Multiple Sclerosis References 2003; Authors: P-Q
(50 References)
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.
Pender, M. P., P. A. Csurhes, et al. (2003). "Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis." J Clin Neurosci 10(1): 63-6.
We have previously shown that patients with primary progressive multiple sclerosis (MS) have significantly elevated plasma levels of antibody to GM3 ganglioside compared to patients with relapsing-remitting MS, healthy subjects and patients with other neurological diseases. Anti-GM3 antibody levels were elevated also in patients with secondary progressive MS but to a lesser extent than in primary progressive MS. As gangliosides are particularly enriched in the axonal membrane, these findings suggested that antiganglioside immune responses might contribute to the axonal damage in progressive forms of MS. The present study was performed to determine whether peripheral blood T cell responses to GM3 are also increased in progressive MS. Blood was collected from 98 untreated patients with MS (40 with relapsing-remitting, 27 with secondary progressive and 31 with primary progressive MS), 50 healthy subjects and 24 patients with other disorders of the CNS, and reactivity to GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed by 6-day T cell proliferation assays. Increased T cell reactivity to GM3 and GQ1b occurred significantly more often in patients with primary progressive MS than in healthy subjects and patients with other CNS diseases. These findings suggest that ganglioside-specific T cells may contribute to the axonal damage in primary progressive MS.
Penderis, J., S. A. Shields, et al. (2003). "Impaired remyelination and depletion of oligodendrocyte progenitors does not occur following repeated episodes of focal demyelination in the rat central nervous system." Brain 126(Pt 6): 1382-91.
It has been hypothesized that the progressive failure of remyelination in chronic multiple sclerosis is, in part, the consequence of repeated episodes of demyelination at the same site, eventually depleting oligodendrocyte progenitor cells (OPCs) and exhausting the remyelinating capacity. We investigated the effect of previous focal, ethidium bromide-induced demyelination of brain stem white matter (with intervening recovery) on the efficiency of the remyelination process during second and third subsequent episodes of demyelination, and the OPC response during a second episode of demyelination. Previous focal demyelinating lesions followed by recovery did not result in any retardation of the remyelination process, nor did they alter the proportion of Schwann cell versus oligodendrocyte remyelination. The OPC response during remyelination was quantified by in situ hybridization using a probe to platelet-derived growth factor-alpha receptor (PDGF alpha R), an OPC-expressed mRNA. Following recovery from focal, toxin-induced CNS demyelination, the OPC density returned to levels equivalent to those in normal white matter. Further more, there was no depletion of OPCs following repeated episodes of focal, toxin-induced CNS demyelination at the same site. These results indicate that repeated CNS demyelination, which has the opportunity to repair in the intervening period, is not characterized by impaired remyelination or depletion of OPCs.
Penkowa, M., C. Espejo, et al. (2003). "Metallothionein expression in the central nervous system of multiple sclerosis patients." Cell Mol Life Sci 60(6): 1258-66.
Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS by tissue injury, stress and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In fact, MT-I+II-deficient mice are more susceptible to developing experimental autoimmune encephalomyelitis (EAE), and treatment of Lewis rats with Zn-MT-II reduces EAE severity. We show here that, as in EAE, MT-I+II proteins were expressed in brain lesions of MS patients. Cells expressing MT-I+II were mainly astrocytes and activated monocytes/macrophages. Interestingly, the levels of MT-I+II were slightly increased in the inactive MS lesions in comparison with the active lesions, suggesting that MTs may be important in disease remission.
Penkowa, M. and J. Hidalgo (2003). "Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis." J Neurosci Res 72(5): 574-86.
Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). EAE and MS are characterized by significant inflammation, demyelination, neuroglial damage, and cell death. Metallothionein-I and -II (MT-I + II) are antiinflammatory and neuroprotective proteins that are expressed during EAE and MS. We have shown recently that exogenous administration of Zn-MT-II to Lewis rats with EAE significantly reduced clinical symptoms and the inflammatory response, oxidative stress, and apoptosis of the infiltrated central nervous system areas. We show for the first time that Zn-MT-II treatment during EAE significantly prevents demyelination and axonal damage and transection, and stimulates oligodendroglial regeneration from precursor cells, as well as the expression of the growth factors basic fibroblast growth factor (bFGF), transforming growth factor (TGF)beta, neurotrophin-3 (NT-3), NT-4/5, and nerve growth factor (NGF). These beneficial effects of Zn-MT-II treatment could not be attributable to its zinc content per se. The present results support further the use of Zn-MT-II as a safe and successful therapy for multiple sclerosis.
