of FFI and CJD178--that result respectively from the coupling of M or V at codon 129 with the D178N mutation. On the normal allele, it may modulate the severity of the phenotype. A PrPSc subtype is encoded by the PRNP haplotype, and subsequently is generated by a conformational conversion process that transforms the cellular isoform to the pathogenic protein. The site for the formation of a specific PrPSc conformer and its accumulation in different brain regions are likely to contribute to the clinical features and pathologic lesions. The phenotypic homogeneity in other neurologic diseases, including Alzheimer's disease, may be due, in part, to the lack of a powerful genetic modifier such as the codon 129 polymorphism in the PrP gene, and the lack of the ability of affected gene products such as PrP to assume multiple protein conformations. Clearly, the remaining issue in the understanding of pathogenesis of prion disease is a detailed and accurate knowledge of the in vivo processes and conditions for the formation of PrPSc that inevitably lead to the development and expression of the disease. This knowledge will enable the development of a rational and effective strategy for therapeutic intervention.


Gandelman-Marton, R., J. M. Rabey, et al. (2003). "Periodic lateralized epileptiform discharges in multiple sclerosis: a case report." J Clin Neurophysiol 20(2): 117-21.

            The occurrence of epileptiform abnormalities on the EEG in patients with multiple sclerosis (MS) is rare. The following case correlates the clinical, EEG, MRI, and single photon emission computed tomographic (SPECT) findings in a patient with a long history of MS and acute onset of focal motor seizures and confusion. Two routine EEGs, brain MRI, and brain SPECT were performed. The patient was a 44-year-old woman with a long history of clinically definite MS of the relapsing-remitting and secondary progressive form with three events of focal motor seizures followed by generalized tonic-clonic seizures and postictal confusion. The first EEG done during admission showed periodic lateralized epileptiform discharges in the right temporal region. Brain MRI done several weeks later showed scattered T2 hyperintensities in several locations, including the periventricular and subcortical white matter bilaterally. Brain SPECT using Tc99-Neurolite demonstrated decreased perfusion on the right parietal and temporal lobes. This case suggests that focal motor seizures and a transient state of altered consciousness can be the result of an exacerbation of MS. The neurophysiologic expression of these clinical manifestations may present as periodic lateralized epileptiform discharges on the EEG and decreased regional perfusion on brain SPECT.


Ganor, Y., M. Besser, et al. (2003). "Human T Cells Express a Functional Ionotropic Glutamate Receptor GluR3, and Glutamate by Itself Triggers Integrin-Mediated Adhesion to Laminin and Fibronectin and Chemotactic Migration." J Immunol 170(8): 4362-72.

            T cells may encounter glutamate, the major excitatory neurotransmitter in the nervous system, when patrolling the brain and in glutamate-rich peripheral organs. Moreover, glutamate levels increase in the CNS in many pathological conditions in which T cells exert either beneficial or detrimental effects. We discovered that normal human T cells, human T leukemia cells, and mouse anti-myelin basic protein T cells express high levels of glutamate ion channel receptor (ionotropic) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype 3 (GluR3). The evidence for GluR3 on T cells includes GluR3-specific RT-PCR, Western blot, immunocytochemical staining and flow cytometry. Sequencing showed that the T cell-expressed GluR3 is identical with the brain GluR3. Glutamate (10 nM), in the absence of any additional molecule, triggered T cell function: integrin-mediated T cell adhesion to laminin and fibronectin, a function normally performed by activated T cells only. The effect of glutamate was mimicked by AMPA receptor-agonists and blocked specifically by the selective receptor-antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo[f]quinoxalin-2,3-dione (NBQX), and by relevant anti-integrin mAbs. Glutamate also increased the CXCR4-mediated T cell chemotactic migration toward the key chemokine CXCL12/stromal cell-derived factor-1. GluR3 expression on normal, cancer and autoimmune-associated T cells and the ability of glutamate to directly activate T cell function could be of substantial scientific and clinical importance to normal neuroimmune dialogues and to CNS diseases and injury, and especially to: 1) T cell transmigration to the CNS and patrolling in the brain, 2) T cell-mediated multiple sclerosis, and 3) autoimmune epilepsy, as neurotoxic anti-GluR3 Abs are found and suspected to cause/potentiate seizures and neuropathology in several types of human epilepsies. Thus far, GluR3 was found only on neurons and glia cells; our results reveal a novel peripheral source of this antigenic receptor.


Garcia, D. M., S. E. Weigum, et al. (2003). "GFAP and nuclear lamins share an epitope recognized by monoclonal antibody J1-31." Brain Res 976(1): 9-21.

            Monoclonal antibody J1-31 was raised against plaque materials taken from brains of patients who had suffered from multiple sclerosis (MS). Preliminary characterization of the antigen revealed it to be a protein of M(w) 68-70 kDa with both a cytoplasmic and nuclear localization. Here we report the results of isolation and peptide sequencing of the antigen from human brains, and immunocytochemical analysis of the antigen in F98 glioma cells. Purification and peptide sequencing indicate that the antibody recognizes a form of glial fibrillary acidic protein, possibly a phosphorylated variant. However, confocal immunocytochemistry and western analysis of F98 glioma cells raise the possibility that it also recognizes a phosphorylated epitope found in nuclear lamins. Analysis of the expression of the J1-31 epitope in F98 cells with respect to time in culture, cell density, and DNA synthesis showed a developmental relationship: cells that were engaged in rapid growth and DNA synthesis exhibited strong J1-31 staining in nuclei, whereas quiescent cells did not. We conclude that mAB J1-31 remains a useful antibody for studying multiple sclerosis, and is likely to prove useful in studies of the dynamics of nuclear lamins, particularly in models for wound-healing.


Garcia Merino, J. A., M. R. Blasco Quitez, et al. (2003). "[Combined therapy in multiple sclerosis]." Rev Neurol 36(6): 545-9.

            INTRODUCTION. The availability of new drugs has been a significant advance in the therapy of multiple sclerosis over the last years. However, the control of the disease is far from being complete, and some patients respond poorly or not at all to the new drugs. DEVELOPMENT. The present paper reviews the approved therapies for multiple sclerosis and examines the advantages of the association of drugs, both with known and possible efficacy, as well as the theoretical basis for such associations and their possible clinical indications. Different designs for clinical trials in combination therapy are analyzed with a consideration of the current difficulties for the use of placebo in multiple sclerosis forms associated with relapses. CONCLUSIONS. The achievement of a higher efficacy than the present one is a major challenge in multiple sclerosis therapy. Combination therapy appears to be a reasonable option for that purpose.


Garcion, E., L. Sindji, et al. (2003). "Treatment of experimental autoimmune encephalomyelitis in rat by 1,25-dihydroxyvitamin D3 leads to early effects within the central nervous system." Acta Neuropathol (Berl) 105(5): 438-48.

            We report here that curative treatment of the multiple sclerosis paradigm, chronic relapsing experimental autoimmune encephalomyelitis (EAE) of the Lewis rat, by 1,25-dihydroxyvitamin D(3 )(1,25-D3) leads to a rapid clinical improvement accompanied by an inhibition of CD4, MHC class II and type II nitric oxide synthase (NOS II) expression in the posterior areas of the central nervous system (CNS). In contrast, the hormone has no effect on transforming growth factor-beta1 transcripts. Computer analysis of the NOS II promoter, expressed by microglia and astrocytes, reveals consensus sequence for vitamin D receptor binding, emphasizing the idea that 1,25-D3 may regulate some aspects of EAE by acting directly on CNS constituent cells. We also demonstrate that vitamin D deprivation leads to minimal effects on the kinetic profile of EAE accompanied by a moderate exacerbation of the clinical symptoms. Interestingly, curative treatment of vitamin D-deprived rats with a non-toxic-1,25-D3 analogue (MC1288) strongly inhibited EAE symptoms, thus promulgating the potential interest of such compounds in the management of multiple sclerosis.


Garg, R. K. (2003). "Acute disseminated encephalomyelitis." Postgrad Med J 79(927): 11-7.

            Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, and is characterised by multifocal white matter involvement. Diffuse neurological signs along with multifocal lesions in brain and spinal cord characterise the disease. Possibly, a T cell mediated autoimmune response to myelin basic protein, triggered by an infection or vaccination, underlies its pathogenesis. ADEM is a monophasic illness with favourable long term prognosis. The differentiation of ADEM from a first attack of multiple sclerosis has prognostic and therapeutic implications; this distinction is often difficult. Most patients with ADEM improve with methylprednisolone. If that fails immunoglobulins, plasmapheresis, or cytotoxic drugs can be given. Recent literature suggests that a significant proportion of patients with ADEM will later develop multiple sclerosis; however, follow up experience from developing countries does not support this view.


Garner, D. J. and J. J. Widrick (2003). "Cross-bridge mechanisms of muscle weakness in multiple sclerosis." Muscle Nerve 27(4): 456-64.

            Vastus lateralis muscle biopsies were obtained from six individuals with multiple sclerosis (MS) having an Expanded Disability Status Score of 4.75 +/- 0.28, and from six age- and gender-matched individuals without MS. Biopsies from the MS group showed fewer fibers (31 +/- 4 vs. 46 +/- 4%) containing the type IIa myosin heavy chain (MHC) isoform exclusively. However, the percentage of fibers coexpressing type IIa and IIx MHC increased in direct proportion with MS disability status. The average unloaded shortening velocity of skinned fibers containing type I or IIa MHC did not differ between subject groups. Peak Ca(2+)-activated force was 11-13% lower in fibers from the MS group due to atrophy (type I and IIa fibers) and reduced specific force (type I fibers). Increasing intracellular inorganic phosphate (0-30 mM) or hydrogen ion (pH 7.0-6.2) reduced Ca(2+)-activated force in a manner that was independent of MS status. Thus, fibers from the MS group showed a subtle shift in fast MHC isoform coexpression and a modest reduction in cross-bridge number, density, or average force, with no change in maximal cross-bridge cycling rate or susceptibility to intracellular metabolites. These changes explain part of the muscle weakness and fatigue experienced by individuals with MS.


Gatehouse, P. D. and G. M. Bydder (2003). "Magnetic resonance imaging of short T2 components in tissue." Clin Radiol 58(1): 1-19.

            The most widely used clinical magnetic resonance imaging techniques for the diagnosis of parenchymal disease employ heavily T(2)-weighted sequences to detect an increase or decrease in the signal from long T(2) components in tissue. Tissues also contain short T(2) components that are not detected or only poorly detected with conventional sequences. These components are the majority species in tendons, ligaments, menisci, periosteum, cortical bone and other related tissues, and the minority in many other tissues that have predominantly long T(2) components.The development and clinical application of techniques to detect short T(2) components are just beginning. Such techniques include magic angle imaging, as well as short echo time (TE), and ultrashort TE (Ute) pulse sequences. Magic angle imaging increases the T(2) of highly ordered, collagen-rich tissues such as tendons and ligaments so signal can be detected from them with conventional pulse sequences. Ute sequences detect short T(2) components before they have decayed, both in tissues with a majority of short T(2) components and those with a minority. In the latter case steps usually need to be taken to suppress the signal from the majority of long T(2) components. Fat suppression of different types may also be helpful. Once signal from short T(2) components has been detected, different pulse sequences can be used to determine increases or decreases in T(1) and T(2) and study contrast enhancement.Using these approaches, signals have been detected from normal tissues with a majority of short T(2) components such as tendons, ligaments, menisci, periosteum, cortical bone, dentine and enamel (the latter four tissues for the first time) as well as from the other tissues in which short T(2) components are a minority. Some diseases such as chronic fibrosis, gliosis, haemorrhage and calcification may increase the signal from short T(2) components while others such as loss of tissue, loss of order in tissue and an increase in water content may decrease them. Changes of these types have been demonstrated in tendonopathy, intervertebral disc disease, ligament injury, haemachromatosis, pituitary perivascular fibrosis, gliomas, multiple sclerosis and angiomas.Use of these techniques has reduced the limit of clinical detectability of short T(2) components by about two orders of magnitude from about 10 ms to about 100 micros. As a consequence it is now possible to study tissues that have a majority of short T(2) components with both "bright" and "dark" approaches, with the bright (high signal) approach offering options for developing tissue contrast of different types, as well as the potential for tissue characterization. In addition, tissues with a minority of short T(2) components may demonstrate changes in disease that are not apparent with conventional heavily T(2)-weighted sequences.


Gaudez, C., S. Regnier, et al. (2003). "[Livedo-like dermatitis (Nicolau's syndrome) after injection of Copolymer-1 (Glatiramer acetate)]." Rev Neurol (Paris) 159(5 Pt 1): 571-3.

            We report the first case of a 33-year-old woman with multiple sclerosis, who developed a livedo-like dermatitis after injection of Copolymere-1. This disease is characterized by the development of acute violent pain during or immediately after injection, and a livedo-like plaque followed by necrosis corresponding to an arterial ischemia by vasospasm or thrombosis. Early treatment with vasoactive and anticoagulation agents is required. Surgery may be necessary.


Gaupp, S., D. Pitt, et al. (2003). "Experimental autoimmune encephalomyelitis (EAE) in CCR2(-/-) mice: susceptibility in multiple strains." Am J Pathol 162(1): 139-50.

            Chemokines are low molecular weight cytokines which act as chemoattractants for infiltrating cells bearing appropriate receptors (CCR) to sites of inflammation. It has been proposed that CCR2 on monocytes is responsible for their recruitment into the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, and two previous reports have described resistance of CCR2(-/-) mice to EAE. The present study examined three different mouse strains with CCR2 deletions for susceptibility to EAE. Animals were studied up to 4 months post-sensitization and were examined by neuropathology, RNase protection assay, in situ hybridization, and in vitro assays. All three strains were found to be susceptible to EAE: C57BL/6 x J129 and Balb c strains, 100%; and C57BL/6, 67%. Unusual in CNS lesions of CCR2(-/-) mice was an overabundance of neutrophils versus monocytes in wild-type animals. An attempt of the immune system to develop compensatory mechanisms for the lack of CCR2 was evidenced by a corresponding increase in mRNA for other chemokines and CCR. Inasmuch as neutrophils replaced monocytes and led to demyelination, our findings support the concept that promiscuity of chemokines and CCR was able to surmount the deletion of CCR2, still resulting in full expression of this autoimmune disease.


Gbadamosi, J., C. Buhmann, et al. (2003). "Effects of mitoxantrone on multiple sclerosis patients' lymphocyte subpopulations and production of immunoglobulin, TNF-alpha and IL-10." Eur Neurol 49(3): 137-41.

            We designed this longitudinal study to clarify the short- and long-term effects of mitoxantrone on the immune system in a subgroup of multiple sclerosis patients treated at our centre. After 14 days we found a highly significant sustained reduction of leucocytes, primarily affecting neutrophils and most lymphocyte subsets except for naive and activated T lymphocytes. The CD4/CD8 ratio and serum immmunoglobulin levels were not affected. Furthermore, whole blood-stimulated mononuclear cell IL-10 production showed a significant lower level 2 weeks treatment, whereas basal IL-10 as well as stimulated and basal TNF-alpha secretion showed no significant changes. Longitudinal data disclosed a persistent decrease of B lymphocytes, while secretion of immunoglobulins, IL-10, and TNF-alpha was not altered in the follow-up. In conclusion, we confirmed a selective short-term effect of mitoxantrone therapy on most lymphocyte subpopulations, but not on immunoglobulines or the pro- and anti-inflammatory cytokines TNF-alpha and IL-10, which do not serve as possible response markers.


Gbadamosi, J., A. Munchau, et al. (2003). "Severe heart failure in a young multiple sclerosis patient." J Neurol 250(2): 241-2.


Geschwind, D. H. (2003). "DNA microarrays: translation of the genome from laboratory to clinic." Lancet Neurol 2(5): 275-82.

            As the complete sequences of human and other mammalian genomes become available we are faced with the challenge of understanding how variation in sequence and gene expression contributes to neurological and psychiatric disorders. DNA microarrays, or DNA chips, provide the means to measure simultaneously where and when thousands of genes are expressed. Microarrays are changing the way that researchers approach work at the bench and have already yielded new insights into brain tumours, multiple sclerosis, acute neurological insults such as stroke and seizures, and schizophrenia. The study of disease-related changes in gene expression is the first step in the long process in translation of genome research to the clinic. Eventually, the changes observed in microarray studies will need to be independently confirmed and we wil need to understand how gene expression changes translate into functional effects at the cellular level in the nervous system. Progress in these studies will translate into array-based disease classification schemes and help optimise therapy for individual patients based on gene expression patterns or their genetic background.


Geurts, J. J., G. Wolswijk, et al. (2003). "Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis." Brain 126(Pt 8): 1755-66.

            Recent evidence supports a role for glutamate receptors in the pathophysiology of multiple sclerosis. In the present study, we have focused specifically on the expression of metabotropic glutamate receptors (mGluRs) in multiple sclerosis brain tissue. The expression of group I (mGluR1alpha and mGluR5) and group II (mGluR2/3) mGluRs was studied using immunohistochemistry in tissue from 12 multiple sclerosis cases and seven non-neurological controls. The expression patterns of both group I and II mGluRs in multiple sclerosis tissue differed significantly from those in control tissue. Strong mGluR1alpha immunoreactivity was observed in axons of the subcortical white matter, particularly in the centre of actively demyelinating lesions and in the borders of chronic active lesions. mGluR1alpha axonal immunopositivity was also found in normal appearing multiple sclerosis white matter, but axons in control white matter were generally negative. mGluR1alpha axonal labelling was associated with the presence of non-phosphorylated neurofilaments and beta-amyloid precursor protein, which are sensitive markers for axonal injury and disturbed axonal transport. Changes in mGluR immunoreactivity were also observed in glia. A diffuse increase in the expression of mGluR5 and mGluR2/3 was detected in reactive astrocytes in multiple sclerosis lesions. However, only a subpopulation of reactive astroglial cells expressed mGluR1alpha. In addition, labelling with antibodies to mGluR2/3 and, to a lesser extent labelling with antibodies to mGluR1alpha, was detected in a population of cells of the microglial/macrophage lineage that displayed a macrophage-like morphology. Our data suggest that mGluRs, like ionotropic glutamate receptors, play a role in the complex processes that are associated with the progressive brain damage in multiple sclerosis, including both glial activation and pathological changes in axons.


Gherardi, R. K. (2003). "[Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome]." Rev Neurol (Paris) 159(2): 162-4.

            Macrophagic myofasciitis is a condition first reported in 1998, which cause remained obscure until 2001. Over 200 definite cases have been identified in France, and isolated cases have been recorded in other countries. The condition manifests by diffuse myalgias and chronic fatigue, forming a syndrome that meets both Center for Disease Control and Oxford criteria for the so-called chronic fatigue syndrome in about half of patients. One third of patients develop an autoimmune disease, such as multiple sclerosis. Even in the absence of overt autoimmune disease they commonly show subtle signs of chronic immune stimulation, and most of them are of the HLADRB1*01 group, a phenotype at risk to develop polymyalgia rheumatica and rheumatoid arthritis. Macrophagic myofasciitis is characterized by a stereotyped and immunologically active lesion at deltoid muscle biopsy. Electron microscopy, microanalytical studies, experimental procedures, and an epidemiological study recently demonstrated that the lesion is due to persistence for years at site of injection of an aluminum adjuvant used in vaccines against hepatitis B virus, hepatitis A virus, and tetanus toxoid. Aluminum hydroxide is known to potently stimulate the immune system and to shift immune responses towards a Th-2 profile. It is plausible that persistent systemic immune activation that fails to switch off represents the pathophysiologic basis of chronic fatigue syndrome associated with macrophagic myofasciitis, similarly to what happens in patients with post-infectious chronic fatigue and possibly idiopathic chronic fatigue syndrome. Therefore, the WHO recommended an epidemiological survey, currently conducted by the French agency AFSSAPS, aimed at substantiating the possible link between the focal macrophagic myofasciitis lesion (or previous immunization with aluminium-containing vaccines) and systemic symptoms. Interestingly, special emphasis has been put on Th-2 biased immune responses as a possible explanation of chronic fatigue and associated manifestations known as the Gulf war syndrome. Results concerning macrophagic myofasciitis may well open new avenues for etiologic investigation of this syndrome. Indeed, both type and structure of symptoms are strikingly similar in Gulf war veterans and patients with macrophagic myofasciitis. Multiple vaccinations performed over a short period of time in the Persian gulf area have been recognized as the main risk factor for Gulf War syndrome. Moreover, the war vaccine against anthrax, which is administered in a 6-shot regimen and seems to be crucially involved, is adjuvanted by aluminium hydroxide and, possibly, squalene, another Th-2 adjuvant. If safety concerns about long-term effects of aluminium hydroxide are confirmed it will become mandatory to propose novel and alternative vaccine adjuvants to rescue vaccine-based strategies and the enormous benefit for public health they provide worldwide.


Gibson, J. C. and A. O. Frank (2003). "Supporting individuals with disabling multiple sclerosis." J R Soc Med 96(5): 256-7.


Gielen, A., M. Khademi, et al. (2003). "Increased brain-derived neurotrophic factor expression in white blood cells of relapsing-remitting multiple sclerosis patients." Scand J Immunol 57(5): 493-7.

            Central nervous system (CNS)-autoreactive immune responses can exert neuroprotective effects, possibly mediated via the release of neurotrophic factors from infiltrating leucocytes. Herein, we analysed neurotrophin and cytokine mRNA levels using TaqMan polymerase chain reaction in unstimulated peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients in remission and controls. We demonstrate that mRNA for brain-derived neurotrophic factor (BDNF), but not neurotrophin-3 or nerve growth factor (NGF), is readily detectable in PBMC and that levels in MS are increased by approximately 60% compared with patients with other neurological diseases or healthy subjects. These results provide additional evidence that a potentially neuroprotective facet of autoimmune inflammation is present in MS.


Giovannoni, G. and C. T. Bever, Jr. (2003). "Patients with clinically isolated syndromes suggestive of MS: does MRI allow earlier diagnosis?" Neurology 60(1): 6-7.


Gironi, M., R. Furlan, et al. (2003). "Beta endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis." J Neurol Neurosurg Psychiatry 74(4): 495-7.

            The possible link between the opioid peptide beta endorphin and the heterogeneity of the clinical course of multiple sclerosis (MS) was investigated. Peripheral blood mononuclear cells (PBMC) concentrations of beta endorphin were measured in 50 patients in different phases of MS. Thirty nine patients also underwent post-contrast magnetic resonance imaging of the brain. Among MS forms, the highest beta endorphin concentrations were found in PBMC from patients with relapsing remitting MS and the lowest in patients with the progressive forms. Average beta endorphin concentrations were lower, although not significantly, in patients with than in those without magnetic resonance imaging enhanced lesions. These data suggest that beta endorphin may have a role in the downregulation of the inflammatory process.


Giuliani, F., C. G. Goodyer, et al. (2003). "Vulnerability of human neurons to T cell-mediated cytotoxicity." J Immunol 171(1): 368-79.

            Axonal and neuronal loss occurs in inflammatory diseases of the CNS such as multiple sclerosis. The cause of the loss remains unclear. We report that polyclonally activated T cells align along axons and soma of cultured human neurons leading to substantial neuronal death. This occurs in an allogeneic and syngeneic manner in the absence of added Ag, requires T cells to be activated, and is mediated through cell contact-dependent mechanisms involving FasL, LFA-1, and CD40 but not MHC class I. Activated CD4(+) and CD8(+) T cell subsets are equally neuronal cytotoxic. In contrast to neurons, other CNS cell types (oligodendrocytes and astrocytes) are not killed by T cells. These results demonstrate for the first time the high and selective vulnerability of human neurons to T cells, and suggest that when enough activated T cells accumulate in the CNS, neuronal cytotoxicity can result through Ag-independent non-MHC class I mechanisms.


Giunti, D., G. Borsellino, et al. (2003). "Phenotypic and functional analysis of T cells homing into the CSF of subjects with inflammatory diseases of the CNS." J Leukoc Biol 73(5): 584-90.

            The recruitment of lymphocytes across the blood brain barrier (BBB) is mediated by adhesion molecules and chemokines. The expression of activation markers and of chemokine receptors on T cells homing to the nervous system (NS) may help define their functional state. In the cerebrospinal fluid (CSF) of subjects with inflammatory neurological diseases (IND), including multiple sclerosis, we observed an increased number of T cells coexpressing CXCR3 and CCR5 as well as T cells with a CD45RO+ CCR7+ CD27+ memory phenotype. A subset of CCR7+ T cells coexpressed CXCR3 and CCR5. We also detected an increased number of interferon-gamma-producing T cells in the CSF compared with peripheral blood, mostly but not exclusively in the CD45RO+ CCR7- CD27- compartment. T helper 1 (Th1) clones, established from the CSF of individuals with IND and from a healthy subject, similarly migrated to CXCL10, CXCL12, and CCL5. CXCL10, CXCL12, and CCL19 were increased in the CSF of individuals with neuroinflammation. These findings suggest that CSF is enriched in Th1-polarized memory T cells capable of differentiating into effector cells upon antigen encounter. These cells are recruited into the CSF by inducible chemokines. Thus, CSF represents a transitional station for T cells trafficking to and from the NS.


Glabinski, A. R., B. Bielecki, et al. (2003). "Chemokine upregulation follows cytokine expression in chronic relapsing experimental autoimmune encephalomyelitis." Scand J Immunol 58(1): 81-8.

            Chronic relapsing experimental autoimmune encephalomyelitis (ChREAE) is an autoimmune disease of the central nervous system (CNS) induced by CNS myelin components. In the early active stage, both ChREAE and multiple sclerosis (MS) are characterized by the presence of perivascular inflammatory cuffs disseminated in the CNS. There is growing evidence that chemoattractant cytokines (chemokines) play an important role in this process. The main goal of the present study was to analyse the hypothesis that chemokine expression in the CNS during autoimmune inflammation is regulated by proinflammatory cytokines. To address this concept, we analysed temporal relations between chemokine and cytokine expression during ChREAE. Phasic upregulation of gene expression for chemokines T-cell activation gene 3 (TCA-3)/CCL1, monocyte chemoattractant protein-1 (MCP-1)/CCL2, macrophage inflammatory protein-1 alpha (MIP-1alpha)/CCL3, MIP-1beta/CCL4, regulated on activation normal T cell expressed and secreted (RANTES)/CCL5 and MIP-2/CXCL2-3 as well as cytokines tumour necrosis factor-alpha (TNF-alpha), -beta, LT-beta, interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) in the CNS was observed during attacks of ChREAE. Expression of cytokines TNF-beta and LT-beta preceded, and the expression of TGF-beta1 followed chemokine upregulation. Our results suggest that chemokine expression during CNS autoimmune inflammation may be regulated by some proinflammatory cytokines.


Glass, W. G. and T. E. Lane (2003). "Functional expression of chemokine receptor CCR5 on CD4(+) T cells during virus-induced central nervous system disease." J Virol 77(1): 191-8.

            Intracranial infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a demyelinating disease similar in pathology to the human disease multiple sclerosis (MS). CD4(+) T cells are important in amplifying demyelination by attracting macrophages into the central nervous system (CNS) following viral infection; however, the mechanisms governing the entry of these cells into the CNS are poorly understood. The role of chemokine receptor CCR5 in trafficking of virus-specific CD4(+) T cells into the CNS of MHV-infected mice was investigated. CD4(+) T cells from immunized CCR5(+/+) and CCR5(-/-) mice were expanded in the presence of the immunodominant epitope present in the MHV transmembrane (M) protein encompassing amino acids 133 to 147 (M133-147). Adoptive transfer of CCR5(+/+)-derived CD4(+) T cells to MHV-infected RAG1(-/-) mice resulted in CD4(+)-T-cell entry into the CNS and clearance of virus from the brain. These mice also displayed robust demyelination correlating with macrophage accumulation within the CNS. Conversely, CD4(+) T cells from CCR5(-/-) mice displayed an impaired ability to traffic into the CNS of MHV-infected RAG1(-/-) recipients, which correlated with increased viral titers, diminished macrophage accumulation, and limited demyelination. Analysis of chemokine receptor mRNA expression by M133-147-expanded CCR5(-/-)-derived CD4(+) T cells revealed reduced expression of CCR1, CCR2, and CXCR3, indicating that CCR5 signaling is important in increased expression of these receptors, which aid in trafficking of CD4(+) T cells into the CNS. Collectively these results demonstrate that CCR5 signaling is important to migration of CD4(+) T cells to the CNS following MHV infection.


Gniadek, P., O. Aktas, et al. (2003). "Systemic IFN-beta treatment induces apoptosis of peripheral immune cells in MS patients." J Neuroimmunol 137(1-2): 187-96.

            In multiple sclerosis (MS), an impaired apoptotic deletion of activated CNS-specific immune cells, leading to their pathogenic persistence, has been suggested to maintain chronic brain inflammation. We here investigated whether interferon-beta (IFN-beta) therapy induces apoptosis of peripheral immune cells. Serial blood samples from 127 relapsing-remitting MS patients were analyzed prior to the initiation of a weekly IFN-beta 1a therapy and 4, 26, and 52 weeks thereafter. Peripheral immune cells were investigated for apoptosis and for the expression of apoptosis-regulatory genes CD95, CD95 ligand, FLIP, Bcl-2, Bcl-X(L), Bag-1, and caspase 3 by quantitative real-time PCR. Biological efficacy of IFN-beta treatment was checked by quantification of Mx expression (ELISA and real-time PCR). We found a significant increase in the apoptosis rate of immune cells in response to IFN-beta treatment, compared to baseline levels. While Bcl-2 levels were permanently and Bag-1 levels transiently elevated upon therapy, other apoptosis-regulatory genes revealed no alterations. Upregulation of Mx expression confirmed the activity of IFN-beta in vivo. These findings indicate that immunomodulatory IFN-beta therapy involves the induction of apoptotic cell death with the observed RNA upregulation of Bcl-2 family members rather reflecting a possible compensatory mechanism. The increased apoptosis susceptibility of peripheral immune cells may contribute to the known reduction of brain inflammatory lesions during IFN-beta treatment.


Goeb, J. L., A. Cailleau, et al. (2003). "Acute delirium, delusion, and depression during IFN-beta-1a therapy for multiple sclerosis: a case report." Clin Neuropharmacol 26(1): 5-7.

            Adverse effects of interferon (IFN) treatment are common, and efforts to minimize these reactions are of considerable importance. IFN-beta-1a is an established therapy for patients with relapsing-remitting multiple sclerosis (MS). Its psychiatric side effects are debated and not yet fully established. The authors report here the case of a patient on IFN-beta-1a therapy for MS who developed acute delirium, delusion, and depression that ceased with treatment discontinuation. Although he had a history of recurrent major depressive disorder, his prior psychiatric illness had followed a course that was clinically independent of other signs of MS. This observation points out psychiatric vulnerability of patients taking IFN-beta-1a therapy for MS and suggests that IFN-beta-1a may induce or exacerbate preexisting psychotic symptoms.


Goertz, B., W. J. Fassbender, et al. (2003). "Vitamin D receptor genotypes are not associated with rheumatoid arthritis or biochemical parameters of bone turnover in German RA patients." Clin Exp Rheumatol 21(3): 333-9.

            OBJECTIVE: Vitamin D is known to exert immunomodulatory effects. An overrepresentation of the b allele of the vitamin D receptor (VDR) has been detected in autoimmune diseases as type-1-diabetes and multiple sclerosis. VDR polymorphisms have been shown to influence bone metabolism and bone density. The aim of the present study was to examine the distribution of VDR alleles in German rheumatoid arthritis (RA) patients and their relation to bone turnover parameters. METHODS: 62 German RA patients were included and compared to 40 controls. Three VDR alleles were examined (Bsm I, Taq I and Fok I). In addition, serum intact osteocalcin (OC), parathyroid hormone, bone specific alkaline phosphatase (B-ALP), the carboxyterminal extension peptide of type I procollagen, 25-OH-vitamin D and urinary deoxypyridinoline (DPD) excretion were measured. Furthermore, C-reactive protein, erythrocyte sedimentation rate and rheumatoid factor were measured. RESULTS: We found a slightly higher frequency of the bB and tT-genotype in RA patients compared to controls, which was not statistically significant. OC and B-ALP were found to be significantly higher in RA patients with positive correlations between bone formation and resorption parameters indicating higher bone turnover in RA patients with maintained coupling. CRP in RA patients correlated with DPD and inversely with PTH. VDR genotype showed no association with bone turnover, family history or the presence of rheumatoid factor. CONCLUSIONS: Our results suggest that VDR polymorphisms do not play a major role in RA predisposition in Germans.


Gold, S. M., K. H. Schulz, et al. (2003). "Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls." J Neuroimmunol 138(1-2): 99-105.

            Neurotrophins like brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are thought to play an important role in neuronal repair and plasticity. Recent experimental evidence suggests neuroprotective effects of these proteins in multiple sclerosis (MS). We investigated the response of serum NGF and BDNF concentrations to standardized acute exercise in MS patients and controls. Basal NGF levels were significantly elevated in MS. Thirty minutes of moderate exercise significantly induced BDNF production in MS patients and controls, but no differential effects were seen. We conclude that moderate exercise can be used to induce neutrophin production in humans. This may mediate beneficial effects of physical exercise in MS reported recently.


Gomes, A. C., G. Jonsson, et al. (2003). "Upregulation of the apoptosis regulators cFLIP, CD95 and CD95 ligand in peripheral blood mononuclear cells in relapsing-remitting multiple sclerosis." J Neuroimmunol 135(1-2): 126-34.

            Multiple sclerosis (MS) is a chronic disease involving an inflammatory reaction within the white matter of the CNS, mediated by T cells, B cells and macrophages. The pathogenesis of MS may involve impaired activation-induced cell death of activated myelin-specific mature T cells. We investigated the mRNA expression of the apoptosis mediators cellular FLICE-inhibitory protein (cFLIP), caspase-8, CD95 and CD95L in peripheral blood mononuclear cells (PB MNCs) from MS patients using real-time PCR. The overall increased expression of the four key players in the CD95 pathway in relapsing-remitting MS suggests their involvement in the inflammatory process in this disease.


Gomez, G. and M. V. Sitkovsky (2003). "Targeting G protein-coupled A2a adenosine receptors to engineer inflammation in vivo." Int J Biochem Cell Biol 35(4): 410-4.

            G protein-coupled adenosine receptors are the subject of intense study as immunomodulators of inflammation especially since the recent demonstration that the A2a receptor acts to down-regulate inflammation and inhibit tissue damage in vivo [Nature 414 (6866) (2001) 916]. The adverse effects of overactive inflammation are evident in diseases e.g. sepsis, rheumatoid arthritis, and multiple sclerosis underscoring the importance of inhibiting inflammation or selectively enhancing inflammatory processes. It has been shown recently that the A2a adenosine receptor is a critical component of an endogenous "immunosuppressive loop" in which extracellular adenosine that accumulates due to local hypoxia caused by inflammatory insult signals through cAMP-elevating A2a receptors in a delayed negative feedback manner. Understanding how tissues regulate inflammation will provide the information necessary to allow for the engineering, or selective targeting, of endogenous inflammatory pathways. Recognition of A2a receptors as "natural" or endogenous brakes of inflammation provides the intellectual scaffolding needed to pursue these goals.


Gomez-Lira, M., M. Liguori, et al. (2003). "CD45 and multiple sclerosis: the exon 4 C77G polymorphism (additional studies and meta-analysis) and new markers." J Neuroimmunol 140(1-2): 216-21.

            We re-evaluated the association with multiple sclerosis (MS) of the C77G splicing regulatory variation in the CD45 gene and screened for new mutations the three alternatively spliced exons (#4, 5 and 6). No association with C77G was detected in two groups of patients (total=448) and controls (total=559) from Northern and Southern Italy. When excluding the first published study indicating a positive association, a meta-analysis of the five further studies conducted to date (including the present one) led to a non-significant combined odds ratio (OR) of 1.11. None of the four newly identified nucleotide substitutions, namely C77T (Pro59Pro) in exon 4, G69C (Asp121His) in exon 5, T127A (Ile187Asn) and A138G (Thr191Ala) in exon 6, was significantly associated to MS.


Gonsette, R. E. (2003). "Mitoxantrone in progressive multiple sclerosis: when and how to treat?" J Neurol Sci 206(2): 203-8.

            Mitoxantrone (MX) has been approved by the Food and Drug Administration (FDA) for the treatment of patients with worsening relapsing-remitting (RR) or secondary progressive (SP) multiple sclerosis (MS). However, indications should be refined and mitoxantrone reserved as a rescue therapy to: (1) patients in the relapsing-remitting phase with frequent and disabling exacerbations likely leading to permanent severe disability and (2) to patients in the secondary progressive phase whose disability progression rate increases by one EDSS point or more per year and who do not respond to other current therapies. An induction phase with the monthly intravenous administration of 12 mg/m(2) followed by a maintenance phase with 12 mg/m(2) every 3 months for 2 years seems the most effective and safe treatment regimen, not exceeding the maximum cumulative dose of 140 mg/m(2). Given the potent myelosuppressive activity of mitoxantrone, dosage should be carefully adapted to the body surface and hematological changes. Long-term toxicities (amenorrhoea and therapy-related leukemia) seem acceptable but a valid evaluation will need a longer follow-up in more patients. Cardiotoxicity, the major long-term toxicity, is clearly dose-dependent and is a strict treatment duration limiting factor. To reduce the risk of cardiac events, the drug should be administered by slow infusion (over 30 min). Analogs of mitoxantrone with a much lower cardiotoxicity are currently investigated in animal experimental models.


Goodin, D. S. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1821; author reply 1823-4.


Goodman, A. D., D. J. Mock, et al. (2003). "Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions." J Infect Dis 187(9): 1365-76.

            Evidence for a candidate multiple sclerosis (MS) virus, human herpesvirus 6 (HHV-6), was sought in biopsy specimens of acute lesions that presented clinically as cerebral tumors obtained from 5 patients. Histopathology, magnetic resonance imaging, and clinical course confirmed the diagnosis of MS in each case. A sensitive in situ polymerase chain reaction (ISPCR) method was used to detect HHV-6 genome, in conjunction with immunocytochemical staining (ICC) to detect viral and cellular antigens. ISPCR revealed numerous oligodendrocytes, lymphocytes, and microglia containing HHV-6 genome within all lesions, whereas ICC showed only the HHV-6 glycoprotein 116 antigen in some reactive astrocytes and microglia. High frequencies of neuroglial and inflammatory cells containing HHV-6 genome were present in acute-phase lesion tissue from patients who were free of the effects of chronic MS and had not been received immunomodulatory therapy for MS. The prevalence of HHV-6 genome-containing cells, including oligodendrocytes, in each lesion suggests that HHV-6 plays a role in the demyelinative pathogenesis of MS; the significance of the discrepant expression of viral antigens remains uncertain.


Granger, C. V., K. Wende, et al. (2003). "Use of the FIM instrument in a trial of intramuscular interferon beta-1a for disease progression in relapsing-remitting multiple sclerosis." Am J Phys Med Rehabil 82(6): 427-36.

            OBJECTIVE: This study is a secondary analysis of results from the Multiple Sclerosis Collaborative Research Group multicenter trial. We investigated the effect of interferon beta-1a on disability in patients with relapsing-remitting multiple sclerosis (MS), using the FIM instrument to assess levels of decline in total, motor, and cognitive items. DESIGN: Of the 301 patients enrolled in the trial, 274 subjects with relapsing-remitting multiple sclerosis with baseline FIM and Kurtzke Expanded Disability Status Scale scores were studied in this secondary analysis. Mildly disabled patients were chosen, as indicated by a Kurtzke Expanded Disability Status Scale score of 1.0-3.5. Matched subjects were assigned to receive either interferon beta-1a or placebo. Kurtzke Expanded Disability Status Scale and FIM scores were measured serially every 6 mo. Failure was defined as a 4-point reduction in total FIM score sustained for 6 mo. Analysis was by Kaplan-Meier methodology. The Mann-Whitney test (log rank) compared mean change and Spearman's rank-correlation test determined correlation. RESULT: A significant difference in treatment groups was seen, with a FIM score decline of > or = 4 points, with placebo subjects demonstrating greater loss of function than subjects treated with interferon beta-1a. There was no statistically significant difference in total, cognitive, or motor activities, with a decline of < or = 3 points. CONCLUSION: Disability, as measured by the FIM instrument, was slowed by treatment with interferon beta-1a compared with placebo. The treatment effect determined using the FIM instrument, with its motor and cognitive components, indicates an additional level of response to therapy for mild to moderate multiple sclerosis.


Greenwood, J., C. E. Walters, et al. (2003). "Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis." Faseb J 17(8): 905-7.

            Neuroinflammatory diseases, such as multiple sclerosis (MS), result from aberrant leukocyte traffic into the central nervous system (CNS). To breach the specialized blood-brain barrier, activated leukocytes interact with CNS endothelial cells (EC) and activate a CD54-mediated signaling pathway controlling the Rho GTPase. To function correctly Rho requires posttranslational prenylation, and this can be inhibited by depleting the supply of isoprenoids through inhibition of the cholesterol synthesis pathway with 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) inhibitors (statins). Here we show that treatment of brain EC in vitro with lovastatin inhibits Rho-mediated transendothelial T cell migration. This effect can be reversed by supplementation with mevalonolactone, the downstream product of HMG-CoA reductase, or by ectopic expression of myristoylated Rho, which remains active in the absence of prenylation. In a relapsing-remitting mouse model of MS, lovastatin treatment inhibited leukocyte migration into the CNS and significantly attenuated the development of both acute and relapsing clinical disease. These studies demonstrate that the indirect pharmacological inhibition of Rho proteins in brain EC by statins can inhibit a key stage in the pathogenesis of neuroinflammation, namely leukocyte migration across the blood-brain barrier. These studies demonstrate a novel effect of statins in modulating the immune response in neuroinflammtory diseases and may provide additional rationale for their use in the treatment of MS.


Groom, A. J., T. Smith, et al. (2003). "Multiple sclerosis and glutamate." Ann N Y Acad Sci 993: 229-75; discussion 287-8.

            Experimental autoimmune encephalomyelitis reproduces in rodents the features of multiple sclerosis, an immune-mediated, disabling disorder of the human nervous system. No adequate therapy is available for multiple sclerosis, despite anti-inflammatory, immunosuppressive, and immunomodulatory measures. Increasingly glutamate is implicated in the pathogenesis of neurodegenerative diseases. Here we (1) review changes in the glutamatergic system in multiple sclerosis and (2) reveal the effects of glutamate AMPA antagonists in acute and chronic rodent models of multiple sclerosis. Administration of structurally diverse competitive and non-competitive AMPA antagonists reduces neurologic disability in rodents subjected to acute experimental autoimmune encephalomyelitis. In addition, AMPA antagonists are active in both the adoptive transfer and in chronic models of experimental autoimmune encephalomyelitis in rats and mice and affect both the acute and chronic relapsing phases. Moreover, short-term therapy with AMPA antagonists leads to sustained benefit well into the progressive phases. These results imply that therapeutic strategies for multiple sclerosis should be complemented by glutamate AMPA antagonists to reduce neurologic disability.


Gudiene, D. and B. Burba (2003). "[Mental disorders and their relation to brain lesion location: diagnostic problems]." Medicina (Kaunas) 39(2): 114-21.