Penner, I. K., M. Rausch, et al. (2003). "Analysis of impairment related functional architecture in MS patients during performance of different attention tasks." J Neurol 250(4): 461-72.
More than 50 % of patients with multiple sclerosis (MS) suffer from cognitive deficits. Attention is one of the most frequently affected cognitive functions. It has been shown that MS patients suffer from a specific but not necessarily from a generalized decrease in performance and that different severity grades of impaired attentional processing can be distinguished. Little is known about patterns of brain activation in MS patients with different grades of attentional deficits. The objective was to examine if different severity grades in attentional impairment are reflected by altered patterns of brain activation in specific attention tasks. In the present study cerebral activation induced by three attention tasks of different complexity was assessed in 14 MS patients and seven healthy controls by functional MRI (fMRI). Based on their performance on the tests recorded off-line with a computerized test battery and during the fMRI investigation, patients were classified as mildly and severely impaired. MS patients with mild impairment showed increased and additional activation of brain areas which were in part not activated in normal subjects. Those were located mainly in the frontal cortex and posterior parietal cortex. This effect decreased with increasing task complexity and was strongest for the alertness task. In MS patients with severe impairment no additional activation was found in prefrontal structures and activation in the premotor cortex was not significantly different from controls. These findings suggest that compensation in MS patients is in part achieved by functional integration of frontal and parietal association areas. The extent of compensation seems to depend on the brain's capacity to access additional brain structures. Exhaustion of this capacity may finally lead to severe cognitive impairment.
Perez Castrillon, J. L., M. Cano Del Pozo, et al. (2003). "[Bone mineral density in patients with multiple sclerosis: the effects of interferon]." Rev Neurol 36(10): 901-3.
INTRODUCTION. Patients with multiple sclerosis (MS) are at greater risk of suffering from osteoporosis and pathological fractures, and the use of corticoids together with immobilisation and vitamin D deficiency is one of the causes of low bone mass (BM). AIMS. Our aim was to evaluate the effect of interferon, a drug that has only recently been introduced in the treatment of the disease, on bone mineral density (BMD) and bone remodelling markers. PATIENTS AND METHODS. A total of 30 females and 18 males with MS were studied. A standardised case history report was examined, and determinations of ionic calcium, vitamin D, osteocalcin, iPTH and urinary deoxypyridinoline, together with calcaneus densimetry measurements using a DEXA densimeter were also performed. RESULTS. The females treated with interferon had a BMD similar to that of those who had only received corticoids. Yet the males treated with interferon had a BMD that was lower than that of those who had not been treated with this drug (0.484 0.104 g/cm2 compared to 0.631 0.143 g/cm2, p= 0.032) and the control group (0.484 0.104 g/cm2 compared to 0.581 0.102 g/cm2, p= 0.015). No differences were found in the bone remodelling parameters. CONCLUSIONS. Males treated with interferon present a decrease in BM, and results are paradoxical because interferon plays a part in regulating bone metabolism and inhibits the development of osteoclasts, the cells responsible for bone resorption.
Pericot, I. and X. Montalban (2003). "[Mitoxantrone]." Neurologia 18(6): 318-23.
Mitoxantrone is an antineoplastic agent that exerts a potent immunosuppresive effect, including suppression of B cell immunity and reduction of T cell numbers. Clinical trials have shown that mitoxantrone has a statistically significant impact on reduction of relapse rate and delays disability progression in patients with relapsing remitting (RR) multiple sclerosis (MS) or secondary progressive (SP) MS. Treatment is well tolerated, but the risk of cardiotoxicity at higher cumulative doses is likely to limit the duration of treatment. The maximum cumulative dose recommended is 140 mg/m2. In 2000, the FDA (Food and Drug Administration) approved the use of mitoxantrone for the treatment of active RRMS, SPMS and progressing relapsing (PR) MS. Neurologia 2003;18(6):318-323
Pericot, I., L. Brieva, et al. (2003). "Myelopathy in seronegative Sjogren syndrome and/or primary progressive multiple sclerosis." Mult Scler 9(3): 256-9.