            Knowledge of symptoms of appropriate brain areas lesion helps to differ psychiatric and neurological disorders. The objective of our work was to find out the situation in scientific research about mental disorder relation to brain lesion location and to except the location of lesions, which are most complicated in differential diagnosis. We discussed the relation of most important mental disorders to brain lesion location. The study of discrete organic cerebral lesions resulting in clearly definable psychiatric disorders may provide an understanding of the underlying pathophysiological basis of these disorders. Different nervous functions need the integrational work of various brain areas. The regions differ from each other by the importance of playing part in corresponding functions. The differential problems appear because various structural brain lesions provide symptoms, similar to mental disorder symptoms. The development of mental disorders and lesion location questions are very urgent. While analyzing the location of lesion, it is important to motivate the theories of development of schizophrenia, organic depression, emotional lability and other disorders.


Guerrero, A. L., V. Bueno, et al. (2003). "[Apolipoprotein e polymorphism AS a predictor of progression of multiple sclerosis]." Neurologia 18(3): 146-8.

            INTRODUCTION: During recent years, different studies have proposed that apolipoprotein E e4 can be a predictor of progression in multiple sclerosis. We aim to evaluate these findings in our country. PATIENTS AND METHODS: We studied 42 patients with relapsing remitting or secondary progressive multiple sclerosis, and a disease duration of at least 2 years. We correlated the presence or absence of e4 allele with markers of progression such as age of onset and diagnosis, disease duration, number of relapses, EDSS at 1, 2, 5 and 10 years, progression index and relapse rate. RESULTS: None of the parameters evaluated significantly correlate with e4 allele of the APOE. CONCLUSIONS: In spite of the limitation due to the small number of patients studied, we cannot confirm that APOE e4 allele is a predictor of progression of disability in multiple sclerosis.


Gulick, E. E. (2003). "Adaptation of the postpartum support questionnaire for mothers with multiple sclerosis." Res Nurs Health 26(1): 30-9.

            The purposes of this study were to determine the dimensionality of the Postpartum Support Questionnaire adapted for mothers with multiple sclerosis through factor-analytic techniques and to provide construct validity for the factored dimensions. One hundred and seventy-four mothers with multiple sclerosis comprised the sample. Using a priori criteria, a three-factor structure, resulting from principal components analysis with an orthogonal rotation consisting of 24 of the 28 items, was found to best represent the dimensionality of the instrument. The three support factors-emotional, instrumental, and informational-showed acceptable coefficient alpha reliabilities at the 1-, 3-, and 6-month administrations. Evidence of construct validity was shown in that, as hypothesized, (a) mothers with comparatively lower emotional distress reported higher levels of emotional and instrumental support, and (b) mothers with one child reported receiving more informational support during the 6-month postpartum period than did mothers with more than one child. The results support the use of the 24-item Postpartum Support Questionnaire in assessing the adequacy of these specific dimensions of social support needed by mothers with multiple sclerosis during the postpartum period.


Gunnarsson, M., P. Sundstrom, et al. (2003). "Native and transformed alpha2-macroglobulin in plasma from patients with multiple sclerosis." Acta Neurol Scand 108(1): 16-21.

            Multiple sclerosis (MS) is an inflammatory demyelinating disease with unknown etiology. Various proteinases have been observed in increased levels in the central nervous system of patients with MS, which may contribute to the release of immunogenic myelin components. alpha2-Macroglobulin (alpha2M) inhibits a broad spectrum of proteinases sterically, undergoing major conformational changes induced by the proteinases themselves. Moreover, alpha2M acts as a carrier of several cytokines in the systemic circulation. By use of radial immunodiffusion, we determined the total alpha2M levels in plasma from 28 MS patients and 15 control subjects [14 patients with other neurologic diseases (OND) and one healthy individual]. No significant differences in total alpha2M concentration were observed between the MS patients and the control subjects. A comparison of the degree of alpha2M transformation in MS patients with different disease courses and controls was performed, using monoclonal antibodies (mAbs) specific for binding to native and transformed alpha2M, respectively. The fractions of transformed alpha2M were significantly increased in patients with secondary or primary progressive disease course compared with the controls. No significant differences were obtained using a native-specific mAb. At least a major proportion of alpha2M from the MS patients was able to change conformation from its native to its transformed state, as demonstrated by a shift in mAb reactivity, following methylamine treatment of the plasma samples. In conclusion, the results indicate that plasma alpha2M may be inactivated at a higher degree in patients with chronic progressive MS compared with patients with OND. This may influence the levels of proteinases and cytokines in the systemic circulation and may furthermore have diagnostic implications.


Gveric, D., B. Herrera, et al. (2003). "Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors." Brain 126(Pt 7): 1590-8.

            Tissue plasminogen activator (tPA), a neuronal as well as the key fibrinolytic enzyme, is found concentrated on demyelinated axons in multiple sclerosis lesions together with fibrin(ogen) deposits. The decreased tPA activity in normal-appearing white and grey matter and lesions of multiple sclerosis is reflected in diminished fibrinolysis as measured by a clot lysis assay. Nonetheless, peptide products of fibrin, including D-dimer, accumulate on demyelinated axons-the result of fibrinogen entry through a compromised blood-brain barrier (BBB). Analysis of tissue samples on reducing and non-reducing polyacrylamide gels demonstrates complexes of tPA with plasminogen activator inhibitor-1 (PAI-1) but not with neuroserpin, a tPA-specific inhibitor concentrated in grey matter. As total tPA protein remains unchanged in acute lesions and the concentration of PAI-1 rises several fold, complex formation is a probable cause of the impaired fibrinolysis. Although the tPA-plasmin cascade promotes neurodegeneration in excitotoxin-induced neuronal death, in inflammatory conditions with BBB disruption it has been demonstrated to have a protective role in removing fibrin, which exacerbates axonal injury. The impaired fibrinolytic capacity resulting from increased PAI-1 synthesis and complex formation with tPA, which is detectable prior to lesion formation, therefore has the potential to contribute to axonal damage in multiple sclerosis.


Haase, C. G., M. Tinnefeld, et al. (2003). "Depression and cognitive impairment in disability-free early multiple sclerosis." Behav Neurol 14(1-2): 39-45.

            Cognitive and emotional capabilities were evaluated in 73 female patients with stable relapsing-remitting definite, and/or laboratory-supported multiple sclerosis (MS) and were compared with 32 matched healthy controls. Patients were categorized according to their score in the expanded disability status scale (EDSS) to either no (EDSS 0, n = 33) or few clinical signs (EDSS 1-2, n = 40) of MS without physical disability. Patients with EDSS > 0 were characterized by significantly (p < 0.001) higher scores on "von Zerssen's" depression scale, compared to controls. Patients with higher EDSS scores (1-2) showed significantly decreased performance with respect to the total score of Kimura's Recurring-Figures-Test (p < 0.001), in addition. Regarding visuo-constructive functioning, patients with EDSS=0 performed to a significantly lower level (p < 0.001), compared to controls. These results indicate that depression may present as an early sign in MS followed by cognitive impairment, in particular visuo-spatial short-term memory, before physical disability appears. Neuropsychological tests as mentioned here could serve as early diagnostic tools to detect subtle disease progression and to initiate and monitor disease modifying therapies.


Haegert, D. G. (2003). "The initiation of multiple sclerosis: a new infectious hypothesis." Med Hypotheses 60(2): 165-70.

            Both genetic and environmental factors cause multiple sclerosis (MS). Few genes have been identified, however, and environmental factors remain elusive. Some postulate an infectious cause, but no pathogens are reproducibly demonstrable in CNS lesions. I postulate that the CNS is not the infectious target in MS, but propose a two-hit infectious hypothesis focusing on nai;ve CD4 T-cells that initiate demyelination: (1) Various common viruses infect the thymus during childhood (first hit) and enhance nai;ve CD4 T-cell reactivity to CNS autoantigens; (2) Heterogeneous pathogens fully activate these T-cells during adulthood (second hit) to initiate myelin injury. The novel concept of thymic infection provides insight into the nature of some susceptibility genes, helps explain the high discordance rates in genetically susceptible individuals, and suggests it is futile to search for pathogens in MS lesions. Pathogen heterogeneity, i.e., the lack of a single infectious cause, implies there can be no simple therapies to prevent or treat MS.


Hakansson, N., P. Gustavsson, et al. (2003). "Neurodegenerative diseases in welders and other workers exposed to high levels of magnetic fields." Epidemiology 14(4): 420-6; discussion 427-8.

            BACKGROUND: Previous work has suggested an increase in risk of amyotrophic lateral sclerosis (ALS) and Alzheimer's disease among workers exposed to extremely low-frequency magnetic fields (ELF-MF). We evaluated the relation between ELF-MF from occupational exposures and mortality from neurodegenerative diseases. METHODS: The study was based on a cohort of Swedish engineering industry workers, comprising 537,692 men and 180,529 women. The cohort was matched against the 3 most recent censuses and The Causes of Death Registry. Levels of ELF-MF exposure were obtained by linking occupation according to the censuses to a job exposure matrix. We used 4 levels of exposure and considered both the primary and contributing causes of death, 1985-96. RESULTS: The risk of Alzheimer's disease as primary or contributing cause of death increased with increasing exposure to ELF-MF among both men and women, with a relative risk (RR) of 4.0 and a 95% confidence interval (95% CI) of 1.4-11.7 in the highest exposure group for both sexes combined. There was a RR of 2.2 (95% CI: 1.0-4.7) for ALS in the highest exposure group with the suggestion of an exposure-response relationship. No evidence of increased risk was seen for Parkinson's disease or multiple sclerosis. CONCLUSIONS: The findings support previous observations of an increased risk of Alzheimer's disease and ALS among employees occupationally exposed to ELF-MF. Further studies based on morbidity data are warranted.


Halfpenny, C. A. and N. J. Scolding (2003). "Immune-modifying agents do not impair the survival, migration or proliferation of oligodendrocyte progenitors (CG-4) in vitro." J Neuroimmunol 139(1-2): 9-16.

            Limited intrinsic myelin repair occurs in multiple sclerosis (MS), mediated by oligodendrocyte progenitors that divide and migrate into demyelinated lesions. Experimental remyelination suggests that this repair restores function and may protect axons from subsequent degeneration. Immunomodulatory drugs such as corticosteroids, interferon-beta and azathioprine are widely used in MS. However, their influence on disease progression is modest, for reasons that are not fully explained. The direct effects of these drugs on remyelination biology remain relatively unexplored. We have investigated the effect of these MS therapies on oligodendrocyte progenitors to identify whether drug treatment might directly compromise repair, either therapeutic or spontaneous. None of these drugs affected CG-4 survival, migration or proliferation.


Hallal, D. E., A. S. Farias, et al. (2003). "Costimulatory molecule expression on leukocytes from mice with experimental autoimmune encephalomyelitis treated with IFN-beta." J Interferon Cytokine Res 23(6): 293-8.

            Interferon-beta (IFN-beta) is of benefit in the treatment of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), but the mechanisms by which it exerts this beneficial effect remain uncertain. The present data demonstrate that IFN-beta therapy impairs the proliferative response to concanavalin A (ConA) and myelin basic protein (MBP), decreases expression of the CD80 molecule on leukocytes of treated mice, and may thereby impede the Th1 cell activation-promoting anergy in EAE. Moreover, IFN-beta therapy increases expression of the CTLA4 molecule, which induces a counterregulatory Th2 response. The reduction of CD80 expression with concomitant increase of CTLA4 expression alters the course of EAE and may be useful as a monitor in therapy with IFN-beta.


Halper, J., P. Kennedy, et al. (2003). "Rethinking cognitive function in multiple sclerosis: a nursing perspective." J Neurosci Nurs 35(2): 70-81.

            Cognitive impairment is a common problem in multiple sclerosis (MS); up to 65% of patients exhibit some neuropsychological dysfunction during the course of their disease. It is a major contributing factor to unemployment, accidents, impairment of daily functioning, and loss of social activity in those affected by MS. The areas of cognition typically impaired are memory, attention, information processing, executive functions, and visuospatial skills. Cognitive dysfunction is independent of disease duration and level of disability; cognitive decline may begin in the earliest stages of MS before patients become even mildly disabled. Structural brain imaging studies show a positive correlation between the extent of brain atrophy and cognitive dysfunction. Despite its prevalence in MS, cognitive dysfunction often goes undiagnosed or is misdiagnosed as depression, stress, stubbornness, lack of intelligence, or psychosis. Because nurses play such an important role in the care of patients with MS, they are in a position to identify patients with cognitive dysfunction, educate patients and their families on ways to cope with cognitive deficits, and counsel patients on available treatment options. Practical guidelines help nurses identify and care for cognitively impaired MS patients.


Hand, J. L. and R. S. Rogers, 3rd (2003). "Oral manifestations of genodermatoses." Dermatol Clin 21(1): 183-94.

            Many genodermatoses have distinct oral features that may help identify or confirm a genetic diagnosis. Oral features of the disorders described here are summarized in Table 1. These conditions provide clear examples of rapid progress in the field of genetic technology relevant to patient care. Less than a decade ago, the exact genetic locus of most of these disorders was unknown. Today, for many of these disorders, the exact location of the disease-causing mutation is known and clinical genetic testing is available for patients. This information has impact not only for genetic counseling and anticipatory medical care, but also provides insight into the mechanisms of disease. How this rapid progress will impact care, and ultimately treatment of patients, remains to be seen.


Hansen, F. (2003). "Rising above despair. Finding hope beyond MS." J Christ Nurs 20(1): 14-5.


Harney, S. M., J. L. Newton, et al. (2003). "Molecular genetics of rheumatoid arthritis." Curr Opin Pharmacol 3(3): 280-5.

            Following the successful determination of the molecular genetics of single-gene disorders, attention has not surprisingly turned to complex genetic disorders. However, preliminary experience suggests that unravelling the genetic component of common inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, might be a harder nut to crack.


Hartelius, L., D. Theodoros, et al. (2003). "Comparability of perceptual analysis of speech characteristics in Australian and Swedish speakers with multiple sclerosis." Folia Phoniatr Logop 55(4): 177-88.

            The aims of the present study were to compare the perceptual assessments of deviant speech signs (dysarthria) exhibited by Australian and Swedish speakers with multiple sclerosis (MS) and to explore whether judgements of dysarthria differed depending on whether the speakers and the judges spoke the same or different languages. Ten Australian and 10 Swedish individuals with MS (matched as closely as possible for age, gender, progression type and severity of dysarthria) were assessed by 2 Australian and 2 Swedish clinically experienced judges using a protocol including 33 speech parameters. Results show that the following perceptual dimensions were identified by both pairs of judges in both groups of speakers to a just noticeable or moderate degree: imprecise consonants, inappropriate pitch level, reduced general rate, and glottal fry. The reliability (Spearman rank-order correlation) of the consensus ratings from the Australian and the Swedish judges was high, with a mean rho of 85.7 for the Australian speakers and mean rho of 84.3 for the Swedish speakers. The most difficult perceptual parameters to assess (i.e. to agree on) included harshness, level of pitch and loudness, precision of consonants and general stress pattern. The study indicated that perceptual assessments of speech characteristics in individuals with MS are informative and can be achieved with high inter-judge reliability irrespective of the judge's knowledge of the speaker's language.


Hartelius, L. and M. Lillvik (2003). "Lip and tongue function differently affected in individuals with multiple sclerosis." Folia Phoniatr Logop 55(1): 1-9.

            Clinical dysarthria test scores on lip function and tongue function were compared for 77 dysarthric as well as non-dysarthric subjects with multiple sclerosis (MS) and 15 control subjects. Results show that tongue function was significantly more severely affected than lip function in individuals with MS. Furthermore, tongue function, but not lip function, was significantly more severely affected in the MS individuals with no dysarthria compared to the control group. Test items requiring increased rate of movement (oral and verbal diadochokinesis) were significantly more severely affected than the items requiring range and force of movement, but only in the dysarthric MS subgroup. Moderate correlations were found between tongue and lip function and neurological deficit scores, number of years in disease progression, and perceptually perceived consonant and vowel precision. Consequently, tongue dysfunction can be detected clinically and subclinically using a dysarthria test procedure, and as an early sign of articulatory dysfunction it should be an early target in therapeutic interventions.


Harting, I., J. Sellner, et al. (2003). "[Multiple sclerosis: imaging, diagnostic criteria and differential diagnosis]." Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 175(5): 613-22.

            Multiple sclerosis (MS) is the most common demyelinating inflammatory disease of the central nervous system (CNS), presenting with multifocal, disseminated inflammatory lesions referred to as plaques. Magnetic resonance imaging (MRI) typically depicts multiple, round to oval, circumscript lesions predominantly involving periventricular and subcortical white matter, brainstem and cerebellum. More recent investigations have demonstrated that the macroscopically visible plaques only present the tip of the iceberg: Already early in its course, MS causes neuroaxonal damage and diffusely involves the entire brain parenchyma including normal appearing white matter. These changes are reflected by strongly T 1 w hypointense lesions and atrophy of early onset, by reduction of the neuronal Marker N-acetylaspartate (NAA) on spectroscopy, by a decrease of the magnetization transfer ratio (MTR), by an increased in diffusibility and decreased anisotropy on diffusion-weighted imaging (DWI). MRI imaging is an important tool in the diagnosis of MS by revealing the characteristic spatial and temporal dissemination of the cerebral and spinal manifestations of this disease. Diagnostic criteria increase the diagnostic specificity and allow better differentiation from other diseases with multifocal white matter abnormalities.


Hartrich, L., B. Weinstock-Guttman, et al. (2003). "Dynamics of immune cell trafficking in interferon-beta treated multiple sclerosis patients." J Neuroimmunol 139(1-2): 84-92.

            PURPOSE: To investigate the effects of interferon-beta-1a (IFN-beta-1a) on the trafficking of cell populations in peripheral blood cells of multiple sclerosis (MS) patients. METHODS: In this open-label pharmacodynamic study, peripheral blood was obtained from 10 relapsing-remitting (RR) MS patients just prior to and at 1, 2, 4, 8, 24, 48, 120, and 168 h after intramuscular injection of 30-microg IFN-beta-1a. Timed samples were also obtained from five controls at 0, 8, 24, 48 and 168 h. The blood cells were analyzed using four-color flow cytometry with antibody conjugates directed against cell surface proteins specific for T cells, B cells, NK cells, and the activation marker, CD69. RESULTS: IFN-beta-1a treatment resulted in selective, time-dependent effects on many cell populations in peripheral blood. The trafficking of T-helper and T-suppressor/cytotoxic subsets of T cells were qualitatively different. The most prominent effects were on the trafficking of natural killer cells, the levels of which decreased to 23.5% of pretreatment values at 8 h after treatment. The levels of CD69-positive NK cells increased to a peak value of 606% of pretreatment levels at the 24-h time point. In untreated controls, these characteristic trafficking effects were not observed. There was inter-patient heterogeneity in the levels of activated NK cells at the 6-month time point that may potentially be relevant for individualizing IFN-beta therapy. CONCLUSIONS: IFN-beta treatment can induce specific, selective, and time-dependent trafficking of cells and its effects on different subsets of a given cell type are not qualitatively similar. The dynamics indicate that the activation of NK cells by IFN-beta is possibly dependent on the trafficking of NK cells. The activated NK cell levels after prolonged therapy may potentially provide a surrogate marker for IFN-beta exposure.


Hartrumpf, M., J. M. Albes, et al. (2003). "The hemodynamic performance of standard bileaflet valves is impaired by a tilted implantation position." Eur J Cardiothorac Surg 23(3): 283-91.

            OBJECTIVES: Severe sclerosis of the native aortic annulus can result in a tilted implantation position of mechanical prostheses. In this study, the effects of tilting and rotation on the hemodynamic performance of standard bileaflet valves were assessed in an extracorporeal mock circulatory system. METHODS: A pulsatile mock circulation driven by a Berlin Heart system was developed. Main physiological components of the human circulation were mimicked. SJM-AHPJ prostheses (21, 23, 25 mm) were mounted in an artificial aortic root containing physiologically oriented coronary ostia. All experiments were performed under constant conditions (stroke volume 60 ml, heart rate 70 bpm, systolic pressure 130 mmHg). Hydrostatic pressures were measured via fluid-filled catheters, transvalvular flow by ultrasonic probes. Data were digitally recorded at 50 Hz. Multiple pressure, volume, energy, and dimension parameters were derived off-line. Each valve was tested in a 0 degrees (untilted) versus 20 degrees (tilted) position at three axial rotation angles (0 degrees, 45 degrees, 90 degrees ). Tilting was performed independent of rotation by elevation of the prosthesis in the non-coronary sinus. RESULTS: In all valves and all rotation angles, tilting resulted in a size-dependent significant increase of mean pressure gradient (range, 28-35% [21 mm valve], 59-96% [23 mm valve], 124-220% [25 mm valve]), valvular resistance (39-51, 84-121, 177-332%), regurgitation volume (84-148, 32-131, 93-118%), and systolic energy loss (113-146, 30-132, 69-213%), as well as a decrease of total stroke volume (2-5, 0-11, 3-10%), effective stroke volume (6-11, 9-14, 14-22%), cardiac output (6-11, 8-14, 13-22%), and effective opening area (16-24, 32-37, 47-57%). The strongest impairment of hemodynamic performance was seen at 90 degrees rotation with reference to total and effective stroke volume, cardiac output, mean pressure gradient, and regurgitation fraction. CONCLUSIONS: Tilting of bileaflet valves resulted in a significant impairment of systolic and diastolic hemodynamics. Superiority of larger valves diminished in the tilted position. The strongest tilting effect was seen at 90 degrees rotation. Such a position should therefore be avoided or surgically corrected by rotating the valve.


Harzheim, M., M. Altenschmidt, et al. (2003). "IFN-beta1a (Rebif((R))) Modifies the Expression of Microfilament-Associated Cell-Cell Contacts in C6 Glioma Cells." J Interferon Cytokine Res 23(2): 83-9.

            Multiple sclerosis (MS) is a chronic inflammatory disease characterized by multifocal demyelination and axonal damage in the central nervous system (CNS). The disruption of the endothelial blood-brain barrier (BBB) with consecutive transmigration of inflammatory cells into the brain parenchyma is of critical importance in the pathogenesis of MS. The integrity of the BBB and the adjacent network of glial cells partially depends on the assembly of intercellular contacts between astrocytes. We demonstrate that recombinant interferon-gamma (rIFN-gamma), a proinflammatory cytokine critically involved in the disruption of the BBB, downregulates the expression of the cell adhesion molecules N-cadherin and vinculin in astrocytic C6 cells using Western blot and immunofluorescence microscopy. By contrast, IFN-beta1a, an established treatment for relapsing-remitting MS, increases the expression of N-cadherin and vinculin and partly inhibits the downregulation of these adhesion molecules by phytohemagglutinin (PHA)-stimulated IFN-gamma-secreting human T lymphocytes in coculture experiments. In summary, we demonstrate that IFN-beta1a modifies the assembly of N-cadherin- and vinculin-mediated intercellular contacts between astrocytic C6 cells in vitro. This effect may also contribute to the therapeutic action of IFN-beta1a in MS.


Haufschild, T., H. J. Kaiser, et al. (2003). "Influence of red wine on visual function and endothelin-1 plasma level in a patient with optic neuritis." Ann Neurol 53(6): 825-6.


Haupts, M., G. Elias, et al. (2003). "[Quality of life in patients with remitting-relapsing multiple sclerosis in Germany]." Nervenarzt 74(2): 144-50.

            The concept of health-related quality of life (QoL) includes physical, psychological,and social aspects.This pertains to consequences of chronic diseases and their therapies beyond biological or pharmacological relations. A considerable amount of literature concerning QoL has been published with regard to neurological and non-neurological entities.This study summarizes data from a study in 717 persons with remitting-relapsing multiple sclerosis (MS).Of them,576 could be reevaluated longitudinally after 1 year of treatment with interferon-beta 1a (44 microg subcutaneous Rebif once weekly). Compared to populations of healthy controls or other patients, considerable reductions in the eight subscales and both physical and emotional sum scales of the German version of the short form of the Rand Health Questionnaire (SF-36) questionnaire were assessed. These reductions were even more pronounced in persons with gait impairments. Most SF-36 scales only modestly correlated to physical disability.This indicates that QoL as reported by patients does not depend solely on the physical symptoms of MS.Most findings remained stable for the study population as a whole during 1 year of therapy, while statistically significant improvements were found in clinical responders as defined in this study (relapse-free, physically stable, stable or improved in physician's judgement). Side effects of therapy were not reflected in lower QoL scale values. Implications of findings for future concepts in MS therapy are discussed.


Hawke, C. G., D. M. Painter, et al. (2003). "Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus." Immunology 108(1): 70-8.

            Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antibodies directed against self antigens. Immune complex glomerulonephritis (GN) is one of the most serious complications of this disorder and can lead to potentially fatal renal failure. The aetiology of SLE is complex and multifactorial, characterized by interacting environmental and genetic factors. Here we examine the nature of the renal pathology in mycobacteria-treated non-obese diabetic (NOD) mice, in order to assess its suitability as a model for studying the aetiopathogenesis of, and possible treatment options for, lupus nephritis (LN) in humans. Both global and segmental proliferative lesions, characterized by increased mesangial matrix and cellularity, were demonstrated on light microscopy, and lesions varied in severity from very mild mesangiopathic GN through to obliteration of capillary lumina and glomerular sclerosis. Mixed isotype immune complexes (IC) consisting of immunoglobulin G (IgG), IgM, IgA and complement C3c were detected using direct immunofluorescence. They were deposited in multiple sites within the glomeruli, as confirmed by electron microscopy. The GN seen in mycobacteria-treated NOD mice therefore strongly resembles the pathology seen in human LN, including mesangiopathic, mesangiocapillary and membranous subclasses of LN. The development of spontaneous mixed isotype IC in the glomeruli of some senescent NOD mice suggests that mycobacterial exposure is accelerating, rather than inducing, the development of GN in this model.


Heesen, C., J. Kolbeck, et al. (2003). "Delivering the diagnosis of MS results of a survey among patients and neurologists." Acta Neurol Scand 107(5): 363-8.

            OBJECTIVES : The need for an early disclosure of the diagnosis of multiple sclerosis (MS) has become more pressing with the publication of two recent randomized trials which have indicated that very early treatment may favourably alter the disease course. We assessed the current status of diagnostic and therapeutic information on MS from the point of view of patients and neurologists. METHODS : A standardized questionnaire was sent out through the patients' self-help organization in Hamburg, Germany and to all neurologists. RESULTS : A total of 434 of 1300 patients and 80 of 250 neurologists replied. Neurologists gave 90% of the diagnoses but only 50% of patients reported them as the major aid helping to understand the disease. Fifty per cent of patients were not informed about any form of therapy at the time of diagnosis regardless of whether their MS diagnosis was disclosed within the last 5 years or earlier. In contrast to physicians, patients voted for information about a possible MS even if the diagnosis may not yet be clear. CONCLUSION : From the patients' perspective, information about the diagnosis of MS should be more straightforward, and more information about therapies should be provided.


Heesen, C., M. Bruegmann, et al. (2003). "Therapy-related acute myelogenous leukaemia (t-AML) in a patient with multiple sclerosis treated with mitoxantrone." Mult Scler 9(2): 213-4.


Heinrich, P. C., I. Behrmann, et al. (2003). "Principles of IL-6-type cytokine signalling and its regulation." Biochem J Pt.

            The IL-6-type cytokines IL-6, IL-11, LIF, OSM, CNTF, CT-1 and CLC are an important family of mediators involved in the regulation of the acute phase-response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in hematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signaling contributes to the onset and maintenance of several diseases such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e. g. multiple myeloma and prostate cancer). IL-6 type cytokines exert their action via the signal transducers gp130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT and MAPK cascades.This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signaling pathway mediated by tyrosine phosphatases, the SOCS feedback inhibitors and PIAS proteins. Also the cross-talk between the JAK/STAT pathway with other signaling cascades is dicussed.


Helms, G. (2003). "T2-based segmentation of periventricular paragraph sign volumes for quantification of proton magnetic paragraph sign resonance spectra of multiple sclerosis lesions." Magma 16(1): 10-6.

            Partial volume averaging of signal from multiple sclerosis lesions influences biexponential fitting of the water T2 relaxation as used for tissue/CSF segmentation of spectroscopic volumes. Periventricular volumes-of-interest comprising CSF, lesion and normal-appearing white matter in varying proportion were studied. The relaxation of the localized water signal was measured at 12 echo times (STEAM, geometric spacing from 30 ms to 2000 ms, least-squares fit). Magnetization transfer (MT) was applied to identify contributions of tissue signal to the CSF component. The T2 of the longlived component (T2(long)=433-1782 ms) and its prolongation after MT were inversely correlated to the MT ratio. Hence, short T2(long) is associated with overestimation of CSF partial volume, and thus metabolite concentrations. A T2-correction for the CSF partial volume was suggested and applied to the quantification of MR spectra of large MS lesions. The T2 of bulk CSF (2280+/-87 ms) and the influence of the TE sampling scheme were also studied.


Hemmer, B., B. Kieseier, et al. (2003). "New immunopathologic insights into multiple sclerosis." Curr Neurol Neurosci Rep 3(3): 246-55.

            Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. Although the immune system seems to play an important role in the pathogenesis of disease, target antigens are still uncertain and pathways leading to tissue destruction have not been fully elucidated. Recent studies have significantly contributed to a better understanding of the disease process and broadened our view on possible scenarios of disease initiation and progression. We review the role of the immune system for the manifestation and evolution of MS and discuss different pathogenetic concepts. We conclude with an outlook on future strategies to identify the cause of MS.


Hempling, S. (2003). "Multiple sclerosis. Interview by Harriet Gaze." Bmj 326(7402): 1323-4.


Hendriks, J. J., H. E. de Vries, et al. (2003). "Flavonoids inhibit myelin phagocytosis by macrophages; a structure-activity relationship study." Biochem Pharmacol 65(5): 877-85.

            Demyelination is a characteristic hallmark of the neuro-inflammatory disease multiple sclerosis. During demyelination, macrophages phagocytose myelin and secrete inflammatory mediators that worsen the disease. Here, we investigated whether flavonoids, naturally occurring immunomodulating compounds, are able to influence myelin phagocytosis by macrophages in vitro. The flavonoids luteolin, quercetin and fisetin most significantly decreased the amount of myelin phagocytosed by a macrophage cell line without affecting its viability. IC(50) values for these compounds ranged from 20 to 80 microM. The flavonoid structure appeared to be essential for observed effects as flavonoids containing hydroxyl groups at the B-3 and B-4 positions in combination with a C-2,3 double bond were most effective. The capacity of the various flavonoids to inhibit phagocytosis correlated well with their potency as antioxidant, which is in line with the requirement of reactive oxygen species for the phagocytosis of myelin by macrophages. Our results implicate that flavonoids may be able to limit the demyelination process during multiple sclerosis.


Henkel, G. (2003). "Successful management of multiple sclerosis and persistent vegetative state requires frequent reassessment." J Am Med Dir Assoc 4(4 Suppl): H23-4.


Hennemann, A. (2003). "[Selective adhesion molecule inhibitors. Natalizumab in multiple sclerosis and Crohn's disease]." Med Monatsschr Pharm 26(5): 146-8.


Hennig, H., N. Osterrieder, et al. (2003). "Detection of Marek's disease virus DNA in chicken but not in human plasma." J Clin Microbiol 41(6): 2428-32.

            Marek's disease virus (MDV) causes a common lymphomatous and neuropathic disease in domestic chickens and, less commonly, turkeys and quail. It is a member of the alpha-herpesviruses and until now was considered to be strongly cell associated. In 1991, MDV was suggested to be the causative infectious agent of multiple sclerosis (MS) in humans. In a previous study, we investigated the leukocytes of 107 well-defined MS patients for the presence of MDV DNA but were unable to confirm a role for MDV in the pathogenesis of MS. A recent report (S. Laurent, E. Esnault, G. Dambrine, A. Goudeau, D. Choudat, and D. Rasschaert, J. Gen. Virol. 82:233-240, 2001) described the detection of MDV DNA in 20% of 202 human serum samples, regardless of whether the individuals were exposed to poultry. The detection of MDV DNA in chicken serum samples was reported as well. The aim of the present study was to investigate whether we can confirm the presence of MDV DNA in chickens and humans if we use plasma as the source for nucleic acid isolation. Leukocytes and plasma specimens from 16 chickens experimentally infected with MDV serotype 1 and plasma specimens from 300 volunteer blood donors were tested for MDV DNA by two different TaqMan PCR assays. MDV DNA was repeatedly found in the leukocytes as well as in the plasma specimens of all 16 animals. All human samples analyzed, however, tested negative by both assays. Accordingly, Marek's disease in chickens can be diagnosed by detection of MDV DNA in plasma as well as in leukocytes. Once again, we found no evidence for the spread of MDV to humans.


Hensel, M., C. Fiehn, et al. (2003). "[Stem cell transplantation in primary systemic vasculitis]." Med Klin 98(1): 13-8.

            BACKGROUND: Many patients with various autoimmune diseases fail to respond to conventional immunosuppressive therapy and develop irreversible organ damage. In some cases the complications might be fatal. Furthermore, prolonged immunosuppression with cyclophosphamide or corticosteroids often leads to long-term side effects, cumulative organ damage, and development of secondary malignancies. THERAPY: Thus, short-term, high-dose immunosuppressive therapy with autologous stem cell transplantation might be an alternative for otherwise refractory patients. This concept has been used mainly in patients with scleroderma, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. PATIENTS: Patients with primary systemic vasculitis (PSV) seem to be suitable candidates for high-dose chemotherapy (HDCT). Although complete, long-term remissions are possible with standard immunosuppressive therapy, there is a subgroup of patients who cannot be cured by standard therapy. They need long-term immunosuppression and eventually die due to progression of the disease or cumulative therapy-related toxicity. In large series, the 5-year mortality rate was > 20%. The severity of vasculitis rather than the distinction between subgroups should determine whether HDCT might be a life-saving treatment. RESULTS AND CONCLUSION: Careful patient selection with the help of scoring systems and determination of the optimal time in the course of disease are now the major goals in the approach to HDCT. First reports as well as our own single-center experience in HDCT with a limited number of patients with severe PSV have shown that long-term remissions are possible even in patients refractory to conventional immunosuppression.


Herrera, B. M. and G. C. Ebers (2003). "Progress in deciphering the genetics of multiple sclerosis." Curr Opin Neurol 16(3): 253-8.

            PURPOSE OF REVIEW: Multiple sclerosis is the most common neurological disease affecting young adults. The aetiology is unknown, although many clues point to an autoimmune inflammatory nature. Family studies of multiple sclerosis have shown familial aggregation, and therefore suggest that the disease entails a genetic component that has been widely studied. Some of the studies from the extensive literature in the field of multiple sclerosis genetics published in the past year are discussed here. RECENT FINDINGS: A number of the recent publications considered in this review have reconfirmed the well-known association with the major histocompatibility complex as well as identifying that there are at least two important loci within this region. These findings add further complexity to the role of the major histocompatibility complex in multiple sclerosis. Links to other diseases have been few for multiple sclerosis, but the association with diabetes in the Sardinian population and, perhaps, a 'protective' effect of Down's syndrome can now be added. Numerous candidate genes for susceptibility and disease-modifying effect have also been studied in the literature, but with few replications. Associations with components of the endocrine and the neuro-endocrine system have also been considered in this review along with the potential value of microarray analysis. SUMMARY: Multiple sclerosis is a complex trait that is associated with the major histocompatibility complex, although the form of this association may not be as straightforward as previously thought. Recent findings raise the possibility of an association with haplotype blocks rather than with single alleles. The finding of allelic heterogeneity within the major histocompatibility complex, as with the Sardinians, adds an additional layer of complexity. Genome scans for this and other autoimmune diseases have often been notably disappointing despite many claims for linkages. The reasons for the difficulty may encompass locus heterogeneity, small effects and phenocopies, among others. A variety of attempts to study more restricted populations are in progress, including rare individual pedigrees with high recurrence risk.


Heystek, H. C., B. den Drijver, et al. (2003). "Type I IFNs differentially modulate IL-12p70 production by human dendritic cells depending on the maturation status of the cells and counteract IFN-gamma-mediated signaling." Clin Immunol 107(3): 170-7.

            Type I IFNs (IFNalpha/beta) are approved for the treatment of a variety of diseases, including the autoimmune disease multiple sclerosis (MS). The proinflammatory cytokines IL-12 and IFN-gamma have been proposed to contribute to the pathogenesis of MS. Since dendritic cells (DCs) are recognized as major producers of IL-12p70 and promote the development of IFN-gamma-producing Th1 cells, we investigated the direct effect of IFNalpha/beta on monocyte-derived DCs at different stages of development. We demonstrate that IFNalpha/beta enhance IL-12p70 production by immature DCs but inhibit IL-12p70 production by mature DCs. Importantly, IFNalpha/beta strongly counteracted the IL-12-enhancing effect of IFN-gamma on DCs irrespective of their maturation status. Exposure of DCs to IFNalpha/beta during maturation does not affect their maturation or cytokine profile upon CD40 ligation. The differential modulatory effect of IFNalpha/beta on the IL-12-producing capacity of DCs and their cross-regulatory effect on IFN-gamma may reduce inflammatory processes and therefore be therapeutically effective in MS.


Hisahara, S., H. Okano, et al. (2003). "Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination." Neurosci Res 46(4): 387-97.

            Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. MS is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory and cytokines that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, nitric oxide, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. Transgenic mice that express the anti-apoptotic protein specifically in OLGs and caspase-11-deficient mice are significantly resistant to EAE induction. Histopathological analyses show that the number of caspase-activated OLGs and dead OLGs are reduced in the CNS of these mice. The numbers of infiltrating immune cells and the amounts of cytokines are also markedly reduced in EAE lesions. Therefore, caspase-mediated OLG death leads to the exacerbation of demyelination and the deterioration of neurological manifestations by inducing local inflammatory events.


Hobart, J. C., A. Riazi, et al. (2003). "Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12)." Neurology 60(1): 31-6.

            OBJECTIVE: To develop a patient-based measure of walking ability in MS. METHODS: Twelve items describing the impact of MS on walking (12-Item MS Walking Scale [MSWS-12]) were generated from 30 patient interviews, expert opinion, and literature review. Preliminary psychometric evaluation (data quality, scaling assumptions, acceptability, reliability, validity) was undertaken in the data generated by 602 people from the MS Society membership database. Further psychometric evaluation (including comprehensive validity assessment, responsiveness, and relative efficiency) was conducted in two hospital-based samples: people with primary progressive MS (PPMS; n = 78) and people with relapses admitted for IV steroid treatment (n = 54). RESULTS: In all samples, missing data were low (< or =3.8%), item test-retest reproducibility was high (> or =0.78), scaling assumptions were satisfied, and reliability was high (> or =0.94). Correlations between the MSWS-12 and other scales were consistent with a priori hypotheses. The MSWS-12 (relative efficiency = 1.0) was more responsive than the Functional Assessment of Multiple Sclerosis mobility scale (0.72), the 36-Item Short Form Health Survey physical functioning scale (0.33), the Expanded Disability Status Scale (0.03), the 25-ft Timed Walk Test (0.44), and Guy's Neurologic Disability Scale lower limb disability item (0.10). CONCLUSIONS: The MSWS-12 satisfies standard criteria as a reliable and valid patient-based measure of the impact of MS on walking. In these samples, the MSWS-12 was more responsive than other walking-based scales.


Hoffmann, V., S. Schimrigk, et al. (2003). "Efficacy and safety of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients." J Neurol Sci 211(1-2): 81-4.

            Available immunomodulatory and conventional steroid treatment options for patients with progressive multiple sclerosis (MS) only provide limited symptomatic benefit. We performed an open trial on the short-term and long-term efficacy and safety of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 36 progressive MS patients. Six TCA administrations, performed every third day, reduced the EDSS score (initial: 5.6+/-0.93 [mean+/-S.D.]; end: 4.9+/-1.0; p<0.001) and increased the walking distance (WD) (initial: 294+/-314 m; end: 604+/-540 m; p<0.001). Twenty MS patients continued intrathecal TCA treatment with one TCA injection performed with a variable frequency ranging from 6 to 12 weeks. Both EDSS and walking distance remained stable in these patients until the end of the follow-up investigation period. No serious side effects occurred. We conclude that repeated intrathecal TCA injection provides substantial benefit for progressive MS patients with predominantly spinal symptoms.


Holick, M. F. (2003). "Vitamin D: A millenium perspective." J Cell Biochem 88(2): 296-307.

            Vitamin D is one of the oldest hormones that have been made in the earliest life forms for over 750 million years. Phytoplankton, zooplankton, and most plants and animals that are exposed to sunlight have the capacity to make vitamin D. Vitamin D is critically important for the development, growth, and maintenance of a healthy skeleton from birth until death. The major function of vitamin D is to maintain calcium homeostasis. It accomplishes this by increasing the efficiency of the intestine to absorb dietary calcium. When there is inadequate calcium in the diet to satisfy the body's calcium requirement, vitamin D communicates to the osteoblasts that signal osteoclast precursors to mature and dissolve the calcium stored in the bone. Vitamin D is metabolized in the liver and then in the kidney to 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. 1,25(OH)(2)D receptors (VDR) are present not only in the intestine and bone, but in a wide variety of other tissues, including the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin, gonads, etc. 1,25(OH)(2)D is one of the most potent substances to inhibit proliferation of both normal and hyperproliferative cells and induce them to mature. It is also recognized that a wide variety of tissues, including colon, prostate, breast, and skin have the enzymatic machinery to produce 1,25(OH)(2)D. 1,25(OH)(2)D and its analogs have been developed for treating the hyperproliferative disease psoriasis. Vitamin D deficiency is a major unrecognized health problem. Not only does it cause rickets in children, osteomalacia and osteoporosis in adults, but may have long lasting effects. Chronic vitamin D deficiency may have serious adverse consequences, including increased risk of hypertension, multiple sclerosis, cancers of the colon, prostate, breast, and ovary, and type 1 diabetes. There needs to be a better appreciation of the importance of vitamin D for overall health and well being. J. Cell. Biochem. 88: 296-307, 2003.


Hollsberg, P., H. J. Hansen, et al. (2003). "Altered CD8+ T cell responses to selected Epstein-Barr virus immunodominant epitopes in patients with multiple sclerosis." Clin Exp Immunol 132(1): 137-43.

            An increased frequency of antiviral CD8+ T cells is seen in chronic viral infections. During herpes virus infections the expanded CD8+ T cells are thought to control the reactivation of the latent infection. Because multiple sclerosis (MS), a presumed autoimmune disease of the central nervous system, has been associated with a late Epstein-Barr virus (EBV) infection, we wished to examine whether the CD8+ T cell response to EBV epitopes differed between MS patients and healthy controls. Here we report an increased frequency of CD8+ T cells responding to EBV epitopes from nuclear antigen 3 A (HLA-A2/CLG) and latent membrane protein 2 (HLA-B7/RPP) in MS patients. Noticeably, the altered CD8+ T cell response occurred to some but not all EBV epitopes and did not reach the high level seen during acute infection. The responses towards two immunodominant epitopes from human cytomegalovirus (HCMV) were similar in MS patients and normal controls. Together, our data demonstrate the presence of an increased frequency of CD8+ T cells reacting with two epitopes from EBV in patients with MS. The altered response to only two of the tested EBV epitopes would be consistent with the presence of cross-reactive epitopes.


Holmoy, T., B. Vandvik, et al. (2003). "T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid." Mult Scler 9(3): 228-34.

            Idiotopic sequences are created after V, D and J recombinations and by somatic mutations during affinity maturation of immunoglobulin (Ig) molecules, and may therefore be potential immunogenic epitopes. Idiotope-specific T cells are able to activate and sustain the B cells producing such idiotopes. It is therefore possible that idiotope-specific intrathecal T cells could help maintain the persisting intrathecal synthesis of oligoclonal IgG observed in patients with multiple sclerosis (MS). This study was undertaken to examine T-cell responses to cerebrospinal fluid (CSF) IgG. Peripheral blood mononuclear cells (PBMC) from 14 of 21 MS patients and four of 17 control patients with other neurological diseases proliferated upon stimulation with autologous CSF IgG, while five and three, respectively, responded to serum IgG. By comparison, responses to myelin basic protein were recorded in only four MS and three control patients. Data from a limited number of patients indicate that the CSF IgG responsive cells were CD4+ and human leucocyte antigen DR restricted, that PBMC also respond to CSF IgG from other MS patients and that the CSF may contain T cells responding to autologous CSF IgG. This suggests that CSF IgG, or substances bound to this IgG, may represent T-cell immunogens, which could contribute to the intrathecal immune response in MS.


Holtmannspotter, M., M. Inglese, et al. (2003). "A diffusion tensor MRI study of basal ganglia from patients with ADEM." J Neurol Sci 206(1): 27-30.

            Using diffusion tensor (DT) MRI and histogram analysis, we measured mean diffusivity ((-)D) of basal ganglia grey matter (GM) from eight patients with acute disseminated encephalomyelitis (ADEM), 10 patients with multiple sclerosis (MS), and 10 healthy controls. Patients with ADEM had higher average (-)D (p=0.02) and lower (-)D histogram peak height (p=0.008) of the basal ganglia GM than patients with MS. Microscopic tissue damage occurs in the basal ganglia of ADEM patients, but not in MS patients with a similar burden of MRI-visible brain lesions.


Hoogervorst, E. L., M. J. Eikelenboom, et al. (2003). "One year changes in disability in multiple sclerosis: neurological examination compared with patient self report." J Neurol Neurosurg Psychiatry 74(4): 439-42.

            OBJECTIVE: To characterise prospectively the relation between one year changes in neurologist rating of neurological exam abnormalities as measured by the Expanded Disability Status Scale (EDSS) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS) in patients with multiple sclerosis. METHODS: Two hundred and fifty patients with MS were recruited at an outpatient clinic. Disability at baseline and one year follow-up was assessed using the EDSS and GNDS. Correlations between change in EDSS, GNDS-sum score, Functional Systems and GNDS subcategories were studied as well as the significance of changes in EDSS associated with changes in perceived disability. RESULTS: The correlation between one year changes in EDSS versus GNDS was substantially lower (0.19) than cross-sectional correlations between EDSS and GNDS either at baseline (0.62) or at follow-up (0.77). Notably, changes in functional system scores that are based on neurological examination are poorly or not at all correlated with changes in disability as perceived by the patient. Analysing the impact of a significant worsening in EDSS-score, a commonly applied outcome criterion in clinical trials, we found that this was associated with significant worsening, insignificant change, and significant improvement in the patients' perceived disability in 45%, 39% and 15% of patients, respectively. CONCLUSION: Patients' perception of change in disability differs not only quantitatively but also qualitatively from that of an examining physician. This seems to be due both to the fact that there are true differences in change as perceived by the patient and that measured by the physician and to the fact that changes in many dimensions of disability that are relevant to the patient have no measurable impact on the EDSS.


Hoogervorst, E. L., P. de Jonge, et al. (2003). "The INTERMED: a screening instrument to identify multiple sclerosis patients in need of multidisciplinary treatment." J Neurol Neurosurg Psychiatry 74(1): 20-4.

            OBJECTIVE: To analyse the value of the INTERMED, a screening instrument to assess case complexity, compared with the Expanded Disability Status Scale (EDSS) and the Guy's Neurological Disability Scale (GNDS) to identify multiple sclerosis (MS) patients in need of multidisciplinary treatment. METHODS: One hundred MS patients underwent INTERMED, EDSS, and GNDS examinations. Patient care needs were assessed by a multidisciplinary team and a goal oriented treatment plan was defined. Correlations between INTERMED, individual INTERMED domains, EDSS, GNDS sum score, and total number of proposed disciplines involved in the treatment plan were studied. RESULTS: Mean (SD) age was 40.6 (10.1) years. Median scores were 14.0 for the INTERMED, 4.0 for the EDSS, and 13.5 for the GNDS sum score. Moderate correlations were found between the INTERMED sum score and EDSS (r=0.59) and GNDS sum score (r=0.60). The number of disciplines as proposed by the multidisciplinary team showed the highest statistically significant correlation with the INTERMED sum score (r=0.41) compared with EDSS (r=0.32) and GNDS sum score (r=0.34). No significant or only weak correlations were found between the psychological domain of the INTERMED and EDSS or GNDS. CONCLUSION: The findings in this study show that there is an additional value of the INTERMED compared with the EDSS and GNDS in identifying MS patients in need of multidisciplinary treatment. The INTERMED domains show the area of the patient's vulnerability and care needs: especially the INTERMED's psychological and social domains may guide the clinician to deal with specific problems that complicate healthcare delivery.


Hooper, J. and I. R. Whittle (2003). "Costs of thalamic deep brain stimulation for movement disorders in patients with multiple sclerosis." Br J Neurosurg 17(1): 40-5.

            Several studies have shown that thalamic deep brain stimulation (DBS) reduces tremor and improves hand performance in patients with multiple sclerosis (MS). The purpose of this paper is to describe the cost implications of DBS in MS patients and to highlight postoperative medical requirements that can be associated with this therapy. In a prospective study of thalamic DBS in MS patients the mean equipment costs were pounds 4769 (median pounds 7010, Medtronic, 1998 prices); mean neurosurgical inpatient costs per operated patient (n = 15) were pounds 4848 (range pounds 1982-8920, median pounds 5110); and mean in-patient postoperative rehabilitation cost pounds 4602 (range pounds 0-32,225, median pounds 1783). In addition there were transport and follow up costs. Mean neurosurgical inpatient stay following stereotactic DBS implantation was 15 days (median 12 days); and mean inpatient, postoperative rehabilitation stay 54 days (median 25 days). Although there were significant improvements in hand function and tremor reduction at 12 months postoperation, the level of patient performance in activities of daily living, their perception of their handicap and ipse facto the amount of home support required were unchanged from preoperative levels. This study has highlighted significant unforeseen medical requirements and costs that can occur in MS patients who have thalamic DBS surgery.


Horsfield, M. A., G. J. Barker, et al. (2003). "Guidelines for using quantitative magnetization transfer magnetic resonance imaging for monitoring treatment of multiple sclerosis." J Magn Reson Imaging 17(4): 389-97.

            Quantitative evaluation of brain magnetic resonance imaging (MRI) scans is now an accepted part of the trial of new putative treatments for multiple sclerosis (MS). However, conventional MRI is not pathologically specific, and it does not reveal the details of the pathological processes that underlie the progression of the disease. Magnetization transfer (MT) imaging is a relatively new quantitative technique that appears to offer some pathological specificity, and can be used to monitor the changes over time in both individual lesions and the central nervous system as a whole. This paper considers the case for incorporating MT imaging into new clinical trials, so that the utility of MT for monitoring the modification of MS progression by treatment can be assessed. Specific guidelines for implementing MT imaging as part of a large multicenter clinical trial are given, and practical considerations when planning such a trial are detailed. It is anticipated that MT imaging will be incorporated into many new trials in the near future. J. Magn. Reson. Imaging 2003;17:389-397.


Hosokawa, M., A. Klegeris, et al. (2003). "Expression of complement messenger RNAs and proteins by human oligodendroglial cells." Glia 42(4): 417-23.

            Neurons, astrocytes, microglia, and endothelial cells are capable of synthesizing most, if not all, of the complement proteins. Little is known, however, about the capacity of oligodendroglial cells to generate complement components. This study evaluated expression of complement mRNAs and their protein products by human oligodendrocytes. Cells were isolated and cultured from white matter of seven adult cases that had undergone surgical temporal lobe resection for epilepsy. Oligodendroglial cultures were characterized by the expression of such cell type-specific mRNAs as myelin proteolipid protein (PLP), oligodendrocyte-specific protein (OSP), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and were further characterized by immunostaining for such differentiation markers as myelin basic protein (MBP), PLP, CNPase, and O4. RT-PCR analysis showed that the oligodendroglial cells expressed detectable levels of complement mRNAs for the C1q B-chain, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 gamma subunit, and C9. Immunostaining was positive for C1q, C1s, C2, C3, C4, C5, C6, C7, C8, and C9. Double immunostaining for the oligodendrocyte marker O4 and the complement protein C3 demonstrated that all O4-positive cells were also positive for C3, indicating constitutive C3 expression. These results indicate that oligodendroglial cells may be a source of complement proteins in human brain and thus could contribute to the pathogenesis of several neurodegenerative and inflammatory diseases of the CNS, such as Alzheimer's disease, multiple sclerosis, and progressive supranuclear palsy, where complement-activated oligodendrocytes are abundant. GLIA 42:417-423, 2003. Copyright 2003 Wiley-Liss, Inc.


Houzen, H., M. Niino, et al. (2003). "The prevalence and clinical characteristics of MS in northern Japan." J Neurol Sci 211(1-2): 49-53.

            In Japan, there is a low prevalence rate (PR) of multiple sclerosis (MS; 0.8-4.0/100,000) but a relatively high frequency of "optic-spinal form" MS (OS-MS). There have been no intensive epidemiologic frequency studies, however, in over 30 years. We performed a province-wide prevalence study of MS in the Tokachi province of Hokkaido, the northernmost island of Japan, and compared the observed clinical features with other populations in Japan and Western countries. Prevalence was determined on March 31, 2001. The primary sources for the case ascertainment were 13 hospitals that treated patients with neurologic diseases including MS in Tokachi. Patients were classified according to Poser's criteria. The prevalence rate of clinically definite or laboratory-supported definite MS (LSDMS) was 8.57 per 100,000 [31/361,726; male/female ratio=1:2.9, and age at onset=29.1+/-14.2 (mean+/-SD) years]. Out of the 31 patients, 5 (16%) were classified as OS-MS. The prevalence rate of MS in the Tokachi province was the highest reported in Orientals to date, although still low in comparison with Western communities at a similar latitude. In contrast to the previous reports in Japan, there was a relatively low frequency of OS-MS in Hokkaido.


Howard, A. K., D. K. Li, et al. (2003). "MRI contributes to the differentiation between MS and HTLV-I associated myelopathy in British Columbian coastal natives." Can J Neurol Sci 30(1): 41-8.

            BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in British Columbian Coastal Natives has, to date, been a clinical and laboratory diagnosis. However, magnetic resonance imaging (MRI) abnormalities have been well-described in other populations in which HAM/TSP is endemic. METHODS: In order to assess the usefulness of MRI as a diagnostic tool in this population, we compared scans of HAM/TSP patients with those of HTLV-I positive non-HAM/TSP British Columbian Coastal Natives (carriers) and multiple sclerosis patients presenting with progressive paraparesis. Results: The typical nonspecific findings of thoracic cord atrophy and increased signal in the periventricular and subcortical white matter on T2-weighted images were confirmed in the HAM/TSP patients. Despite a lack of specificity of the MRI findings between HAM/TSP patients and HTLV-I carriers, criteria that could effectively differentiate HAM/TSP patients from multiple sclerosis patients with similar clinical presentations were determined. CONCLUSIONS: Clinical and radiological correlations suggest that longitudinal MRI investigations charting the course of HAM/TSP may reveal the clinical significance of these lesions and further define the role of MRI in the diagnosis of this entity. Magnetic resonance imaging is an important supplement to immunological and clinical data in differentiating multiple sclerosis from HAM/TSP.


Hug, A., M. Korporal, et al. (2003). "Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis." J Immunol 171(1): 432-7.

            Multiple sclerosis (MS) is an inflammatory and possibly autoimmune mediated demyelinating disease of the CNS. Autoimmunity within the CNS may be triggered by dysfunction of peripheral immune tolerance mechanisms via changes in the homeostatic composition of peripheral T cells. We have assessed the release of naive T lymphocytes from the thymus in patients with relapsing remitting MS (RRMS) to identify alterations in the equilibrium of the peripheral T cell compartment. Thymic T cell production was estimated by measuring TCR excision circles (TRECs) as a traceable molecular marker in recent thymic emigrants. A total of 46 treatment-naive patients with active RRMS and 49 gender- and age-matched healthy persons were included in the study. The levels of TREC-expressing CD4(+) and CD8(+) T lymphocytes were significantly decreased in MS patients, and TREC quantities overall matched those of 30 years older healthy individuals. The average concentrations of TRECs/10(6) CD4(+) and CD8(+) T lymphocytes derived from MS patients and healthy donors were 26 x 10(3)/10(6) and 28 x 10(3)/10(6) vs 217 x 10(3)/10(6) and 169 x 10(3)/10(6), respectively. To account for any influence of T cell proliferation on TREC levels, we assayed T lymphocytes from additional patients with MS and normal individuals for telomere length (n = 20) and telomerase activity (8 MS patients, 16 controls), respectively. There were no significant differences between CD4(+) and CD8(+) T cells from MS patients and controls. Altogether, our findings suggest that an impaired thymic export function and, as a consequence, altered ability to maintain T cell homeostasis and immune tolerance may play an important pathogenic role in RRMS.


Hughes, G. R. (2003). "Migraine, memory loss, and "multiple sclerosis ". Neurological features of the antiphospholipid (Hughes') syndrome." Postgrad Med J 79(928): 81-3.

            The antiphospholipid syndrome (APS, Hughes' syndrome), first described in 1983, is a prothrombotic disease in which neurological events feature prominently. Strokes, transient ischaemic attacks, and headaches (including migraine) are important complications. However, it is clear that other neurological symptoms, including diplopia, memory loss, ataxia, and "multiple sclerosis-like" features are common. A notable feature of Hughes' syndrome is the clinical response to anticoagulants; features such as headache and memory loss often improving dramatically with appropriate warfarin dosage. APS may well become recognised as an important (and potentially treatable) cause of neurological disease.


Hughes, R. A. (2003). "Interferon beta 1a for secondary progressive multiple sclerosis." J Neurol Sci 206(2): 199-202.

            This non-systematic review identified four randomised trials that have tested the efficacy of interferon beta in secondary progressive multiple sclerosis (SPMS). Two were trials of interferon beta 1a (IFNb1a) and two of interferon beta 1b (IFNb1b). All have shown significant reductions in relapse rates and accumulation of new magnetic resonance imaging (MRI) lesions, but only one trial (of IFNb1b) showed significant slowing of disability progression. Post hoc analyses of these trials suggest that the differences in outcomes might be partly explained by the differences between the trials in the proportions of patients with relapsing disease. In one of the trials of IFNb1a (the SPECTRIMS trial), the hazard ratio for progression in the treated relapsing patients with relapses in the two pre-study years was 0.74 compared to placebo patients with pre-study relapses and 1.01 in the treated patients compared to the placebo patients without pre-study relapses. In the same trial, the treatment effects on MRI parameters were more marked in the patients who had recent pre-study relapses compared with those who had not. These observations have led to the recommendation in national guidelines that prescribing of IFNb in SPMS be limited to those patients who have had disabling relapses in the last 2 years. These conclusions should be reviewed when the full results of all four trials have been published.


Huitinga, I., Z. A. Erkut, et al. (2003). "The hypothalamo-pituitary-adrenal axis in multiple sclerosis." Ann N Y Acad Sci 992: 118-28.

            During multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), activation of the hypothalamo-pituitary-adrenal (HPA) axis is considered to modulate the immune system in such a way that the probability of recovery from a relapse is increased. In a series of postmortem studies we observed a significant activation of corticotropin releasing hormone (CRH) neurons and increased cortisol in the cerebrospinal fluid (CSF) of MS patients, indicating activation of the HPA axis in this disease. On the other hand, sepsis, while elevating cortisol in control subjects, did not associate with a further increase of cortisol in MS patients. Thus, the activated HPA-system in MS does not respond to an acute inflammatory stimulus. In order to investigate the role of chronic inflammation in the CNS in the activation of the HPA axis in MS, MS lesions in the hypothalamus were quantified and interleukin (IL)-6 levels in the CSF were determined. There was no difference in IL-6 levels between MS and control patients. A positive correlation was found between cortisol and IL-6 in control subjects with sepsis, but not in MS patients with sepsis or MS and control groups without sepsis. Thus, IL-6 in the CSF of MS patients is not the cause of the activation of the HPA system in MS. We found a remarkably high incidence (95% of the patients) of MS lesions in the hypothalamus, of which the majority (60%) were active. The more active lesions were present in the hypothalamus, the shorter the disease duration to the moment of death, indicative of a worse disease course. Preliminary data show suppression of the activation of CRH neurons by active hypothalamic MS lesions. We propose that this suppression of CRH neurons by active hypothalamic MS lesions causes the concomitant unfavorable disease course via an inadequate cortisol response during relapses of MS.


Ilyas, A. A., Z. W. Chen, et al. (2003). "Antibodies to sulfatide in cerebrospinal fluid of patients with multiple sclerosis." J Neuroimmunol 139(1-2): 76-80.

            The identity of target antigen(s) in multiple sclerosis (MS) remains elusive despite much effort to identify it. We analyzed cerebrospinal fluid (CSF) from patients with MS, other neurological diseases (OND), other diseases (OD) and healthy controls for antibodies against purified sulfatide, a major glycosphingolipid of human myelin, by an enzyme-linked immunosorbent assay (ELISA) and a thin-layer chromatogram (TLC)-immunostaining technique. Elevated anti-sulfatide antibodies were significantly higher in MS patients as compared with the OND group (p<0.05) and all controls combined (P<0.025). Binding of high titer antibodies to sulfatide was confirmed with TLC-immunostaining. Anti-sulfatide antibodies were detected in all subtypes of MS although the frequency was higher in patients with secondary progressive MS (SPMS) than in patients with primary progressive (PPMS) and relapsing-remitting MS (RRMS). The data demonstrate a humoral response to sulfatide in the CSF of patients with MS.


Inglese, M., B. S. Li, et al. (2003). "Diffusely elevated cerebral choline and creatine in relapsing-remitting multiple sclerosis." Magn Reson Med 50(1): 190-5.

            It is well known that multiple sclerosis (MS) pathogenesis continues even during periods of clinical silence. To quantify the metabolic characteristics of this activity we compared the absolute levels of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) in the normal-appearing white matter (NAWM) between relapsing-remitting (RR) MS patients and controls. Metabolite concentrations were obtained with 3D proton MR spectroscopy at 1.5 T in a 480 cm(3) volume-of-interest (VOI), centered on the corpus callosum of 11 MS patients and 9 matched controls. Gray/white-matter/cerebral-spinal-fluid (CSF) volumes were obtained from MRI segmentation. Patients' average VOI tissue volume (V(T)), 410.8 +/- 24.0 cm(3), and metabolite levels, NAA = 6.33 +/- 0.70, Cr = 4.67 +/- 0.52, Cho = 1.40 +/- 0.17 mM, were different from the controls by -8%, -9%, +22% and +32%. The Cho level was the only single metric differentiating patients from controls at 100% specificity and >90% sensitivity. Diffusely elevated Cho and Cr probably reflect widespread microscopic inflammation, gliosis, or de- and remyelination in the NAWM. Both metabolites are potential prognostic indicators of current disease activity, preceding NAA decline and atrophy.


Issa, Y., D. C. Watts, et al. (2003). "Mercuric chloride: toxicity and apoptosis in a human oligodendroglial cell line MO3.13." Biomaterials 24(6): 981-7.

            A human-human oligodendroglial cell line MO3.13 was chosen in this study to model the loss of oligodendrocytes that occurs during episodes of multiple sclerosis. The influence of mercuric chloride (HgCl(2)) upon cell viability specifically the mode of cell death, whether by an active apoptotic mechanism or passive necrosis was determined by morphological and biochemical analysis. Mitochondrial dehydrogenase activity MTT assay showed that HgCl(2) had toxic effects on MO3.13 cells at levels of (5-25 microM) with approximately 50% cell death observed at 58 microM. Death of cells was dependent on both time and concentrations of HgCl(2). Differentiated MO3.13 cells exposed to low concentrations (25 microM) of HgCl(2) exhibited features of apoptotic cell death, including cell shrinkage and chromatin condensation. High doses of HgCl(2) (>100 microM) induced death with characteristics of necrosis. Biochemical analysis showed that HgCl(2) activated the caspase family of proteases. This was measured directly by cleavage of fluorescent substrates and by immunoblotting assay of caspase substrate proteins; alpha-fodrin, lamin B and poly (ADP-ribose) polymerase (PARP). These results indicate that HgCl(2) is toxic at low concentrations for oligodendroglial cells and that the MO3.13 cell line dies in an apoptotic manner when exposed to low concentrations of HgCl(2). However, blood mercury concentrations in vivo in a normal population with amalgam restorations are lower by a factor of some 500 times than those causing toxicity in vitro suggesting a good safety margin in respect of environmental uptake.


Ito, S., T. Hattori, et al. (2003). "Is atopic dermatitis a risk factor for intervertebral disc degeneration? A preliminary clinical and MRI study." J Neurol Sci 206(1): 39-42.

            Atopic dermatitis (AD) is a common allergic disease that has recently been reported to be complicated with acute myelitis. To clinically evaluate the occurrence of myelitis in AD, 65 consecutive AD patients were neurologically examined. Of these, 37 underwent cervical MRI scans. Unexpectedly, the neurologic and MRI findings did not suggest myelitis, but rather, in most cases, cervical spondylosis. Therefore, we assessed the relationship between AD and cervical spondylosis. In addition, cervical MRI findings in 26 patients with multiple sclerosis (MS) and in 12 normal controls were also evaluated. The neurologic examinations in the AD patients frequently showed hyperreflexia in the legs, and sensory and motor disturbances were often present in the limbs. Cervical MRI findings suggestive of spondylosis, such as intervertebral disc degeneration and bulging/protrusion, were found more frequently in AD patients than in MS patients, with statistical significance. Posterior spondylolisthesis was observed with higher frequency in AD and MS patients than in normal controls. We concluded that AD might be a risk factor for intervertebral disc degeneration. As far as we know, this is the first paper describing the potential association between disc degeneration and AD.


Iversen, L. (2003). "Cannabis and the brain." Brain 126(Pt 6): 1252-70.

            The active compound in herbal cannabis, Delta(9)-tetrahydrocannabinol, exerts all of its known central effects through the CB(1) cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated by the availability of selective antagonists acting at CB(1) receptors and the generation of CB(1) receptor knockout mice. Particularly important classes of neurons that express high levels of CB(1) receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB(1) receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2-arachidonylglycerol act as endogenous ligands for CB(1) receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarization-induced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.


Izquierdo, G. and J. L. Ruiz Pe a (2003). "[Clinical evaluation of multiple sclerosis: quantification by use of scales]." Rev Neurol 36(2): 145-52.

            INTRODUCTION. Clinical evaluation is indispensable in multiple sclerosis (MS) for the quantitative measurement of the extent of the disorder, which is in turn required to find out how the disease is evolving and the influence the different forms of treatment are having on it, both in the experimental phase and in the usual monitoring they are subjected to. METHOD. We review the different scales that are used to evaluate the distinct symptomatic and functional aspects of MS and the repercussions these have on the extent of disability displayed in the patient s social and personal life. Although in recent years, the EDSS has been an essential, irreplaceable scale in MS, other instruments of measurement that complement it have also begun to appear. The fatigue, cognitive function and quality of life scales are being used more and more frequently. The Multiple Sclerosis Functional Composite is an instrument that is used more and more frequently in MS and has proved to be highly sensitive in the evaluation of very important clinical trials. CONCLUSIONS. The lack of correlation between the distinct scales corroborates the fact that they measure complementary aspects of MS.


Jan, M. H. and C. J. Jankosky (2003). "Multiple sclerosis presenting as neurological decompression sickness in a U.S. navy diver." Aviat Space Environ Med 74(2): 184-6.

            A case of clinically definite multiple sclerosis presenting as neurological decompression sickness is presented. A 23-yr-old U.S. Navy diver experienced onset of hypesthesia of the left upper trunk approximately 19 h after making two SCUBA dives. She did not seek medical attention until 3 wk later, at which time she was diagnosed with possible neurological decompression sickness. She was treated with hyperbaric oxygen, but demonstrated no improvement. Further evaluation led to the diagnosis of multiple sclerosis. This case underscores the potential similarity in neurological presentation between multiple sclerosis and decompression sickness. The differential diagnosis of neurological decompression sickness, particularly in atypical cases, should include multiple sclerosis. The appropriateness of medically clearing multiple sclerosis patients for diving is discussed.


Janssens, A. C., J. B. de Boer, et al. (2003). "Expectations of wheelchair-dependency in recently diagnosed patients with multiple sclerosis and their partners." Eur J Neurol 10(3): 287-93.

            The aim of the present paper was to quantify expectations of wheelchair-dependency in patients recently diagnosed with MS (n = 101) and their partners (n = 78). Expectations focused on the risk and seriousness of becoming wheelchair-dependent in 2 years, 10 years or lifetime. Expectations were compared with natural history data, compared between patients and their partners, and related to clinical characteristics. Our results show that patients overestimated their 2-year and 10-year risks of wheelchair-dependency, but underestimated their lifetime risks. A large number of patients were uncertain about their 2-year risk, even those with no or only minimal disability [Expanded Disability Status Scale (EDSS) <3.0]. One-third of the patients perceived the 10-year and lifetime risk to be 50%, which, as they explained in the interviews, reflected their uncertainty: they did not know what to expect - it might happen or not. Patients with more functional limitations had higher perceptions of risk, but lower perceptions of seriousness. Concordance in perceived risk and seriousness between patients and partners was moderate. The overestimation of the short-term risks and the substantial differences in expectations within couples warrant further research on the impact of expectations on their treatment decisions and psychological well-being.


Jarrett, L., A. Bradford, et al. (2003). "Attitudes to long-term care in multiple sclerosis." Nurs Stand 17(17): 39-43.

            At a recent conference workshop, a group of specialist nurses examined their attitudes towards individuals with multiple sclerosis moving into long-term care. This article summarises how the group members examined their attitudes, the literature reviewed and what was learnt by sharing experiences. It also suggests how nurses could promote positive attitudes towards, and ease, the transition of patients into long-term residential care.


Jarus-Dziedzic, K., E. Kasper, et al. (2003). "Incidental stereotactic diagnosis of cerebral insults." Neurol Res 25(2): 173-8.

            Among the patients (6854 patients 1990-1999) who underwent computer-assisted stereotactic biopsy most were referred with the presumptive diagnosis of a brain mass lesion. Forty-three cases (0.63%) were found in which the final histopathological diagnosis excluded a neoplastic, infectious or inflammatory lesion but disclosed a cerebral insult. Histologically these could be subdivided into ischemic insults in 38 cases (88%) and hemorrhagic insults in five cases (12%). On the basis of clinical and radiological findings in this group, 35 patients (81%) were sent to our department because of suspected neoplasmatic lesions, two patients (5%) because of multiple sclerosis, two patients (5%) because of inflammatory disease and one patient (2%) because of a suspected infectious parasitic disease. All patients underwent initial CT examinations which showed hypodense lesions of the brain in 38 patients (88%) and hyperdense lesions in five cases (12%). Constant enhancement on CT scans of the mass lesion was found in 12 patients (28%) only. Fourteen lesions (33%) were located in the right hemisphere, five lesions (12%) in the left hemisphere, nine lesions (21%) in the basal ganglia, four lesions (9%) in the midbrain, two lesions (4.5%) in the corpus callosum and one lesion (2%) in a thalamus. Multiple lesions were present in eight cases (19%). The most common initial neurological symptoms upon clinical presentation were hemiparesis (18 patients, 42%), epilepsy (eight patients, 18%), a change in mental status (six patients, 14%). There was no mortality and no operative morbidity associated with the stereotactic biopsy in this group of patients. The most common neurological disorder, cerebrovascular insult, rarely poses diagnostic problems. If there are doubts a serial stereotactic biopsy can safely clarify the situation.


Jean, I. and C. Fressinaud (2003). "Spontaneous central nervous system remyelination is not altered in NFH-lacZ transgenic mice after chemical demyelination." J Neurosci Res 73(1): 54-60.

            Harmonious functioning of the nervous system depends on neuron-glia interactions, particularly between the axons and their myelinating cells, i.e., oligodendrocytes (OL) in the central nervous system (CNS). In human demyelinating diseases such as multiple sclerosis (MS), demyelination may be associated with axonal damage, but alterations of the axonal cytoskeleton, which is composed mainly of neurofilaments (NF) and microtubules, are largely unknown, as are the consequences on remyelination. In a model of demyelination induced by lysophosphatidylcholine (LPC), we have shown that demyelination was correlated with a decrease in NF immunolabelling, and that these axonal abnormalities were reduced by platelet-derived growth factor (PDGF)-enhanced remyelination in adult rats. We have analysed the spontaneous remyelination after LPC stereotaxic injection in the CNS of transgenic NFH-lacZ mice, which present axonal atrophy caused by abnormal distribution of NF, associated with hypermyelination in the PNS, and normal myelin thickness in the CNS. Axonal atrophy in the CNS of NFH-lacZ mice was confirmed, but it was not worsened by demyelination. On the contrary, demyelination induced axonal atrophy in wild-type mice, demonstrating that NF are essential for axonal calibre determination. Moreover, an efficient spontaneous remyelination occurred in NFH-lacZ as well as in wild-type mice, indicating that the NF are not necessary for CNS remyelination. These findings point out that NF modifications observed in MS may not be responsible for the lack of remyelination in this disease. Copyright 2003 Wiley-Liss, Inc.


Jellinger, K. A. (2003). "New Frontiers of MR-Based Technique in Multiple Sclerosis." Eur J Neurol 10(4): 467.


Jin, Y. P., J. de Pedro-Cuesta, et al. (2003). "Predicting multiple sclerosis at optic neuritis onset." Mult Scler 9(2): 135-41.

            Using multivariate analyses, individual risk of clinically definite multiple sclerosis (CDMS) after monosymptomatic optic neuritis (MON) was quantified in a prospective study with clinical MON onset during 1990-95 in Stockholm, Sweden. During a mean follow-up time of 3.8 years, the presence of MS-like brain magnetic resonance imaging (MRI) lesions and oligoclonal immunoglobulin (Ig) G bands in cerebrospinal fluid (CSF) were strong prognostic markers of CDMS, with relative hazard ratios of 4.68 [95% confidence interval (CI) 2.21-9.91] and 5.39 (95% CI 1.56-18.61), respectively. Age and season of clinical onset were also significant predictors, with relative hazard ratios of 1.76 (95% CI 1.02-3.04) and 2.21 (95% CI 1.13-3.98), respectively. Based on the above two strong predictors, individual probability of CDMS development after MON was calculated in a three-quarter sample drawn from a cohort, with completion of follow-up at three years. The highest probability, 0.66 (95% CI 0.48-0.80), was obtained for individuals presenting with three or more brain MRI lesions and oligoclonal bands in the CSF, and the lowest, 0.09 (95% CI 0.02-0.32), for those not presenting with these traits. Medium values, 0.29 (95% CI 0.13-0.53) and 0.32 (95% CI 0.07-0.73), were obtained for individuals discordant for the presence of brain MRI lesions and oligoclonal bands in the CSF. These predictions were validated in an external one-quarter sample.


Jin, Y. P., J. De Pedro-Cuesta, et al. (2003). "Birth cohort effects in multiple sclerosis." Ann Epidemiol 13(4): 252-60.

            PURPOSE: To identify potential birth cohort effects in multiple sclerosis in Sweden and particularly in Stockholm county.METHODS: Data on multiple causes of death from multiple sclerosis during 1962 to 1995 in Sweden and 1968 to 1995 in Stockholm county were analyzed using age-period-cohort models and curvature.RESULTS: Mortality from multiple sclerosis was higher in Sweden than in Stockholm county, with stable time trends, slight period effects and marked age effects. Cohorts born before or after a central period, from 1910 through 1930, registered lower mortality. A periodic wave-form mortality pattern was identified, following a 5-to-6-year cycle for cohorts born before 1925 both in and outside Stockholm county, and changing to longer or irregular cycles for cohorts born after 1930.CONCLUSIONS: Although methodological constraints inducing the saw-tooth pattern cannot be excluded, these results are consistent with etiologic hypotheses claiming a role for environmental factors in multiple sclerosis.


Jinochova, M., Z. Seidl, et al. (2003). "[Multiple sclerosis and magnetic resonance]." Cas Lek Cesk 142(3): 144-9.

            Multiple sclerosis is a demyelinating process presently referred to autoimmune diseases. Its diagnostics is based on clinical examination and paraclinical tests (magnetic resonance, examination of CSF and evoked potentials recording). Magnetic resonance (MR) has the highest significance, both for the diagnostics and for the monitoring of the course of disease and results of treatment. Results of magnetic resonance are not specific for the multiple sclerosis and therefore for the reliable diagnosis the McDonadl's criteria have to be fulfilled. It appears that magnetic resonance is more sensitive to progression of disease than the clinical examination. Monitoring of the course of disease requires new techniques of MR imaging. Automatic, software assisted determination of plaque volumes in T2 and T1 weighted images--so called "lesion load", is checked during the patient's treatment. Assessment of brain volume determines progression of atrophy. The aim of all the new methods of MR imaging is to search for a reliable technique of the disease monitoring and namely for the prediction of disease progression.


Johnson, J. (2003). "On receiving the diagnosis of multiple sclerosis: managing the transition." Mult Scler 9(1): 82-8.

            This article reports on one aspect of a wider study into multiple sclerosis (MS) specialist nurse roles in the UK. Insights gained from in-depth patient interviews are discussed in relation to literature regarding the meaning of health-related events, such as diagnosis. The findings of this project indicated that for many people, intense feelings of abandonment and isolation were generated at the time of diagnosis and stayed with the person for many months or years. Differing expectations between patient and neurologist following confirmation of diagnosis could contribute to these findings. It is suggested that imparting a diagnosis of MS should be seen as the start of a transition that needs to be made explicit to the patient and closely linked to the provision of sources of information, advice and ongoing support as people learn to live with and manage the disease.


Jolivalt, C. G., R. B. Howard, et al. (2003). "A novel nitric oxide scavenger in combination with cyclosporine A ameliorates experimental autoimmune encephalomyelitis progression in mice." J Neuroimmunol 138(1-2): 56-64.

            Immunotherapy improves experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), while excessive production of nitric oxide (NO) has been implicated in the pathogenesis of this disease. Here, we show that disease progression in SJL/J mice with EAE is improved after treatment with either a subtherapeutic dose of cyclosporine A (CsA) or NOX-100, a nitric oxide scavenger. Importantly, the impact of subtherapeutic doses of CsA in combination with NOX-100 on disease progression in EAE was greater than that attained with either agent alone and led to near total protection. CNS inflammation and gene expression of proinflammatory cytokines and iNOS were also significantly reduced after treatment. These observations point to the potential therapeutic utility of NOX-100 as a dose-reducing agent for CsA in the treatment of MS.


Jones, R. E., D. Bourdette, et al. (2003). "Epitope spreading is not required for relapses in experimental autoimmune encephalomyelitis." J Immunol 170(4): 1690-8.

            The sequential emergence of specific T lymphocyte-mediated immune reactivity directed against multiple distinct myelin epitopes (epitope spreading) has been associated with clinical relapses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Based on this association, an appealing and plausible model for immune-mediated progression of the advancing clinical course in MS and EAE has been proposed in which epitope spreading is the cause of clinical relapses in T cell-mediated CNS inflammatory diseases. However, the observed association between epitope spreading and disease progression is not universal, and absolute requirements for epitope spreading in progressive EAE have not been tested in the absence of multiple T cell specificities, because most prior studies have been conducted in immunocompetent mouse strains that possessed broad TCR repertoires. Consequently, the precise nature of a causal relationship between epitope spreading and disease progression remains uncertain. To determine whether relapsing or progressive EAE can occur in the absence of epitope spreading, we evaluated the course of disease in mice which possessed only a single myelin-specific TCR. These mice (transgenic/SCID +/+) exhibited a progressive and sometimes remitting/relapsing disease course in the absence of immune reactivity to multiple, spreading myelin epitopes. The results provide direct experimental evidence relevant to discussions on the mechanisms of disease progression in MS and EAE.


Jones, S. J. and A. Brusa (2003). "Neurophysiological evidence for long-term repair of MS lesions: implications for axon protection." J Neurol Sci 206(2): 193-8.

            After recovery from the acute stage of optic neuritis, a marked prolongation in the latencies of visual evoked potentials (VEPs) is typically observed. We have conducted three studies (one cross-sectional, two prospective), aimed at elucidating the progressive shortening of VEP latency, which frequently ensues over the following months or years. This has been shown to be a progressive process and a prevalent tendency in the patient population, proceeding for more than 2 years in spite of the fact that very little functional improvement in vision occurs after the first few months. We argue that the underlying process of repair is most likely to involve remyelination of demyelinated optic nerve axons. Rather than restoration of visual function (which may be virtually complete after as short a period as 3 months), the main importance of the long-term myelin repair process may consist in protecting demyelinated axons from subsequent, permanent degeneration. In the VEPs of the acutely unaffected fellow eyes followed up over 3 years, we observed an asymptomatic deterioration, possibly due to insidious processes of demyelination and/or axonal degeneration. Even in the relapsing/remitting stage of MS, therefore, there is electrophysiological evidence for involvement of clinically asymptomatic axons, which, in the later stages, may be manifested as progressive functional deterioration.


Jopson, N. M. and R. Moss-Morris (2003). "The role of illness severity and illness representations in adjusting to multiple sclerosis." J Psychosom Res 54(6): 503-11; discussion 513-4.

            OBJECTIVE: Multiple sclerosis (MS) is an incurable, chronic and unpredictable disease of the central nervous system. The purpose of this study was to investigate whether MS patients' illness representations impact on their adjustment to this debilitating illness even when controlling for the severity of their condition. METHODS: One hundred and sixty-eight MS patients completed a questionnaire booklet comprised of the Illness Perceptions Questionnaire-Revised and a range of adjustment variables including the Sickness Impact Profile, the Fatigue Scale, the Hospital Anxiety and Depression Scale and the Rosenberg Self-Esteem Scale. The severity of patients' MS was measured by the type of MS, length of illness, remission status and ambulatory ability. RESULTS: Hierarchical multiple regression analyses demonstrated that illness severity accounted for the majority of the variance in physical and role dysfunction, while patients' illness representations were the most significant predictors of levels of social dysfunction, fatigue, anxiety, depression and self-esteem. CONCLUSIONS: Patients' illness representations play a significant role in adjustment to MS. These results suggest that a psychological intervention, which addresses patients' illness representations, may assist in their adjustment to MS.


Jordan, J. F., P. Walter, et al. (2003). "Intermediate uveitis in childhood preceding the diagnosis of multiple sclerosis: a 13-year follow-up." Am J Ophthalmol 135(6): 885-6.

            PURPOSE: An association between multiple sclerosis during childhood and uveitis is exceptionally rare. This is a report of a female patient who presented at the age of 8 years with bilateral intermediate uveitis and whose final diagnosis of multiple sclerosis was made at age 21 years. DESIGN: Case report. METHOD: Retrospective chart review of a 13-year follow-up history. RESULTS: Over 10 years our patient was treated systemically and underwent bilateral vitrectomy to reduce permanent side effects. Owing to good visual function and low inflammatory signs, systemic therapy was stopped. Multiple sclerosis was diagnosed at the age of 21, after a 13-year history of uveitis and after 3 years without medication. CONCLUSIONS: In the constellation of uveitis in childhood and later diagnosis of multiple sclerosis, the outlined therapy provided good functional results. Moreover, it may have delayed the manifestation of the underlying disease for 13 years.


Jurewicz, A., M. Matysiak, et al. (2003). "TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3." Brain 126(Pt 6): 1358-70.

            Tumour necrosis factor (TNF) induces death of oligodendrocytes, the putative cell target in multiple sclerosis. We defined that the intracellular transduction pathway involved in TNF-induced death of human adult oligodendrocytes (hOLs) is dependent on c-jun NH(2)-terminal kinase (JNK) activation, but not the other mitogen-activated protein kinase (MAPK), p38. JNK activation, measured by c-jun phosphorylation and induction of the phosphorylated form of JNK, was enhanced, prolonged and correlated with cell death in hOLs exposed to TNF. Comparative autoradiographic analysis revealed that JNK-3, but not JNK-1 or JNK-2, is responsible for prolonged JNK activation in TNF exposed hOLs. Expression of a dominant-negative mutant of JNK upstream kinase, MKK4/SEK1, inhibited apoptosis induced by TNF, whereas expression of a constitutive active mutant of MEKK1, an upstream kinase to JNK, accelerates TNF-induced apoptosis. JNK activation occurred prior to changes of mitochondrial membrane potential in hOLs exposed to TNF. These results demonstrate that TNF-induced death in adult hOLs depends on prolonged JNK-3 activation, and that this apoptosis requires the mitochondrial dysfunction that occurs after JNK activation. This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis.


Kadhim, H., C. De Prez, et al. (2003). "In situ cytokine immune responses in acute disseminated encephalomyelitis: insights into pathophysiologic mechanisms." Hum Pathol 34(3): 293-7.

            Acute disseminated encephalomyelitis (ADEM) is thought to be an autoimmune disorder of the central nervous system in which myelin is targeted. Pathological studies on closely related human diseases (eg, multiple sclerosis) and on animal models for these demyelinating disorders have suggested the involvement of cytokines. Studies on peripheral immunocytes and on cerebrospinal fluid revealed the presence of cytokine-mediated responses in ADEM. We carried out this neuroimmunopathologic exploration and report for the first time the in situ expression of "inflammatory" cytokines in ADEM. Moreover, we note a particular spatial and molecular pattern whereby tumor necrosis factor-alpha and interleukin (IL)-1beta are intensely expressed, whereas IL-6 is absent. Differential expression at different levels of the neuraxis was also noticed. Our findings suggest that these cytokines, reported to be toxic to myelin, are implicated in the molecular cascade, resulting in the neural damage. These observations might provide insights into molecular pathways involved in the immunopathogenesis of ADEM and might open new horizons in neuroimmunomodulation and anticytokine treatment.


Kahl, K. G., J. Zielasek, et al. (2003). "Protective role of the cytokine-inducible isoform of nitric oxide synthase induction and nitrosative stress in experimental autoimmune encephalomyelitis of the DA rat." J Neurosci Res 73(2): 198-205.

            The pathogenic role of nitric oxide (NO) in multiple sclerosis (MS) remains controversial. Some groups have reported a pathogenic role of NO in experimental autoimmune encephalomyelitis (EAE), an animal model of some aspects of MS, whereas we and others have found a disease-suppressive effect of NO in EAE. Because the previously used EAE models have a mainly monophasic inflammatory disease course, distinct from MS, we here studied EAE in the DA rat, which better models the demyelinating and relapsing disease course of human MS. The induction of EAE in DA rats led to 1) severe inflammatory infiltrates mainly in the lumbar spinal cord; 2) an up-regulation of the activity of the cytokine-inducible isoform of NO synthases (NOS-II); and 3) increased tissue protein tyrosine nitration, as indicated by peroxynitrite (ONOO(-)), as a marker of nitrosative stress. Sources of superoxide metabolism, i.e., NADPH oxidase, myeloperoxidase, and superoxide dismutase, remained unchanged. Early treatment of animals with aminoguanidine, a relatively selective inhibitor of NOS-II, lowered nitrotyrosine immunoreactivity but at the same time led to more severe disease and pronounced inflammatory infiltrates in the lumbar spinal cord. Our results suggest a rather protective role of NOS-II induction and nitrosative stress in EAE in DA rats and support the hypothesis of a disease-mitigating immunomodulatory role of NO in this animal model of MS.