OBJECTIVE: The relationship between multiple sclerosis (MS) and Sjogren syndrome (SS) is controversial. Nine patients, previously diagnosed with primary progressive MS (PPMS) and who fulfilled the diagnostic criteria for SS, are described. METHODS: The European classification criteria for SS were used to study nine PPMS patients that complained of sicca complex symptoms. The following tests were performed: Schirmer test, rose bengal staining, salivary scintigraphy, minor salivary gland biopsy and serologic tests (antibodies Ro/SS-A, La/SS-B and antinuclear antibodies). RESULTS: The nine patients met criteria to be diagnosed with SS (at least four criteria). All patients were women with a mean age of 46.6 years at symptom onset. Spastic paraparesis was the presenting symptom in all patients, and spinal cord magnetic resonance imaging (MRI) showed abnormalities in most; anti-Ro and anti-La antibodies were mostly negative. CONCLUSIONS: Some MS patients, predominantly women over 45 years of age, with progressive spastic paraparesis, antiextractable nuclear antigen antibodies (Ro/SS-A or La/SS-B) negative and with abnormalities in spinal cord MRI, may have SS as an additional or alternative diagnosis.
Pericot, I., J. Rio, et al. (2003). "Serial gadolinium-enhanced MRI in acute attack of multiple sclerosis treated with plasma exchange." J Neurol 250(2): 243-4.
Perry, V. H., T. A. Newman, et al. (2003). "The impact of systemic infection on the progression of neurodegenerative disease." Nat Rev Neurosci 4(2): 103-12.
Petereit, H. F., H. Lindemann, et al. (2003). "Effect of immunomodulatory drugs on in vitro production of brain-derived neurotrophic factor." Mult Scler 9(1): 16-20.
Multiple sclerosis (MS), a disease of presumably autoimmune aetiology, is characterized by inflammation, demyelination and axonal degeneration in the central nervous system. Current treatment concepts target the inflammatory activity, reducing the number of relapses and inflammatory lesions on magnetic resonance imaging as well as the proinflammatory cytokine production in blood lymphocytes. Recently, the neuroprotective aspect of inflammation has been documented and is thought to be mediated by neurotrophins, like brain-derived neurotrophic factor (BDNF). The question whether the in vitro BDNF production in MS patients and healthy controls is influenced by the immunomodulatory agents interferon beta (IFN-beta) and immunoglobulin G (Ig) is addressed. A significantly increased BDNF production in MS patients was found compared with normal controls (mean +/- SD: 492 +/- 172 pg/mL versus 217 +/- 55 pg/mL, P < 0.001). IFN-beta and low-dose Ig had no effect on BDNF production, whereas high-dose Ig reduced in vitro BDNF production in MS patients significantly (to 409 +/- 125 pg/mL, P = 0.001). These in vitro findings might indicate that Igs in high doses potentially interfere with neuroprotective mechanisms despite their potent anti-inflammatory properties.
Petereit, H. F., R. Pukrop, et al. (2003). "Low interleukin-10 production is associated with higher disability and MRI lesion load in secondary progressive multiple sclerosis." J Neurol Sci 206(2): 209-14.
Abnormalities in T-cell-derived cytokine production are a well-known phenomenon in multiple sclerosis (MS). An association between disability and the production of interferon gamma has been demonstrated recently. The present study investigated associations between disability, cytokine production in stimulated blood lymphocytes and magnetic resonance imaging data in 37 patients with the secondary progressive course in the stable phase of the disease. Patients with high interleukin-10 (IL-10) production had significantly lower disability scores (p=0.009) and lower T2 lesion load (p=0.03). Interleukin-10 might not only play a role in the pathological process of multiple sclerosis but has an impact on disease outcome as well.
Pihlaja, H., T. Rantamaki, et al. (2003). "Linkage disequilibrium between the MBP tetranucleotide repeat and multiple sclerosis is restricted to a geographically defined subpopulation in Finland." Genes Immun 4(2): 138-46.
We have previously found evidence for linkage as well as allelic and haplotype association between the myelin basic protein (MBP) gene and multiple sclerosis (MS). These findings have, however, not been reproduced in other populations. Here, we have analyzed association between MBP and MS in a new set of 349 Finnish triad families. Families with a parent born in the Southern Ostrobothnian region in western Finland (Bothnia families, n=98) were analyzed as a separate group since our previous studies included a high proportion of patients and families from this high-incidence region. Other families (n=251) were collected at five hospitals in southern, eastern, and northern Finland. The MBP short tandem repeat was genotyped, and haplotype patterns were verified by sequencing. In the Bothnia families, the previously detected associations with the 1.27 kb allele and haplotype 1.27-B10 were confirmed (P=0.01 and 0.02, respectively), whereas in the other families there was not even a trend toward association. These results demonstrate a geographic/genealogical restriction in the association between MS and the MBP short tandem repeat, highlight the importance of genealogical information in genetic studies of complex traits, and may provide an explanation why the association has not been found in many other populations.Genes and Immunity (2003) 4, 138-146. doi:10.1038/sj.gene.6363943
Piperidou, H. N., I. N. Heliopoulos, et al. (2003). "Epidemiological data of multiple sclerosis in the province of Evros, Greece." Eur Neurol 49(1): 8-12.
The frequency of multiple sclerosis (MS) in Greece is still debated. Our previous epidemiological field survey with a cross-check study of MS on March 31, 1984, in the province of Evros in north-eastern Greece showed a prevalence rate of 10.1/100,000. In 1990, Milonas et al. recorded a prevalence rate of 29.5/100,000 in northern Greece. So Greece is classified in the medium-frequency zone according to Kurtzke. This study was performed to estimate the prevalence of MS in the province of Evros and the annual incidence rates from 1974 to 1999. Patients were identified from several sources. A clinical follow-up was performed in 95% of the cases, and, if clinically indicated, new paraclinical examinations were performed and cases classified by Poser's criteria. The prevalence rate of the definite MS cases on December 31, 1999, was 38.9/100,000 and places the area in the high-risk zone. The mean annual incidence measured in 5-year intervals increased from 0.66/100,000 in 1974-1978 to 2.36/100,000 in 1994-1999 (p < 0.01). The increase in prevalence can be attributed to other causes than etiological changes, but the increase in the annual incidence rate indicates the possibility of a variation in risk factors of the disease.
Piras, M. R., I. Magnano, et al. (2003). "Longitudinal study of cognitive dysfunction in multiple sclerosis: neuropsychological, neuroradiological, and neurophysiological findings." J Neurol Neurosurg Psychiatry 74(7): 878-85.
OBJECTIVE: (1) To assess cognitive function and cerebral magnetic resonance imaging (MRI) involvement in relapsing-remitting multiple sclerosis; (2) to monitor disease evolution, cognitive dysfunction, and cerebral lesion burden over time (mean 8.5 year follow up period); (3) to study the relation between clinical, neuropsychological, and MRI data. On follow up assessment, visual and auditory oddball event related potentials (ERPs) were recorded as psychophysiological evaluation of cognitive status. Correlations between neuropsychological, MRI, and ERP data were also analysed. METHODS: Neuropsychological study assessed verbal and non-verbal IQ, deterioration index (DI) from WAIS subtests, conceptual reasoning, attention, verbal and visuospatial short-term and long term memory. MRI assessment detected presence of demyelinating lesions by using a semiquantitative method as well as cortical and subcortical atrophy over time. RESULTS: Attention, short-term and long term visuospatial memory were mildly impaired at baseline and remained unaltered longitudinally. At retesting a significant worsening of verbal long term memory (p=0.023), DI presence (p=0.041) and the increase of supratentorial and subtentorial MRI lesions load (p=0.001) emerged. Expanded disability status scale score correlated significantly with total lesion burden at both evaluations (p=0.043 and p=0.024 respectively). Temporal, occipital, and frontal horn lesions as well as cortical atrophy correlated significantly with attention and memory tests at baseline. Follow up assessment revealed significant correlation between cortical atrophy and attention as well as visuospatial short-term memory; spatial long term memory correlated significantly with lesions in body of lateral ventricle and frontal lobe. ERP study showed P300 latency abnormalities in 75% of patients, involving specifically more visual P300 (58.4 % of cases) than auditory wave (41.6 %). Visual P300 latency and amplitude correlated significantly with DI and auditory P300 latency with frontal horn and brain stem lesions. CONCLUSIONS: These findings revealed mild cognitive impairment in MS patients particularly consistent with slowing information processing over time. Increased MRI lesions do not correlate with the clinical course of the disease and cognitive deficit evolution. Thus, cognitive dysfunction could be related to disease peculiarity and not to the time course. Correlations between P300, neuropsychological, and MRI findings provide further information about ERP application to examine cognitive impairment in MS and probably to investigate their neural origin.
Plas, D. R. and C. B. Thompson (2003). "Akt activation promotes degradation of tuberin and FOXO3a via the proteasome." J Biol Chem 278(14): 12361-6.
Growth factor receptors promote cell growth and survival by stimulating the activities of phosphatidylinositol 3-kinase and Akt/PKB. Here we report that Akt activation causes proteasomal degradation of substrates that control cell growth and survival. Expression of activated Akt triggered proteasome-dependent declines in the protein levels of the Akt substrates tuberin, FOXO1, and FOXO3a. The addition of proteasome inhibitors stabilized the phosphorylated forms of multiple Akt substrates, including tuberin and FOXO proteins. Activation of Akt triggered the ubiquitination of several proteins containing phosphorylated Akt substrate motifs. Together the data indicate that activated Akt stimulates proteasomal degradation of its substrates and suggest that Akt-dependent cell growth and survival are induced through the degradation of negative regulators of these processes.