Kalanie, H., K. Gharagozli, et al. (2003). "Multiple sclerosis: report on 200 cases from Iran." Mult Scler 9(1): 36-8.

            Clinical findings of 200 patients in Iran with definite multiple sclerosis (MS) according to Poser et al.'s criteria and positive findings on magnetic resonance imaging (MRI) have been reviewed. The clinical course was relapsing-remitting (RR) for 88%, primary progressive (PP) for 7% and secondary progressive (SP) for 5% of cases. The mean age of onset was 27 +/- 7.4 years for the whole group and 37.1 +/- 8.8 years for PPMS. The gender ratio was 2.5:1 female:male. Involvement of the pyramidal system was the most common mode of presentation. Five per cent of patients had positive family history for the disease, 14% of patients had benign MS and 12% with disease duration longer than five years had an Expanded Disability Status Scale < or = 2. The optico-spinal form was not a common form of presentation in the group.


Kalman, B. and T. P. Leist (2003). "A mitochondrial component of neurodegeneration in multiple sclerosis." Neuromolecular Med 3(3): 147-58.

            Neurodegeneration is the main pathological correlate of accumulating disability in progressive stages of Multiple Sclerosis (MS), but both histologic and imaging studies detect significant tissue loss even in early disease. These observations raise the question as to whether neurodegeneration in MS is a primary mechanism or whether it develops secondary to inflammation and demyelination. Recent data suggest that the atrophy of brain and cord is directly linked to inflammation and may partly be independent of demyelination. Released products of both residential and infiltrating immune cells can induce ultrastructural changes and celldeath by multiple mechanism. We propose that the inflammation-induced tissue response is controlled by genetic variations and to some extent involves a mitochondrion-driven mechanism in MS, similar to that described in the final pathway of other neurodegenerative disorders. Current therapeutic strategies primarily target the immune system which results in a successful down-regulation of plaque formation and of relapse rate. However, measures of clinical disability best correlate with the degree of neurodegeneration rather than with the volume of plaques, and these immune-modulating regimens may only incompletely affect the accumulating tissue loss. Considering the need for additional therapeutic strategies, we emphasize the degenerative components, and review a mitochondrial mechanism of tissue loss potentially involved in the process of MS.


Kankonkar, S., G. Jeyanti, et al. (2003). "Evidence for novel DRB1*15 allele association among clinically definite multiple sclerosis patients from mumbai, india." Hum Immunol 64(4): 478-82.

            Multiple sclerosis (MS) is a clinically heterogeneous demylinating disease and an important cause of acquired neurologic disability. MS has been reported from different regions of India and its infrequency has been attributed to have genetic implications. Further, a high incidence of MS and its human leukocyte antigen B12 (HLA-B12) associations have been reported among highly inbred Parsi population from Mumbai. However, consistent HLA associations have not been reported from India. We analyzed the HLA-B, -Cw, and -DRB1 allele associations among 23 clinically definite Western Indian non-Parsi MS patients and compared them with 146 ethnically matched clinically normal individuals. HLA serologic (A, B, and Cw) as well as molecular (DRB1) typing methodology was followed. The study revealed a significant increase of HLA-A11 (24% vs. 13%; OR = 2.6; EF = 0.14; 95%CI = 1.1-3.05), B16 (4.3% vs 0.3%; OR = 13.8; EF = 0.03; 95% CI = 1.19-134.44), Cw7 (15.2% vs 3.7%; OR = 5.46; EF = 0.12; 95% CI = 0.944-17.86), and DRB1*15 (21.7% vs 2.2%; OR = 16.15; EF = 0.19; 95% CI = 1.33-68.64). Further molecular subtyping of HLA-DRB1*15 among the patients revealed two novel alleles, DRB1*1506 (20%) and DRB1*1508 (30%), along with the commonly reported DRB1*1501 (50%) for the first time in MS patients that were hitherto unidentified from other parts of India and world as well. This study reveals that there is a complexity of the genetic susceptibility to MS in different populations studied and reported.


Kantarci, O. H., J. L. Schaefer-Klein, et al. (2003). "A population-based study of IL4 polymorphisms in multiple sclerosis." J Neuroimmunol 137(1-2): 134-9.

            Previous studies have suggested a role for interleukin-4 gene (IL4) in susceptibility to multiple sclerosis (MS) as well as other autoimmune diseases. We screened the promoter region, exons 1-4 and their splice sites for polymorphisms and tested the association between novel polymorphisms E1(33)*C-->T and I3(2580)*C-->A, and the established 5'(-523)*C-->T and I3(709)*VNTR polymorphisms with susceptibility to, age of onset in, and course and severity of MS in sporadic cases. I3(709)*VNTR was associated with susceptibility to MS (p=0.004) due to a dearth of heterozygotes in patients (29/122; 23.8%) compared to controls (91/244; 37.3%). Homozygotes for the uncommon I3(709)*allele-2 may have increased susceptibility (p=0.044; OR=5.17, 95% CI: 0.83-54.95) as might carriers for the extended haplotypes 5'(-523)*T/E1(33)*T/I3(709)*allele-2/I3(2580)*C (p=0.003; OR: 3.75, 95% CI: 1.18-11.93) or 5'(-523)*C/E1(33)*C/I3(709)*allele-1/I3(2580)*A (p=0.004; OR: 4.22, 95% CI: 1.22-14.54). We could not confirm the previously reported association between carriage of I3(709)*allele-2 and older age of onset. However, we found a trend for association between the homozygous state for this allele and older age of onset.


Kantarci, O. H., D. D. Hebrink, et al. (2003). "CTLA4 is associated with susceptibility to multiple sclerosis." J Neuroimmunol 134(1-2): 133-41.

            We comprehensively screened CTLA4 for novel genetic variations in patients with MS. We studied genetic variations by association methods in a population-based sample of 122 sporadic patients with MS and 244 age-, gender- and ethnicity-matched controls, and by linkage and family-based association methods in 395 individuals from 59 American multiplex pedigrees with 141 affected individuals. Being homozygous for AT(8) (common) allele of the 3'(514) microsatellite (OR: 1.69; CI: 0.99-2.86) and for the common 5'(318)*C/E1(49)*A/3'(514*AT(8) haplotype (OR: 1.96; CI: 1.13-3.39) was associated with increased susceptibility to MS in Olmsted County. The genotype frequencies of other individual polymorphisms were not significantly different between cases and controls. A pooled analysis of association studies revealed an odds ratio of 1.28 (95% CI: 1.01-1.63; p=0.043) for 5'(-318)*C homozygotes and 1.28 (95% CI: 1.08-1.51; p=0.005) for the 3'(514)*AT(8) allele. We did not detect linkage with MS susceptibility in multiplex families. We did not find a strong association with age at onset, disease course or severity. CTLA-4 is associated with susceptibility to MS.


Kantor, R., M. Bakhanashvili, et al. (2003). "A mutated CCR5 gene may have favorable prognostic implications in MS." Neurology 61(2): 238-40.

            The authors investigated the association between Delta32CCR5, a mutated allele of the chemokine receptor CCR5, and disease progression in 256 patients with multiple sclerosis (MS). The mutated allele frequency in the study cohort was 7.4%, similar to that reported in the general Israeli population. Progression to disability was prolonged in Delta32CCR5 homozygotes and heterozygotes compared with MS patients with the CCR5 wild-type genotype (p < 0.005). Mutated CCR5 allele may be considered a favorable prognostic factor in MS.


Kapoor, R., M. Davies, et al. (2003). "Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration." Ann Neurol 53(2): 174-80.

            Axonal degeneration can be an important cause of permanent disability in neurological disorders in which inflammation is prominent, including multiple sclerosis and Guillain-Barre syndrome. The mechanisms responsible for the degeneration remain unclear, but it is likely that axons succumb to factors produced at the site of inflammation, such as nitric oxide (NO). We previously have shown that axons exposed to NO in vivo can undergo degeneration, especially if the axons are electrically active during NO exposure. The axons may degenerate because NO can inhibit mitochondrial respiration, leading to intraaxonal accumulation of Na(+) and Ca(2+) ions. Here, we show that axons can be protected from NO-mediated damage using low concentrations of Na(+) channel blockers, or an inhibitor of Na(+)/Ca(2+) exchange. Our findings suggest a new strategy for axonal protection in an inflammatory environment, which may be effective in preventing the accumulation of permanent disability in patients with neuroinflammatory disorders.


Kappos, L. and J. Kesselring (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1821-2; author reply 1823-4.


Kargwell, H., B. A. Yaqub, et al. (2003). "Response to beta interferon 1b among Saudi patients with multiple sclerosis." Saudi Med J 24(1): 44-8.

            OBJECTIVE: To determine the efficacy and tolerability of subcutaneous beta interferon 1b (B1F1b) among Saudi patients with remitting-relapsing multiple sclerosis (R-R MS). METHODS: An open label study held at the Neurology Division of the Armed Forces Hospital, Riyadh from March 1997 until December 2001. Thirty-two consecutive patients below the age of 50 years with clinically definite R-R MS according to Poser's Criteria and expanded disability status scale below 5.5 were enrolled in treatment with subcutaneous B1F1b 8 million IU 3 times a week. The primary outcome measures used were: reduction in annual relapses, proportion of relapse-free patients, and the mean time to the first relapse after treatment was started. The secondary outcome measures used were the time to progression in disability, tolerability and safety of the beta interferon. RESULTS: Only 28 patients were analyzed to assess the outcome measures, the other 4 patients dropped out and were followed-up. Twenty were women and 8 were men (female:male ratio of 2.5:1). There was a significant reduction in relapse-rate in all patients, 32.5% were relapse-free, while 37.5% showed reduction in the number of relapses. None of our patients showed progression of disability (P<0.0249). Mild adverse reactions were seen in 38.5%, influenza-like illness occurred in 53.6%, and injection-site reaction in 35.7%. CONCLUSION: Subcutaneous B1F1b is effective in patients with R-R MS, especially in reducing relapse rate, probable disability, and it is well tolerated. However, longer follow-up is necessary to evaluate the role of B1F1b in preventing disability.


Karni, A., E. Kahana, et al. (2003). "The frequency of multiple sclerosis in jewish and arab populations in greater jerusalem." Neuroepidemiology 22(1): 82-6.

            A comparison of the incidence rate (IR) and the prevalence rate (PR) of multiple sclerosis (MS) in subgroups of the same ethnic origin, but born and living in different geographical areas, may delineate the relationship between environmental and genetic risk factors for MS. Previous epidemiological studies of MS in Israel did not include the Arab population and used diagnostic criteria that did not include MRI findings. Therefore, we studied the age-adjusted IR and PR of MS in a more recent sample in different population groups, including Arabs, of Greater Jerusalem. We found that the PR of MS in Israeli Jews is higher than previously described. Furthermore, the PR was significantly lower among immigrant Jews from Asia/Africa (A/A) than among native-born Jews of Asian/African origin (I-A/A). Since these groups have similar genetic susceptibilities to MS, the higher PR in the latter is probably due to environmental factors. Our study does not support the effect of latitude on the risk of developing MS since no difference in the PR was found between immigrant Jews from Europe/America (E/A) and native-born Jews of European/American origin (I-E/A). Among Arabs, the PR was similar to that among A/A. Therefore, we hypothesized similarity in environmental etiologic factors for MS between the countries of origin of A/A immigrants and of Arabs communities in Greater Jerusalem. The IR of I-E/A was higher than that of I-A/A and Arabs, although this difference did not reach statistical significance.


Karpus, W. J., B. T. Fife, et al. (2003). "Immunoneutralization of chemokines for the prevention and treatment of central nervous system autoimmune disease." Methods 29(4): 362-8.

            Chemokine-induced lymphocyte migration has long been hypothesized to regulate the appearance and continued presence of lymphocytes and monocytes in tissue-specific autoimmune diseases, including central nervous system autoimmune diseases such as multiple sclerosis. For instance, a large body of evidence points to the temporal association of chemokine expression with the appearance of T lymphocytes and monocytes/macrophages. Furthermore, experiments using mice with targeted mutations for chemokines have shown the importance of those molecules in the development of central nervous system autoimmune disease. We have hypothesized that temporal and spatial expression of chemokines is a key factor in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis. To test our hypothesis we have employed the strategy of eliminating chemokine function by the passive transfer of chemokine-specific polyclonal antibodies. This approach has allowed us not only to test the function of chemokines in experimental autoimmune encephalomyelitis development, but also to ask questions about the roles of chemokines during disease progression. Moreover, this approach has allowed us to assess the efficacy of targeting chemokines and their receptors for treatment of ongoing disease. In the present report we summarize our experience using anti-chemokine administration for the prevention and treatment of experimental autoimmune encephalomyelitis as well as provide specific examples of how this approach is efficacious for disease treatment.


Kasser, S. L., J. A. McCubbin, et al. (2003). "Variability in constraints and functional competence in adults with multiple sclerosis." Am J Phys Med Rehabil 82(7): 517-25.

            OBJECTIVE: Examine intraindividual change in physical and psychological impairments associated with multiple sclerosis and assess the relationship between changes in specific deficits and functional competence in activities of daily living. DESIGN: A multivariate, replicated, single-subject, repeated-measures design was used to examine variability patterns across subjects. Five adults with multiple sclerosis were assessed on leg strength, upright postural control, mood, fatigue, stress, and self-efficacy for 4 mo. Functional competence in three activities of daily living was also evaluated. P-technique factor analyses were performed to examine which variables covaried with time. RESULTS: Analyses revealed covariation among physical and psychological variables for four of the five participants. Across all participants, coefficients of variation revealed greater variability in stress (32.3%-53.4%) and fatigue (23.4%-5.9%) than in any of the physical variables (<20%), and variability in all impairments was greater than variability in the functional tasks (0%-12.6%). CONCLUSIONS: The greater stability in functional performance compared with both physical and psychological constraints provides important insight into symptom management and clinical intervention. The magnitude of variability found in the psychological variables across individuals also has implications concerning psychological adjustment to the disease.


Kassubek, J., H. Tumani, et al. (2003). "Age-related brain parenchymal fraction is significantly decreased in young multiple sclerosis patients: a quantitative MRI study." Neuroreport 14(3): 427-30.

            The extent of brain atrophy was determined in 33 patients with multiple sclerosis (MS) and in 60 healthy subjects (21-76 years) by calculating brain parenchymal fractions (BPF, the ratio of brain parenchymal to intracranial volume) from 3D MRI. Within the normal data base, subjects at higher ages showed significantly lower BPF values. In younger MS patients, BPF was significantly decreased compared with age-matched controls (20-29 years, p= 0.0022; 30-39 years, =p 0.0001; 40-49 years,p = 0.0444) and was significantly correlated with disease duration and disease severity, but not with the number of detectable MS lesions. Determination of age-related BPF demonstrated significant brain atrophy in early MS and can be considered as a useful biological marker for monitoring MS.


Kastenbauer, S., U. Koedel, et al. (2003). "CSF and serum levels of soluble fractalkine (CX3CL1) in inflammatory diseases of the nervous system." J Neuroimmunol 137(1-2): 210-7.

            The new CX(3)C-chemokine fractalkine (CX(3)CL1) was measured by Western blot in the cerebrospinal fluid (CSF) and serum of patients with inflammatory diseases of the peripheral and central nervous system (Bell's palsy, BP; Guillain-Barre Syndrome, GBS; multiple sclerosis, MS; viral meningitis, VM; bacterial meningitis, BM) and patients with noninflammatory neurological diseases (controls). In controls, fractalkine was detectable at low concentrations in the CSF and, at much higher levels, in serum. In all inflammatory neurological diseases under study, CSF fractalkine levels were significantly (p<0.01) increased vs. controls (BM>>GBS>VM>MS>BP>controls). In serum, fractalkine levels were significantly increased only in MS patients. The fractalkine CSF/serum ratios (a measure of the chemotactic gradient) were significantly elevated in BM, VM and GBS; furthermore, they tended to be increased in BP and to be decreased in MS. The elevated fractalkine CSF/serum ratios in diseases without CSF pleocytosis (GBS, BP) and a lack of correlation between fractalkine levels and CSF leukocyte counts suggested that soluble fractalkine is not a major chemokine in the CSF. There was no evidence of significant intrathecal production of fractalkine as the mean fractalkine indices (fractalkine CSF/serum ratio:albumin CSF/serum ratio) were <1 in all inflammatory diseases and not significantly elevated vs. controls.


Kaufman, M. D., S. K. Johnson, et al. (2003). "Multiple sclerosis: severity and progression rate in african americans compared with whites." Am J Phys Med Rehabil 82(8): 582-90.

            ABSTRACT Kaufman MD, Johnson SK, Moyer D, Bivens J, Norton HJ: Multiple sclerosis: Severity and progression rate in African Americans compared with whites. Am J Phys Med Rehabil 2003;82:582-590.OBJECTIVE Although epidemiology indicates that multiple sclerosis is more common among whites than African Americans, the course of disease may be more aggressive among African Americans. This study examines disease course in a large multiple sclerosis clinic population.DESIGN A case-controlled, retrospective record review compared the severity of multiple sclerosis for African Americans and for whites. Because the baseline demographics of the two groups differed, we performed analyses of multiple subgroups in an attempt to control for various characteristics.RESULTS Consistent evidence of more disability in African Americans compared with whites was found, although subgroups were often too small to establish statistical significance. African Americans had a higher mean Expanded Disability Status Scale score than whites in a subgroup selected to minimize differences in access to care and disease perceptions. African Americans reported limb weakness as a presenting symptom of multiple sclerosis more frequently than did whites. When patients were followed at our multiple sclerosis center, rates of disease progression were nearly identical.CONCLUSIONS More African Americans than whites experience pyramidal system involvement early in multiple sclerosis, leading to greater disability as measured by the ambulation-sensitive Expanded Disability Status Scale. Once patients have moderate difficulty walking, the rate of progression is the same for both groups, albeit occurring at a later age for whites than for African Americans.


Kennel De March, A., M. De Bouwerie, et al. (2003). "Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis." J Neuroimmunol 135(1-2): 117-25.

            Humoral auto-immunity to the myelin oligodendrocyte glycoprotein (MOG) is likely involved in the pathogenesis of multiple sclerosis (MS). In 44 MS patients and 30 controls, Ig-producing B cells were identified by their isotype and as MOG-specific spot-forming cells (SFC). Peripheral anti-MOG antibodies were assayed in ELISA as well as anti-butyrophilin antibodies to investigate for molecular mimicry. MS patients had significantly higher levels of IgA- and MOG-SFC than controls, as well as significantly higher antibody responses to MOG and butyrophilin. These data provide added support for the implication of anti-MOG humoral immunity in the pathophysiology of MS, and suggest a balance of systemic (anti-self) and mucosal (environment-modulated) immune reactions in an attempt at regulating the pathogenic specific immune response.


Kerschensteiner, M., C. Stadelmann, et al. (2003). "Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases." Ann Neurol 53(3): 292-304.

            Inflammatory reactions in the central nervous system usually are considered detrimental, but recent evidence suggests that they also can be beneficial and even have neuroprotective effects. Intriguingly, immune cells can produce various neurotrophic factors of various molecular families. The concept of "neuroprotective immunity" will have profound consequences for the pathogenesis and treatment of neuroinflammatory diseases such as multiple sclerosis. It also will prove important for neurodegenerative disorders, in which inflammatory reactions often occur. This review focuses on recent findings that immune cells produce brain-derived neurotrophic factor in multiple sclerosis lesions, whereas neurons and astrocytes express the appropriate tyrosine kinase receptor TrkB. Together with functional evidence for the neuroprotective effects of immune cells, these observations support the concept of "neuroprotective immunity." We next examine current and future therapeutic strategies for multiple sclerosis and experimental autoimmune encephalomyelitis in light of neuroprotective immunity and finally address the broader implications of this new concept for other neuroinflammatory and neurodegenerative diseases.


Khare, M., M. Rodriguez, et al. (2003). "HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis." Int Immunol 15(4): 535-46.

            Myelin oligodendrocyte glycoprotein (MOG) is a potential target antigen of the central nervous system (CNS), known to induce autoreactive T cell response and demyelinating anti-MOG antibodies in multiple sclerosis (MS) patients. Association of HLA class II genes with MS is well established. To better understand the role of HLA class II molecules in disease pathogenesis, we generated transgenic mice that express HLA-DR2, -DR3, -DR4, -DQB1*0601, -DQB1*0604 and -DQ8 without mouse class II (Abeta(0)). We have for the first time characterized the T and B cell epitopes of human MOG restricted by different HLA class II molecules. Immunization with recombinant MOG (rMOG) generated a strong CD4(+) T cell-mediated response in an HLA class II-restricted manner. Cytokine analysis revealed an increase in pro-inflammatory (IFN-gamma, IL-12 and IL-6) and anti-inflammatory (IL-10) cytokines. T cell autoreactivity to MOG was directed against peptides 1-20, 31-50, 61-80 and 91-110, of which three are also immunodominant epitopes for MOG in MS. A strong B cell response to MOG was observed in all transgenic mice, and major B cell epitopes recognized were located within amino acids 1-30, 51-80 and 101-120 of human MOG, which consists of two epitopes reported in MS. Transgenic mice used in this study recognized the immunodominant MOG epitopes similar to HLA class II-restricted human T cells, and would therefore be valuable in elucidating the roles of HLA class II genes and autoantigens in MS.


Kielian, T. and P. D. Drew (2003). "Effects of peroxisome proliferator-activated receptor-gamma agonists on central nervous system inflammation." J Neurosci Res 71(3): 315-25.

            Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a critical role in glucose and lipid metabolism. More recently, PPAR-gamma ligands have been reported to inhibit the expression of proinflammatory molecules by monocytes/macrophages. Of relevance to CNS disease is that PPAR-gamma agonists have been demonstrated to have similar effects on microglia. PPAR-gamma agonists also ameliorate experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. This Mini-Review summarizes the effects of PPAR-gamma agonists in mediating immune responses and the potential of these agonists in the treatment of inflammatory disorders of the CNS.


Kieseier, B. C. and H. P. Hartung (2003). "Multiple paradigm shifts in multiple sclerosis." Curr Opin Neurol 16(3): 247-52.

            PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate of our changing views on the pathogenesis of multiple sclerosis and the therapeutic strategies currently available for multiple sclerosis. RECENT FINDINGS: The most important observations include that (a) axonal loss accounts for permanent disability in multiple sclerosis, (b) remyelination should be possible in theory but fails for unknown reasons in the multiple sclerosis lesion, (c) inflammation can be beneficial, (d) treatment should be initiated early, and (e) immunosuppressive strategies exhibit beneficial effects in progressive forms of the disease. SUMMARY: Our current understanding of the immunopathogenesis of multiple sclerosis has changed in the past. Whereas demyelination was originally thought to be relevant for the lasting neurological deficit, it is nowadays commonly accepted that the extent of axonal loss dictates the degree of permanent clinical disability. How axonal damage can be prevented remains elusive. The interaction between the myelinating cell and the neuron gains increasing attention, however the evolving knowledge has not yet yielded new treatment concepts. Hence for the time being, it seems prudent to make optimal use of current approved therapies. Recent trials underlined the need for early initiation of treatment with immunomodulatory drugs. The superiority of one of the interferons is still a matter of debate, and a conclusive answer cannot be given at present. Finally, with mitoxantrone we have a drug at hand which can be used in progressive forms of multiple sclerosis, especially when other disease modifying drugs are not or no longer effective.


Kieseier, B. C., H. Pischel, et al. (2003). "ADAM-10 and ADAM-17 in the inflamed human CNS." Glia 42(4): 398-405.

            Inflammatory demyelinating disorders of the CNS, such as multiple sclerosis (MS), are mediated, at least in part, by various cytokines and proteases. In the present study, we investigated the expression of A disintegrin and metalloproteinase (ADAM)-17, an important sheddase for various proteins, including tumor necrosis factor-alpha (TNF-alpha), and the p75- and p55-TNF receptors, as well as ADAM-10, a protease implicated in myelin degradation, in post mortem CNS tissue samples from patients with MS, and normal brain tissue (as control) by immunohistochemistry. ADAM-10 was found to be expressed by astrocytes in all MS and control sections studied; however, in some MS sections, perivascular macrophages were determined as an additional cellular source as well. ADAM-17 could be observed exclusively in acute and chronic active MS plaques and localized to invading T lymphocytes. The staining pattern of ADAM-17 in MS plaques was mirrored in distribution and extent by the pattern obtained with an antibody against the p75-TNF-receptor (TNFR-2), whereas TNF-alpha was found to be expressed primarily by perivascular macrophages. In studying cerebrospinal fluid (CSF) samples from MS patients, we were able to detect increased protein levels of ADAM-17 as compared with noninflammatory controls. In addition, increased levels of soluble TNFR-2 could be measured, suggestive of an active shedding process mediated by ADAM-17. The stimulation of peripheral blood mononuclear cells (PBMC) obtained from MS patients and healthy individuals corroborated these findings by revealing expression of ADAM-17 by T lymphocytes and ADAM-10 by macrophages in vitro. Our results indicate that ADAM-10 is expressed constitutively by astrocytes in the normal and inflamed human CNS. In contrast, under inflammatory conditions, ADAM-10, expressed by perivascular macrophages, and ADAM-17, expressed by invading T cells, may actively contribute to the pathogenesis of inflammatory disorders of the CNS. GLIA 42:398-405, 2003. Copyright 2003 Wiley-Liss, Inc.


Kilinc, M., I. Saatci-Cekirge, et al. (2003). "Serial Analysis of Soluble Intercellular Adhesion Molecule-1 Level in Relapsing-Remitting Multiple Sclerosis Patients During IFN-beta1b Treatment." J Interferon Cytokine Res 23(3): 127-33.

            In this controlled study, we investigated the serum and cerebrospinal fluid (CSF) levels of soluble intercellular adhesion molecule-1 (sICAM-1) in relapsing-remitting multiple sclerosis (RRMS) patients and changes in the levels of this adhesion molecule during interferon-beta1b (IFN-beta1b) treatment. We also investigated the changes in the levels of sICAM-1 in correlation with disease activity and with findings on magnetic resonance images (MRI). The study included 24 patients (16 females and 8 males) who were confirmed to have RRMS based on the criteria of Poser et al. Sixteen of the patients received IFN-beta1b (Betaseron((R)), Berlex Laboratories, Schering AG Germany, Berlin) treatment, and 8 did not receive this therapy. The levels of sICAM-1 in the MS patients' serum and CSF were significantly higher than levels in individuals with noninflammatory neurologic disease (p = 0.0081 and p = 0.0001, respectively). In the first 3 months of the study, MS patients treated with IFN-beta1b showed a significant rise in sICAM-1 levels (p = 0.0023), whereas their untreated counterparts showed no significant change. Neither of the groups showed a significant correlation between sICAM-1 level and disease activity demonstrated by MRI or between sICAM-1 level and clinical disease activity. The findings suggest that IFN-beta1b treatment may have a short-term upregulating effect on sICAM-1.


Killestein, J., E. L. Hoogervorst, et al. (2003). "Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis." J Neuroimmunol 137(1-2): 140-3.

            Cannabinoids can modulate the function of immune cells. We here present the first human in vivo study measuring immune function in 16 MS patients treated with oral cannabinoids. A modest increase of TNF-alpha in LPS-stimulated whole blood was found during cannabis plant-extract treatment (p=0.037), with no change in other cytokines. In the subgroup of patients with high adverse event scores, we found an increase in plasma IL-12p40 (p=0.002). The results suggest pro-inflammatory disease-modifying potential of cannabinoids in MS.


Kim, H., J. M. Suh, et al. (2003). "Thyrotropin-mediated repression of class II trans-activator expression in thyroid cells: involvement of STAT3 and suppressor of cytokine signaling." J Immunol 171(2): 616-27.

            It has been suggested that class I and class II MHC are contributing factors for numerous diseases including autoimmune thyroid diseases, type 1 diabetes, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis. The class II trans-activator (CIITA), which is a non-DNA-binding regulator of class II MHC transcription, regulates the constitutive and inducible expression of the class I and class II genes. FRTL-5 thyroid cells incubated in the presence of IFN-gamma have a significantly higher level of cell surface rat MHC class II RTI.B. However, the IFN-gamma-induced RT1.B expression was suppressed significantly in cells incubated in the presence of thyrotropin. Thyrotropin (TSH) represses IFN-gamma-induced CIITA expression by inhibiting type IV CIITA promoter activity through the suppression of STAT1 activation and IFN regulatory factor 1 induction. This study found that TSH induces transcriptional activation of the STAT3 gene through the phosphorylation of STAT3 and CREB activation. TSH induces SOCS-1 and SOCS-3, and TSH-mediated SOCS-3 induction was dependent on STAT3. The cell line stably expressing the wild-type STAT3 showed a higher CIITA induction in response to IFN-gamma and also exhibited TSH repression of the IFN-gamma-mediated induction of CIITA. However, TSH repression of the IFN-gamma-induced CIITA expression was not observed in FRTL-5 thyroid cells, which stably expresses the dominant negative forms of STAT3, STAT3-Y705F, and STAT3-S727A. This report suggests that TSH is also engaged in immunomodulation through signal cross-talk with the cytokines in thyroid cells.


Kim, J. K., F. G. Mastronardi, et al. (2003). "Multiple Sclerosis: An important role for post-translational modifications of myelin basic protein in pathogenesis." Mol Cell Proteomics.

            SUMMARY Myelin basic protein (MBP) represents a candidate autoantigen in multiple sclerosis (MS). We isolated MBP from normal and MS human white matter and purified six components (charge isomers) to compare the post-translational modifications on each. The sites and extent of methylation, deimination and phosphorylation were documented for all tryptic peptides by mass spectrometry. We found that mono and dimethylated arginine 107 was increased in MS samples; deimination of arginine occurred at a number of sites and was elevated in MS; phosphorylation was observed in 10 peptides in normal samples but was greatly reduced or absent in most peptides from MS samples. Data obtained with MBP isolated from fresh brain obtained from a spontaneously demyelinating mouse model supported the view that the changes observed in human brain were probably related to pathogenesis of demyelination, i.e., we found decreased phosphorylation and decreased amounts of glycogen synthesis kinase (GSK) in brain homogenates using specific antibodies. This study represents the first to define post-translational modifications in demyelinating disease and suggest an important role in pathogenesis.


Kim, N. R., M. P. Chung, et al. (2003). "Pulmonary lymphangioleiomyomatosis and multiple hepatic angiomyolipomas in a man." Pathol Int 53(4): 231-5.

            Pulmonary lymphangioleiomyomatosis (LAM) is an uncommon disease that to this point has been known to occur exclusively in reproductive women. To our knowledge, only one case of pulmonary LAM that was proven pathologically has been reported in a genotypical and phenotypical man. Multiple occurrence of hepatic angiomyolipomas is also rare, and only six cases have been found in the literature. Here, we report a biological and phenotypical man who had pulmonary LAM and multiple hepatic angiomyolipomas, leading to a presumptive diagnosis of tuberous sclerosis. This unsual presentation further broadens the wide spectrum of various clinicopathological aspects of pulmonary lymphangioleiomyomatosis and hepatic angiomyolipoma. Here, we emphasize that multiple hepatic angiomyolipomas should be distinguished from hepatic tumors, particularly in an endemic area for hepatocellular carcinoma. Further, pulmonary lymphangioleiomyomatosis can be a cause of cystic pulmonary disease even in a man.


Kira, J. (2003). "Multiple sclerosis in the Japanese population." Lancet Neurol 2(2): 117-27.

            Multiple sclerosis (MS) in Asian populations is characterised by the selective and severe involvement of the optic nerve and spinal cord as well as low prevalence rates. 15-40% of cases of MS in Japan are of this "opticospinal" type. This form of MS generally has a higher age at onset and a higher female to male ratio than conventional MS. Opticospinal MS is also characterised by frequent relapses, severe disability, few brain lesions visible on MRI, long lesions extending over many vertebral segments visible on spinal-cord MRI, pleocytosis and an absence of oligoclonal bands in the CSF, and a pronounced shift in the responses of T-helper-1 and T-cytotoxic-1 cells throughout relapse and remission phases. Conventional MS in Japanese people is, like MS in white people, associated with HLA-DRB1*1501, whereas opticospinal MS is associated with HLA-DPB1*0501. In Japanese people born after modernisation in the 1960s, the ratio of conventional to opticospinal MS has increased rapidly. Opticospinal MS is likely to have a distinct immune-mediated mechanism, which is not operative in conventional MS.


Kneebone, II, E. C. Dunmore, et al. (2003). "Symptoms of depression in older adults with multiple sclerosis (MS): comparison with a matched sample of younger adults." Aging Ment Health 7(3): 182-5.


Kob, M., J. Harvey, et al. (2003). "A novel and rapid assay for the detection of neutralizing antibodies against interferon-beta." Mult Scler 9(1): 32-5.

            There is evidence that neutralizing antibodies (NAB) have a negative influence on the clinical and magnetic resonance imaging effects of interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. The current methods for NAB detection are restricted to specialized laboratories because they require a cell culture and sometimes a viral culture. Results are typically obtained after several weeks. Therefore, the development of a simple and rapid assay for the detection of NAB was sought. Whole blood samples from 28 NAB-positive patients and 110 NAB-negative patients (52 with IFNbeta and 58 without IFNbeta therapy) were incubated with IFNbeta 976 IU/mL for 24 hours. MxA protein levels--a specific marker of class I IFN bioactivity--were measured in paired samples with and without IFNbeta incubation and the difference in MxA levels was calculated. The mean increase of MxA levels after stimulation with IFNbeta in the NAB-positive group was 8 ng/mL (range 0-44 ng/mL) and in the NAB-negative group was 84 ng/mL (range 0-302 ng/mL). Using an increase of 22.5 ng/mL as cut-off) the specificity of the MxA stimulation assay was 81.2% and the sensitivity was 96.4%. The whole blood MxA stimulation assay is virtually as sensitive as the conventional NAB assay but somewhat less specific. However, this is outweighed by the procedural advantage of the assay, which is simpler, quicker and much less expensive.


Koike, F., J. Satoh, et al. (2003). "Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis." J Neuroimmunol 139(1-2): 109-18.

            The molecular mechanisms for the interferon beta (IFNbeta) treatment of multiple sclerosis (MS) remain to be characterized. Using cDNA microarray technology, we have compared the gene expression profile of T and non-T cells derived from relapsing-remitting MS before and after treatment with IFNbeta-1b. IFNbeta treatment significantly altered expression of 21 genes out of 1263 at 3 and 6 months after treatment. These genes included nine with IFN-responsive promoter elements. Whereas there was no change in Th1 or Th2 marker genes, some of the changes were unexpected but coincided with the beneficial effect of IFNbeta in MS.


Kolar, O. J., J. A. Bauerle, et al. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1825.


Kolitz, B. P., R. D. Vanderploeg, et al. (2003). "Development of the Key Behaviors Change Inventory: a traumatic brain injury behavioral outcome assessment instrument." Arch Phys Med Rehabil 84(2): 277-84.

            OBJECTIVE: To describe the development and initial validation of a neurobehavioral outcome measure, the Key Behaviors Change Inventory (KBCI), for individuals with traumatic brain injury (TBI). DESIGN: Scale construction and development, and validity study. SETTING: Large state university and postal survey. PARTICIPANTS: Seventy-five volunteer undergraduate students and 25 volunteer collateral informants of individuals with TBI participated in the item-analysis phase. Thirty members of the Brain Injury Association and 20 members of the National Multiple Sclerosis Society rated both an identified patient and an age- and gender-equated control in the validation phase. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Content validity was examined through expert panel item sorts. Scale internal consistencies were examined with the Cronbach alpha. Construct validity was examined by comparing scale elevations between controls and 2 neurologic groups. RESULTS: Item-analysis procedures resulted in 8 scales of 8 items each: inattention, impulsivity, unawareness of problems, apathy, interpersonal difficulties, communication problems, somatic difficulties, and emotional adjustment. Internal consistency reliability coefficients ranged from.82 to.91. Multivariate analysis of variance revealed significant (P</=.001) differences in scale elevations among TBI, multiple sclerosis (MS), and control groups. The TBI and MS groups scored significantly higher than the control group on all scales; a subset of KBCI scales discriminated between the 2 neurologic groups. CONCLUSION: The KBCI was both sensitive and specific to typical behavioral changes after TBI, thus supporting its usefulness in rehabilitation settings. Cross-validation and development of a normative database are future steps necessary in its development.


Koopman, W. (2003). "Needs assessment of persons with multiple sclerosis and significant others: using the literature review and focus groups for preliminary survey questionnaire development." Axone 24(4): 10-5.

            The purpose of this study was to conduct focus group interviews to obtain information for development of a needs assessment questionnaire. Four focus groups were conducted with 10 people with multiple sclerosis (MS) and five significant others. A facilitator from the learning services department at the hospital conducted the interviews guided by questions developed by the researcher. The focus group interviews were audiotaped and transcribed. The researcher analyzed the transcribed interviews. Content analysis was used to analyze the transcribed data creating categories from key words and phrases as they appeared. The findings were grouped by themes. The results highlighted the participants' experiences and needs regarding physical changes; sources of assistance; unmet needs; psychological, employment, leisure, and informational needs. A comparison of themes developed from the focus groups and in the literature captured categories for questionnaire development. One new theme, leisure, was not found in the literature and was incorporated based on the findings of this study. The final categories for questionnaire development were: physical, health, psychological, financial, employment/meaningful daytime activity and leisure, accessibility and information. A survey questionnaire was developed from the focus group data using the phraseology of the participants.


Kottler, U. B., H. J. Trojan, et al. (2003). "[Multiple tumors of the facial skin]." Ophthalmologe 100(4): 338-9.


Kozuka, T., K. Kojima, et al. (2003). "Autoimmune neutropenia associated with multiple sclerosis." Intern Med 42(1): 102-4.

            A 53-year-old Japanese man with multiple sclerosis developed autoimmune neutropenia. The neutrophil count was consistently less than 0.2 x 10(9)/l, irrespective of the disease activity of multiple sclerosis or the administration of immunosuppressive agents or granulocyte colony-stimulating factor. After high-dose gamma-globulin therapy was started, temporary increases in the neutrophil count were observed. Despite a wide spectrum of clinical manifestations in multiple sclerosis, autoimmune neutropenia has never been reported previously.


Kralik, D., T. Koch, et al. (2003). "The salience of the body: transition in sexual self-identity for women living with multiple sclerosis." J Adv Nurs 42(1): 11-20.

            AIM: The purpose of this paper is to outline understandings about the construction of sexuality and the impact of a changing body for women living with multiple sclerosis (MS). We suggest that the process of transition towards incorporating the experience of chronic illness into one's life is influenced by the (re)construction of self-identity. DESIGN AND METHODS: A participatory action process guided the research. The women joined the authors for five group sessions that totalled 15 hours of contact time. In addition, we offered women the opportunity for one-to-one interviews at home. Nine women volunteered to participate. This allowed us to gain additional in-depth data about individual experiences. The interpretive framework was guided by the self-identity literature. When reading the transcripts we questioned: What is going on here? What does this say about the construction of self? What does this say about the construction of identity? What influence does the body have in the construction of self-identity? Analysis was collaborative (with the women) and the resultant emerging construction of sexuality is shared in this paper. Data generated during one-to-one interviews are privileged and we include two accounts from women who live with MS. The women's stories focus on sexuality, however, within this sexual context, we observed shifts in self-identity which we contend may shape the illness transition experience. FINDINGS: The rationale for privileging only two accounts is to expand understanding of Ordinariness and Extraordinariness with particular focus on the salience of the body in the 'sexual' lives of the women. Self-identity was shaped by how they felt about themselves as sexual beings, how they experienced their body, how they felt about sexual activities and by the way others reacted to them. Importantly, we view the women's sense of self, identity and the relationship to the body and find that shifts in self identity shape the woman's transition towards Ordinariness. CONCLUSIONS: This exploration of illness experiences is a reminder that our bodies are vehicles for our sense of self and identity. Cultural, educational, social, religious and family contexts all impact on women's capacity to shape the consequences of illness and the choices available to them. Facilitating women towards an awareness of the choices available in order to sustain or reclaim self may in turn expedite transition towards Ordinariness so that illness may become a part of their life.


Kreisler, A., J. de Seze, et al. (2003). "Multiple sclerosis, interferon beta and clinical thyroid dysfunction." Acta Neurol Scand 107(2): 154-7.

            The objective of this study was to investigate frequency and presentation of clinical thyroid dysfunction in patients treated with interferon beta (IFN-beta). We have collected the cases of clinical thyroid dysfunction in 700 consecutive patients receiving IFN-beta for multiple sclerosis (MS). Five patients (four women, one man) treated with IFN-beta1b developed hyperthyroidism. Three of them have secondary progressive MS, and two have relapsing-remitting MS. It was necessary to stop IFN-beta in three cases; these patients still require carbimazole after several months. In the two other cases, hyperthyroidism disappeared spontaneously. Two patients (one man and one woman) treated with IFN-beta1a developed hypothyroidism. One of them required l-thyroxine. Lastly, an increased thyroid volume without modification of thyroid hormones plasma levels was discovered in a patient receiving IFN-beta1a. Among patients treated with IFN-beta, clinical thyroid dysfunction is much rarer than laboratory thyroid dysfunction. However, this side-effect is sometimes severe.


Krivickas, L. S. (2003). "Amyotrophic lateral sclerosis and other motor neuron diseases." Phys Med Rehabil Clin N Am 14(2): 327-45.

            The anterior horn cell diseases, with the exception of polio, are progressive degenerative diseases of the motor neurons. These disorders include SMA types I to III in children and familial and sporadic ALS and its variants (PMA, PLS, and PBP), Kennedy's disease, and SMA type IV in adults. The electrodiagnostic study is a crucial step in the diagnostic process for all of these disorders. In general, motor NCS may be normal or reveal low CMAP amplitudes with relatively normal conduction velocities. Sensory NCS, except in the case of Kennedy's disease, are normal. The NEE is notable for the often abundant presence of abnormal spontaneous activity, including fibrillation potentials and positive sharp waves, fasciculation potentials, and complex repetitive discharges. Motor unit morphology is abnormal, with polyphasic motor units and large amplitude and duration MUAPs when the disease is slowly progressive. Recruitment in affected muscles is reduced with abnormally rapidly firing motor units. To diagnose a widespread disorder of the motor neurons, abnormalities must be present in multiple muscles with different nerve root and peripheral nerve innervation in multiple limbs. The Lambert Criteria and the El Escorial Criteria are the two most widely accepted sets of electrodiagnostic criteria for ALS. The electrodiagnostic diagnosis must be supported by appropriate history and physical examination findings and the exclusion, via neuroimaging and laboratory testing, of other diseases that may mimic a generalized disorder of the motor neurons.


Kriz, J., G. Gowing, et al. (2003). "Efficient three-drug cocktail for disease induced by mutant superoxide dismutase." Ann Neurol 53(4): 429-36.