Pluchino, S., A. Quattrini, et al. (2003). "Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis." Nature 422(6933): 688-94.
Widespread demyelination and axonal loss are the pathological hallmarks of multiple sclerosis. The multifocal nature of this chronic inflammatory disease of the central nervous system complicates cellular therapy and puts emphasis on both the donor cell origin and the route of cell transplantation. We established syngenic adult neural stem cell cultures and injected them into an animal model of multiple sclerosis--experimental autoimmune encephalomyelitis (EAE) in the mouse--either intravenously or intracerebroventricularly. In both cases, significant numbers of donor cells entered into demyelinating areas of the central nervous system and differentiated into mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of them being of donor origin and actively remyelinating axons. Furthermore, a significant reduction of astrogliosis and a marked decrease in the extent of demyelination and axonal loss were observed in transplanted animals. The functional impairment caused by EAE was almost abolished in transplanted mice, both clinically and neurophysiologically. Thus, adult neural precursor cells promote multifocal remyelination and functional recovery after intravenous or intrathecal injection in a chronic model of multiple sclerosis.
Plumb, J., M. A. Armstrong, et al. (2003). "CD83-positive dendritic cells are present in occasional perivascular cuffs in multiple sclerosis lesions." Mult Scler 9(2): 142-7.
Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.
Pollak, Y., H. Ovadia, et al. (2003). "The EAE-associated behavioral syndrome: II. Modulation by anti-inflammatory treatments." J Neuroimmunol 137(1-2): 100-8.
EAE is associated with sickness behavior symptoms that are temporally correlated with inflammatory processes. To further elucidate the role of inflammatory mediators in the behavioral syndrome, EAE mice were injected daily with anti-inflammatory drugs, beginning at disease onset. Dexamethasone or interleukin-1 (IL-1) receptor antagonist or the prostaglandins synthesis inhibitor indomethacin attenuated the behavioral symptoms. Administration of the tumor necrosis-factor alpha (TNF-alpha) synthesis inhibitor pentoxifylline or targeted deletion of the type I TNF receptor had no behavioral effects whereas administration of pentoxifylline in IL-1ra-treated mice further reversed the behavioral depression. These findings demonstrate the critical involvement of pro-inflammatory cytokines and prostaglandins in the EAE-associated behavioral syndrome, and may have implications for understanding and treating the neuropsychiatric disturbances in multiple sclerosis (MS) patients.
Polman, C. H., B. N. Uitdehaag, et al. (2003). "Ocular comorbidity in multiple sclerosis." Lancet 361(9364): 1230.
Polman, C., L. Kappos, et al. (2003). "Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b." Neurology 60(1): 37-43.
OBJECTIVE: To investigate the relationship between neutralizing antibodies (NAB) and disease progression, relapses, and MR measures of MS. METHODS: Sequential serum samples from all 718 patients of the European Study Group in Interferon beta-1b in Secondary Progressive MS were analyzed to investigate relations between NAB and disease progression, relapses, and MR measures. RESULTS: This study showed no attenuating effect of NAB development on progression in disability. The effects of NAB on relapse rate showed substantial variation, depending on the statistical approach and definition of positivity, though analyses comparing low- and high-NAB+ periods with NAB- periods suggested a titer-related effect. MR T2 lesion volume changes from baseline were significantly higher for NAB+ patients but remained lower than for placebo patients. A substantial proportion of NAB+ patients became NAB-. No untoward effect of NAB development on safety was observed. CONCLUSION: These results support the conclusion that even though high NAB titers appear to have impact on treatment efficacy with respect to relapses, treatment decisions should be based primarily on clinical grounds.
Pon, R. A. and M. S. Freedman (2003). "Study of Herpesvirus saimiri immortalization of gammadelta T cells derived from peripheral blood and CSF of multiple sclerosis patients." J Neuroimmunol 139(1-2): 119-32.