            There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). Because evidence suggests that multiple pathways may contribute to ALS pathogenesis, we tested in a mouse model of ALS (SOD1(G37R) mice) a combination approach consisting of three drugs for distinct targets in the complex pathway to neuronal death: minocycline, an antimicrobial agent that inhibits microglial activation, riluzole, a glutamate antagonist, and nimodipine, a voltage-gated calcium channel blocker. The efficacy of this three-drug cocktail was remarkable when administered in the diet from late presymptomatic stage (8-9 months). It delayed the onset of disease, slowed the loss of muscle strength, and increased the average longevity of SOD1(G37R) mice by 6 weeks. The protective effect of the treatment was corroborated by the reduced immunodetection signals for markers of gliosis and neurodegeneration in the spinal cord of SOD1(G37R) mice. These results indicate that such three-drug combination may represent an effective strategy for ALS treatment.


Kroll, T., P. W. Beatty, et al. (2003). "Primary care satisfaction among adults with physical disabilities: the role of patient-provider communication." Manag Care Q 11(1): 11-9.

            OBJECTIVES: To determine overall satisfaction with primary care among people with cerebral palsy, multiple sclerosis, and spinal cord injury, and to identify potential differences in primary care satisfaction between managed care (MC) and fee-for-service (FFS) enrollees with these physical disabilities. PARTICIPANTS: The sample consisted of 195 people with cerebral palsy (CP), multiple sclerosis (MS), and spinal cord injury (SCI), between the ages of 18 and 65 who had received primary care services in the six months prior to the survey. MEASUREMENTS: Satisfaction with various aspects of primary care were assessed using a 10-item self-report measure. Respondents were compared with regard to service satisfaction based on disability and insurance type (MC vs. FFS). Satisfaction items were summed up to produce an unweighted index of overall satisfaction. In the analysis we used non-parametric statistics, such as Kruskal-Wallis One Way ANOVA and Mann-Whitney Rank tests. Post hoc alpha corrections were performed using the Holms Stepdown Procedure. CONCLUSIONS: The lack of disability-specific knowledge among primary care providers is consistent with findings of other studies. People with physical disabilities in managed care plans are less satisfied with how their providers communicate with them, relative to those in FFS plans. Poor patient-provider communication may place individuals with certain physical disabilities at risk for not receiving appropriate care.


Krum, H. and D. Liew (2003). "Current status of endothelin blockade for the treatment of cardiovascular and pulmonary vascular disease." Curr Opin Investig Drugs 4(3): 298-302.

            With recognition of the significant role of the endothelin system in cardiovascular and pulmonary vascular diseases, attention has turned to the therapeutic application of agents that antagonize this system. Three strategies can be employed: dual endothelin receptor (ETA and ETB) antagonism, selective ETA antagonism and inhibition of endothelin-converting enzymes. The first two strategies have been evaluated in late-phase clinical trials, with mixed results. The use of the dual endothelin receptor antagonist bosentan in pulmonary arterial hypertension has been successful. Available data are less compelling, but nonetheless promising, for the use of bosentan in digital ulceration secondary to systemic sclerosis, and tezosentan (another dual receptor blocker) in acute heart failure. Both types of receptor antagonists, however, have been evaluated in systemic hypertension and chronic systolic heart failure and are unlikely to be further developed in these areas. For the treatment of hypertension, their (moderate) efficacy and safety/tolerability profiles appear no more favorable than existing antihypertensive agents. In terms of treatment for chronic heart failure, these agents appear to offer no further benefit over standard therapy for the treatment of chronic heart failure, and in fact, may be associated with poorer outcomes. The complexity of the endothelin system and its diverse roles in multiple disease states will ensure its position as a target for drug development.


Krupp, L. B. (2003). "Fatigue in multiple sclerosis: definition, pathophysiology and treatment." CNS Drugs 17(4): 225-34.

            Fatigue is a common disabling symptom of multiple sclerosis (MS). It is often considered a state of exhaustion distinct from depressed mood or physical weakness. Fatigue can be assessed by either self-report scales or performance-based measures; however, neither method captures all features of fatigue. Fatigue in MS frequently leads to unemployment. It is associated with a sense of loss of control over one's environment, low positive affect, psychological distress and neurological impairment. To date there is no reproducible neuroimaging marker or biological correlate that has been identified. Proposed pathological mechanisms of fatigue in MS include neuronal factors such as dysfunction of premotor, limbic, basal ganglia or hypothalamic areas; disruption of the neuroendrocrine axis leading to low arousal; alteration in serotoninergic pathways; changes in neurotransmitter levels; and altered CNS functioning caused by a disruption of the immune response. Treatment of fatigue is best approached in a multidisciplinary fashion that incorporates nonpharmacological interventions as well as medication. Amantadine and modafinil are among the most commonly used medications for fatigue associated with MS. Both medications have been studied with positive results in controlled clinical trials. Additional research towards measurement and pathogenesis of fatigue will hopefully lead to improved therapies.


Kumakura, S. and S. Kobayashi (2003). "Autoimmune neutropenia." Intern Med 42(2): 133-4.


Kwiatkowska-Patzer, B., B. Baranowska, et al. (2003). "Influence of spinal cord protein hydrolysate upon the blood brain barrier changes due to experimental allergic encephalomyelitis in Lewis rats. Ultrastructural study." Folia Neuropathol 41(1): 29-34.

            A specific protein (antigen) given orally is a known method of introducing tolerance of immunological response to this antigen. This method has recently been reviewed by some authors as a possible tool in the treatment of autoaggressive diseases, such as multiple sclerosis. The experimental allergic encephalomyelitis (EAE) respected animal model for MS was used for the study. The aim of the study was the evaluation of the effect of pig spinal cord protein hydrolysate given orally upon the ultrastructural changes in the blood-brain barrier image in EAE. Changes of EAE are as follows: opened channels from basal membrane (tight junction) on the border with astrocytes, fragments of organelles of the cells, oedema of astrocytes, presence of vesicles with fluid, presence of macrophages with phagolysosomes. After pre-treatment with spinal cord hydrolysate up to 6 weeks all the above changes were normalised. These findings are promising as a possible tool in the clinical treatment of sclerosis multiplex.


Lakatos, A., P. M. Smith, et al. (2003). "Meningeal cells enhance limited CNS remyelination by transplanted olfactory ensheathing cells." Brain 126(Pt 3): 598-609.

            Olfactory ensheathing cells (OECs) are candidate cells for transplant-mediated repair of persistent demyelination in diseases such as multiple sclerosis. If this approach is to make the transition from laboratory to clinic, an important issue is the most suitable composition of the OEC transplant. Isolation of OECs involves concurrent isolation of other cell types, and specific selection techniques are required to produce purified OECs. In this study we address whether the purity of the OEC transplant affects their ability to remyelinate. Surprisingly, we find that a purified preparation of OECs, selected on the basis of low-affinity nerve growth factor receptor (p75) expression, results in less extensive remyelination than an unpurified preparation following transplantation into areas of persistent demyelination in rodent CNS in the X-irradiation/ethidium bromide (X-EB) model. A distinctive feature of the unpurified preparation both in vitro and following transplantation is the presence of meningeal cells. When meningeal cells are added to purified OECs there is a significant improvement in the extent of remyelination compared with the purified OECs, although if the cells are present in too great an abundance this beneficial effect is lost. These results highlight the important concept that the regenerative properties of OECs are profoundly influenced by the cells with which they are transplanted.


Lampe, J. B., S. Schneider-Schaulies, et al. (2003). "Expression of the interferon-induced MxA protein in viral encephalitis." Neuropathol Appl Neurobiol 29(3): 273-9.

            MxA protein accumulates cytoplasmically in response to interferon stimulation, and mediates resistance against several viruses. In order to test whether MxA may serve as a diagnostic tool for viral infections of the central nervous system (CNS), we performed MxA immunohistochemistry on biopsies and autopsies of 57 patients with neurological disorders of known viral and nonviral aetiology. MxA was detectable in all HIV patients with proven opportunistic viral encephalitis, in all patients suffering from isolated viral encephalitis, in one of three HIV patients with cerebral toxoplasmosis, and in one case of micronodular encephalitis. No MxA was detectable in HIV patients with isolated HIV encephalitis or HIV infection accompanied by an opportunistic nonviral disorder. We were unable to show MxA expression in a variety of nonviral inflammatory and noninflammatory disorders of the CNS. Several cases of Rasmussen's encephalitis and multiple sclerosis tested negative, arguing against their possible viral aetiology. Two-colour immunohistochemistry identified macrophages and activated microglia as MxA expressing cells. In all studied cases MxA expression was accompanied by a marked T-cell infiltrate. Therefore, the detection of MxA-protein is a sensitive adjuvant marker for those cases of viral encephalitis which are accompanied by pronounced lymphocytic infiltrates.


Landtblom, A. M., K. A. Thuomas, et al. (2003). "Hypointensity in T2-weighted images of the basal ganglia in solvent-exposed patients with multiple sclerosis: clinical, MRI and CSF characteristics." Neurol Sci 24(1): 2-9.

            Several studies have indicated an association between MS and organic solvent exposure. Our objective was to analyse differences regarding cerebrospinal fluid (CSF) properties, magnetic resonance imaging (MRI) features and cerebral metabolites, measured by proton spectroscopy (1H-MRS), in 20 patients with spontaneous multiple sclerosis (MS) and in 20 patients with MS after solvent exposure; 15 healthy subjects served as controls. CSF examinations were retrospectively reviewed from the medical files. There were no significant differences in the CSF regarding pleocytosis, spinal-serum albumin ratio or mean extended IgG index. However, T2-weighted images of the solvent-exposed MS patients showed more hypointenseareas in the basal ganglia. Hypointensity on T2-weighted images of the basal ganglia in the solvent-exposed MS patients may correspond to neurodegeneration and could be an early event in MS.


Lappe-Siefke, C., S. Goebbels, et al. (2003). "Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination." Nat Genet 33(3): 366-74.

            Myelination of axons by oligodendrocytes enables rapid impulse propagation in the central nervous system. But long-term interactions between axons and their myelin sheaths are poorly understood. Here we show that Cnp1, which encodes 2',3'-cyclic nucleotide phosphodiesterase in oligodendrocytes, is essential for axonal survival but not for myelin assembly. In the absence of glial cyclic nucleotide phosphodiesterase, mice developed axonal swellings and neurodegeneration throughout the brain, leading to hydrocephalus and premature death. But, in contrast to previously studied myelin mutants, the ultrastructure, periodicity and physical stability of myelin were not altered in these mice. Genetically, the chief function of glia in supporting axonal integrity can thus be completely uncoupled from its function in maintaining compact myelin. Oligodendrocyte dysfunction, such as that in multiple sclerosis lesions, may suffice to cause secondary axonal loss.


Lappin, M. S., F. W. Lawrie, et al. (2003). "Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial." Altern Ther Health Med 9(4): 38-48.

            CONTEXT: There is a growing literature on the biological and clinical effects of pulsed electromagnetic fields. Some studies suggest that electromagnetic therapies may be useful in the treatment of chronic illnesses. This study is a follow-up to a placebo controlled pilot study in which multiple sclerosis (MS) patients exposed to weak, extremely low frequency pulsed electromagnetic fields showed significant improvements on a composite symptom measure. OBJECTIVE: To evaluate the effects of a pulsed electromagnetic therapy on MS related fatigue, spasticity, bladder control, and overall quality of life. DESIGN: A multi-site, double-blind, placebo controlled, crossover trial. Each subject received 4 weeks of the active and placebo treatments separated by a 2-week washout period. SETTING: The University of Washington Medical Center in Seattle Wash, the Neurology Center of Fairfax in Fairfax, Va, and the headquarters of the Multiple Sclerosis Association of America in Cherry Hill, NJ. SUBJECTS: 117 patients with clinically definite MS. INTERVENTION: Daily exposure to a small, portable pulsing electromagnetic field generator. MAIN OUTCOME: The MS Quality of Life Inventory (MSQLI) was used to assess changes in fatigue, bladder control, spasticity, and a quality of life composite. RESULTS: Paired t-tests were used to assess treatment differences in the 117 subjects (81% of the initial sample) who completed both treatment sessions. Improvements in fatigue and overall quality of life were significantly greater on the active device. There were no treatment effects for bladder control and a disability composite, and mixed results for spasticity. CONCLUSIONS: Evidence from this randomized, double-bind, placebo controlled trial is consistent with results from smaller studies suggesting that exposure to pulsing, weak electromagnetic fields can alleviate symptoms of MS. The clinical effects were small, however, and need to be replicated. Additional research is also needed to examine the possibility that ambulatory patients and patients taking interferons for their MS may be most responsive to this kind of treatment.


Lashley, F. R. (2003). "A review of sleep in selected immune and autoimmune disorders." Holist Nurs Pract 17(2): 65-80.

            Evidence for the reciprocal role of the immune system in sleep is growing. Sleep disturbances are believed to be both a cause and a consequence of various immune and autoimmune conditions.


Lassmann, H., M. Reindl, et al. (2003). "A new paraclinical CSF marker for hypoxia-like tissue damage in multiple sclerosis lesions." Brain 126(Pt 6): 1347-57.

            Recent studies on the immunopathology of multiple sclerosis revealed a heterogeneity in the patterns of demyelination, suggesting interindividual differences in the mechanism responsible for myelin destruction. One of these patterns of demyelination, characterized by oligodendrocyte dystrophy and apoptosis, closely mimics myelin destruction in acute white matter ischaemia. In the course of a systematic screening for virus antigen expression in multiple sclerosis brains, we identified a monoclonal antibody against canine distemper virus, which detects a cross-reactive endogenous brain epitope, highly expressed in this specific subtype of actively demyelinating multiple sclerosis lesions with little or no immunoreactivity in other active multiple sclerosis cases. The respective epitope, which is a phosphorylation-dependent sequence of one or more proteins of 50, 70 and 115 kDa, is also expressed in a subset of active lesions of different virus-induced inflammatory brain diseases, but is present most prominently and consistently in acute lesions of white matter ischaemia. Its presence is significantly associated with nuclear expression of hypoxia-inducible factor-1 alpha within the lesions of both inflammatory and ischaemic brain diseases. The respective epitope is liberated into the CSF and, thus, may become a useful diagnostic tool to identify clinically a defined multiple sclerosis subtype.


Lassmann, H. (2003). "Axonal injury in multiple sclerosis." J Neurol Neurosurg Psychiatry 74(6): 695-7.


Lassmann, H. (2003). "Brain damage when multiple sclerosis is diagnosed clinically." Lancet 361(9366): 1317-8.


Lassmann, H. (2003). "Hypoxia-like tissue injury as a component of multiple sclerosis lesions." J Neurol Sci 206(2): 187-91.

            Recent data suggest that the mechanisms of demyelination and tissue damage in multiple sclerosis (MS) are heterogenous. In this review, evidence is discussed, which show that in a subset of multiple sclerosis patients the central nervous system (CNS) lesions show profound similarities to tissue alterations found in acute white matter stroke, thus suggesting that a hypoxia-like metabolic injury is a pathogenetic component in a subset of inflammatory brain lesions. Both, vascular pathology as well as metabolic disturbances induced by toxins of activated macrophages and microglia may be responsible for such lesions in multiple sclerosis.


Lazeron, R. H., S. A. Rombouts, et al. (2003). "A paced visual serial addition test for fMRI." J Neurol Sci 213(1-2): 29-34.

            BACKGROUND AND PURPOSE: The Paced Auditory Serial Attention Task (PASAT) is an attention and information processing task used in patients with diffuse brain disorders, like cerebral trauma and multiple sclerosis (MS). Based on the PASAT we used a adapted version of the test to assess several cognitive functions with fMRI. In this study we investigated the activation pattern on a group and individual level and upon parametric stimulation. METHODS: Nine young, healthy, right-handed subjects (mean age 24 years) were studied. The test contrasts an adding-and-memory stage with a control stage in a block design, at two different speeds. Group average maps (random effects analysis, p=0.05) were created to identify the brain areas subserving this task. For each area found active in the group map, the percentage of individuals showing activation in that same anatomical area was calculated. RESULTS: Group activation was localized in the superior and inferior parietal lobe bilaterally, the superior frontal gyrus bilaterally, the left medial frontal gyrus, the left inferior frontal gyrus and adjacent part of the insula, the anterior part of the cingulate gyrus and some cerebellar areas. For the main activated areas, 78-100% of the individual subjects showed activation in that same area. Contrasting the low speed with the high speed condition yielded activation with a considerable individual variation. CONCLUSION: The group mean activated areas were located mainly in the frontal and parietal lobes and those areas were also activated in the majority of the subjects, indicating limited inter-individual variation, rendering this test suitable for clinical applications in a variety of neurological disorders.


Leary, S. M. and A. J. Thompson (2003). "Interferon beta-1a in primary progressive multiple sclerosis." J Neurol Sci 206(2): 215-6.

            There is currently no disease-modifying treatment proven to be of efficacy in primary progressive multiple sclerosis (PPMS). However, a number of therapeutic trials have recently been specifically designed for this group. These include a randomised controlled trial of interferon beta-1a which is discussed here. It is hoped that therapeutics in primary progressive multiple sclerosis will continue to expand and effective therapeutic agents will be developed.


Leary, S. M., D. H. Miller, et al. (2003). "Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial." Neurology 60(1): 44-51.

            BACKGROUND: Patients with primary progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to primary progressive MS. METHODS: Fifty subjects were randomized to weekly IM interferon beta-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability. Secondary outcomes included the timed 10-meter walk, nine-hole peg test, and on MRI, T2 and T1 brain lesion loads and brain and spinal cord atrophy. RESULTS: The 30- microg dose of interferon beta-1a was well tolerated, but the 60- microg dose caused severe flulike reactions and raised liver enzymes. No treatment effect was seen on the primary endpoint. Subjects on interferon beta-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of ventricular enlargement than controls (p = 0.025). CONCLUSIONS: This study has demonstrated that interferon beta-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.


Lebrun, C., V. Bourg, et al. (2003). "[Relapsing-remitting inflammatory disease of the central nervous system with normal MRI: multiple sclerosis or phenocopy in a series of 15 patients]." Rev Neurol (Paris) 159(4): 397-404.

            Multiple sclerosis is a demyelinating disease of central nervous system. Although many sub-types and clinical forms are identified, diagnosis is clearly related to the detection of MS lesions on brain MRI. We report data of 15 patients admitted in Nice for suspicion of MS after clinical relapsing-remitting or progressive symptoms. Extensive screening tests (i.e blood sample, CSF, MRI, spectroscopy) were performed at onset and at each relapse. All patients had normal-appearing white matter on spinal cord and brain MRI. Nevertheless, 11 patients can be considered as MS according to McDonald criteria.


Lechner-Scott, J., L. Kappos, et al. (2003). "Can the Expanded Disability Status Scale be assessed by telephone?" Mult Scler 9(2): 154-9.

            Information from patients who are unable to continue their visits to a study centre may be of major importance for the interpretation of results in multiple sclerosis (MS) clinical trials. To validate a questionnaire based on the Expanded Disability Status Scale (EDSS), patients in five different European centres were assessed independently by pairs of trained EDSS raters, first by telephone interview and a few days later by standardized neurological examination. Seventy women and 40 men with an average age of 43.7 years (range 19-74 years) were included in the study. Mean EDSS score at the last visit was 4.5 (0-9). EDSS assessment by telephone was highly correlated with the EDSS determined by physical examination (Pearson's correlation coefficient = 0.95). An intraclass correlation coefficient (ICC) of 94.8% was found for the total sample; 77.6% and 86%, respectively, for patients with EDSS < 4.5 (n = 46) and > 4.5 (n = 64). Kappa values for full agreement were 0.48; for variation by +0.5 steps and +1.0 steps, 0.79 and 0.90, respectively. Best agreement could be found in higher EDSS scores, where assessment by telephone interview might be needed most. The telephone questionnaire is a valid tool to assess EDSS score in cases where the patient is unable to continue visiting a study centre or in long-term follow-up of trial participants.


Ledeboer, A., A. Wierinckx, et al. (2003). "Regional and temporal expression patterns of interleukin-10, interleukin-10 receptor and adhesion molecules in the rat spinal cord during chronic relapsing EAE." J Neuroimmunol 136(1-2): 94-103.

            Adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mediate leukocyte infiltration into the CNS, in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). Because exogenous interleukin-10 (IL-10) inhibits ICAM-1 and VCAM-1 expression and clinical EAE, we hypothesize that endogenous IL-10 signaling may suppress expression of adhesion molecules. In a rat model of chronic relapsing EAE, expression levels of IL-10 and its receptor (IL-10R1), ICAM-1 and VCAM-1 mRNA in the spinal cord are markedly increased, whereas levels of IL-10 mRNA remain relatively low. The temporal pattern of mRNA and protein expression showed marked differences between spinal cord levels. During relapse, IL-10, IL-10R1, ICAM-1, VCAM-1 mRNA levels and neurological scores show positive correlations. We conclude that endogenous IL-10 is not a crucial factor inhibiting adhesion molecule expression in this model.


Lee, D. M., H. S. Jeon, et al. (2003). "Transverse myelitis in a patient with primary antiphospholipid syndrome." Yonsei Med J 44(2): 323-7.

            The neurological manifestations of antiphospholipid syndrome (APS) are diverse. Transverse myelitis (TM) is an uncommon, but well-known neurological complication of systemic lupus erythematosus (SLE). On the other hand, the reported cases associated with primary APS are extremely rare. To our knowledge, this is the first report of TM in a patient with primary APS in Korea. A 32-year-old male patient was admitted with the sudden onset of numbness, a tingling sensation, and weakness in both lower extremities. He had a 19 months history of external iliac and femoral arterial thromboses prior to admission. The laboratory results indicated the presence of anticardiolipin antibodies of the IgG class and lupus anticoagulant. No other autoantibodies were detected and there were no apparent clinical manifestations of SLE or multiple sclerosis. A T2-weighted magnetic resonance (MR) image showed swelling and increased intensity of the cervical and thoracic spinal cord between C6 and T7 with slight enhancement by contrast medium. After steroid pulse therapy, the patient's symptoms were gradually relieved and the abnormal findings on MR imaging disappeared.


Lee, J., H. Ryu, et al. (2003). "Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox." Proc Natl Acad Sci U S A 100(8): 4843-8.

            L-Arginine is the only endogenous nitrogen-containing substrate of NO synthase (NOS), and it thus governs the production of NO during nervous system development as well as in disease states such as stroke, multiple sclerosis, Parkinson's disease, and HIV dementia. The "arginine paradox" refers to the dependence of cellular NO production on exogenous L-arginine concentration despite the theoretical saturation of NOS enzymes with intracellular L-arginine. Herein, we report that decreased availability of L-arginine blocked induction of NO production in cytokine-stimulated astrocytes, owing to inhibition of inducible NOS (iNOS) protein expression. However, activity of the promoter of the iNOS gene, induction of iNOS mRNA, and stability of iNOS protein were not inhibited under these conditions. Our results indicate that inhibition of iNOS activity by arginine depletion in stimulated astrocyte cultures occurs via inhibition of translation of iNOS mRNA. After stimulation by cytokines, uptake of L-arginine negatively regulates the phosphorylation status of the eukaryotic initiation factor (eIF2 alpha), which, in turn, regulates translation of iNOS mRNA. eIF2 alpha phosphorylation correlates with phosphorylation of the mammalian homolog of yeast GCN2 eIF2 alpha kinase. As the kinase activity of GCN2 is activated by phosphorylation, these findings suggest that GCN2 activity represents a proximal step in the iNOS translational regulation by availability of l-arginine. These results provide an explanation for the arginine paradox for iNOS and define a distinct mechanism by which a substrate can regulate the activity of its associated enzyme.


Lee, Y., B. Zhu, et al. (2003). "Statistical method for analysis of the disease curve in animals with experimental autoimmune encephalomyelitis." J Biopharm Stat 13(1): 141-58.

            Experimental autoimmune encephalomyelitis (EAE) is a procedure used in the laboratory to examine drugs that may have utility in treating multiple sclerosis (MS). The problem of modeling the disease curve in animals with EAE is studied. The classification of animals after each experiment is considered and the chi-square test is proposed to test a homogeneity between treatment groups. A mixture type of nonlinear mixed-effects model with repeated measurements is considered, assuming that the onset and/or remission of disease is the fixed effect as well as the random effect. Statistical inference on the parameters of the disease curves is discussed. The proposed model is shown to be efficient for comparing the disease curves with different treatments. Examples concerning the study of the effects of test compounds in EAE are presented to illustrate the proposed model and statistical methodologies.


Lee, W. B., J. R. Berger, et al. (2003). "Parinaud syndrome heralding MS." Neurology 60(2): 322.


Lefournier, V., M. Peoc'h, et al. (2003). "[Magnetic resonance cerebral blood volume maps. Comparison with histologic findings in different types of brain lesions]." J Neuroradiol 30(1): 3-9.

            Recent developments in magnetic resonance (MR) have made it possible to obtain measurements of the microvasculature within brain lesions. Cerebral blood volume (CBV) maps calculated from dynamic contrast-enhanced MR imaging are particularly sensitive for depicting the microvasculature, and can enable the detection of neovascularization as well as its quantification in relative terms. The purpose of the present work is to compare the results of CBV maps calculated from MR imaging with those from histologic examination of the same region of interest: the biopsy site. Nineteen patients with brain lesions were studied (18 brain tumors and one case of multiple sclerosis). All patients underwent stereotactic biopsy, and calculation of CBV was performed from perfusion MR imaging. Three histopathologic parameters were assessed: the number of vessels (vessel density), the vessel size and the surface area filled by vessels (%). We observed a statistically significant correlation between the vessel density and the CBV, which is consistent with some previous publications. A noninvasive imaging method for characterizing the functional properties, especially hemodynamic activity, of malignant processes seems to be of great benefit to clinical practice.


Lendvay, T. S. and F. F. Marshall (2003). "The tuberous sclerosis complex and its highly variable manifestations." J Urol 169(5): 1635-42.

            PURPOSE: Tuberous sclerosis is an autosomal dominant neurocutaneous syndrome affecting multiple organ systems and demonstrating highly variable clinical manifestations. Mutations in 2 tumor suppressor genes, TSC1 and TSC2, are linked to the evolution of the hamartomatous lesions. We describe the incidence and epidemiology, variable clinical manifestations and their relationships to renal pathology, and the management of morbid sequelae. MATERIALS AND METHODS: Using the search term tuberous sclerosis, we performed a MEDLINE search of the literature identifying 3,196 articles and selected those from urological, surgical, oncological, genetic and pediatric journals. Special focus was placed on the incidence and management of renal lesions and on different clinical manifestations and how they relate to renal tumors. RESULTS: Due to improved identification of the variable phenotypic expression, the reported incidence has increased. TSC1 and TSC2 mutations are related to various phenotypic manifestations and risks of malignancy, such as an increased incidence of the TSC2 mutation in patients with renal cell carcinoma. Renal sparing surgery and selective embolization techniques have mitigated the morbidity of the lesions. CONCLUSIONS: We now have a better understanding of the variability at the genotypic and phenotypic levels of the disease. We recommend that patients with tuberous sclerosis complex be evaluated by a multidisciplinary group of clinicians, including urologists, dermatologists, neurologists, pediatricians and geneticists. Close attention to these manifestations is necessary to ensure appropriate treatment of the sequelae of the tuberous sclerosis complex.


Leocani, L., V. Martinelli, et al. (2003). "Somatosensory evoked potentials and sensory involvement in multiple sclerosis: comparison with clinical findings and quantitative sensory tests." Mult Scler 9(3): 275-9.

            Sensory disturbances are one of the most common findings in patients with multiple sclerosis (MS). However, they are usually assessed at the standard neurological examination only. Quantitative Sensory Tests (QSTs) for temperature and vibratory sense allow a more objective evaluation. In a group of 19 clinically definite MS patients, we compared vibratory and temperature thresholds with sensory symptoms or signs at clinical neurological examination and somatosensory evoked potentials (SEPs) at the four limbs. The frequency of abnormalities of clinical symptoms/signs, vibration threshold and median SEPs were 69%, 33% and 55%, respectively. Correlation between degree of abnormality of SEPs and clinically assessed vibration sense (V) was statistically significant (P<0.007; Spearmann rank coefficient), as well as between SEPs and vibration perception threshold (P<0.02). Clinical evaluation of thermal sense did not show false positive results compared to quantitative thermal threshold, but false negative findings (35%). This study suggests that the combined use of vibration threshold and SEPs allows a better objectivation of sensory function, allowing the detection of subclinical abnormalities and possibly reducing the number of false positive results introduced by clinical assessment. Moreover QSTs are to be preferred to clinical evaluation in the assessment of thermal sense, due to their superior sensitivity.


Leone, D. R., K. Giza, et al. (2003). "An assessment of the mechanistic differences between two integrin alpha 4 beta 1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis." J Pharmacol Exp Ther 305(3): 1150-62.

            Integrin alpha 4 beta 1 plays an important role in inflammatory processes by regulating the migration of lymphocytes into inflamed tissues. Here we evaluated the biochemical, pharmacological, and pharmacodynamic properties and efficacy in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, of two types of alpha 4 beta 1 inhibitors, the anti-rat alpha 4 monoclonal antibody TA-2 and the small molecule inhibitor BIO5192 [2(S)-[[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino] -4-[4-methyl-2(S)-(methyl-[2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl]-amino)- pentanoylamino]-butyric acid]. TA-2 has been extensively studied in rats and provides a benchmark for assessing function. BIO5192 is a highly selective and potent (KD of <10 pM) inhibitor of alpha 4 beta 1. Dosing regimens were identified for both inhibitors, which provided full receptor occupancy during the duration of the study. Both inhibitors induced leukocytosis, an effect that was used as a pharmacodynamic marker of activity, and both were efficacious in the EAE model. Treatment with TA-2 caused a decrease in alpha 4 integrin expression on the cell surface, which resulted from internalization of alpha 4 integrin/TA-2 complexes. In contrast, BIO5192 did not modulate cell surface alpha 4 beta 1. Our results with BIO5192 indicate that alpha 4 beta 7 does not play a role in this model and that blockade of alpha 4 beta 1/ligand interactions without down-modulation is sufficient for efficacy in rat EAE. BIO5192 is highly selective and binds with high affinity to alpha 4 beta 1 from four of four species tested. These studies demonstrate that BIO5192, a novel, potent, and selective inhibitor of alpha 4 beta 1 integrin, will be a valuable reagent for assessing alpha 4 beta 1 biology and may provide a new therapeutic for treatment of human inflammatory diseases.


Leoni, V., T. Masterman, et al. (2003). "Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers." J Lipid Res 44(4): 793-9.

            The side chain oxidized oxysterol 24S-hydroxycholesterol (24-OH-chol) is formed almost exclusively in the brain, and there is a continuous passage of this oxysterol through the circulation to the liver. 27-Hydroxycholesterol (27-OH-chol) is produced in most organs and is also taken up by the liver. The 27-OH-chol-24-OH-chol ratio is about 0.1 in the brain and about 2 in the circulation. This ratio was found to be about 0.4 in cerebrospinal fluid (CSF) of asymptomatic patients, consistent with a major contribution from the circulation in the case of 27-OH-chol. In accordance with this, we demonstrated a significant flux of deuterium labeled 27-OH-chol from plasma to the CSF in a healthy volunteer. Patients with a defective blood-brain barrier were found to have markedly increased absolute levels (up to 10-fold) of both 27-OH-chol and 24-OH-chol in CSF, with a ratio between the two sterols reaching up to 2. There was a significant positive correlation between the levels of both oxysterols in CSF and the albuminCSF-albuminplasma ratio. The 27-OH-cholCSF-24-OH-cholCSF ratio was found to be about normal in patients with active multiple sclerosis and significantly increased in patients with meningitis, polyneuropathy, or hemorrhages. Results are discussed in relation to the possible use of 24-OH-cholCSF as a surrogate marker of central nervous system demyelination and/or neuronal death.


Levin, L. A. and S. Lessell (2003). "Optic neuritis and multiple sclerosis." Arch Ophthalmol 121(7): 1039-40.


Levin, L. I., K. L. Munger, et al. (2003). "Multiple sclerosis and Epstein-Barr virus." Jama 289(12): 1533-6.

            CONTEXT: Infection with Epstein-Barr virus (EBV) has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear. OBJECTIVE: To determine whether antibodies to EBV are elevated before the onset of MS. DESIGN, SETTING, AND POPULATION: Nested case-control study conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. Cases were identified as individuals granted temporary or permanent disability because of MS. For each case (n = 83), 2 controls matched by age, sex, race/ethnicity, and dates of blood sample collection were selected. MAIN OUTCOME MEASURES: Antibodies including IgA against EBV viral capsid antigen (VCA) and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus. RESULTS: The average time between blood collection and MS onset was 4 years. The strongest predictors of MS were serum levels of IgG antibodies to VCA or EBNA complex. The risk of MS increased monotonically with these antibody titers; relative risk (RR) in persons in the highest category of VCA (> or =2560) compared with those in the lowest (< or =160) was 19.7 (95% confidence interval [CI], 2.2-174; P for trend =.004). For EBNA complex titers, the RR for those in the highest category (> or =1280) was 33.9 (95% CI, 4.1-283; P for trend <.001) vs those in the lowest category (< or =40). Similarly strong positive associations between EBV antibodies and risk of MS were already present in samples collected 5 or more years before MS onset. No association was found between cytomegalovirus antibodies and MS. CONCLUSION: These results suggest a relationship between EBV infection and development of MS.


Li, B. S., J. Regal, et al. (2003). "Brain metabolite profiles of T1-hypointense lesions in relapsing-remitting multiple sclerosis." AJNR Am J Neuroradiol 24(1): 68-74.

            BACKGROUND AND PURPOSE: Persistent T1-hypointense lesions ("black holes") are thought to represent permanent damage of brain parenchyma. We attempted to ascertain whether the metabolic profiles of these hypointense areas support this hypothesis and whether these profiles correlate with these hypointense findings. METHODS: Four patients with relapsing-remitting multiple sclerosis and four matched control volunteers underwent MR imaging and 3D proton MR spectroscopy. Absolute levels of N-acetylaspartate (NAA), creatine, and choline (Cho) were obtained in 0.19 cm(3) voxels containing 14 T1-hypointense lesions (average volume, 0.4 cm(3); range, 0.2-1.0 cm(3)) in patients. Metabolite levels were analyzed, by using Pearson correlation, against their respective lesions' hypointensity relative to the surrounding normal-appearing white matter. RESULTS: Moderate correlation, r = 0.56, was found between the NAA level and MR imaging hypointensity. Of the 14 lesions studied, 12 were deficient in NAA and 11 had excess Cho compared with corresponding brain regions in control volunteers. Only one lesion was significantly deficient in all three metabolites, indicative of total damage or matrix loss. CONCLUSION: No relationship was found between the hypointensity of the lesions and their metabolic profile. Specifically, lesions with the same hypointensity on T1-weighted MR images were metabolically variable (ie, displayed disparate metabolite levels and behavior). Also, although 86% of the lesions exhibited abnormally low NAA, 71% also had increased Cho. This indicates that although neuronal damage had already occurred (lower NAA), these lesions were still "smoldering" with active membrane turnover (high Cho), most likely because of de- and remyelination, indicative of shadow plaques (remyelinated lesions). Consequently, relapsing-remitting hypointense lesions represent neither final-stage nor static pathologic abnormality.


Libich, D. S., C. M. Hill, et al. (2003). "Interaction of the 18.5-kD isoform of myelin basic protein with Ca2+ -calmodulin: effects of deimination assessed by intrinsic Trp fluorescence spectroscopy, dynamic light scattering, and circular dichroism." Protein Sci 12(7): 1507-21.

            The effects of deimination (conversion of arginyl to citrullinyl residues) of myelin basic protein (MBP) on its binding to calmodulin (CaM) have been examined. Four species of MBP were investigated: unmodified recombinant murine MBP (rmMBP-Cit(0)), an engineered protein with six quasi-citrullinyl (i.e., glutaminyl) residues per molecule (rmMBP-qCit(6)), human component C1 (hMBP-Cit(0)), and human component C8 (hMBP-Cit(6)), both obtained from a patient with multiple sclerosis (MS). Both rmMBP-Cit(0) and hMBP-Cit(0) bound CaM in a Ca(2+)-dependent manner and primarily in a 1:1 stoichiometry, which was verified by dynamic light scattering. Circular dichroic spectroscopy was unable to detect any changes in secondary structure in MBP upon CaM-binding. Inherent Trp fluorescence spectroscopy and a single-site binding model were used to determine the dissociation constants: K(d) = 144 +/- 76 nM for rmMBP-Cit(0), and K(d) = 42 +/- 15 nM for hMBP-Cit(0). For rmMBP-qCit(6) and hMBP-Cit(6), the changes in fluorescence were suggestive of a two-site interaction, although the dissociation constants could not be accurately determined. These results can be explained by a local conformational change induced in MBP by deimination, exposing a second binding site with a weaker association with CaM, or by the existence of several conformers of deiminated MBP. Titration with the collisional quencher acrylamide, and steady-state and lifetime measurements of the fluorescence at 340 nm, showed both dynamic and static components to the quenching, and differences between the unmodified and deiminated proteins that were also consistent with a local conformational change due to deimination.


Lieb, K., S. Engels, et al. (2003). "Inhibition of LPS-induced iNOS and NO synthesis in primary rat microglial cells." Neurochem Int 42(2): 131-7.

            Nitric oxide (NO) has been implicated in the etiopathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), and inhibition of NO synthesis has been proposed to be a possible mechanism of action of drugs to treat MS. In the present study, we investigated the inhibitory effect on NO synthesis of various steroids, cytokines and drugs used or proposed for the treatment of MS. As a model system, we used primary rat microglial cells which produce NO synthase and subsequently release NO upon stimulation with lipopolysaccharide (LPS). Among the substances tested, the glucocorticoids prednisone, hydrocortisone, dexamethasone and progesterone as well as transforming growth factor-beta (TGF-beta) dose-dependently inhibited LPS-induced nitric oxide synthase (iNOS) and NO synthesis. In contrast, COP-1, the phosphodiesterase inhibitors rolipram and pentoxifylline, the cytokines interleukin-10 (IL-10) and interferon-beta (IFN-beta) as well as the steroids beta-estradiol, testosterone, and dehydroepiandrosterone (DHEA) showed no inhibitory effect. Cholesterol slightly, but not significantly, increased LPS-induced nitric oxide synthesis. We conclude from the present study that with respect to treatment of MS, inhibition of NO synthesis may be an important mechanism of action of glucocorticoids and transforming growth factor-beta, but not of other drugs used or proposed to treat MS.


Lily, O. (2003). "Epstein-Barr virus and risk of multiple sclerosis." Jama 290(2): 192; author reply 193.


Liu, Y., B. Zhu, et al. (2003). "Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis." J Neuroimmunol 139(1-2): 27-35.

            Increasing evidence shows that oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). In recent years, bilirubin has been demonstrated to be a potent antioxidant in vitro. In this study, we administered bilirubin to rats with acute and chronic EAE. Bilirubin prevented both acute and chronic EAE effectively. More significantly, bilirubin suppressed ongoing clinical EAE and halted EAE progression when given after disease onset. Subsequent histological examination showed that if administered to rats before the onset of EAE, bilirubin interfered with the invasion of inflammatory cells into the central nervous system (CNS) because it protected the blood-brain barrier (BBB) from free radical-induced permeability changes. However, in some cases, inflammation still occurred even when no clinical illness was observed. In rats with treatment initiated after the onset of EAE, despite the clinical improvements, treatment with bilirubin did not reduce the degree of CNS inflammation, or change cytokine expression in CNS lesions, indicating a lack of immunosuppressive effect of this treatment. By contrast, bilirubin treatment significantly alleviated oxidative damage in the spinal cord, and the clinical signs of EAE correlated well with the degree of oxidative injury in the lesions. Our results suggest that free radicals play an important role in the final effector stages of EAE, and that antioxidant therapies may have potential for the treatment of MS.


Lobell, A., R. Weissert, et al. (2003). "Suppressive DNA vaccination in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis involves a T1-biased immune response." J Immunol 170(4): 1806-13.

            Vaccination with DNA encoding a myelin basic protein peptide suppresses Lewis rat experimental autoimmune encephalomyelitis (EAE) induced with the same peptide. Additional myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG), may be important in multiple sclerosis. Here we demonstrate that DNA vaccination also suppresses MOG peptide-induced EAE. MOG(91-108) is encephalitogenic in DA rats and MHC-congenic LEW.1AV1 (RT1(av1)) and LEW.1N (RT1(n)) rats. We examined the effects of DNA vaccines encoding MOG(91-108) in tandem, with or without targeting of the hybrid gene product to IgG. In all investigated rat strains DNA vaccination suppressed clinical signs of EAE. There was no requirement for targeting the gene product to IgG, but T1-promoting CpG DNA motifs in the plasmid backbone of the construct were necessary for efficient DNA vaccination, similar to the case in DNA vaccination in myelin basic protein-induced EAE. We failed to detect any effects on ex vivo MOG-peptide-induced IFN-gamma, TNF-alpha, IL-6, IL-4, IL-10, and brain-derived neurotropic factor expression in splenocytes or CNS-derived lymphocytes. In CNS-derived lymphocytes, Fas ligand expression was down-regulated in DNA-vaccinated rats compared with controls. However, MOG-specific IgG2b responses were enhanced after DNA vaccination. The enhanced IgG2b responses together with the requirement for CpG DNA motifs in the vaccine suggest a protective mechanism involving induction of a T1-biased immune response.


Lockhart, A., B. Davis, et al. (2003). "The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant alpha1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker." Nucl Med Biol 30(2): 199-206.

            The peripheral benzodiazepine receptor ligand PK11195 has been used as an in vivo marker of neuroinflammation in positron emission tomography studies in man. One of the methodological issues surrounding the use of the ligand in these studies is the highly variable kinetic behavior of [(11)C]PK11195 in plasma. We therefore undertook a study to measure the binding of [(3)H]PK11195 to whole human blood and found a low level of binding to blood cells but extensive binding to plasma proteins. Binding assays using [(3)H]PK11195 and purified human plasma proteins demonstrated a strong binding to alpha1-acid glycoprotein (AGP) and a much weaker interaction with albumin. Immunodepletion of AGP from plasma resulted in the loss of plasma [(3)H]PK11195 binding demonstrating: (i) the specificity of the interaction and (ii) that AGP is the major plasma protein to which PK11195 binds with high affinity. PK11195 was able to displace fluorescein-dexamethasone from AGP with IC(50) of <1.2 microM, consistent with a high affinity interaction. These findings are important for understanding the behavior of the ligand in positron emission tomography studies for three reasons. Firstly, AGP is an acute phase protein and its levels will vary during infection and pathological inflammatory diseases such as multiple sclerosis. This could significantly alter the free plasma concentrations of the ligand and contribute to its variable kinetic behavior. Secondly, AGP and AGP-bound ligand may contribute to the access of [(11)C]PK11195 to the brain parenchyma in diseases with blood brain barrier breakdown. Finally, local synthesis of AGP at the site of brain injury may contribute the pattern of [(11)C]PK11195 binding observed in neuroinflammatory diseases.


Loher, T. J., K. Gutbrod, et al. (2003). "Thalamic stimulation for tremor. Subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect." J Neurol 250(6): 707-13.