Human gammadelta T cells are an integral part of the innate immune system and have been difficult to study owing primarily to their relatively low abundance and their fastidious culture properties associated with short in vitro lifespan. Their increased presence within multiple sclerosis (MS) white matter plaques compared to peripheral blood (PB) suggests a specific interaction with central nervous system (CNS) tissues. This fact, together with their innate ability to lyse human oligodendrocytes in culture implicate them possibly in the pathogenesis of MS. To further investigate their potential role in MS, we studied whether gammadelta T cells could be effectively immortalized using Herpesvirus saimiri (HVS), so that they could be studied in longer-term cultures. Effective culture conditions were established resulting in efficient HVS growth transformation of multiple PB and CSF gammadelta T cell lines and clones that could exist in IL-2-dependent culture for periods in excess of 2 years. Phenotypic and functional comparison studies with parental nontransformed gammadelta T cells were performed to characterize the changes that possibly induced by viral transformation. Using panels of transformed gammadelta T cell clones representing discrete gammadelta TcR subtypes, there was no apparent correlation between intracytoplasmic cytokine expression or tumor cell cytotoxicity with a specific TcR. All transformed gammadelta T cells analyzed, regardless of their compartment of origin, strongly expressed intracytoplasmic IFN-gamma and TNF-alpha, but little IL-2 or anti-inflammatory IL-4 or IL-10. These results indicate that HVS transformation of gammadelta T cells can be used to generate lines and clones from both the CSF and PB compartments for further study and elucidation of their potential role in MS pathogenesis.
Porter, B. and E. Keenan (2003). "Nursing at a specialist diagnostic clinic for multiple sclerosis." Br J Nurs 12(11): 650, 652-6.
People with multiple sclerosis (MS) need support, information, education and guidance in order to adapt effectively to the impact of the disease (Sheridan, 1997). The care received at the time of diagnosis is central to this adaptation process as the information given and received may impact on the person with MS for the rest of his/her life. In order to achieve effective coping strategies, the person with MS needs to develop a collaborative relationship with the team of healthcare professionals. At the National Hospital for Neurology and Neurosurgery (NHNN), University College London Hospital (UCLH), the MS team believes that the foundations of this relationship should be cemented at the diagnostic stage. This article describes a diagnostic model that facilitates accurate timely diagnosis of MS and the role of the MS nurse in providing expert clinical assessment, guidance, support and education in order to help the patient adjust to the disease.
Poser, C. M. and V. V. Brinar (2003). "Epilepsy and multiple sclerosis." Epilepsy Behav 4(1): 6-12.
A review of 29 published clinical series of adult patients who had epileptic seizures and multiple sclerosis (MS) yielded a prevalence of 2.3%, about three to six times that in the general adult population. The probable anatomic basis for the seizures is areas of inflammation, edema, and/or demyelination in the cerebral cortex and the juxtacortical white matter generated by a mechanism that is not completely understood; the fact that these plaques are very common suggests that other factors must operate in view of the rarity of seizures in MS. Seizures have been observed before and presumably marking the clinical onset of the disease, and during acute bouts. In some instances convulsions appear to be the only manifestations of an attack of MS, but there is no general acceptance of seizures as the first and only symptoms of the disease. The coincidental occurrence of both diseases, the nonspecific triggering effect of MS on latent epilepsy, and actual causation by MS are all possible explanations, but the last named is, in our opinion, extremely unusual.
Pozzilli, C., V. Tomassini, et al. (2003). "'Gender gap' in multiple sclerosis: magnetic resonance imaging evidence." Eur J Neurol 10(1): 95-7.
The authors evaluated the gender difference in the magnetic resonance imaging characteristics of the lesions occurring in the brain of 413 multiple sclerosis (MS) patients. Men had fewer contrast-enhancing lesions (P = 0.01), but a higher proportion of lesions evolving into 'black holes' (P = 0.001), when compared with women. Thus, our data indicate that men with MS are prone to develop less inflammatory, but more destructive lesions than women. This study results provides support for a modulation of the MS pathological changes by gender.
Prasad, R. S., S. J. Smith, et al. (2003). "Lower abdominal pressure versus external bladder stimulation to aid bladder emptying in multiple sclerosis: a randomized controlled study." Clin Rehabil 17(1): 42-7.
OBJECTIVE: To investigate the change in post-void residual bladder volumes (PVR) with 'abdominal vibration' using a percutaneous bladder stimulator in multiple sclerosis (MS) patients compared with either 'no treatment' or 'abdominal pressure'. DESIGN: Randomized controlled cross-over study. SETTING: Regional neurorehabilitation clinics. SUBJECTS: Twenty-eight MS patients with urinary symptoms and PVR > 100 ml. Twelve patients had urinary incontinence. METHODS: MS patients with voiding dysfunction and elevated PVR of 100-500 ml on BVI-3000 Ultrasound Scanner were randomized to either 'abdominal pressure' or 'vibration' by a portable, percutaneous, vibrating device (Queen Square Bladder Stimulator; Malem Medical) or to 'no treatment'. PVR was assessed at the end of each two-week phase. Outcome measure: PVR reduction by greater than 100 ml. RESULTS: The 28 patients ranged in age from 29 to 71 years with a mean age of 49 years and a mean duration of MS of 12 years (range 1-37 years). The PVR decreased from 231 (SD 119) ml during no treatment to 191 (SD 132) ml with abdominal pressure (p = 0.242). Using suprapubic vibration the PVR reduced further to 126 (SD 121) ml, which was highly significant (p = 0.002) compared with no treatment. The difference between abdominal pressure and vibration just failed to reach significance (p = 0.059). There was no significant reduction in either the frequency of micturition or episodes of incontinence. The device was well-tolerated by patients. CONCLUSION: Abdominal vibration is an effective method of reducing PVR in MS patients and appears more effective than abdominal pressure alone.
Pretorius, P. M. and G. Quaghebeur (2003). "The role of MRI in the diagnosis of MS." Clin Radiol 58(6): 434-48.
Magnetic resonance imaging (MRI) is the most widely used imaging technique in the investigation of multiple sclerosis (MS). Although MS remains a clinical diagnosis, MRI has become an invaluable tool in understanding and monitoring the disease, and is commonly used to confirm the clinical diagnosis. Various imaging techniques can be used but T2-weighted brain imaging remains the standard tool. The officially endorsed imaging criteria for MS places greater emphasis on the spatial and temporal distribution of lesions than on their individual appearance. This review focuses on the more typical findings in MS, and considers the current role of MRI in the diagnosis.
Prieto, J. M. and M. Lema (2003). "[Interferon in multiple sclerosis]." Rev Neurol 36(10): 980-90.
INTRODUCTION and METHOD. The mechanism of action of interferons We do not know in the multiple sclerosis but, although exist discrepancies in relation to their degree of effectiveness, fundamentally the dose to use and the administration route, the three available ones have proven to be effective in the reduction of the number of the bouts. We reviewed the more important clinical tests made with three interferons in the remitent recurrent (RR) forms, the isolated neurologic syndromes and the secondary progressive (SP) forms of the disease and reviewed the comparative studies between interferons. CONCLUSIONS. The three interferons are well tolerated although the intramuscular form produces less skin effects; in the RR forms the number of bouts are reduced in significant form. Only the study with 1a intramuscular was demonstrated effectiveness in the SP forms and with the subcutaneous IFN b 1b exists discrepancies between the European and the American studies. The early treatment with subcutaneous IFN b 1a slow down the evolution of the disease. Except in relation to the side effects, there are not evidence that the dose and the administration route are important in the effectiveness in the long term.
Prosser, L. A., K. M. Kuntz, et al. (2003). "Patient and community preferences for treatments and health states in multiple sclerosis." Mult Scler 9(3): 311-9.
OBJECTIVE: To examine preferences for treatments and health states for patients with relapsing-remitting MS and members of the community. METHODS: A survey was developed to evaluate health-related quality-of-life measures (utilities) for three treatments and six MS health states using a utility-elicitation software package, U-Titer II. Sixty-two MS patients at two large teaching hospitals in Boston, MA, and 67 members of the general community in San Diego, CA, completed the health-related quality-of-life survey using a computer. RESULTS: Assessment of quality of life decreased as disability level of MS health states increased for both respondent groups. Respondents rated less-disabled health states relatively highly (> 0.94 for patients and > 0.89 for community respondents). Quality-of-life measures for treatments in mean utilities ranged from 0.80 to 0.96. Patients assigned higher utilities for both MS health states and treatment states than community respondents; the ratings became more disparate as health states worsened. CONCLUSIONS: On average, respondents assigned utilities to currently available treatments for MS that are comparable to those of mild to moderate stages of the disease itself. These results underscore the importance of including preferences for health states and treatment alternatives in the decision to initiate treatment for individual patients or in the evaluation of effectiveness or cost-effectiveness of these treatments in patients with MS.
Pucci, E. (2003). "Is the internet transforming the physician-consumer relationship? Preliminary data in a neurological setting." Eur J Neurol 10(2): 192.
Qin, Y., P. Duquette, et al. (2003). "Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis." Lab Invest 83(7): 1081-8.