            The aim of this study was to investigate the impact of unilateral deep brain stimulation (DBS) of the ventrointermediate (Vim) thalamic nucleus on neuropsychological functioning comparing stimulation-on with stimulation-off conditions. Nine patients [five patients with Parkinson's Disease (PD), two patients with essential tremor (ET) and 2 patients with multiple sclerosis (MS)] underwent comprehensive neuropsychological testing for cognitive functions, including general mental impairment, aphasia, agnosia, executive and constructional abilities, learning, memory, cognitive processing speed and attention as well as depression. The neuropsychological assessments were performed at least 6 months postoperatively (mean 9 months). Testing in the stimulation-on and stimulation-off condition was obtained within a period of 3 to 4 weeks. Unilateral DBS resulted in improvement of tremor in all patients. There were no significant differences between the stimulation-on and the stimulation-off condition with the exception of a decrement of word-recall in the short delay free-recall subtest of the Rey Auditory-Verbal Learning Test (RAVLT). Subgroup analysis indicated that the impairment in word-recall was related to left-sided thalamic stimulation. Our study confirms that chronic unilateral DBS is a safe method with regard to cognitive function. The subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect.


Lombardi, G., G. Miglio, et al. (2003). "Abnormal response to glutamate of T lymphocytes from multiple sclerosis patients." Neurosci Lett 340(1): 5-8.

            Multiple sclerosis (MS) is an immune-mediate, inflammatory and demyelinating disease of the central nervous system (CNS). Since glutamate (Glu) is a modulator of T lymphocyte function and Glu excitotoxicity has been proposed as one of the mechanisms of the demyelination, we studied the responses of T lymphocytes from normal controls (NC), MS or other non-inflammatory neurological disease (ONND) patients to Glu, by measuring phytohemagglutinin-induced intracellular Ca(2+) ([Ca(2+)](i)) rise (Fura-2 method) and cell proliferation (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay). No differences in the Glu (1 microM)-induced potentiation of the [Ca(2+)](i) rise were measured in T lymphocytes from all groups of subjects, while a significant decrease in the Glu (1 mM)-induced inhibition of cell proliferation was observed in T lymphocytes from MS patients. These data demonstrate that MS T lymphocytes abnormally respond to Glu.


Longstaff, M. G. and R. A. Heath (2003). "The influence of motor system degradation on the control of handwriting movements: A dynamical systems analysis." Hum Mov Sci 22(1): 91-110.

            The complex dynamics of the human hand/arm system need to be precisely controlled to produce fine movements such as those found in handwriting. This study employs dynamical systems analysis techniques to further understand how this system is controlled when it is functioning well and when it is compromised through motor function degradation (e.g. from tremor). Seven people with and 16 people without multiple sclerosis (MS) participated in this study. Tremor was assessed using spirography with participants being separated into "tremor" (6 people with and 1 person without MS; 2 male, 5 female; age range 40-68) and control (1 person with and 15 people without MS; 5 male, 11 female, age range 18-59) groups. Participants wrote the pseudo-word "lanordam" six times on a digitizer, in a quiet as well as a noisy, mildly stressful environment. Velocity profiles of the pen tip for the best four trials were concatenated and analyzed to determine their dimensionality (a measure of the number of control variables) and Lyapunov exponents (a measure of predictability). Results indicate that the velocity profiles for people with tremor were lower dimensional and had less predictable dynamics than for controls, with no effect of sound condition. Interpreted in the context of related research, it was speculated that the lower dimensionality reflected the loss of control of variables related to the minimization of movement variability, resulting in less predictable movements.


Lopatinskaya, L., A. H. van Boxel-Dezaire, et al. (2003). "The development of clinical activity in relapsing-remitting MS is associated with a decrease of FasL mRNA and an increase of Fas mRNA in peripheral blood." J Neuroimmunol 138(1-2): 123-31.

            In this longitudinal study, we examined the expression of Fas, FasL, CCR3, CCR5 and CXCR3 mRNA in peripheral blood mononuclear cells (PBMCs) of secondary progressive (SP) and relapsing-remitting (RR) multiple sclerosis (MS) patients.In RR patients, FasL, CCR3 and CCR5 mRNA levels were increased prior to the exacerbations, but these decreased during clinical activity, while mRNA levels of Fas increased. SP patients have increased the levels of Fas and FasL mRNA; the latter was particularly increased during lesional activity.Our data support the hypothesis that changes in Fas and FasL mRNA related to clinical activity are due to the migration of inflammatory cells to the central nervous system (CNS).


Lopez, E., L. Escovich, et al. (2003). "Tuberous sclerosis: presentation of a clinical case with oral manifestations." Med Oral 8(2): 122-8.

            Tuberous sclerosis (TS) is a genetic disorder affecting multiple body systems, and resulting from alterations in cell differentiation and proliferation. The disease is characterized by the development of benign hamartomatous tumors: neurofibromas and angiofibromas, located in the skin, central nervous system, mucosas and other organs. Abnormal neural cell migration plays an important role in the neurological dysfunctions found in TS, the predominant features being mental retardation, seizures and behavioral disorders. The condition is produced by mutations in genes TSC1 of chromosome 9q34 and TSC2 of chromosome 16p13.3, and exhibits a dominant autosomal hereditary trait--though 60-70% of cases are sporadic and represent new mutations. The phenotype is highly variable. The prevalence of TS varies between 1/6000 and 1/10,000 live births. The present study reports the case of a 21-year-old male with TS and oral manifestations of the disease. The clinical characteristics are described, along with the diagnostic criteria and the management strategies, with a review of the literature on the disease.


Lopez del Val, L. J. and S. Santos (2003). "[Gabapentin in the treatment of tremor]." Rev Neurol 36(4): 322-6.

            PATIENTS AND METHODS: We evaluated the efficacy of gabapentin added to basal tremor treatment by means of a 16 month non randomized open study conducted at our Unit on treated and monitored patients. Efficacy was evaluated by means of the following scales: Tremor Scale (TS), Global Disability Examiner Scale (GDE) and Global Disability Patient Scale (GDP). For the GDE and GDP scales we constructed a dichotomic result evaluation variable (improvement vs. non improvement) and adjusted a logistic regression model (independent variables: age, gender, tremor duration and number of antitremor drugs associated with gabapentin). Two multiregression models were adjusted for the TS (12 month score result variable). Model 1: TS (items 1 14) and model 2: TS (items 15 21). Independent variables: age, gender, tremor duration, initial test score and number of antitremor drugs associated with gabapentin. We studied 63 patients aged 59.4 years (SD, 16 years): 34 essential tremor, 16 Parkinson s disease tremor, 10 multiple sclerosis tremor, 4 writing tremor and 3 orthostatic tremor. RESULTS: At 12 months gabapentin improved the clinical results. The largest decrease (absolute terms) was observed in multiple sclerosis tremor, and in percentage terms the largest decrease was in orthostatic tremor. Logistic regression showed that masculine gender and a shorter tremor duration predicted a better result. Multiregression showed association between end and basal score, on the one hand, and a better result in males and shorter tremor duration, on the other


Lucas, M., M. C. Rodriguez, et al. (2003). "Regulation by interferon beta-1a of reactive oxygen metabolites production by lymphocytes and monocytes and serum sulfhydryls in relapsing multiple sclerosis patients." Neurochem Int 42(1): 67-71.

            The activation of lymphocytes and monocytes and the concentration of reduction equivalents in serum were studied in a cohort of multiple sclerosis (MS) patients undergoing weekly treatment with 30 microg intramuscular interferon beta-1a for 2 years. The degree of activation of monocytes and lymphocytes and reactive oxygen species (ROS) production was higher in MS patients than in healthy controls and decreased in the course of interferon beta-1a treatment approaching control values. The concentration of reduced sulfhydryls in the serum of MS patients was lower than in healthy controls and the treatment with interferon beta-1a (IFNbeta-1a) raised the levels approaching the values of healthy controls.


Luo, H. Y., H. C. Wang, et al. (2003). "[Significance of Phosphorylation of Mitogen-Actived Protein Kinase and Signal Transducer and Activator of Transcription 3 and Cyclin D1 Protein Expression in Hodgkin's Lymphomas]." Ai Zheng 22(3): 266-9.

            BACKGROUND & OBJECTIVE: Signal cascades of mitogen-actived protein kinase(MAPK) and signal transducer and activator of transcription 3 (Stat3) are two main signal transduction pathways which were associated with cell proliferation and malignant transformation.MAPK and Stat3 proteins are activated by phosphorylation. The biological effects which are caused by multiple cytokines produced by Hodgkin's lymphoma(HL) cells are mediated through MAPK and Stat3 signal pathways. This study was designed to investigate significance of MAPK and Stat3 phosphorylation(p-MAPK and p-Stat3) and cyclin D1 protein expression in HL. METHODS: SP immunohistochemistry was used to detect expression of p-MAPK, p-Stat3, and cyclin D1 protein in 45 cases of HL of various types. RESULTS: The expression positive rates of p-MAPK, p-Stat3, and cyclin D1 proteins were 73.3%(33/45),64.4%(29/45), and 68.9%(31/45), respectively. The positive expression levels of p-MAPK and cyclin D1 protein gradually increased(P< 0.05), whereas that of p-stat3 had no significant difference(P >0.05) in four subsets(LR:lymphocyte-rich classical type; NS:nodular sclerosis type; MC:mixed cellularity type; LD:lymphocyte depletion type) of all cases.The expression of p-MAPK was positively related to that of cyclin D1 protein (r(s)=0.7254,P< 0.01), but the expression of p-Stat3 was not related to that of cyclin D1 protein (r(s)=0.2197,P >0.05). CONCLUSION: The data suggest that activation of MAPK may play an important role in genesis and progression of HL, but Stat3 activation is not associated with the progression of HL. MAPK may induce overexpression of cyclin D1 protein and results in persistent proliferation of RS/H cells in genesis and development of HL.


Luttichau, H. R., I. Clark-Lewis, et al. (2003). "A highly selective CCR2 chemokine agonist encoded by human herpesvirus 6." J Biol Chem 278(13): 10928-33.

            The chemokine-like, secreted protein product of the U83 gene from human herpesvirus 6, here named vCCL4, was chemically synthesized to be characterized in a complete library of the 18 known human chemokine receptors expressed individually in stably transfected cell lines. vCCL4 was found to cause calcium mobilization as efficiently as the endogenous chemokine ligand CCL2 through the CCR2 receptor, whereas the virally encoded chemokine did not affect any of the other 17 human chemokine receptors tested. Mutual cross-desensitization between CCL2 and vCCL4 was demonstrated in the CCR2-transfected cells. The affinity of vCCL4 for the CCR2 receptor was 79 nm as determined in competition binding against radioactively labeled CCL2. In the murine pre-B lymphocyte cell line L1.2 stably transfected with the CCR2 receptor, vCCL4 acted as a relatively low potency but highly efficacious chemoattractant being equally or more efficacious in causing cell migration than CCL2 and CCL7 and considerably more efficacious than CCL8 and CCL13. It is concluded that human herpesvirus 6 encodes a highly selective and efficacious CCR2 agonist, which will attract CCR2 expressing cells, for example macrophages and monocytes, conceivably for the virus to infect and to establish latency in. It is suggested that vCCL4 during reactivation of the virus in for example monocyte-derived microglia could perhaps be involved in the pathogenesis of the CCR2-dependent disease, multiple sclerosis.


Lycklama a Nijeholt, G. and F. Barkhof (2003). "Differences between subgroups of MS: MRI findings and correlation with histopathology." J Neurol Sci 206(2): 173-4.


Lythgoe, M. F., N. R. Sibson, et al. (2003). "Neuroimaging of animal models of brain disease." Br Med Bull 65: 235-57.

            The main aim of this review is to describe some of the many animal models that have proved to be valuable from a neuroimaging perspective. This paper complements other articles in this volume, with a focus on animal models of the pathology of human brain disorders for investigations with modern non-invasive neuroimaging techniques. The use of animal model systems forms a fundamental part of neuroscience research efforts to improve the prevention, diagnosis, understanding and treatment of neurological conditions. Without such models it would be impossible to investigate such topics as the underlying mechanisms of neuronal cell damage and death, or to screen compounds for possible anticonvulsant properties. The adequacy of any one particular model depends on the suitability of information gained during experimental conditions. It is important, therefore, to understand the various types of animal model available and choose an appropriate model for the research question.


Mackowiak, A., V. Jamart, et al. (2003). "[General practitioners' approach to relapsing multiple sclerosis]." Rev Neurol (Paris) 159(2): 196-8.

            Management of multiple sclerosis depends on close multidisciplinary collaboration but general practitioners play a particularly important role, especially in case of relapse, due to their close relationship with the patient. The purpose of this work was to conduct a survey of general practitioners' knowledge of relapsing multiple sclerosis and ascertain their main difficulties in patient management. One hundred seventy-seven practitioners answered a written questionnaire with two headings, diagnostic criteria for relapse and therapeutic approaches. Analysis of the results showed that this common event is under recognized. While 55.9 p.cent of the general practitioners stated they diagnosed relapse by themselves, only 2.8 p.cent knew its exact definition. Differential diagnosis accounted for a large number of mistakes. Our survey also underlined the use of certain therapeutic options (low-dose oral corticosteroid therapy) for which the effectiveness has not been demonstrated. It would be important to propose specific education on relapsing multiple sclerosis for general practitioners and improve cooperation with specialists. An integrated care network might be useful.


Mahad, D. J., J. Lawry, et al. (2003). "Longitudinal study of chemokine receptor expression on peripheral lymphocytes in multiple sclerosis: CXCR3 upregulation is associated with relapse." Mult Scler 9(2): 189-98.

            The interaction between chemokines and their receptors leads to selective recruitment of cells to foci of inflammation. Cross-sectional studies have reported significantly different expression of chemokine receptors CXCR3, CCR5 and CCR2 on peripheral blood lymphocytes in multiple sclerosis (MS) compared with controls. Cells expressing these receptors are likely to play a pathogenic role as suggested by studies of experimental autoimmune encephalomyelitis. Also, immunogenetic studies of nonfunctional CCR5 receptors in MS patients, due to 32delta deletion, demonstrated a delay in time to next relapse. The aims of this study were to detect any changes in the serial expression of chemokine receptors CCR2, CCR3, CCR5 and CXCR3 on peripheral blood CD4+ lymphocytes from patients with MS and to correlate the changes with relapses. Upregulation of CXCR3 expression on peripheral blood CD4+ lymphocytes was associated with all relapses and CCR5 expression was significantly affected with all relapses. Clinical recovery, with or without intravenous methylprednisolone treatment, coincided with the return of CXCR3 towards baseline in all but one case. Fluctuation in the expression of CXCR3 and CCR5 was also significantly greater in clinically stable patients with MS compared with controls, which may be due to subclinical disease activity. These findings provide further support for the view that CXCR3 and CCR5 antagonists could have a therapeutic value in MS.


Mahad, D. J. and R. M. Ransohoff (2003). "The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE)." Semin Immunol 15(1): 23-32.

            Multiple sclerosis (MS) is the commonest inflammatory demyelinating disease of the human central nervous system (CNS). In MS, CNS inflammation is associated with demyelination and axonal degeneration, which leads to clinical presentation. Expression and cellular localization of CCL2/MCP-1 and CCR2 in MS have been described in the three compartments: brain, cerebrospinal fluid (CSF) and blood. Evidence from descriptive, transgenic, knockout and neutralizing studies of experimental autoimmune encephalomyelitis (EAE) points towards a nonredundant role of CCL2 and CCR2 in the recruitment of inflammatory infiltrate into the CNS. Hence, CCL2 and CCR2 may be targets for specific and effective treatment in MS.


Mahnke, K., Y. Qian, et al. (2003). "Dendritic cells, engineered to secrete a T-cell receptor mimic peptide, induce antigen-specific immunosuppression in vivo." Nat Biotechnol.

            A T-cell receptor mimic peptide (TCRpep) consisting of an 8-amino-acid peptide, homologous to the transmembrane region of the T-cell receptor (TCR) alpha chain, blocks T-cell activation after systemic application. When dendritic cells (DCs) were transduced to secrete the TCRpep and injected into mice, evidence of immunosuppression was observed. In a CD8-driven allergy model, the injection of DCs transduced with the TCRpep reduced inflammation markedly and in a CD4(+) T cell-dependent model of multiple sclerosis (experimental autoimmune encephalitis, EAE), injection of TCRpep-secreting DCs abrogated EAE symptoms and prolonged survival. These effects were antigen specific, because transduced DCs that did not express the respective antigen failed to convey protection in the allergy model as well as in the EAE model. Thus these data show that DCs expressing the TCRpep are able to suppress T-cell activation and might be a useful tool for inducing antigen-specific immune suppression in vivo.


Mahon, B. D., S. A. Gordon, et al. (2003). "Cytokine profile in patients with multiple sclerosis following vitamin D supplementation." J Neuroimmunol 134(1-2): 128-32.

            Multiple sclerosis (MS) patients were randomized, in a double blind design, and placed into either a vitamin D supplemented group or a placebo control group. As expected, serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation (17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months). Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later. Placebo treatment had no effect on serum TGF-beta 1 levels. Tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-13 were not different following vitamin D supplementation. IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance. Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1.


Mak, B. C., K. Takemaru, et al. (2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity." J Biol Chem 278(8): 5947-51.

            Tuberous sclerosis complex (TSC) is characterized by the formation of hamartomas in multiple organs resulting from mutations in the TSC1 or TSC2 gene. Their protein products, hamartin and tuberin, respectively, form a functional complex that affects cell growth, differentiation, and proliferation. Several lines of evidence, including renal tumors derived from TSC2+/- animals, suggest that the loss or inhibition of tuberin is associated with up-regulation of cyclin D1. As cyclin D1 can be regulated through the canonical Wnt/beta-catenin signaling pathway, we hypothesize that the cell proliferative effects of hamartin and tuberin are partly mediated through beta-catenin. In this study, total beta-catenin protein levels were found to be elevated in the TSC2-related renal tumors. Ectopic expression of hamartin and wild-type tuberin, but not mutant tuberin, reduced beta-catenin steady-state levels and its half-life. The TSC1-TSC2 complex also inhibited Wnt-1 stimulated Tcf/LEF luciferase reporter activity. This inhibition was eliminated by constitutively active beta-catenin but not by Disheveled, suggesting that hamartin and tuberin function at the level of the beta-catenin degradation complex. Indeed, hamartin and tuberin co-immunoprecipitated with glycogen synthase kinase 3 beta and Axin, components of this complex in a Wnt-1-dependent manner. Our data suggest that hamartin and tuberin negatively regulate beta-catenin stability and activity by participating in the beta-catenin degradation complex.


Malamud, V., A. Vaaknin, et al. (2003). "Tryptase activates peripheral blood mononuclear cells causing the synthesis and release of TNF-alpha, IL-6 and IL-1beta: possible relevance to multiple sclerosis." J Neuroimmunol 138(1-2): 115-22.

            Presence of mast cells and an increase in the concentration of their products has been reported in multiple sclerosis (MS) plaques. The most abundant secretory mediator of the human mast cell is the tetrameric protease tryptase. We demonstrate that tryptase can activate peripheral mononuclear cells (PBMCs), isolated from healthy donors as well as MS patients for the release of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1beta. Cytokine secretion was significantly higher in secondary progressive (SP) MS patients and healthy control (HC) individuals than in relapsing-remitting (RR) patients. Our findings suggest that tryptase is, most probably, an important mediator of inflammation in MS.


Marcisz, C., E. J. Kucharz, et al. (2003). "Pulmonary functional abnormalities in asymptomatic patients with systemic sclerosis." Eur J Intern Med 14(3): 162-165.

            BACKGROUND: Systemic sclerosis (SSc) is a disease characterized by widespread fibrosis of the skin and multiple organs, including the lungs. This study was designed to evaluate pulmonary function in SSc patients without symptoms of lung involvement. METHODS: Spirometric measurements were done in 26 female SSC patients without symptoms of pulmonary involvement. RESULTS: Maximal voluntary ventilation was found to be decreased in half of the patients, and forced vital capacity was decreased in 23% of the patients. Forced expiratory flow rate was impaired in about half of the SSc patients, especially the flow at 50-75% of forced vital capacity. Peak expiratory flow rate was decreased in 77% of asymptomatic patients. CONCLUSIONS: A functional defect, mainly of the restrictive type, was observed in the majority of asymptomatic patients with SSc. Pulmonary function testing is recommended for all SSc patients.


Markovic, M., V. Trajkovic, et al. (2003). "Antibodies against myelin oligodendrocyte glycoprotein in the cerebrospinal fluid of multiple sclerosis patients." J Neurol Sci 211(1-2): 67-73.

            Antibodies against myelin oligodendrocyte glycoprotein (MOG) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) in different animal species and are implicated in the immunopathogenesis of multiple sclerosis (MS). In order to evaluate the anti-MOG response, we have analyzed the cerebrospinal fluids (CSFs) from 44 MS patients and 51 controls, 11 with other inflammatory neurological disorders (OIND) and 40 with non-inflammatory neurological disorders (NIND). The frequency of anti-MOG antibodies positive patients in the MS group (30%) was significantly higher compared to the NIND (8%, p=0.02), but not compared to the OIND group (55%, p=0.228). Interestingly, all six patients with neurosarcoidosis had MOG-specific antibodies in their CSF. Frequency of anti-MOG antibodies was similar in patients with clinically active and stable MS (32% and 26%, respectively; p=0.921). However, in clinically active MS patients, antibody titers were higher in comparison with patients with stable disease, although the difference did not reach the level of statistical significance (p=0.06). These results further support the potential role of anti-MOG antibodies in the immunopathology of MS in the subset of patients with this disease. Furthermore, our findings suggest for the first time that anti-MOG antibodies could be an accessory diagnostic tool in neurosarcoidosis.


Marta, C. B., C. M. Taylor, et al. (2003). "Antibody cross-linking of myelin oligodendrocyte glycoprotein leads to its rapid repartitioning into detergent-insoluble fractions, and altered protein phosphorylation and cell morphology." J Neurosci 23(13): 5461-71.

            Myelin oligodendrocyte glycoprotein (MOG) is, quantitatively, a relatively minor component of the myelin membrane. Nevertheless, peritoneal administration of MOG evokes potent cellular and humoral immunoreactivity, resulting in an experimental allergic encephalitis with immunopathology similar to multiple sclerosis. Moreover, antibodies against MOG cause myelin destruction in situ. Therefore, it appears that MOG-related demyelination is dependent on anti-MOG antibody, but the mechanism(s) by which it occurs is unclear. Of potential significance are observations that some proteins are selectively partitioned into specialized plasma membrane microdomains rich in glycosphingolipids and cholesterol ("lipid rafts"). In particular, during ligand or antibody cross-linking, various plasma membrane receptors undergo enhanced partitioning into rafts as an obligatory first step toward participation in early signal transduction events. In contrast to mature myelin, in oligodendrocytes (OLs) in culture MOG is not raft associated [Triton X-100 (TX-100) soluble, 4 degrees C]. However, in this study we show that antibody cross-linking (anti-MOG plus secondary antibody) of MOG on the surface of OLs results in the repartitioning of approximately 95% of MOG into the TX-100-insoluble fraction. This repartitioning of MOG is rapid (<or=1 min), antibody dose dependent, requires an intact cytoskeleton, leads to phosphorylation or dephosphorylation of tyrosine, serine, and threonine residues in specific proteins (e.g., beta-tubulin, Gbeta1-2), and invokes a rapid retraction of OL processes. After removal of the cross-linking antibodies, these events are reversed. We hypothesize that antibody-mediated repartitioning of MOG into TX-100-insoluble glycosphingolipid-cholesterol-rich microdomains initiates specific cellular signaling that could be related to initial steps of MOG-mediated demyelination.


Martinez, L., S. Rivas, et al. (2003). "Aggressive conservative treatment of esophageal perforations in children." J Pediatr Surg 38(5): 685-9.

            Background/Purpose: In contrast with adult patients in whom surgical closure of the defect is preferred, nonoperative treatment has been the usual approach for esophageal perforation (EP) in children. This report aims to assess whether this strategy stands the passage of time. METHODS: We reviewed retrospectively the charts of 17 patients aged 5.3 +/- 0.9 years (mean +/- SD) treated at our institution for EP between 1991 and 2001. RESULTS: Nineteen episodes of EP were caused by stricture dilation in 9 cases, foreign body extraction in 3, and blunt trauma and sclerosis of varices in 2 cases each. The remaining child had multiple gastrointestinal perforations in the course of chemotherapy for leukemia. Vigorous treatment, consisting of nasopharyngeal aspiration, wide spectrum antibiotics, prompt drainage of effusions and either parenteral or infraesophageal nutritition, was implemented immediately after diagnosis. Perforations were closed without direct surgery in 18 of 19 episodes (16 of 17 children). One or more pleural drains were inserted in 12 cases, and pericardial drainage was required once. Seven gastrostomies, 2 jejunostomies, and one esophagostomy were performed. Several major abdominal operations were necessary to repair concomitant lesions in a child who sustained severe blunt abdominal trauma and in the patient with leukemic perforations. All patients survived, and all recovered esophageal function. However, 2 with intractable lye strictures ultimately required esophageal replacement. The only patient in whom a direct approach for esophageal necrosis due to variceal endosclerosis was unavoidable, lost her organ and had a retrosternal colonic interposition after a successful portosystemic shunt. Excluding patients with other concomitant lesions and the patient who underwent surgery, median length of stay was 11 days (range, 6 to 47). CONCLUSIONS: Prompt and aggressive nonoperative treatment of esophageal perforations in children allows survival with conservation of the organ in most cases and remains, in the authors' hands, the first therapeutic choice at this age. J Pediatr Surg 38:685-689.


Matheu, V., A. Treschow, et al. (2003). "Upregulation of B7 molecules (CD80 and CD86) and exacerbated eosinophilic pulmonary inflammatory response in mice lacking the IFN-beta gene." J Allergy Clin Immunol 111(3): 550-7.

            BACKGROUND: IFN-beta has been shown to be effective as therapy for multiple sclerosis. Some reports attributed its beneficial effects to the capacity to induce a T(H)2 response. However, other studies have suggested that endogenous type I IFN might downregulate the allergic response in mice. OBJECTIVE: We sought to define the differential role of endogenous IFN-beta in controlling the development of allergic inflammation. METHODS: We assessed whether deletion of the gene encoding IFN-beta (IFNB) with knockout mice participated in the development of allergic response in ovalbumin (OVA)-sensitized and OVA-challenged mice. RESULTS: OVA-sensitized and OVA-challenged mice with lack of the IFNB gene had more severe pulmonary inflammation with increased lung local response, including IL-4, IL-5, IL-13, IgE, eosinophilia, and goblet cells, than their litter mates (IFN-beta+/-), whereas no differences were observed in regard to local levels of IFN-gamma. Moreover, systemic response with IgE production is also enhanced. Lack of IFN-beta also results in significantly higher antigen-specific T cells, with higher levels of IL-4, IL-5, and IL-13, whereas no significant differences in IFN-gamma response could be observed. We have also detected a higher ratio of CD4+/CD8+ T cells and increased expression of B7.1/B7.2 on B cells and antigen-presenting cells in IFNB knockout mice. CONCLUSIONS: These results demonstrate that IFN-beta plays an important role in immunoregulation of allergic response in mice. The stronger pulmonary inflammation could be a consequence of significantly expanded antigen-specific CD4+ T(H)2 cells as a result of efficient antigen presentation by antigen-presenting cells and hence increased production of IgE by B cells.


Mathisen, P. M. (2003). "Gene discovery and validation for neurodegenerative diseases." Drug Discov Today 8(1): 39-46.

            Treatment of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis (ALS), represents a major challenge for the pharmaceutical industry. These disorders have common and unique molecular pathological characteristics that result in serious reductions in nervous-system functionality. Key to developing novel and efficacious therapeutics is the discovery of new gene targets. Genomic, proteomics and bioinformatic analyses are identifying vast amounts of genes whose expression is associated with the pathology of a specific disease. Extensive validation studies performed in parallel with drug development are crucial for the selection of appropriate target genes. This review outlines some of the current progress in gene discovery for neurodegenerative disease.


Matsumoto, Y., W. K. Yoon, et al. (2003). "Complementarity-determining region 3 spectratyping analysis of the TCR repertoire in multiple sclerosis." J Immunol 170(9): 4846-53.

            Multiple sclerosis (MS) is considered to be an autoimmune disease mediated by T cells reactive with Ags in the CNS. Therefore, it has been postulated that neuroantigen-reactive T cells bearing particular types of TCRs are expanded clonally during the course of the disease. However, there is a controversy with regard to the TCR usage by T cells associated with the development of MS. By the use of complementarity-determining region 3 spectratyping analysis that is shown to be a useful tool for identification of pathogenic TCR in autoimmune disease models, we tried to demonstrate that spectratype was T cells bearing particular types of TCR are activated in MS patients. Consequently, it was found that Vbeta5.2 were often oligoclonally expanded in peripheral blood of MS patients, but not of healthy subjects. Sequence analysis of the complementarity-determining region 3 region of spectratype-derived TCR clones revealed that the predominant TCR clone was different from patient to patient, but that similar results were obtained in a patient examined at different time points. More importantly, examination of cerebrospinal fluid T cells and longitudinal studies of PBLs from selected patients revealed that Vbeta5.2 expansion was detectable in the majority of patients examined. These findings suggest that Vbeta5.2 spectratype expansion is associated with the development of MS and that TCR-based immunotherapy can be applicable to MS patients if the TCR activation pattern of each patient is determined at different stages of the disease.


May, M., M. Seehafer, et al. (2003). "[Angiomyolipoma of the kidneys as a rare cause of retroperitoneal hemorrhage. Two case reports with tuberous sclerosis Bourneville-Pringle]." Urologe A 42(5): 693-701.

            Tuberous sclerosis (Bourneville-Pringle-disease, TSC) is an autosomal dominant disorder characterized by seizures, mental retardation and hamartomatous tumours in multiple organs, including subependymal giant cell astrocytomas, cardiac rhabdomyomas and renal angiomyolipomas. Recent population-based studies suggest a prevalence of 1 case per 25,000 individuals. Renal angiomyolipomas, which may be found sporadically or associated with TSC, become evident as an acute retroperitoneal haemorrhage or by symptoms of a flank mass. Ultrasound and computed tomography provide clear evidence of lipomatous formation while, in rare instances, angiography can demonstrate the existence of multiple vascular tumour compartments. In view of two cases which were admitted with the clinical picture of an acute abdomen on the basis of retroperitoneal haemorrhage, the therapeutic strategies for TSC patients with renal angiomyolipomas are discussed, paying regard to the literature in this field.


Mazzeo, L., L. Ricciardi, et al. (2003). "Severe urticaria due to recombinant interferon beta-1a." Br J Dermatol 148(1): 172.


McDonnell, G. V., J. Cabrera-Gomez, et al. (2003). "Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical stage of primary progressive multiple sclerosis may last 10 years." Mult Scler 9(2): 204-9.

            BACKGROUND: Subclinical multiple sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated magnetic resonance imaging (MRI) changes consistent with MS, and 'MRI relapses' are several times more common than clinical relapses. CASE DESCRIPTION: A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's disease study, where his father was the proband. MRI indicated multiple areas of abnormal signal intensity in a periventricular and grey-white matter junction distribution. Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand. MRI now indicated a further area of high signal intensity in the right posterior cord at the level of C5/C6. There was mild pyramidal distribution weakness in the right leg with an extensor plantar response on the same side. Over the next five years there has been mild progression in weakness and fatigue and intermittent Lhermitte's phenomenon. At no stage has there been a history of relapse, cerebrospinal fluid examination was normal and evoked responses (visual and somatosensory) are normal. CONCLUSION: This case demonstrates the phenomenon of subclinical MS, unusually supported by prolonged clinical and MRI follow-up. The patient eventually became symptomatic nine years after MRI diagnosis and is following a primary progressive course. Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of primary progressive MS and is compatible with the later onset seen in this subgroup of patients.


McGuire, T. R., P. Gwilt, et al. (2003). "High-dose cyclophosphamide in multiple sclerosis patients undergoing autologous stem cell transplantation." Int Immunopharmacol 3(2): 279-83.

            High-dose cyclophosphamide (CTX) is commonly used in preparation for autologous and allogeneic stem cell transplantation. CTX is a pro-drug, which undergoes complex oxidative metabolism with the metabolites being eliminated both renally and hepatically. In the following study, we evaluated the pharmacokinetic characteristics of high-dose CTX in three patients undergoing autologous stem cell transplantation for multiple sclerosis. The plasma concentration-time profiles for CTX and its hydroxy-metabolite were similar in multiple sclerosis patients to those reported in cancer patients undergoing stem cell transplantation. There was an increase in drug clearance after the second CTX dose indicating that the drug induced its own metabolism consistent with reports in other populations receiving high-dose CTX. One of the three patients cleared the drug slowly but this was not associated with greater toxicity. The patient with the slow clearance value and therefore highest drug exposure had stable disability scores at 2 years posttransplant compared with baseline values taken prior to transplantation. In conclusion, in this small case series, there was no indication that CTX metabolism was different than that in other populations undergoing transplantation.


McKeown, L. P., A. P. Porter-Armstrong, et al. (2003). "The needs and experiences of caregivers of individuals with multiple sclerosis: a systematic review." Clin Rehabil 17(3): 234-48.

            PRIMARY OBJECTIVE: To appraise recent studies regarding the needs and experiences of caregivers of individuals with multiple sclerosis (MS). DESIGN: The following computerized databases were searched: CINAHL, BIDS IBSS, ASSIA, MEDLINE, PSYCHINFO, British Nursing Index, ISI Web of Science, Zetoc, AMED (1990-April 2002). The computer-based search was supplemented by manual searches of the reference lists of all retrieved studies and review articles. Inclusion and exclusion criteria were formulated. RESULTS: Twenty-four studies from across the world that met the inclusion criteria were reviewed. The majority of studies were descriptive in nature. The studies covered a variety of topics, including how carers assist people with MS, the effect of providing care on a carer's physical and psychological well-being, social life, financial situation and overall quality of life, and how carers cope with the stresses of providing care. CONCLUSIONS: Providing care for a person with MS has a major impact on all areas of the caregiver's life. Perceived social support has been shown to have a beneficial impact on the caregiver. Limitations in design and variation in methodology of studies limits the generalizability of findings. There is a need for further research, in particular the development of reliable and valid disease-specific caregiver assessment instruments.


McLeod, B. C. (2003). "Plasmapheresis in multiple sclerosis." J Clin Apheresis 18(2): 72-4.


Meager, A., M. Wadhwa, et al. (2003). "Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis." Clin Exp Immunol 132(1): 128-36.

            We have screened for spontaneous anticytokine autoantibodies in patients with infections, neoplasms and autoimmune diseases, because of their increasingly reported co-occurrence. We tested for both binding and neutralizing autoantibodies to a range of human cytokines, including interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, interferon-alpha2 (IFN-alpha2), IFN-omega, IFN-beta, IFN-gamma, tumour necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1) and granulocyte-macrophage colony stimulating factor (GM-CSF), in plasmas or sera. With two notable exceptions described below, we found only occasional, mostly low-titre, non-neutralizing antibodies, mainly to GM-CSF; also to IL-10 in pemphigoid. Strikingly, however, high-titre, mainly IgG, autoantibodies to IFN-alpha2, IFN-omega and IL-12 were common at diagnosis in patients with late-onset myasthenia gravis (LOMG+), thymoma (T) but no MG (TMG-) and especially with both thymoma and MG together (TMG+). The antibodies recognized other closely related type I IFN-alpha subtypes, but rarely the distantly related type I IFN-beta, and never (detectably) the unrelated type II IFN-gamma. Antibodies to IL-12 showed a similar distribution to those against IFN-alpha2, although prevalences were slightly lower; correlations between individual titres against each were so modest that they appear to be entirely different specificities. Neither showed any obvious correlations with clinical parameters including thymoma histology and HLA type, but they did increase sharply if the tumours recurred. These antibodies neutralized their respective cytokine in bioassays in vitro; although they persisted for years severe infections were surprisingly uncommon, despite the immunosuppressive therapy also used in most cases. These findings must hold valuable clues to autoimmunizing mechanisms in paraneoplastic autoimmunity.


Medana, I. M. and M. M. Esiri (2003). "Axonal damage: a key predictor of outcome in human CNS diseases." Brain 126(Pt 3): 515-30.

            Axonal damage has recently been recognized to be a key predictor of outcome in a number of diverse human CNS diseases, including head and spinal cord trauma, metabolic encephalopathies, multiple sclerosis and other white-matter diseases (acute haemorrhagic leucoencephalitis, leucodystrophies and central pontine myelinolysis), infections [malaria, acquired immunodeficiency syndrome (AIDS) and infection with human lymphotropic virus type 1 (HTLV-I) causing HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP)] and subcortical ischaemic damage. The evidence for axonal damage and, where available, its correlation with neurological outcome in each of these conditions is reviewed. We consider the possible pathogenetic mechanisms involved and how increasing understanding of these may lead to more effective therapeutic or preventive interventions.


Mehta, P. D., B. A. Patrick, et al. (2003). "Detection of apolipoprotein E phenotype in unconcentrated cerebrospinal fluid." J Clin Lab Anal 17(1): 18-21.

            We developed a simple method to detect apolipoprotein E (Apo E) polymorphism distribution in approximately 20 microL of unconcentrated cerebrospinal fluid (CSF). A combination of isoelectric focusing in 3 M urea gel and immunoblotting was employed. Apo E phenotypes were identified in CSF samples from 45 patients with probable Alzheimer disease (AD), 15 with multiple sclerosis (MS), and 25 with other neurological diseases (OND). When the data were compared with a set of matched plasma samples, the results were identical. The method is useful for Apo E phenotyping from fresh or frozen unconcentrated CSF, when blood or plasma is not available.


Melhem, E. R., E. H. Herskovits, et al. (2003). "Defining thresholds for changes in size of simulated T2-hyperintense brain lesions on the basis of qualitative comparisons." AJR Am J Roentgenol 180(1): 65-9.

            OBJECTIVE: Our purpose was to define thresholds below which trained reviewers cannot detect changes in the size of T2-hyperintense brain lesions. MATERIALS AND METHODS: We generated T2-weighted brain MR images (TR/TE, 4000/80) with simulated hyperintense lesions derived from a real multiple sclerosis plaque. The size of the original multiple sclerosis lesion was varied by scaling up or down the lesion using a bicubic interpolation method. Three hundred seventy-eight composite images, in which two T2-weighted images containing lesions were paired, were presented to three equally trained neuroradiologists to define thresholds below which changes in original lesion size could not be detected. Stepwise logistic regression was used to evaluate the dependency of size thresholds on the original size of the lesion. RESULTS: Thresholds ranged from a 5% to 15% increase in the original lesion diameter. For increases greater than 15%, all three reviewers detected the change in lesion size irrespective of the diameter of the original lesion. There was a dependency of the threshold on the diameter of the original lesion (p = 0.02). CONCLUSION: Using an MR simulator, we can define thresholds below which changes in original lesion size cannot be reliably detected. These results may guide the design of clinical trials that rely on trained reviewers to assess change in lesion burden.


Mellai, M., M. Giordano, et al. (2003). "Prolactin and prolactin receptor gene polymorphisms in multiple sclerosis and systemic lupus erythematosus." Hum Immunol 64(2): 274-84.

            Genes encoding for prolactin (PRL) and its receptor (PRLR) are possible candidates for multiple sclerosis (MS) and systemic lupus erythematosus (SLE) susceptibility. In fact: (1) a prolactin secretion dysfunction has been described in several autoimmune diseases including SLE and MS and their animal models; (2) both PRL and PRLR are structurally related to members of the cytokine/hematopoietin family and have a role in the regulation of the immune response; and (3) both PRL and PRLR genes map in genomic regions that showed linkage with autoimmunity. Prolactin maps on chromosome 6p, about 11-kb telomeric to HLA-DRB1 and PRLR in 5p12-13, which revealed evidence of linkage with MS in different populations. To evaluate a possible role of these two genes in SLE and MS we performed an association study of 19 PRL and PRLR single nucleotide polymorphisms (SNPs). These were directly searched by DHPLC in a panel of SLE and MS patients and selected from databases and the literature. The SNP allele frequencies were determined on patient and control DNA pools by primer-extension genotyping and HPLC analysis. Moreover a panel of HLA typed SLE and control individuals were individually genotyped for the PRL G-1149T polymorphism previously described to be associated with SLE. No statistically significant difference in the allele distribution was observed for any of the tested variations.


Melo, T. M., C. Larsen, et al. (2003). "Manganese, Copper, and Zinc in Cerebrospinal Fluid from Patients with Multiple Sclerosis." Biol Trace Elem Res 93(1-3): 1-8.

            The concentrations of manganese, copper, and zinc in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) and patients with no known neurological disease (control group) were measured. Manganese and copper levels were determined by two different analytical methods: atomic absorption spectrometry (AAS) and high-resolution inductively coupled plasma-mass spectrometry (HR-ICP-MS), whereas zinc levels were determined by HR-ICP-MS only. Manganese levels (mean+/-SEM) were significantly decreased in the CSF of MS patients (1.07+/-0.13 &mgr;g/L, ICP-MS; 1.08+/-0.11 &mgr;g/L, AAS) compared to the levels in the control group (1.78+/-0.26 &mgr;g/L, ICP-MS; 1.51+/-0.17 &mgr;g/L, AAS). Copper levels were significantly elevated in the CSF of MS patients (10.90+/-1.11 &mgr;g/L; ICP-MS, 11.53+/-0.83 &mgr;g/L, AAS) compared to the levels in the control group (8.67+/-0.49 &mgr;g/L, ICP-MS; 9.10+/-0.62 &mgr;g/L, AAS). There were no significant differences between the CSF zinc levels of MS and control patients. The physiological basis for the differences in manganese and copper concentrations between MS patients and controls is unknown, but could be related to alterations in the manganese- containing enzyme glutamine synthetase and the copper-containing enzyme cytochrome oxidase.


Mennel, E. A. and S. D. John (2003). "Osteosclerotic metaphyseal dysplasia: a skeletal dysplasia that may mimic lead poisoning in a child with hypotonia and seizures." Pediatr Radiol 33(1): 11-4.

            We report the case of a 23-month-old male with hypotonia, developmental delay, and complex seizures. Radiographs revealed profound sclerosis of the metaphyses and epiphyses of the long and short bones in the extremities, with a unique pattern of distribution. Sclerosis also involved the anterior ribs, iliac crests, talus, and calcaneus. The skull and vertebral bodies appeared unaffected. Blood lead levels were normal. We believe that this constellation of clinical and radiographic abnormalities closely resembles osteosclerotic metaphyseal dysplasia (OMD) due to an autosomal recessive defect. Characteristic skeletal findings were instrumental in determining the diagnosis. OMD is a very rare sclerosing bone disorder, first described in 1993. The syndrome is characterized clinically by developmental delay of a progressive nature, hypotonia, elevated alkaline phosphatase, and late-onset spastic paraplegia. We encountered a young child with these neurologic symptoms who displayed sclerotic metaphyseal changes on hand radiographs obtained to determine the bone age. Lead poisoning, a known cause of metaphyseal sclerosis, was initially suspected. Careful analysis of the metaphyseal bone changes helped to distinguish this bone dysplasia from lead poisoning and other causes of metaphyseal sclerosis.


Merkelbach, S., J. Konig, et al. (2003). "Personality traits in multiple sclerosis (MS) patients with and without fatigue experience." Acta Neurol Scand 107(3): 195-201.