SUMMARY: The development of somatically mutated memory and plasma B cells is a consequence of T cell-dependent antigen-challenged humoral immunity. To investigate the role of B cell-mediated humoral immunity in the initiation and evolution of multiple sclerosis (MS), we analyzed Ig variable heavy chain genes of intrathecal B cells derived from patients with a first clinical manifestation suggestive of MS. Sequences of Ig variable regions showed that B cells in the cerebrospinal fluid from most of these patients were clonally expanded and carried somatic hypermutated variable heavy chain genes. The mutations showed a high replacement-to-silent ratio and were distributed in a way suggesting that these clonally expanded B cells had been positively selected through their antigen receptor. In comparison, intrathecal B-cell clonal expansion often precedes both oligoclonal IgG bands and multiple magnetic resonance imaging lesions. Clinical follow-up study showed that patients with clonally expanded intrathecal B cells had a high rate of conversion to clinically definite MS. The findings provide direct evidence of recruitment of germinal center differentiated B lymphocytes into the central nervous system during the initiation of MS. These results indicate B cell-mediated immune response in the cerebrospinal fluid is an early event of inflammatory reaction in the central nervous system of MS. This procedure also provides a more sensitive method to evaluate the association of humoral immunity in the evolution of MS.
Quarantelli, M., A. Ciarmiello, et al. (2003). "Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load." Neuroimage 18(2): 360-6.
The aim of this study was to simultaneously measure in vivo volumes of gray matter (GM), normal white matter (WM), abnormal white matter (aWM), and cerebro-spinal fluid (CSF), and to assess their relationship in 50 patients with relapsing-remitting multiple sclerosis (RR-MS) (age range, 21-59; mean EDSS, 2.5; mean disease duration, 9.9 years), using an unsupervised multiparametric segmentation procedure applied to brain MR studies. Tissue volumes were normalized to total intracranial volume providing corresponding fractional volumes (fGM, faWM, fWM, and fCSF), subsequently corrected for aWM-related segmentation inaccuracies and adjusted to mean patients' age according to age-related changes measured in 54 normal volunteers (NV) (age range 16-70). In MS patients aWM was 23.8 +/- 29.8 ml (range 0.4-138.8). A significant decrease in fGM was present in MS patients as compared to NV (49.5 +/- 3.2% vs 53.3 +/- 2.1%; P < 0.0001), with a corresponding increase in fCSF (13.0 +/- 3.8% vs 9.1 +/- 2.4%; P < 0.0001). No difference could be detected between the two groups for fWM (37.5 +/- 2.6% vs 37.6 +/- 2.2%). faWM correlated inversely with fGM (R = -0.434, P < 0.001 at regression analysis), and directly with fCSF (R = 0.473, P < 0.001), but not with fWM. There was a significant correlation between disease duration and EDSS, while no relationship was found between EDSS or disease duration and fractional volumes. Brain atrophy in RR-MS is mainly related to GM loss, which correlates with faWM. Both measures do not appear to significantly affect EDSS, which correlates to disease duration.
Quelvennec, E., O. Bera, et al. (2003). "Genetic and functional studies in multiple sclerosis patients from Martinique attest for a specific and direct role of the HLA-DR locus in the syndrome." Tissue Antigens 61(2): 166-71.
Among candidate genes involved in multiple sclerosis (MS) genetic susceptibility, MHC genes and particularly HLA-DRB1*1501-DQB1*0602 haplotype play a major role. Based on the strong linkage disequilibrium observed in Caucasians between DRB1*1501 and DQB1*0602 alleles, it is still impossible to draw a firm conclusion about the DRB1 or DQB1 locus involvement. In order to address this issue a strategy associating a genetic and a functional approach was conducted in a population of-non-Caucasian MS patients. We observed that in Martinicans (55 MS and 100 controls), the DRB1*15 and DRB1*07 alleles were positively associated with the disease. However in Martinicans the most common DRB1*15 subtype was *1503 and not *1501. Moreover, in Martinicans, the frequency of DQB1*0602, found in association with other DRB1 alleles than DRB1*15 (42% of DQB1*0602 haplotypes), was not increased in DRB1*15-negative MS patients, suggesting a neutral role of DQB1*0602 in MS genetics. In a second step, we demonstrated the capability of the DRB1*1503 allele associated with MS in Martinicans to present the immunodominant autoantigen MBP 85-99 peptide to a DRB1*1501 restricted MBP specific T cell line. Interestingly, structural features of DRB1*1501 or DRB1*1503 molecules are in good fit with the hypothesis that *1501 and *1503 molecules may act similarly in MS development by presenting the same immunodominant MBP peptide. On the whole, our results show a prominent role of the DRB1 locus (DRB1*1501 and/or DRB1*1503 alleles) in the immunodominant MBP 85-99 peptide presentation to genetically different MS patients and suggest a neutral role of the DQB1 encoded molecule in MS susceptibility.