            OBJECTIVES: To determine the impact of personality characteristics on feelings of fatigue in multiple sclerosis (MS) patients and to compare the results with the impact of bodily impairment. PATIENTS AND METHODS: Eighty patients with definite MS (mean age 38.5 +/- 9.0 years, 62 females) were surveyed using questionnaires assessing fatigue experience and personality traits (German Freiburg Personality Inventory-Revised; FPI-R) and by clinical examination assessing the Expanded Disability Status Scale. RESULTS: Increased levels of "neuroticism", and "excitability" and decreased levels of "extraversion" were found to relate independent of fatigue scores (0.21 < beta < 0.52; 0.05 < P < 0.0001). The impact of these personality traits on fatigue (partial R2 ranging up to 0.32; 0.02 < P < 0.0001) was much higher than the impact of physical impairment (partial R2 ranging up to 0.04; not significant). CONCLUSION: Our results support a psychological model of fatigue in MS. FPI-R-items over-weighted somatic sources of the fatigue syndrome in MS and may specifically relate to fatigue experience in chronical disorders.


Mevellec, E., D. Lamotte, et al. (2003). "[Relationship between gait speed and strength parameters in multiple sclerosis]." Ann Readapt Med Phys 46(2): 85-90.

            INTRODUCTION: Recent studies have focused on correlation between strength and gait parameters in hemiplegia, suggesting the interest for strength training in patients with central nervous system lesions. The aim of this study was to evaluate this correlation in multiple sclerosis (MS) patients with special regard to the different clinical forms including proprioceptive loss or cerebellar ataxia. PATIENTS AND METHOD: Gait speed and muscular function were performed in 27 patients with moderate affected gait (EDDS < 6). Gait speed was evaluated with Locometre and peak-torques of quadriceps and hamstrings were evaluated with isokinetic dynamometer. Patients were separated in three groups related to their deficiency: spastic group (8 patients), spastic with proprioceptive loss (12 patients) and spastic with cerebellar ataxia (7 patients). Gait parameters were evaluated in 10 healthy subjects as control group. RESULTS: Gait speeds (spontaneous and maximal) and peak torques of quadriceps and hamstring were similar in the three groups. In the whole patients group, gait speed was reduced and related to hamstring peak torque (r = 0.56 at spontaneous speed and 0.51 at high speed) but not with quadriceps peak torque. Patients with proprioceptive loss exhibited not only a higher correlation between gait speed and hamstring torque (r = 0.76 and 0.65 respectively) than other patients but also with quadriceps torque (r = 0.66 and 0.59 respectively) when patients in other groups did not. CONCLUSION: As it was previously pointed out in hemiplegic patients, MS patients exhibit some correlation between gait speed and muscle strength, mainly with hamstrings. These correlations can change in special sensory conditions suggesting that patients with sensory loss use different muscular strategies to maintain gait speed. Strength training may therefore be discussed in MS including specific modalities as a function of clinical parameters.


Milicevic, I., S. Pekovic, et al. (2003). "Ribavirin reduces clinical signs and pathological changes of experimental autoimmune encephalomyelitis in Dark Agouti rats." J Neurosci Res 72(2): 268-78.

            The effect of ribavirin on development of experimental autoimmune encephalomyelitis (EAE) was investigated. The disease was induced in genetically susceptible Dark Agouti rats with syngeneic spinal cord homogenate in complete Freund's adjuvant (SCH-CFA). Depending on the amount of mycobacteria in CFA, the animals developed either moderate or severe EAE. Ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was applied i.p. at a daily dosage of 30 mg/kg in two treatment protocols: from the start of immunization (preventive treatment) or from the onset of the first EAE signs after the induction (therapeutic treatment). Signs of EAE began between 7 and 9 days after induction and peaked at days 11-13. In moderate EAE (mean maximal severity score 3.33 +/- 0.21), the recovery was completed by days 23-26, whereas, in severe EAE (mean maximal severity score 4.5 +/- 0.23), obvious recovery was not detected. Preventive ribavirin treatment significantly decreased clinical signs after both moderate (score 1.75 +/- 0.25, P < 0.05) and severe (score 3.62 +/- 0.31, P < 0.015) immunization. Also, disease manifestations were reduced by therapeutic treatment of ribavirin (mean maximal severity score 2.5 +/- 0.2 vs. 3.33 +/- 0.21 in controls, P < 0.005) but less so in comparison with preventive treatment. Analysis of the effects of ribavirin on histopathologic changes in the spinal cord tissue revealed a reduction of mononuclear cell infiltrates, composed of T cells and macrophages/microglia, and the absence of demyelination, which were pronounced in control EAE animals. Beneficial effects of preventive and therapeutic treatment with ribavirin on development of EAE suggest this nucleoside analogue as a useful candidate for therapy in multiple sclerosis.


Miller, D. M., R. A. Rudick, et al. (2003). "Factors that predict health-related quality of life in patients with relapsing-remitting multiple sclerosis." Mult Scler 9(1): 1-5.

            Health-Related Quality of Life (HRQoL) research is gaining acceptance in the field of multiple sclerosis (MS). Little is known about what precipitates quality of life change. It was hypothesized that physical aspects of quality of life decline with worsening objective disease measures and psychosocial aspects remain relatively stable regardless of change in objective measures. These assumptions are tested using data from a Phase 3 study of relapsing-remitting MS patients treated with interferon beta-1a and reassessed approximately eight years after study initiation. The Sickness Impact Profile (SIP) questionnaire is the generic quality of life measure used in this study. Three summary scores of the SIP (Physical, Psychosocial, and Total scores), Expanded Disability Status Scores, Multiple Sclerosis Functional Composite, and Brain Parenchymal Fraction were determined at baseline, year 2, and after an average of 8.1 years from study entry. SIP data collected during a clinic visit were available from 137 of the original 172 participants. All objective indicators worsened by follow-up. SIP Physical and Total scores significantly worsened from baseline to follow-up. SIP Psychosocial showed nonsignificant worsening. Regression analysis indicated that final measures of SIP Physical and Total scores were most strongly associated with change in objective measures and follow-up SIP Psychosocial was most strongly related to earlier scores on the same measure.


Miller, A., G. Eninia, et al. (2003). "[Adhesive molecules as immunologic markers of activity of multiple sclerosis]." Zh Nevrol Psikhiatr Im S S Korsakova 103(1): 35-8.

            The correlations between concentrations of the adhesive circulating molecules cICAM-1 and cVCAM-1 in the peripheral blood of patients with relapses-remitting multiple sclerosis (RRMS) in different clinical phases and magnetic resonance imaging (MRI) activity are presented. The patients in clinically active phase with Gd-enhancing lesions had elevated blood levels of cICAM-1. However, 5 patients without Gd-enhancing lesions exhibited elevated cICAM-1 and cVCAM-1 levels in active phase comparing to those in remission stage that indicate a high level of sensibility of these immunologic parameters.


Miller, D. H., O. A. Khan, et al. (2003). "A controlled trial of natalizumab for relapsing multiple sclerosis." N Engl J Med 348(1): 15-23.

            BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.


Minagar, A., D. Ostanin, et al. (2003). "Serum from patients with multiple sclerosis downregulates occludin and VE-cadherin expression in cultured endothelial cells." Mult Scler 9(3): 235-8.

            Disruption of the blood brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). Occludin and vascular endothelial-cadherin (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.


Miscio, G., G. Guastamacchia, et al. (2003). "Are the neurophysiological techniques useful for the diagnosis of diaphragmatic impairment in multiple sclerosis (MS)?" Clin Neurophysiol 114(1): 147-53.

            OBJECTIVE: To characterize cortico-diaphragmatic pathway involvement in multiple sclerosis (MS) by means of transcranial magnetic stimulation (TMS), and verify its clinical impact. METHODS: TMS from diaphragm (Dia), and abductor digiti minimi (AbdV degrees ) was performed in 26 MS patients. Phrenic nerve (PN) conduction study was also performed. Expanded disability status scale (EDSS) and fatigue descriptive scale (FDS) were measured. Forced vital capacity (FVC), forced expiratory volume at the first second (FEV1), peak expiratory flow (PEF) were tested: the predicted percentage value (% pred) was considered. RESULTS: Cortical motor evoked potential (Cx-MEP) latency and central motor conduction time (CMCT) were prolonged, respectively, in 31 and 23% of patients from Dia, in 76 and 79% from AbdV degrees. PN-compound motor action potential (CMAP) was normal. EDSS correlated to Cx-MEP from AbdV degrees (P<0.01), and PN-CMAP amplitude (P<0.05), FEV1 % pred (P<0.01), PEF % pred (P<0.01). PN-CMAP amplitude correlated to FVC % pred P=0.05, FEV1 % pred P<0.01, PEF % pred P<0.01. Fatigue was related to AbdV degrees Cx-MEP and CMCT (P<0.05 and P<0.01). CONCLUSIONS: Cortico-diaphragmatic pathway is impaired only in a minority of MS patients. Lack of correlation between TMS findings from Dia and respiratory tests argues against its routinary use to detect subclinical respiratory alterations. Fatigue seems to be related to the motor impairment rather than to respiratory distress.


Miwa, H., Y. Kajimoto, et al. (2003). "T2-low signal intensity in the cortex in multiple system atrophy." J Neurol Sci 211(1-2): 85-8.

            To determine the clinical significance of T2-low signal intensity in the cortex of patients presenting parkinsonism, T2-weighted magnetic resonance (MR) images of the cortex of patients with multiple system atrophy (MSA), Parkinson's disease (PD) and progressive supranuclear palsy (PSP), and compared with those of patients with amyotrophic lateral sclerosis (ALS) and age-matched normal controls. The MR images were gathered and presented randomly to three neurologists who were blind to information on the patients. There was a significant increase in the frequency of T2-low signal intensity in the cortex of patients with ALS and MSA. Particularly in those with MSA, the T2-low signal intensity was observed not only in the motor cortex but also in the frontal association cortex. The cortical T2-low signal intensity in MSA might reflect the spread of degenerative processes in the cortex.


Mizuno, T., J. Kawanokuchi, et al. (2003). "Production and neuroprotective functions of fractalkine in the central nervous system." Brain Res 979(1-2): 65-70.

            The CX3C-chemokine, fractalkine is reportedly to be expressed in the central nervous system, and up-regulated in certain pathological conditions, such as HIV encephalopathy and multiple sclerosis. In the present study, we examined the production of fractalkine and the expression of its receptor, CX3CR1 in murine glial and neuronal cell in vitro, and investigated its neuroprotective functions. Both fractalkine and CX3CR1 were expressed constitutively in neurons, microglia, and astrocytes. Neither the production of fractalkine nor its receptor expression was up-regulated by lipopolysaccharide (LPS), as measured by mRNA expression and protein synthesis. Fractalkine dose-dependently suppressed the production of nitric oxide (NO), interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha with activated microglia. It also significantly suppressed neuronal cell death induced by microglia activated with LPS and interferon-gamma, in a dose-dependent manner. These results suggest the possible functions of fractalkine as an intrinsic inhibitor against neurotoxicity by activated microglia.


Modin, H., T. Masterman, et al. (2003). "Genome-wide linkage screen of a consanguineous multiple sclerosis kinship." Mult Scler 9(2): 128-34.

            Multiple sclerosis (MS), like Alzheimer's disease (AD) and Parkinson's disease (PD), is a common neurological disorder thought to be caused by the interaction of several genes with unknown environmental factors. In both AD and PD the identification of disease forms inherited in a classic Mendelian fashion has helped investigators elucidate pathogenetic mechanisms. In this study a whole-genome screen, with an average of 608 successful genotypes per person, was performed on nine members of a consanguineous family: the index case, three of her siblings and her daughter, all of whom have been diagnosed with definite MS; as well as the parents of the index case (first cousins), one of her five healthy siblings and her husband (who is also her first cousin). Nonparametric linkage analysis was performed on genotyping data. Based on the presence of consanguinity, the a priori hypothesis was that the disease is transmitted in an autosomal recessive fashion in the pedigree. Linkage analysis revealed a suggestive logarithm of odds (LOD) score of 2.29 on the long arm of chromosome 9. Four of five affected family members were identically homozygous for a haplotype under this peak, spanning approximately 43 cM, while the fifth affected subject and all unaffected family members were heterozygous for the haplotype.


Mogenet, I., E. Simiand-Erdociain, et al. (2003). "Acute myelogenous leukemia following mitoxantrone treatment for multiple sclerosis." Ann Pharmacother 37(5): 747-8.


Mohamed, A., A. Shoker, et al. (2003). "Improvement of experimental allergic encephalomyelitis (EAE) by thymoquinone; an oxidative stress inhibitor." Biomed Sci Instrum 39: 440-5.

            Experimental Allergic Encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system that is widely accepted as an animal model for the human multiple sclerosis. Oxidative stress appears to play a role in the onset and progression of EAE. We reasoned that decreasing oxidative stress might ameliorate symptoms and signs of EAE. Thymoquinone is reported to inhibit oxidative stress. One way of decreasing oxidative stress is to induce glutathione (GSH). We tested the impact of Thymoquinone (1 mg/kg, injected at tail vein) in our EAE model. We induced (EAE) in female Lewis rats using myelin basic protein emulsified with complete Freund's adjuvant. 24 animals were placed into three groups: A) Rats with EAE B) EAE rats with concomitant five day injection of Thymoquinone days 1-5, C) EAE rats with five doses of Thymoquinone injected at day 12-17. Twenty-eight days later, animals were sacrificed; spinal cord tissues collected for glutathione (GSH). RESULTS: 63% of animals in group "A" developed hind limb weakness and/or paralysis while 37% developed mild tail weakness, perivascular inflammation and low spinal cord GSH level. 25% of animals in group "B" exhibited mild tail and hind limb weakness and 75% animals had no symptoms, no perivascular inflammation and high spinal cord GSH level. 63% of animals of group "C" showed improving symptoms following Thymoquinone injections, no perivascular inflammation and higher GSH level while 37% of animals showed no symptoms prior and post Thymoquinone injections. Clinical symptoms correlated well with perivascular inflammation and GSH level. Animals received Thymoquinone at day 12-17 had higher GSH level, no perivascular inflammation and no symptoms compared with other groups. CONCLUSION: Thymoquinone inhibited oxidative stress which leads into improvement in our EAE animals. Thymoquinone may have a role in treatment of Multiple Sclerosis.


Mokhtarian, F., C. M. Huan, et al. (2003). "Semliki Forest virus-induced demyelination and remyelination--involvement of B cells and anti-myelin antibodies." J Neuroimmunol 137(1-2): 19-31.

            Semliki Forest virus (SFV) infection induces a demyelinating encephalomyelitis in the central nervous system (CNS) of mice and serves as a model for multiple sclerosis (MS). This study investigated CNS immune responses at different stages of infection and during SFV-induced demyelination and remyelination. Following the initial CNS inflammation, pathology and viral clearance on days 6-10 post-infection (pi), primary demyelination was observed in cerebellar, brainstem and corpus collosal white matter by days 15-21 pi, with plasma cells and microglia as main participants, and this was followed by remyelination. By day 35 pi, the tissue appeared almost normal. Fluorescent antibody cell sorter (FACS) analysis showed that brain CD8(+) T cells increased during the initial inflammatory response and gradually decreased thereafter. Brain B cell (B220(+)CD19(+)) numbers did not change significantly during the course of infection; however, from days 14 to 35 pi, they matured and produced antibodies to viral and myelin proteins (and peptides) during the period of demyelination and remyelination. The proportion of CD3(-)B220(-)CD11b(+) cells also progressively increased throughout the periods of de- and remyelination. Our results suggest that CD8(+) T cells are involved in the initial destruction of CNS tissue during the first weeks of SFV infection, while B cells, antibodies and microglia may contribute to the myelin pathology seen after recovery.


Molina-Monasterios, M. C. and H. Molina-Abecia (2003). "[Nasu Hakola disease: a report of the first two cases in Bolivia]." Rev Neurol 36(9): 837-40.

            INTRODUCTION: Nasu Hakola disease (NHD) is a progressive dementia that presents accompanied by bone cysts and, at random, epilepsy. It is an autosomal recessive hereditary disease and its genetic defect is located at the 19q13.1 chromosome. The genetic mutation was identified at DAP 12. It appears that DAP 12 is expressed in the microglial activation and the differentiation of macrophages in the central nervous system and, at the same time, in the osteoclasts in charge of bone remodelling. This double character consisting of dementia and bone cysts, which contain triglycerides and thin PAS positive membranes in a bone with cortical erosion and medullary hypoplasia, enables us to differentiate this disease from other frontotemporal neurodegenerative disorders, such as Pick s disease. At the same time this also allows it to be distinguished from multiple sclerosis, metachromatic leukodystrophy, Marchafava Bignami disease, and prion diseases (such as new variant Creutzfeldt Jakob). CASE REPORTS: In this paper we describe two cases of NHD, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, in which progressive dementia, bone cysts and epilepsy were identified. Serious brain atrophy was found and confirmed by imaging studies and brain biopsies, which were also used to rule out other degenerative diseases of the frontal lobe, as well as Creutzfeldt Jakob disease. CONCLUSIONS: Both cases meet all the necessary criteria to satisfy a diagnosis of NHD. This is a hereditary, little known disease whose genetic alterations (i.e. mutations) are still in need of further study. It mainly affects males, who suffer the onset of dementia in their thirties. The neurological disorders constitute a frontal syndrome, due to predominant prefrontal involvement, and they occur in the dorsolateral area, with disorders affecting the executive and planning functions; in the orbitofrontal area, which is reflected in social maladjustment and clear obsessive compulsive traits; and also in the medial or cingulate area, which manifests itself as apathy and lack of motivation. When dealing with this disease, in addition to symptomatic therapy, genetic counselling is also important.


Monge-Argiles, J. A., F. Palacios-Ortega, et al. (2003). "Sympathetic dysfunction is related to the clinical activity of multiple sclerosis." Mult Scler 9(2): 216; author reply 215.


Mpofu, S. and R. J. Moots (2003). "A case of multiple sclerosis associated with rheumatoid arthritis and positive anticardiolipin antibodies." Ann Rheum Dis 62(4): 376.


Munger, K. L., R. W. Peeling, et al. (2003). "Infection with Chlamydia pneumoniae and risk of multiple sclerosis." Epidemiology 14(2): 141-7.

            BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent for multiple sclerosis (MS), but results of previous studies are conflicting. METHODS: Using a nested case-control design, we examined the association between Cpn infection and MS in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) cohorts. Among 32,826 women in the NHS and 29,722 women in the NHS II with blood samples, 141 incident cases of definite or probable MS were documented. Each case was matched to two healthy controls on year of birth and NHS cohort. Serum samples were tested for the presence of Cpn-specific immunoglobin G antibodies using microimmunofluorescence. RESULTS: Cpn immunoglobin G seropositivity was positively associated with risk of MS (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.1-2.7). This association did not change after adjusting for age at blood collection, ancestry, latitude of residence at birth, and smoking (OR = 1.9; CI = 1.1-3.1). Seropositivity for Cpn was only moderately associated with risk of relapsing-remitting MS (OR = 1.7; CI = 0.9-3.2), but it was strongly associated with risk of progressive MS (OR = 7.3; CI = 1.4-37.2). Geometric mean titers of Cpn-specific immunoglobin G antibody were similar in women with relapsing-remitting MS as compared with matched controls (44 vs 39), but they were elevated in women with progressive MS (99 vs 40). CONCLUSIONS: These results support a positive association between Cpn infection and progressive MS.


Muraro, P. A., R. C. Ingoni, et al. (2003). "Hematopoietic stem cell transplantation for multiple sclerosis: current status and future challenges." Curr Opin Neurol 16(3): 299-305.

            PURPOSE OF REVIEW: This article reviews recent advances in clinical trials of hematopoietic stem cell transplantation as a therapy for multiple sclerosis, and progress in exploring the potential for neural repair of hematopoietic-derived precursors. RECENT FINDINGS: Important recent findings are that hematopoietic stem cell transplantation can completely suppress the inflammatory component of multiple sclerosis, hematopoietic stem cells can migrate into the central nervous systems of rodents and humans, and can differentiate into cells expressing neural and glial markers. Hematopoietic stem cells also have neural and myelin repair potential. The heterogeneity of transplant regimens, the selection of patients at different stages of disease in clinical trials, and the limited duration of follow-up all currently preclude the evaluation of the long-term clinical benefits of hematopoietic stem cell transplantation for multiple sclerosis. SUMMARY: Hematopoietic stem cell transplantation is an experimental treatment that shows strong effects on the inflammatory component of multiple sclerosis. On the basis of experience acquired from initial pilot studies, controlled clinical trials are now being designed to verify long-term clinical efficacy. Selecting patients at high risk in the earlier stages of the disease that is dominated by inflammation, and monitoring objectively disease activity by magnetic resonance imaging will be critically important in these studies. Recent advances on the migratory potential and on the differentiation plasticity of hematopoietic stem cells have opened new opportunities for remyelination and axonal repair strategies for multiple sclerosis.


Muraro, P. A., K. P. Wandinger, et al. (2003). "Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders." Brain 126(Pt 1): 20-31.

            T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.


Murphy, C. B., S. A. Hashimoto, et al. (2003). "Clinical exacerbation of multiple sclerosis following radiotherapy." Arch Neurol 60(2): 273-5.

            BACKGROUND: Radiation of the central nervous system in patients with demyelinating disease may have deleterious effects. OBJECTIVE: To describe a 30-year-old woman with multiple sclerosis who developed an attack of demyelination 2 months following radiotherapy for a parotid malignancy. RESULTS: Magnetic resonance imaging demonstrated new hyperintense lesions that corresponded to both the localization of the patient's symptoms and to the area defined by the 50% isodose radiation field. CONCLUSION: Radiation treatment likely triggered an exacerbation of multiple sclerosis.


Mycko, M. P., R. Papoian, et al. (2003). "cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity." Brain 126(Pt 5): 1048-57.

            cDNA microarray analysis of the regions of pathologically proven different activity of multiple sclerosis lesions was performed. Major differences in gene expression (DGE) occurred between the lesion margin and lesion centre in active lesions studied (57 and 69 genes differentially expressed, respectively), whereas the margins and centres of silent lesions showed markedly reduced heterogeneity (only 11 and two genes differentially expressed, respectively). To compare differences between chronic active and silent lesions, we performed DGE comparison of the pooled data from both types of lesions. The major DGE occurred at the lesion margin, 156 (26; 5%), the greater number representing upregulated genes at the margin of active lesions (15%). Fourteen genes were found to be significantly upregulated in marginal versus central zones in active lesions examined. These genes comprised predominantly inflammation/immune-related factors. We also performed DGE analysis of pooled genes upregulated at the margin of active lesions and found that among the 50 genes showing differences, nine out of 14 were identified in the previous analysis of overlapping differentially expressed genes. Thus this microarray analysis has identified a novel set of genes associated with lesion activity in multiple sclerosis, many of them not previously linked with the disease.


Myers, J. A., K. M. McPherson, et al. (2003). "Duration of condition is unrelated to health-state valuation on the EuroQoL." Clin Rehabil 17(2): 209-15.

            OBJECTIVE: To determine whether health valuations, such as those used in economic evaluation, are affected by duration of a health condition. People with disabling health conditions tend to value health more highly than members of the general population, and one explanation for this is that over time their experience of living with a disabling illness changes the way in which they value health. If this is so, a relationship between the duration of an individual's disabling health condition and the valuation they assign to their health-state might reasonably be expected. DESIGN: A postal survey using the EuroQoL (EQ-5D) instrument to collect descriptions and valuations for health from people who reported a diagnosis of either stroke or multiple sclerosis. Contact with participants was made through national support organizations and questionnaires were returned by mail. RESULTS: Eight hundred and ninety-four people completed the survey. One hundred (11 %) had one health-state indicating moderate problems in all five dimensions of the EQ-5D descriptive profile. For people with this health-state, analysis of covariance showed no relationship between valuation of health-state and time from onset of illness (F = 0.38, p = 0.54). This finding applied irrespective of the diagnosis, and for some other less frequently reported health-states. CONCLUSION: Clinical experience suggests that over time people adapt to long-term disability. However we found no evidence to support the proposition that higher health-state valuations by people with disabling conditions are explained by the actual duration of their condition.


Nagai, A., M. Terashima, et al. (2003). "Cathepsin B and H activities and cystatin C concentrations in cerebrospinal fluid from patients with leptomeningeal metastasis." Clin Chim Acta 329(1-2): 53-60.

            BACKGROUND: Cysteine proteases are involved in the extension of cancer into the subarachnoid space. The presence of cathepsins B and H along with their potent inhibitor cystatin C in the cerebrospinal fluid (CSF) was investigated in patients with leptomeningeal metastasis of cancer (LM). MATERIALS AND METHODS: CSF samples were obtained in 16 cases of LM (10 solid tumors and 6 leukemia or lymphoma) and compared with 11 cancer cases without involvement of the central nervous system, 12 multiple sclerosis cases and 34 healthy volunteers. The activity of the enzymes was measured, their molecular forms were analyzed by the Western blotting, and the concentration of cystatin C was measured by ELISA. Immunohistochemistry of the leptomeningeal tissues was also performed in six autopsy cases of LM. RESULTS: High activities of cathepsins B and H along with decreased cystatin C concentration were observed in CSF of LM as compared with three control groups. Western blot analysis revealed higher concentration of the enzyme protein as well as its active forms in samples with higher enzyme activity. Cells metastasizing leptomeningeal tissue were clearly positive in immunohistochemical staining of cathepsins, indicating active production by tumor cells. CONCLUSION: Production of cathepsins B and H by tumor cells and their high activity along with concomitant decrease of their potent inhibitor, cystatin C, in the CSF might contribute in the process of metastasis and spread of the cancer cells in the leptomeningeal tissues. A high enzyme activity/cystatin C concentration ratio in the CSF could be useful when diagnosing LM in combination with other parameters.


Nakahara, J., C. Seiwa, et al. (2003). "Expression of Fc receptor for immunoglobulin M in oligodendrocytes and myelin of mouse central nervous system." Neurosci Lett 337(2): 73-6.

            Recent advances in neuro-immunology are beginning to elucidate several essential roles of the humoral immunity in both repair and pathogenesis of central nervous system diseases. Immunoglobulin M (IgM) was reported to accelerate the rate of remyelination in a demyelinating disease model, while intrathecal IgM synthesis was shown to predict a more worse disease course in a human demyelinating disease, multiple sclerosis. Molecular mechanisms for either of these IgM functions remain to be studied. Here we report that a recently-found Fc receptor for IgM, namely Fcalpha/muR, is expressed in oligodendrocytes, their precursor cells, and myelin. These expressions were confirmed by immunocytochemistry of cultured cells, Western blot analysis of myelin fractions, and also by immunohistochemistry of mouse forebrains at different ages. Our findings suggest a possible direct interaction between IgM and Fcalpha/muR expressed in oligodendrocytes and myelin.


Nakanishi, H. (2003). "Microglial functions and proteases." Mol Neurobiol 27(2): 163-76.

            There is accumulating evidence that intracellular and extracellular proteases of microglia contribute to various events in the central nervous system (CNS) through both nonspecific and limited proteolysis. Cathepsin E and cathepsin S, endosomal/lysosomal proteases, have been shown to play important roles in the major histocompatibility complex (MHC) class II-mediated antigen presentation of microglia by processing of exogenous antigens and degradation of the invariant chain associated with MHC class II molecules, respectively. Some members of cathepsins are also involved in neuronal death after secreted from microglia and clearance of phagocytosed amyloid- beta peptides. Tissue-type plasminogen activator, a serine protease, secreted from microglia participates in neuronal death, enhancement of N-methyl-D-aspartate receptor-mediated neuronal responses, and activation of microglia via either proteolytic or nonproteolytic activity. Calpain, a calcium-dependent cysteine protease, has been shown to play a pivotal role in the pathogenesis of multiple sclerosis by degrading myelin proteins extracellulary. Furthermore, matrix metalloproteases secreted from microglia also receive great attention as mediators of inflammation and tissue degradation through processing of pro-inflammatory cytokines and damage to the blood-brain barrier. The growing knowledge about proteolytic events mediated by microglial proteases will not only contribute to better understanding of microglial functions in the CNS but also may aid in the development of protease inhibitors as novel neuroprotective agents.


Napier, J. C., R. Francis, et al. (2003). "Shared scheme for assessing drugs for multiple sclerosis: cost effective provision of effective treatments for multiple sclerosis." Bmj 326(7400): 1212.


Narayana, K. M., R. Agrawal, et al. (2003). "Recurrent anterior uveitis and healed retinal vasculitis associated with multiple sclerosis." Indian J Ophthalmol 51(1): 77-9.

            We describe the occurrence of anterior uveitis with healed retinal vasculitis in an Asian-Indian woman. She had features of anterior uveitis and healed retinal vasculitis. This rare disease in India may be associated with intraocular inflammation.


Nash, R. A., J. D. Bowen, et al. (2003). "High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis." Blood.

            Twenty-six patients were enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline Expanded Disability Status Scale (EDSS) was 7.0 (5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide and antithymocyte globulin (ATG) and was followed by transplantation of autologous, G-CSF-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were eight infectious events of the lower urinary tract. One patient died from EBV-PTLD associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever +/- rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurological symptoms. Two significant adverse neurologic events occurred, including a flare of MS during mobilization and an episode of irreversible neurological deterioration after HDIT associated with fever. With a median follow-up of 24 (3-36) months, the Kaplan-Meier estimate of progression (>/=1.0 points EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. Four patients developed new enhancing lesions on magnetic resonance imaging of the brain after HDIT. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase III study is planned to fully assess efficacy.


Nayak, S., R. J. Matheis, et al. (2003). "Use of unconventional therapies by individuals with multiple sclerosis." Clin Rehabil 17(2): 181-91.

            OBJECTIVE: To examine the prevalence and patterns of use of complementary and alternative medicine (CAM) among individuals with multiple sclerosis (MS) in the USA and to explore the reasons for use, symptoms treated and perceived effectiveness of these therapies. METHODS: Surveys were mailed to the entire mailing list of the MS Foundation, constituting 11,600 individuals with MS or their family members; 3,140 adults with MS returned surveys, yielding a response rate of 27.1%. RESULTS: More than half of the responding sample (57.1%) had used at least one CAM modality. The longer that people had MS and the less satisfied they were with conventional health care the more likely they were to use CAM therapies. The most common reasons for using CAMs were the desire to use holistic health care (i.e., treatments that recognized the interrelatedness of mind, body and spirit) and dissatisfaction with conventional medicine. Ingested herbs were the most frequently used CAM modalities (26.6%), followed by chiropractic manipulation (25.5%), massage (23.3%) and acupuncture (19.9%). Women were 25% more likely than men and whites were 30% more likely than non-whites to use CAM therapies. There was no significant relationship between the frequency of use and the reported efficacy of the CAM techniques (r = 0.17, p > 0.10). CONCLUSIONS: The prevalence of CAM use in this population warrants more research on the efficacy and safety of these therapies, especially those with high usage or high efficacy ratings, such as herbs, chiropractic manipulation and massage, but for which there is little or no research evidence for efficacy or safety.


Nejentsev, S., M. Laaksonen, et al. (2003). "Intercellular adhesion molecule-1 K469E polymorphism: study of association with multiple sclerosis." Hum Immunol 64(3): 345-9.

            Intercellular adhesion molecule-1 (ICAM-1) is involved in the pathogenesis of multiple sclerosis (MS), whereas sequence variations in the ICAM-1 gene could potentially be responsible for the genetic susceptibility to MS. We studied an association of MS with the 13,848A>G (K469E) polymorphism of the ICAM-1 gene in Finnish and Spanish cases and controls and affected families. An increased risk for the AA (Lys(469)/Lys(469)) genotype was found in both populations. The effect observed was found to be strongest among the HLA-DQB1*0602-positive subjects, which implies genetic heterogeneity of MS. Meta-analysis of all published datasets supports increased risk of MS for the ICAM-1 Lys(469) homozygotes (relative risk = 1.3, p = 0.002).


Nelissen, I., E. Martens, et al. (2003). "Gelatinase B/matrix metalloproteinase-9 cleaves interferon-beta and is a target for immunotherapy." Brain 126(Pt 6): 1371-81.

            Parenteral administration of interferon (IFN)-beta is one of the currently approved therapies for multiple sclerosis. One characteristic of this disease is the increased production of gelatinase B, also called matrix metalloproteinase (MMP) 9. Gelatinase B is capable of destroying the blood-brain barrier, and of cleaving myelin basic protein into immunodominant and encephalitogenic fragments, thus playing a functional role and being a therapeutic target in multiple sclerosis. Here we demonstrate that gelatinase B proteolytically cleaves IFN-beta, kills its activity, and hence counteracts this cytokine as an antiviral and immunotherapeutic agent. This proteolysis is more pronounced with IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline minocycline, which has a known blocking effect in experimental autoimmune encephalomyelitis, an in vivo model of acute inflammation in multiple sclerosis, and other MMP inhibitors prevent the in vitro degradation of IFN-beta by gelatinase B. These data provide a novel mechanism and rationale for the inhibition of gelatinase B in diseases in which IFN-beta has a beneficial effect. The combination of gelatinase B inhibitors with better and lower pharmacological formulations of IFN-beta may reduce the side-effects of treatment with IFN-beta, and is therefore proposed for multiple sclerosis therapy and the immunotherapy of viral infections.


Neri, M. T. and T. Kroll (2003). "Understanding the consequences of access barriers to health care: experiences of adults with disabilities." Disabil Rehabil 25(2): 85-96.

            PURPOSE: The study explores: (1) the scope and nature of the consequences that adults with disabilities perceive as the result of inappropriate access to health care services; (2) the variability of these consequences by demographic attributes such as disability type, gender, and health insurance type; and (3) the inter-relatedness and multidimensionality of these consequences. METHODS: Qualitative, semi-structured, in-depth interviews were administered over the telephone to 30 participants with spinal cord injury, cerebral palsy, or multiple sclerosis as part of a nation-wide study on access and utilisation in the USA. Interviews were transcribed and coded for analysis using the qualitative analysis program, NVivo. RESULTS: Consequences were grouped into one of five categories: social, psychological, physical, economic and independence issues. Responses differed slightly with regard to disability type, gender and health insurance type. There was substantial overlap among consequence categories. For most respondents, negative consequences were not limited to just one area--frequently, one consequence triggered others. CONCLUSIONS: Health insurers and providers need a better understanding of the multiple consequences of access barriers. Based on this knowledge, detrimental and costly effects of inappropriate service delivery could be more effectively prevented. Implications for health care services and policy are discussed.


Neuhaus, O., J. J. Archelos, et al. (2003). "Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection." Trends Pharmacol Sci 24(3): 131-8.

            Multiple sclerosis (MS) is the most common disabling neurological disease of young adulthood. Following advances in the understanding of the immunological mechanisms that underlie the pathogenesis of MS, a growing arsenal of immunomodulatory agents is available. Two classes of immunomodulators are approved for long-term treatment of MS, the efficacy of several promising new concepts is being tested in clinical trials and classical immunosuppressive agents used in MS treatment have been shown to exert specific, immunomodulatory effects. Furthermore, two recent observations have changed our basic understanding of the pathogenesis of MS. First, immune cells in MS lesions have neuroprotective activity, which indicates a beneficial role of neuroinflammation. Second, there is evidence that axonal loss, rather than demyelination, underlies the progression of MS and, hence, constitutes a therapeutic target.


Neumann, H. (2003). "Molecular mechanisms of axonal damage in inflammatory central nervous system diseases." Curr Opin Neurol 16(3): 267-73.

            PURPOSE OF REVIEW: Axonal dysfunction and damage is an early pathological sign of autoimmune central nervous system disease, viral and bacterial infections, and brain trauma. Axonal injury has attracted considerable interest during the past few years because the degree of axonal damage appears to determine long-term clinical outcome. RECENT FINDINGS: Advanced magnetic resonance spectroscopic imaging techniques have suggested that axonal loss and dysfunction is responsible for the persistent neurological deficits that occur in patients with multiple sclerosis. Histopathological methods have shown that axonal damage is defined primarily by dysfunction of axonal transport, and finally by complete transection and degeneration of axons. Recent studies have demonstrated that the extent of axonal damage in the primary demyelinating lesion of multiple sclerosis patients is associated with the number of activated microglia/macrophages and cytotoxic CD8+ T lymphocytes. In addition, diffuse axonal dysfunction independent of demyelination develops in normal appearing white matter, possibly due to indirect effects of inflammation. SUMMARY: The fact that axonal damage in response to overt inflammatory reactions may occur gradually, leaving a window for therapeutical intervention, has important clinical implications. Determination of the exact molecular mechanism might help in finding new therapies for inflammatory axonal damage.


Nguyen, L. T., M. Ramanathan, et al. (2003). "Sex differences in in vitro pro-inflammatory cytokine production from peripheral blood of multiple sclerosis patients." J Neurol Sci 209(1-2): 93-9.

            We compared the patterns of the pro-inflammatory cytokines, interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha), and the anti-inflammatory cytokines, interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) from peripheral blood of male and female patients with relapsing-remitting (RR) and secondary progressive (SP) forms of multiple sclerosis (MS). The relationships between pro-inflammatory cytokines and disability (expanded disability status scale, EDSS) were also examined.Peripheral blood anti-coagulated with heparin was obtained from 47 MS patients (30 women and 17 men) and activated with phorbol-12-myristate 13 acetate (PMA) and ionomycin in the presence of brefeldin A and stained for flow cytometry with fluorescently labeled antibodies against intracellular IFN-gamma, TNF-alpha, IL-2, IL-4 and IL-10. The T cells were delineated with peridinin chlorophyll protein (Per-CP) labeled anti-CD3 antibody. The stained samples were analyzed on a flow cytometer to assess the intracellular pro-inflammatory cytokine patterns. The levels of interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta) were measured in plasma using enzyme-linked immunoassay.The percentage of TNF-alpha-producing CD3 positive cells was significantly higher (P=0.045) in men (mean+/-S.D., 39+/-13%) than in women (mean+/-S.D., 29+/-13%) RR-MS patients. The percentage of CD3 positive cells producing IFN-gamma was significantly correlated with EDSS in females but not in males (Spearman rank correlation r(S)=0.49, P=0.018). The secretion of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha, is influenced by gender in MS patients and may contribute to the sexual dimorphism of MS.


Nicholas, R. S., J. Partridge, et al. (2003). "The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom." J Neurol Neurosurg Psychiatry 74(7): 944-5.

            BACKGROUND: A point mutation in protein tyrosine phosphatase receptor, type c polypeptide (PTPRC) has been associated with familial multiple sclerosis. This CG mutation at position 77 of exon 4 results in altered expression of CD45 isoforms on immune cells. OBJECTIVE: To study the incidence of PTPRC mutations in subjects with multiple sclerosis in the North West region of the United Kingdom. METHODS: Affected and unaffected subjects from five pedigrees with familial multiple sclerosis, 330 non-familial cases of multiple sclerosis, and 197 controls were studied. Genomic DNA was amplified using CD45IE34 and CD45IE44 primers, digested with Mspl, and run on an agarose gel. Polymerase chain reaction products were sequenced to exclude any other mutations. RESULTS: No PTPRC exon 4 genomic mutations were seen in any of the five families. In the non-familial cases the incidence of mutation was 4.1% in 197 controls and 5.1% in 330 multiple sclerosis patients. No significant association was found in this study with this mutation and disease susceptibility, sex, or an extended disability scale score of < 5.5. CONCLUSIONS: This candidate does not appear to influence the development of familial multiple sclerosis in this population. The negative result could arise from a type II error owing to the number of families and non-familial cases screened. Alternatively it might suggest that the contribution of the PTPRC mutation depends upon the genetic background.


Nicot, A., P. V. Ratnakar, et al. (2003). "Regulation of gene expression in experimental autoimmune encephalomyelitis indicates early neuronal dysfunction." Brain 126(Pt 2): 398-412.

            Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Whereas oligodendrocytes have been considered the primary neural cell type most affected, recent evidence indicates that axonal and neuronal degeneration also occurs in both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model reproducing many features of multiple sclerosis. The molecular mechanisms underlying neuronal deficits in multiple sclerosis and EAE remain elusive. To address this issue, we have analysed the expression of genes encoding proteins that play critical roles in ion homeostasis, exocytosis, mitochondrial function and impulse conduction in the Lewis rat lumbar spinal cord during the clinical course of acute EAE. Transcript and protein levels of plasma membrane Ca(2+) ATPase 2 (PMCA2), an essential ion pump expressed exclusively in grey matter and involved in Ca(2+) extrusion, synapsin IIa and syntaxin 1B, important regulators of vesicular exocytosis, were dramatically decreased coincident with the onset of clinical symptoms. In contrast, changes in the expression of several other ion pumps, vesicular proteins, mitochondrial enzymes and sodium channels occurred at more advanced disease stages. Moreover, exposure of spinal cord slice cultures to kainic acid significantly reduced PMCA2 mRNA levels. Taken together, our findings suggest that glutamate, which recently has been implicated in EAE pathogenesis, suppresses neuronal PMCA2 expression leading to Ca(2+) dyshomeostasis at initial clinical phases. Consequently, perturbations in Ca(2+) balance and neurotransmitter exocytosis may partially underlie aberrant neuronal function and communication at onset of symptoms. Altered mitochondrial function and impulse conduction may exacerbate neurological deficits at subsequent disease stages.


Niederwieser, G., W. Buchinger, et al. (2003). "Prevalence of autoimmune thyroiditis and non-immune thyroid disease in multiple sclerosis." J Neurol 250(6): 672-5.

            Since multiple sclerosis (MS) and autoimmune thyroiditis (AIT) are presumed to be of autoimmune origin the correlation of these two diseases is of special interest. The aim of this study was to determine whether there are differences in the prevalence of thyroid disease with special emphasis on AIT compared with MS and normal subjects and whether the presence of thyroid disease correlates with disability, disease course, age, and disease duration. 353 consecutive patients with clinically definite MS, without interferon-beta treatment and 308 patients with low back pain or headache were extensively examined for the presence of non-immune or autoimmune thyroid disease. We found a significantly higher prevalence of AIT in male MS patients (9.4 %) than in male controls (1.9 %; p = 0.03). The prevalence of AIT in female MS patients (8.7 %) did not differ from female controls (9.2 %). Hypothyroidism, caused by AIT in almost all cases, showed a tendency to be more severe and more often present in patients with MS. There was no association between relapsing-remitting and secondary progressive disease course of MS and the prevalence of AIT. MS patients with AIT were significantly older but did not differ in disease duration and expanded disability status scale (EDSS). Further studies are warranted, to see if there is a difference in sex-hormone levels between MS patients with and without AIT and healthy controls. Longitudinal studies comparing MS patients with or without AIT could show whether there is an influence of AIT on the disease course or progression.


Niino, M., S. Kikuchi, et al. (2003). "Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients." J Neuroimmunol 136(1-2): 125-9.

            Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN are present in brains of patients with multiple sclerosis (MS). The aim of this study was to investigate the role of OPN genes in the pathogenesis of MS. Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C genotype at the 8090th position in exon 6 was more prevalent in MS than in control (p<0.0001), and C allele was more prevalent in MS than in control (p<0.0001, OR=2.57, 95% CI=1.65-4.00). For the 9583rd position polymorphism in exon 7, patients with G/G genotype (age; 32.1+/-12.5 years, mean+/-S.D.) showed a later disease onset than G/A (age; 25.9+/-7.8 years, p=0.01) and A/A (age; 25.2+/-8.9 years, p=0.01) genotypes. There were no significant correlations between OPN gene polymorphisms and disease progression. Our results suggest that the 8090th polymorphism might be associated with susceptibility to MS, while the 9583rd polymorphism might be associated with age of onset of MS.


Nilsson, F. M., L. V. Kessing, et al. (2003). "Affective disorders in neurological diseases: a case register-based study." Acta Psychiatr Scand 108(1): 41-50.

            OBJECTIVE: To investigate the temporal relationships between a range of neurological diseases and affective disorders. METHOD: Data derived from linkage of the Danish Psychiatric Central Register and the Danish National Hospital Register. Seven cohorts with neurological index diagnoses and two control group diagnoses were followed for up to 21 years. The incidences of affective disorders in the different groups were compared with the control groups, using competing risks to consider the risk of affective disorder and the risk of death in the same analysis. RESULTS: We found an increased incidence of affective disorders in dementia, Parkinson's disease, epilepsy, stroke and intracerebral haemorrhage compared with control groups. The association was found to be the strongest for dementia and Parkinson's disease. In hospitalized patients, with incident multiple sclerosis, the incidence of affective disorder was lower than the incidence in the control groups. CONCLUSION: In neurological diseases there seems to be an increased incidence of affective disorders. The elevated incidence was found to be particularly high for dementia and Parkinson's disease (neurodegenerative diseases).


Nortvedt, M. W. and T. Riise (2003). "The use of quality of life measures in multiple sclerosis research." Mult Scler 9(1): 63-72.

            Quality of life research contributes knowledge essential to the health and healthcare of multiple sclerosis (MS) patients. This article reviews 83 MS studies in English that have presented data on quality of life. The studies may be classified into three categories, according to the application and the main focus: 1) evaluating the development and validity of quality of life questionnaires and clinical scales (n = 27); 2) evaluating factors that might influence the quality of life or comparing the quality of life among various groups (n = 37); and 3) using quality of life questionnaires as outcome measures in medical trials and other interventions (n = 19). The studies have shown that quality of life questionnaires more broadly measure the impact of MS than do the most frequently used measures of disease activity and effects. Using quality of life measures provides additional information in evaluating the effects of treatment and in studying the development of the disease. Such information is crucial in planning interventions for MS patients. A challenge in this field is to improve the study designs, including reaching some agreement on how to measure the quality of life.


Noseworthy, J. H. (2003). "Management of multiple sclerosis: current trials and future options." Curr Opin Neurol 16(3): 289-97.

            PURPOSE OF THE REVIEW: The present review of multiple sclerosis (MS) therapeutic trials published in 2002 is intended to assist the reader in understanding the most current advances in the care of their patients. RECENT FINDINGS: A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of patients with MS. Several short-term studies in relapsing/remitting MS have demonstrated that it is possible to complete head-to-head comparison trials of active agents in MS (e.g. without a placebo control group). The findings of these trials remain open to interpretation and have generated considerable controversy, as expected. A phase 3 trial [the International MS Secondary Progressive Avonex Controlled Trial (IMPACT)] became the fourth study of the beta interferons (interferon-beta-1a, in this case) to demonstrate a partial effect on disease activity in secondary progressive MS. Two trials demonstrated apparent partial efficacy for the anthrecenedione mitoxantrone in active and progressive MS. Disappointing results were announced for a number of large pivotal trials, although those results have not yet been published (e.g. oral glatiramer acetate in relapsing/remitting MS, glatiramer acetate in primary progressive MS, and intravenous immunoglobulin in secondary progressive MS). SUMMARY: The MS research community needs to determine how best to address two key unanswered questions. Is late clinical deterioration often or invariably tied to the initial inflammatory/demyelinating phase of the disease? What is the optimal research design to address whether current and future experimental strategies affect the later phases of MS (e.g. does early treatment delay or prevent clinical disability)?


Noseworthy, J. H. (2003). "Treatment of multiple sclerosis and related disorders: what's new in the past 2 years?" Clin Neuropharmacol 26(1): 28-37.


Noseworthy, J., L. Kappos, et al. (2003). "Competing interests in multiple sclerosis research." Lancet 361(9354): 350-1.


Nowak, J., D. Januszkiewicz, et al. (2003). "Multiple sclerosis-associated virus-related pol sequences found both in multiple sclerosis and healthy donors are more frequently expressed in multiple sclerosis patients." J Neurovirol 9(1): 112-7.

            In the etiopathogenesis of multiple sclerosis (MS), both genetic and environmental factors play an important role. Among environmental factors, viral infections are most likely connected with the etiology of MS. There are many evidence suggesting possible involvement of retroviruses in the development of autoimmune diseases including MS. Multiple sclerosis-associated retrovirus (MSRV) seems to be the important candidate for viral etiology of MS. The aim of the study was to analyze MSRV pol sequences in patients with MS. As control, groups of myasthenia gravis, Parkinson's disease, and migraine patients, and healthy individuals have been studied. The MSRV pol sequences have been analyzed in RNA isolated from the serum and in DNA and RNA of peripheral blood lymphocytes from untreated MS patients and control groups. The MSRV pol sequences have been detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and PCR technique, using specific oligonucleotide primers. In the serum RNA (cDNA), MSRV pol sequences have been identified in 31/32 MS patients. MSRV pol sequences were detected in serum cDNA of 9/17 myasthenia gravis patients, 7/16 Parkinson's disease patients, 10/21 migraine patients, and 13/27 healthy individuals. MSRV pol sequences were observed also in RNA from lymphocytes of all MS patients, 12/17 myasthenia gravis patients, 9/16 Parkinson's disease patients, 14/21 migraine patients, and 18/27 healthy donors. In the DNA from peripheral blood lymphocytes of all studied patients and healthy individuals, MSRV pol sequences have been found. The observed pattern of fiber-fluorescence in situ hybridization (FISH) signals suggests the presence of multiple copies of MSRV pol sequences, most likely tandemly dispersed in the genome. It can be concluded that MSRV pol sequences are endogenous, widespread in lymphocytes DNA, and transcribed into RNA of MS patients as well as of other studied patients and healthy individuals. However, more frequent expression of MSRV sequences detected in lymphocytes RNA (cDNA), as well as their presence in higher frequency in the serum of MS patients, may suggest the involvement of MSRV in the etiopathogenesis on MS.


Nyul, L. G., J. K. Udupa, et al. (2003). "Incorporating a measure of local scale in voxel-based 3-D image registration." IEEE Trans Med Imaging 22(2): 228-37.

            We present a new class of approaches for rigid-body registration and their evaluation in studying multiple sclerosis (MS) via multiprotocol magnetic resonance imaging (MRI). Three pairs of rigid-body registration algorithms were implemented, using cross-correlation and mutual information (MI), operating on original gray-level images, and utilizing the intermediate images resulting from our new scale-based method. In the scale image, every voxel has the local "scale" value assigned to it, defined as the radius of the largest ball centered at the voxel with homogeneous intensities. Three-dimensional image data of the head were acquired from ten MS patients for each of six MRI protocols. Images in some of the protocols were acquired in registration. The registered pairs were used as ground truth. Accuracy and consistency of the six registration methods were measured within and between protocols for known amounts of misregistrations. Our analysis indicates that there is no "best" method. For medium misregistration, the method using MI, for small add large misregistration the method using normalized cross-correlation performs best. For high-resolution data the correlation method and for low-resolution data the MI method, both using the original gray-level images, are the most consistent. We have previously demonstrated the use of local scale information in fuzzy connectedness segmentation and image filtering. Scale may also have potential for image registration as suggested by this work.


O'Connor, K. C., T. Chitnis, et al. (2003). "Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions." J Neuroimmunol 136(1-2): 140-8.

            The presence of autoantibodies to the immunodominant antigen, myelin basic protein (MBP), in the serum and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) has been poorly characterized. Many studies report detectable levels of autoantibodies to myelin basic protein though other studies, using similar techniques, report their absence. We compared a solution-phase assay that has detected clinically relevant autoantibodies in diabetes and other autoimmune diseases to solid phase assays similar to those used in previous reports. The solution-phase assay consistently measured autoantibodies to MBP in serum from human subjects with Semple rabies vaccine (SRV)-induced demyelinating disease and from MBP-immunized animals. A solid phase assay detected MBP autoantibodies in the serum of a fraction of patients with MS. Autoantibodies capable of binding to MBP in the solution-phase were not detected in the CSF or serum of patients with MS. Additional solution-phase measurements revealed that anti-MBP antibodies from individuals with SRV-induced demyelinating disease demonstrated a binding affinity profile consistent with that of polyclonal antibodies with a range of affinities from low to high. In contrast, antibodies to MBP in the serum of MS patients detected by ELISA did not bind soluble MBP in the same assay. These results indicate that the humoral response in patients with MS does not include moderate- or high-affinity autoantibodies to MBP.


O'Donovan, M. (2003). "Infection and multiple sclerosis." J Neurol Neurosurg Psychiatry 74(5): 693.


Offit, P. A. and C. J. Hackett (2003). "Addressing parents' concerns: do vaccines cause allergic or autoimmune diseases?" Pediatrics 111(3): 653-9.

            Anecdotal case reports and uncontrolled observational studies in the medical literature claim that vaccines cause chronic diseases such as asthma, multiple sclerosis, chronic arthritis, and diabetes. Several biological mechanisms have been proposed to explain how vaccines might cause allergic or autoimmune diseases. For example, allergic diseases might be caused by prevention of early childhood infections (the "hygiene hypothesis"), causing a prolongation of immunoglobulin E-promoting T-helper cell type 2-type responses. However, vaccines do not prevent most common childhood infections, and large well-controlled epidemiologic studies do not support the hypothesis that vaccines cause allergies. Autoimmune diseases might occur after immunization because proteins on microbial pathogens are similar to human proteins ("molecular mimicry") and could induce immune responses that damage human cells. However, wild-type viruses and bacteria are much better adapted to growth in humans than vaccines and much more likely to stimulate potentially damaging self-reactive lymphocytes. Consistent with critical differences between natural infection and immunization, well-controlled epidemiologic studies do not support the hypothesis that vaccines cause autoimmunity. Flaws in proposed biological mechanisms that explain how vaccines might cause chronic diseases are consistent with the findings of many well-controlled large epidemiologic studies that fail to show a causal relationship.


Oikonen, M., M. Laaksonen, et al. (2003). "Ambient air quality and occurrence of multiple sclerosis relapse." Neuroepidemiology 22(1): 95-9.

            Infectious viruses and bacteria can trigger multiple sclerosis (MS) exacerbations. Seasonally changing concentrations of ambient air pollutants are known to predispose to transmissible infections, to induce systemic immune responses and to enhance existing peripheral inflammation. Ambient air quality and monthly MS relapse occurrence in south-western Finland were compared by multivariate logistic regression. The odds ratio of the risk of a relapse onset was over fourfold (4.143, p < 0.001) when the concentration of inhalable particulate matter (PM(10)) was at the highest quartile. Inhalable airborne particulate matter concentrations were connected to relapse occurrence. Poor air quality may enhance the seasonal changes in MS relapse occurrence by an increased susceptibility to transmissible infections.


Okafor, M. C. (2003). "Thalidomide for erythema nodosum leprosum and other applications." Pharmacotherapy 23(4): 481-93.

            Thalidomide, administered as a sedative and antiemetic decades ago, was considered responsible for numerous devastating cases of birth defects and consequently was banned from markets worldwide. However, the drug remarkably has resurfaced with promise of immunomodulatory benefit in a wide array of immunologic disorders for which available treatments were limited. It is approved by the Food and Drug Administration for erythema nodosum leprosum (ENL). Although the relative paucity of leprosy and ENL worldwide may perceivably limit interest in and knowledge about thalidomide, increasing numbers of new and potential uses expand its applicability widely beyond ENL. Thalidomide, an inhibitor of tumor necrosis factor a, is the best known agent for short-term treatment of ENL skin manifestations, as well as postremission maintenance therapy to prevent recurrence. For this indication, it is effective as monotherapy and as part of combination therapy with corticosteroids. Studies of thalidomide in chronic graft-versus-host disease showed benefit in children and adults as treatment, but not as prophylaxis. The agent has been administered successfully for treatment of cachexia related to cancer, tuberculosis, and human immunodeficiency virus infection, although evidence of efficacy is inconclusive. Thalidomide monotherapy effectively induced objective response in trials in patients with both newly diagnosed and advanced or refractory multiple myeloma. Combination therapy with thalidomide and corticosteroids was also effective in these patients, as well as in treatment of aphthous and genital ulcers. Limited evidence supports the drug's benefit in treatment of Kaposi's sarcoma. Other thalidomide applications include Crohn's disease, rheumatoid arthritis, and multiple sclerosis. Somnolence, constipation, and rash were the most frequently cited adverse effects in studies, but thalidomide-induced neuropathy and idiopathic thromboembolism were critical causes for drug discontinuation. Thalidomide is still contraindicated in pregnant women, women of childbearing age, and sexually active men not using contraception. Clinicians should be conversant with thalidomide in ENL (its primary application) in the natural course of leprosy, as well as in the agent's other applications.


Oliveira, E. M., A. Bar-Or, et al. (2003). "CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls." J Autoimmun 20(1): 71-81.

            Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, thought to be mediated in part by an autoimmune response of T cells to protein components of the myelin sheath. The reaction of nai;ve T cells against these antigens requires co-stimulation through CD28. However, the proliferative response of peripheral blood mononuclear cells isolated from patients with MS and stimulated with myelin basic protein (MBP) has been shown to be relatively independent of B7-CD28 co-stimulation, suggesting that dysregulation of co-stimulatory pathways may be involved in the pathogenesis of MS. Here, the role of CTLA-4 engagement was investigated. As expected, blocking CTLA-4-mediated signaling during stimulation of MBP-reactive T cells from healthy controls enhanced the proliferative and cytokine responses. In contrast, CTLA-4 blockade had less effect in patients with MS, suggesting that at least two regulatory mechanisms may be impaired in these individuals. Understanding how co-stimulatory signals may be dysregulated in patients with MS is important at a time when targeting of these pathways is being developed.


Olsson, T. (2003). "[Humanized antibodies against an adhesion molecule block the CNS inflammation in multiple sclerosis]." Lakartidningen 100(19): 1705.


Ooka, S., T. Matsui, et al. (2003). "Autoantibodies to low-density-lipoprotein-receptor-related protein 2 (LRP2) in systemic autoimmune diseases." Arthritis Res Ther 5(3): R174-80.

            We previously reported that autoantibodies (autoAbs) to the main epitope on CD69 reacted to its homologous amino acid sequence in low-density-lipoprotein-receptor-related protein 2 (LPR2), a multiligand receptor for protein reabsorption. In this study, we have investigated the prevalence, autoepitope distribution, and clinical significance of the autoAbs to LRP2 in patients with systemic autoimmune diseases. Using six recombinant proteins (F2-F7) for LRP2 and one for CD69, we detected autoAbs to LRP2 in sera of patients with rheumatoid arthritis (RA), systemic lupus erythematosus, Behcet's disease, systemic sclerosis, and osteoarthritis and then mapped autoepitopes by Western blotting. The autoAbs to LRP2 were detected in 87% of the patients with rheumatoid arthritis, 40% of those with systemic lupus erythematosus, 35% of those with systemic sclerosis, 15% of those with osteoarthritis, and 3% of those with Behcet's disease. Multiple epitopes on LRP2 were recognized by most of the anti-LRP2+ serum samples. All of the tested anti-CD69 autoAb+ samples reacted to LRP2-F3 containing the homologous sequence to the main epitope of CD69; however, only 38% of the anti-LRP2-F3+ samples reacted to CD69. Clinically, the existence of the autoAbs to LRP2-F4, -F5, and -F6 correlated with the presence of proteinuria in RA. This study revealed that LRP2 is a major autoantigen in RA. The autoAbs to LRP2 are probably produced by the antigen-driven mechanism and the autoimmunity to LRP2 may spread to include CD69. The anti-LRP2 autoAbs may play pathological roles by inhibiting the reabsorbing function of LRP2.


Optic Neuritis Study, G. (2003). "High- and Low-Risk Profiles for the Development of Multiple Sclerosis Within 10 Years After Optic Neuritis: Experience of the Optic Neuritis Treatment Trial." Arch Ophthalmol 121(7): 944-949.

            OBJECTIVE: To identify factors associated with a high and low risk of developing multiple sclerosis after an initial episode of optic neuritis. METHODS: Three hundred eighty-eight patients who experienced acute optic neuritis between July 1, 1988, and June 30, 1991, were followed up prospectively for the development of multiple sclerosis. Consenting patients were reassessed after 10 to 13 years. RESULTS: The 10-year risk of multiple sclerosis was 38% (95% confidence interval, 33%-43%). Patients (160) who had 1 or more typical lesions on the baseline magnetic resonance imaging (MRI) scan of the brain had a 56% risk; those with no lesions (191) had a 22% risk (P<.001, log rank test). Among the patients who had no lesions on MRI, male gender and optic disc swelling were associated with a lower risk of multiple sclerosis, as was the presence of the following atypical features for optic neuritis: no light perception vision; absence of pain; and ophthalmoscopic findings of severe optic disc edema, peripapillary hemorrhages, or retinal exudates. CONCLUSIONS: The 10-year risk of multiple sclerosis following an initial episode of acute optic neuritis is significantly higher if there is a single brain MRI lesion; higher numbers of lesions do not appreciably increase that risk. However, even when brain lesions are seen on MRI, more than 40% of the patients will not develop clinical multiple sclerosis after 10 years. In the absence of MRI lesions, certain demographic and clinical features seem to predict a very low likelihood of developing multiple sclerosis. This natural history information is a critical input for estimating a patient's 10-year multiple sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of optic neuritis or other initial demyelinating events in the central nervous system.


Ostenfeld, T. and C. N. Svendsen (2003). "Recent advances in stem cell neurobiology." Adv Tech Stand Neurosurg 28: 3-89.

            1. Neural stem cells can be cultured from the CNS of different mammalian species at many stages of development. They have an extensive capacity for self-renewal and will proliferate ex vivo in response to mitogenic growth factors or following genetic modification with immortalising oncogenes. Neural stem cells are multipotent since their differentiating progeny will give rise to the principal cellular phenotypes comprising the mature CNS: neurons, astrocytes and oligodendrocytes. 2. Neural stem cells can also be derived from more primitive embryonic stem (ES) cells cultured from the blastocyst. ES cells are considered to be pluripotent since they can give rise to the full cellular spectrum and will, therefore, contribute to all three of the embryonic germ layers: endoderm, mesoderm and ectoderm. However, pluripotent cells have also been derived from germ cells and teratocarcinomas (embryonal carcinomas) and their progeny may also give rise to the multiple cellular phenotypes contributing to the CNS. In a recent development, ES cells have also been isolated and grown from human blastocysts, thus raising the possibility of growing autologous stem cells when combined with nuclear transfer technology. 3. There is now an emerging recognition that the adult mammalian brain, including that of primates and humans, harbours stem cell populations suggesting the existence of a previously unrecognised neural plasticity to the mature CNS, and thereby raising the possibility of promoting endogenous neural reconstruction. 4. Such reports have fuelled expectations for the clinical exploitation of neural stem cells in cell replacement or recruitment strategies for the treatment of a variety of human neurological conditions including Parkinson's disease (PD), Huntington's disease, multiple sclerosis and ischaemic brain injury. Owing to their migratory capacity within the CNS, neural stem cells may also find potential clinical application as cellular vectors for widespread gene delivery and the expression of therapeutic proteins. In this regard, they may be eminently suitable for the correction of genetically-determined CNS disorders and in the management of certain tumors responsive to cytokines. Since large numbers of stem cells can be generated efficiently in culture, they may obviate some of the technical and ethical limitations associated with the use of fresh (primary) embryonic neural tissue in current transplantation strategies. 5. While considerable recent progress has been made in terms of developing new techniques allowing for the long-term culture of human stem cells, the successful clinical application of these cells is presently limited by our understanding of both (i) the intrinsic and extrinsic regulators of stem cell proliferation and (ii) those factors controlling cell lineage determination and differentiation. Although such cells may also provide accessible model systems for studying neural development, progress in the field has been further limited by the lack of suitable markers needed for the identification and selection of cells within proliferating heterogeneous populations of precursor cells. There is a further need to distinguish between the committed fate (defined during normal development) and the potential specification (implying flexibility of fate through manipulation of its environment) of stem cells undergoing differentiation. 6. With these challenges lying ahead, it is the opinion of the authors that stem-cell therapy is likely to remain within the experimental arena for the foreseeable future. In this regard, few (if any) of the in vivo studies employing neural stem cell grafts have shown convincingly that behavioural recovery can be achieved in the various model paradigms. Moreover, issues relating to the quality control of cultured cells and their safety following transplantation have only begun to be addressed. 7. While on the one hand cell biotechnologists have been quick to realise the potential commercial value, human stem cell research and its clinical applications has been the subject of intense ethical and legislative considerations. The present chapter aims to review some recent aspects of stem cell research applicable to developmental neurobiology and the potential applications in clinical neuroscience.


Otomo, A., S. Hadano, et al. (2003). "ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics." Hum Mol Genet 12(14): 1671-1687.

            ALS2 mutations account for a number of recessive motor neuron diseases including forms of amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. Although computational predictions suggest that ALS2 encodes a protein containing multiple guanine nucleotide exchange factor (GEF) domains [RCC1-like domain (RLD), the Dbl homology and pleckstrin homology (DH/PH), and the vacuolar protein sorting 9 (VPS9)], the functions of the ALS2 protein have not been revealed as yet. Here we show that the ALS2 protein specifically binds to small GTPase Rab5 and functions as a GEF for Rab5. Ectopically expressed ALS2 protein localizes with Rab5 and early endosome antigen-1 (EEA1) onto early endosomal compartments and stimulates the enlargement of endosomes in cultured cortical neurons. The carboxy-terminus of ALS2 protein carrying a VPS9 domain mediates not only the activation of Rab5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of the ALS2 protein, while the amino-terminal half containing RLD acts suppressive in its membranous localization. Further, the DH/PH domain in the middle portion of ALS2 protein enhances the VPS9 domain-mediated endosome fusions. Taken together, the ALS2 protein as a novel Rab5-GEF, ALS2rab5GEF seems to be implicated in the endosomal dynamics in vivo. Notably, a feature common to eight reported ALS2 mutations among motor neuron diseases is the loss of VPS9 domain, resulting in the failure of Rab5 activation. Thus, a perturbation of endosomal dynamics caused by loss of ALS2 rab5GEF activity might underlie neuronal dysfunction and degeneration in a number of motor neuron diseases.


Owen, W. E. and W. L. Roberts (2003). "Performance characteristics of four immunonephelometric assays for the quantitative determination of IgA and IgM in cerebrospinal fluid." Am J Clin Pathol 119(5): 689-93.

            Measurement of IgA and IgM in cerebrospinal fluid (CSF) can be useful in the diagnosis of multiple sclerosis and other central nervous system disorders. The Dade Behring (Deerfield, IL) N Latex IgA and N Latex IgM tests on the BN II System and Beckman Coulter (Brea, CA) low-concentration IgA and IgM tests on the IMMAGE Immunochemistry System were evaluated for linearity, imprecision, method comparison, and reference interval verification. Both IgA methods were linear from 1.4 to at least 50 mg/L. Both IgM methods were linear from 0.14 to more than 6 mg/L. The total imprecision of the BN II IgA and IgM methods and the IMMAGE IgA method was less than 10%. The imprecision of the IMMAGE IgM method was 10.2% at 0.49 mg/L and less than 5% at higher IgM concentrations. Method comparison studies indicated that IgA and IgM methods on both instruments showed good comparability. Reference interval studies demonstrated that both methods had similar reference intervals that agreed with published values of less than 6 mg/L for IgA and less than 1.3 mg/L for IgM. Methods for quantifying IgA and IgM in CSF on the BN II and IMMAGE nephelometers perform well and give comparable results.


Owens, T. (2003). "The enigma of multiple sclerosis: inflammation and neurodegeneration cause heterogeneous dysfunction and damage." Curr Opin Neurol 16(3): 259-65.

            PURPOSE OF REVIEW: The demyelinating disease multiple sclerosis has an autoimmune inflammatory component, which has dominated the description of multiple sclerosis. A degenerative component to multiple sclerosis was always apparent, but was underappreciated until recently. Recent work has brought axonal pathology and brain atrophy into new focus. The purpose of this review is to highlight the relative roles played by the inflammatory and degenerative processes in multiple sclerosis pathology. RECENT FINDINGS: In the past year reports have been published to show that early disability and disease progression correlate with axonal damage, and that brain atrophy resulting from axonal loss is a feature of early multiple sclerosis, and is not restricted to the secondary progressive forms of the disease. Inflammatory mediators (CD8 T cells and antibodies) are implicated in axonal damage, and treatment with steroids or anti-inflammatory therapies reduce brain atrophy, pointing to the involvement of the inflammatory response in the initiation of degeneration. Reduced regenerative capability also contributes to degeneration, and inflammatory responses are shown to inhibit the growth and migration of precursor cells for oligodendrocytes. SUMMARY: Oligodendrocyte precursors are abundant in multiple sclerosis lesions, but fail to remyelinate. Oligodendrocyte growth and regeneration are probably compromised by the action of growth inhibitory signals and lack of growth stimuli. Inflammatory cells and mediators induce axonal loss as well as demyelination. The degenerative response is therefore an integral and early component of multiple sclerosis.


Ozakbas, S., E. Idiman, et al. (2003). "Childhood and juvenile onset multiple sclerosis: clinical and paraclinical features." Brain Dev 25(4): 233-6.

            It is well known that multiple sclerosis (MS) is a demyelinating disease of the central nervous system that mostly starts in the second to third decade. In the present study, we reviewed our own observations of the clinical and paraclinical features in the 36 of 890 (4.04%) MS patients whose symptoms started before 16 years of age. The average age at onset of the disease in these 36 patients was 12.9 years. In 18 patients, the disease onset was monosymptomatic. Diplopia and sensory disturbances were the most common initial manifestations and occurred in 27.7% of cases. Twenty-one patients (59%) had a relapsing and 11 patients (30.5%) had a secondary progressive course. On the last evaluation, the EDSS score was above 5 in 11 patients and it was below 5 in 21 patients. As a result of this study, we concluded that childhood onset MS does not significantly differ from that it has been typically seen in adults in terms of major clinical manifestations and course of disease.


Ozaki, I., C. Suzuki, et al. (2003). "Multiple sclerosis manifesting as a Brown-Sequard syndrome." Eur J Neurol 10(2): 190-1.


Pache, M., H. J. Kaiser, et al. (2003). "Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis." Eur Neurol 49(3): 164-8.

            In order to evaluate whether plasma levels of the potent vasoconstrictor endothelin-1 (ET-1) are increased in patients with multiple sclerosis (MS) and whether these patients exhibit an ET-1-mediated vascular dysregulation, ET-1 plasma levels were measured in 30 patients with MS. Blood flow velocities in the ophthalmic artery, central retinal artery, central retinal vein, short lateral posterior ciliary artery, and short medial posterior ciliary artery were assessed in parallel. ET-1 plasma levels were significantly increased in MS patients when compared to sex- and age-matched healthy controls (2.0 +/- 0.4 pg/ml, range 1.1-2.8 vs. 1.5 +/- 0.2 pg/ml, range 0.9-2.0; p < 0.001). Moreover, the patients exhibited significant alterations of extraocular blood flow. The role of ET-1 in the inflammatory process remains to be clarified.


Padilla, F., E. Vila, et al. (2003). "["Pseudo-stroke" hemiplegic type multiple sclerosis, a rare form of debut]." Neurologia 18(5): 286-289.


Palace, J. (2003). "Clinical and laboratory characteristics of secondary progressive MS." J Neurol Sci 206(2): 131-4.

            Secondary progressive (SP) MS follows on from but is distinct in its clinical picture from relapsing remitting (RR) MS. Diagnosis is usually straightforward except during the transitional stage when the two phenotypes merge. It is clear that most patients that start with relapsing remitting MS will develop SP disease, although the underlying pathogenesis that causes this change is subject to much debate. Clinical features such as pattern and site of symptoms, and age of onset, in the relapsing remitting stage versus progressive disease, suggests a difference in the pathophysiology. Laboratory markers may give insight into the disease mechanisms. Measures of urinary and CSF myelin basic protein-like material (MBPLM) indicate demyelination and subsequent oligodendrocyte and axonal loss. Tertiary neutralising antibodies to MBP antibodies could attenuate remission and lead to continuous progression, and neuronal antibodies found in SP disease may contribute to the axonal loss. In addition, differences in nitric oxide and other inflammatory cytokine patterns might either be secondary to or causative of the pathological mechanisms.Greater understanding of progressive MS is a priority considering permanent disability results almost entirely from this stage of the disease.


Palma, J. P., D. Kwon, et al. (2003). "Infection with Theiler's murine encephalomyelitis virus directly induces proinflammatory cytokines in primary astrocytes via NF-kappaB activation: potential role for the initiation of demyelinating disease." J Virol 77(11): 6322-31.

            Theiler's virus infection in the central nervous system (CNS) induces a demyelinating disease very similar to human multiple sclerosis. We have assessed cytokine gene activation upon Theiler's murine encephalomyelitis virus (TMEV) infection and potential mechanisms in order to delineate the early events in viral infection that lead to immune-mediated demyelinating disease. Infection of SJL/J primary astrocyte cultures induces selective proinflammatory cytokine genes (interleukin-12p40 [IL-12p40], IL-1, IL-6, tumor necrosis factor alpha, and beta interferon [IFN-beta]) important in the innate immune response to infection. We find that TMEV-induced cytokine gene expression is mediated by the NF-kappaB pathway based on the early nuclear NF-kappaB translocation and suppression of cytokine activation in the presence of specific inhibitors of the NF-kappaB pathway. Further studies show this to be partly independent of dsRNA-dependent protein kinase (PKR) and IFN-alpha/beta pathways. Altogether, these results demonstrate that infection of astrocytes and other CNS-resident cells by TMEV provides the early NF-kappaB-mediated signals that directly activate various proinflammatory cytokine genes involved in the initiation and amplification of inflammatory responses in the CNS known to be critical for the development of immune-mediated demyelination.


Paolillo, A., M. G. Buzzi, et al. (2003). "The effect of Bacille Calmette-Guerin on the evolution of new enhancing lesions to hypointense T1 lesions in relapsing remitting MS." J Neurol 250(2): 247-8.


Parmenter, B. A., D. R. Denney, et al. (2003). "The cognitive performance of patients with multiple sclerosis during periods of high and low fatigue." Mult Scler 9(2): 111-8.

            The objective of this study was to examine whether multiple sclerosis (MS)-related fatigue affects patients' cognitive performance. Thirty patients who had substantial fatigue in conjunction with MS and who reported marked diurnal variability in the severity of their fatigue were tested on two occasions: during a period of high fatigue and during a period of relatively low fatigue. The order of these sessions was counterbalanced across patients. During both sessions, patients completed a questionnaire concerning their present state of fatigue and a battery of neuropsychological tests of planning, selective attention, and paired associate learning. Although patients confirmed greater fatigue during the period of high fatigue and felt they had performed more poorly during this period, there were no differences in cognitive performance that could be attributed to fatigue. Instead, all subjects showed improvement from the first to the second session regardless of whether the latter entailed a period of high or low fatigue. In contrast to studies reporting fatigue-related declines in MS patients' cognitive performance, no differences in performance were found when MS patients were tested during periods of high versus low fatigue. These contrasting results, stemming from differences in experimental design, are discussed in terms of their implications for assessing cognitive function in patients with MS.


Parry, A., R. Corkill, et al. (2003). "Beta-Interferon treatment does not always slow the progression of axonal injury in multiple sclerosis." J Neurol 250(2): 171-8.

            Progression of disability in multiple sclerosis (MS) appears related to axonal damage, which is at least in part associated with white matter lesions. Beta-interferon (BIFN) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of axonal injury. To test the generalisability of this conclusion, particularly in a population with relatively active disease, we used magnetic resonance spectroscopy measures to test whether BIFN can reverse or arrest progression of axonal injury in patients with MS. Eleven patients with a history of active (median, 1.5 relapses/year) relapsing-remitting MS were treated with BIFN and responses to treatment were monitored with serial MRI and single voxel magnetic resonance spectroscopic measurements of relative concentrations of brain N-acetylaspartate (NAA), a measure of axonal integrity from a central, predominantly white matter brain region. BIFN treatment was associated with a significant reduction in relapse rate (p = 0.007) and white matter water T2 relaxation time (p = 0.047) over 12 months. Also consistent with a treatment effect, white matter T2-hyperintense lesion loads did not increase. However, the central white matter NAA/creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02). For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = -0.76, p = 0.006). These data suggest that reduction of new inflammatory activity with BIFN does not invariably halt progression of axonal injury. Nonetheless, there appears to be a relationship between the rate of progression of axonal injury and relapse rate over the previous two years. The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes.


Pashenkov, M., N. Teleshova, et al. (2003). "Inflammation in the central nervous system: the role for dendritic cells." Brain Pathol 13(1): 23-33.

            Dendritic cells (DCs) are a subclass of antigen-presenting cells critical in the initiation and regulation of adaptive immunity against pathogens and tumors, as well as in the triggering of autoimmunity. Recent studies have provided important knowledge regarding distribution of DCs in the central nervous system (CNS) and their role in intrathecal immune responses. DCs are present in normal meninges, choroid plexus, and cerebrospinal fluid, but absent from the normal brain parenchyma. Inflammation is accompanied by recruitment and/or development of DCs in the affected brain tissue. DCs present in different compartments of the CNS are likely to play a role in the defence against CNS infections, and also may contribute to relapses/chronicity of CNS inflammation and to break-down of tolerance to CNS autoantigens. CNS DCs can therefore be viewed as a future therapeutic target in chronic inflammatory diseases such as multiple sclerosis.


Pashenkov, M., M. Soderstrom, et al. (2003). "Secondary lymphoid organ chemokines are elevated in the cerebrospinal fluid during central nervous system inflammation." J Neuroimmunol 135(1-2): 154-60.

            Secondary lymphoid organ chemokines have been implicated in chronic inflammation. Their expression in the central nervous system (CNS) has not been studied. Here, levels of secondary lymphoid organ chemokines CCL19 (Exodus-3, MIP-3beta), CCL21 (Exodus-2, 6Ckine, SLC) and CXCL12 (SDF-1alpha) were analysed by ELISA in cerebrospinal fluid (CSF) and plasma from patients with multiple sclerosis (MS); acute optic neuritis (ON) with oligoclonal IgG in the CSF (i.e., first bout of MS); acute ON without oligoclonal IgG (non-MS-type ON); other inflammatory neurological diseases (OIND); and non-inflammatory neurological diseases (NIND). NIND CSF contained CCL19 and CXCL12, while CCL21 was not detected. Intrathecal production of CCL19 and CCL21 was elevated in MS, MS-type ON, and OIND, but not in non-MS-type ON. In MS, CSF levels of CCL19 weakly correlated with CSF cell counts. Intrathecal production of CXCL12 was elevated only in OIND. The role of elevated CCL19 and CCL21 in MS could be retention of mature dendritic cells (DC) in the CNS, recruitment of nai;ve T cells and activated B cells, as well as de novo formation of secondary lymphoid structures in MS plaques.


Pathak, S. D., L. Ng, et al. (2003). "Quantitative image analysis: software systems in drug development trials." Drug Discov Today 8(10): 451-8.

            Multi-dimensional image analysis is being used increasingly to arrive at surrogate end-points for drug development trials. Various imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and ultrasound are used to analyze treatments for diseases such as cancer, multiple sclerosis, osteoarthritis, and Alzheimer's disease. However, extracting information from images can be tedious and is prone to high user variability. The medical image analysis community is moving towards advanced software systems specifically designed for drug development trials. These systems can automatically identify the anatomy of interest in medical images (segmentation methods), can compare the anatomy over time or between patients (registration methods) and allow the quantitative extraction of anatomical features and the integration of the data and results into a database management system, automatically tracking the changes made to the data (audit trail generation). In this article, we present a case study using a prototype system that is used for quantifying multiple sclerosis lesions from multivariate MRI.


Patte, M., F. N. Rouher, et al. (2003). "[Proliferative retinal vasculitis and multiple sclerosis: a case report]." J Fr Ophtalmol 26(4): 381-5.

            INTRODUCTION: Retinal periphlebitis can precede the neurological effects of multiple sclerosis and reveal the disease. Although these occurrences of vasculitis are noted in 10% - 35% of multiple sclerosis patients, proliferative retinopathy is, on the contrary, an exceptional complication. CASE REPORT: We report the case of a 28-year-old woman who presented bilateral, proliferative, retinal vasculitis complicated with recurrent vitreous hemorrhages occurring with multiple sclerosis. Initially, there was a unilateral, central venous thrombosis in a particularly ischemic and proliferative form. After a neurological, biological and radiological check-up, the diagnosis of multiple sclerosis was pronounced and treatment with Interferon was started. A pan-retinal laser photocoagulation and vitrectomy with proliferative membrane peeling were performed. After a follow-up of 2.5 years, a bilateral epiretinal membrane on the macula with a chronic macular edema persisted, with visual acuity limited to 0.2 Parinaud 4 in the right eye and 0.5 Parinaud 2 in the left eye. DISCUSSION: This case shows that the diagnosis of multiple sclerosis must be established in cases of ischemic retinal vasculitis, especially as the literature does not seem to report a correlation between the retinal vascular affect and how far multiple sclerosis has progressed. Moreover, the visual prognosis of these proliferative lesions remains uncertain. CONCLUSION: Multiple sclerosis can be revealed initially, although exceptionally, by bilateral, proliferative and severe retinal vasculitis complicated with recurrent vitreous hemorrhages and tractional retinal detachment.


Patti, F., M. Cacopardo, et al. (2003). "Health-related quality of life and depression in an Italian sample of multiple sclerosis patients." J Neurol Sci 211(1-2): 55-62.

            Only few publications have been reported on Health-related Quality of Life (HRQoL) in patients with multiple sclerosis (MS). EDSS is the most common outcome measure for either impairment or disability of MS, but it is not able to catch other aspects of MS impact on HRQoL.The authors performed a cross-sectional study on the group of all patients with MS who were diagnosed at least 4 years before 1998 in Catania (South Italy). One hundred and eighty patients out of 308 were enrolled in the study. SF-36 was used to catch the HRQoL of MS patients. EDSS, Beck Depression Inventory (BDI) and time since diagnosis were investigated as variables affecting the HRQoL of MS patients.The patients showed significant lower mean scores for all SF-36 health dimensions compared with sex- and age-adjusted scores in a general healthy Italian population (p<0.001). EDSS scores correlated only with physical functioning (r=-0.76 p<0.001). As expected, the more severe was the disease, the longer its duration and the lower the patients' skillness on HRQoL. BDI showed high partial correlations with all SF-36 health domains with r=-0.38 to -0.65 (p<0.001).This study showed that SF-36 is able to assess the HRQoL of MS patients. Depression strongly influenced the HRQoL of MS patients. EDSS and time since diagnosis also affected the HRQoL of MS patients. Our results are comparable with other European studies.


Paty, D., B. Arnason, et al. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1822; author reply 1823-4.


Peacock, J. W., S. F. Elsawa, et al. (2003). "Exacerbation of experimental autoimmune encephalomyelitis in rodents infected with murine gammaherpesvirus-68." Eur J Immunol 33(7): 1849-58.

            Viral infections have long been suspected to play a role in the pathogenesis of multiple sclerosis. In the present study, two different rodent models of experimental autoimmune encephalomyelitis (EAE) were used to demonstrate the ability of murine gammaherpesvirus-68 (gammaHV-68) to exacerbate development of neurological symptoms. SJL mice received UV-inactivated gammaHV-68 or intranasalgammaHV-68, followed by immunization against proteolipid-protein peptide 139-151. Infected mice became moribund within 10 days post-immunization, whereas mice exposed to UV-inactivated gammaHV-68 recovered. In the second model, Lewis rats were exposed to UV-inactivated gammaHV-68 or to gammaHV-68, followed by passive transfer of encephalitogenic T lymphocytes specific for myelin basic protein. Consistently, infected rats had higher clinical scores, and this result was observed during acute or latent gammaHV-68 infection. It is unlikely that this gammaHV-68-induced exacerbation was due to significant viral replication within the central nervous system since nested PCR, viral plaque assays, and infectious-centers assays demonstrated no detectable virus in spinal cords or brains of infected rodents undergoing EAE. Taken together, these studies demonstrate increased clinical symptoms of EAE in rodents infected by a gammaherpesvirus that has a limited ability to invade the central nervous system.


Pedotti, R., M. Sanna, et al. (2003). "Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus." BMC Immunol 4(1): 2.

            BACKGROUND: Insulin dependent (i.e., "type 1") diabetes mellitus (T1DM) is considered to be a T cell mediated disease in which TH1 and Tc autoreactive cells attack the pancreatic islets. Among the beta-cell antigens implicated in T1DM, glutamic acid decarboxylase (GAD) 65 appears to play a key role in the development of T1DM in humans as well as in non-obese diabetic (NOD) mice, the experimental model for this disease. It has been shown that shifting the immune response to this antigen from TH1 towards TH2, via the administration of GAD65 peptides to young NOD mice, can suppress the progression to overt T1DM. Accordingly, various protocols of "peptide immunotherapy" of T1DM are under investigation. However, in mice with experimental autoimmune encephalomyelitis (EAE), another autoimmune TH1 mediated disease that mimics human multiple sclerosis, anaphylactic shock can occur when the mice are challenged with certain myelin self peptides that initially were administered with adjuvant to induce the disease. RESULTS: Here we show that NOD mice, that spontaneously develop T1DM, can develop fatal anaphylactic reactions upon challenge with preparations of immunodominant GAD65 self peptides after immunization with these peptides to modify the development of T1DM. CONCLUSIONS: These findings document severe anaphylaxis to self peptide preparations used in an attempt to devise immunotherapy for a spontaneous autoimmune disease. Taken together with the findings in EAE, these results suggest that peptide therapies designed to induce a TH1 to TH2 shift carry a risk for the development of anaphylactic reactivity to the therapeutic peptides.


Pedotti, R., J. J. DeVoss, et al. (2003). "Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination." Proc Natl Acad Sci U S A 100(4): 1867-72.

            Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc epsilon receptor 1 (Fc epsilon RI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig Fc gamma RIII or both Fc gamma RIII and Fc epsilon RI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and "allergic" responses.


Pelletier, D., S. J. Nelson, et al. (2003). "MRI lesion volume heterogeneity in primary progressive MS in relation with axonal damage and brain atrophy." J Neurol Neurosurg Psychiatry 74(7): 950-2.

            OBJECTIVES: To investigate whether axonal damage in primary progressive (PP) multiple sclerosis (MS), as measured by proton magnetic resonance spectroscopy (HMRS) imaging and brain atrophy, is a function of T2 weighted brain lesion volume. METHODS: 34 PP MS patients were divided into two categories: low (<3 cm(3), n = 18) or high (>or=3 cm(3), n = 16) T2 lesion load (LL). An Index of Brain Atrophy (IBA) was calculated and HMRS metabolite ratios were derived from a central brain area centred at the corpus callosum. RESULTS: Patient groups did not differ with regard to clinical characteristics and showed lower mean IBA and mean N-acetylaspartate:creatinine (NAA:Cr) ratios compared to healthy controls. CONCLUSION: PP patients with low and high brain T2LL have detectable brain atrophy and NAA:Cr reduction compared to healthy controls. In PP MS, T2 lesions alone are insufficient to explain the presence of brain atrophy and decrease in NAA:Cr.