Multiple Sclerosis References 2003; Authors: R
(34 References)
Rabinstein, A. A. and L. M. Shulman (2003). "Acupuncture in clinical neurology." Neurolog 9(3): 137-48.
BACKGROUND: A majority of people in the United States use alternative or complementary therapy at some point in their lives, and acupuncture is among the most frequently used modalities. Many United States medical schools offer courses in alternative medicine, and a growing number of insurers offer coverage for alternative therapies. This paper critically reviews our current knowledge about the safety and efficacy of acupuncture for neurologic conditions. REVIEW SUMMARY: Acupuncture is a safe procedure when performed by trained professionals. Complications from acupuncture are rare and mainly related to negligence of sterile technique. Studies of the therapeutic value of acupuncture are fraught with challenging methodologic problems, including the choice of a placebo, a suitable control treatment, and the technique of stimulation applied. Clinical trials of the use of acupuncture for pain syndromes (headache, neck, and back pain), stroke rehabilitation, Parkinson's disease, multiple sclerosis, and substance abuse are reviewed. CONCLUSIONS: Based on the current literature, no definitive recommendation can be made regarding the efficacy of acupuncture for common pain syndromes including headache, and neck and back pain. Better quality clinical trials fail to demonstrate efficacy for the use of acupuncture as part of a rehabilitation program following stroke or as a treatment for drug addiction. Acupuncture may have a role in the treatment of sleep disturbance associated with Parkinson's disease but was not efficacious for the primary symptoms of either Parkinson's disease or multiple sclerosis. In light of increasing public interest and use of alternative therapies, this review may be helpful in promoting more discussion between patients and physicians about the use of acupuncture.
Racette, L. and P. A. Sample (2003). "Short-wavelength automated perimetry." Ophthalmol Clin North Am 16(2): 227-36, vi-vii.
Short-wavelength automated perimetry (SWAP) is a visual field test designed to assess the short-wavelength sensitive color system by isolating the blue-yellow pathway. SWAP is a powerful clinical tool able to detect visual field deficits 3 to 5 years before standard automated perimetry (white-on-white) in most glaucoma patients, and progression of visual field defects up to 3 years earlier. SWAP deficits are predictive of the onset and location of future visual field loss, and they correlate well with structural damage associated with glaucoma. The main disadvantage of SWAP remains the longer testing time required. In the clinic, it is recommended that SWAP be performed on patients who are at higher risk for glaucoma. Although SWAP was originally developed to detect visual loss in glaucoma patients, it is also useful for patients with diabetic retinopathy and maculopathy, optic neuropathies, vision loss associated with HIV, migraine, and multiple sclerosis. More sensitive psychophysical tests of visual function, such as SWAP, can significantly shorten clinical trials and aid in the validation of new therapeutic approaches.
Rajabally, Y. A., D. Farrell, et al. (2003). "Oro-mandibular dystonia in a case of multiple sclerosis with capsular plaque." Eur Neurol 49(3): 190-1.
Rammohan, K. W. (2003). "Axonal injury in multiple sclerosis." Curr Neurol Neurosci Rep 3(3): 231-7.
The pivotal role of axons in the pathophysiology and pathogenesis of multiple sclerosis (MS) is increasingly becoming the focus of our attention. Axonal injury, considered at one time to be a late phenomenon, is now recognized as an early occurrence in the inflammatory lesions of MS. There is converging evidence from histopathologic, as well as magnetic resonance imaging and magnetic resonance spectroscopy studies, that axons play a crucial and dynamic role during the evolution of MS pathology and the development of clinical disability. It has been repeatedly demonstrated that neurologic functional impairment correlates best with axonal, rather than myelin, injury. The pathophysiology of axonal injury remains speculative. Although generally considered to be sequelae of demyelination, it is possible that axonal injury in MS is indeed a primary event. The discovery that axonal injury can be reversible has provided an impetus to institute early therapy. The finding that irreversible axonal transection occurs in early lesions has underscored now, more than ever before, the need to curtail inflammation and the need to institute early treatment with disease-modifying agents. The axon will undoubtedly remain the focus of our attention regarding research on MS now and in the future.
Ramsaransing, G., A. Teelken, et al. (2003). "Low leucocyte myeloperoxidase activity in patients with multiple sclerosis." J Neurol Neurosurg Psychiatry 74(7): 953-5.
The gene for myeloperoxidase (MPO) has been implicated in multiple sclerosis (MS). By measuring H(2)O(2) dependent oxidation of 3,3'5,5'-tetramethylbenzidine with spectrophotometry the authors investigated MPO activity in peripheral blood leucocytes from 42 patients with MS (12 with secondary progressive MS, 17 with primary progressive MS, and 13 with relapsing remitting benign MS) and 32 healthy controls. Leucocyte MPO activity was significantly lower in patients with benign MS (mean (SEM) 0.086 (0.029) U/mg protein; p<0.01), secondary progressive MS (0.038 (0.009) U/mg protein; p<0.001), and primary progressive MS (0.057 (0.016) U/mg protein; p<0.001) compared with healthy controls (0.322 (0.053) U/mg protein). These data suggest that low MPO, which may be genetically determined, plays a part in MS pathogenesis.
Ramunni, A., L. F. Morrone, et al. (2003). "Effectiveness of long-term heparin-induced extracorporeal LDL precipitation (HELP) in improving coronary calcifications." Int J Artif Organs 26(3): 252-5.
There is clear clinical evidence that a drastic lowering of plasma LDL-Cholesterol (LDL) concentrations significantly reduces the rate of total and coronary mortality as well as the incidence of cardiovascular events in high risk hypercholesterolemic patients. We describe the case of a 51-year-old woman with coronary heart disease (CHD) who presented with increasing angina on exertion in 1995, at the age of 45. She suffered from a heterozygous familial hypercholesterolemia and in 1985 her total cholesterol (TCHO) was 328 +/- 62 mg/dl (mean value of ten analysis). After ten years of statins her mean values (20 analysis, 2 per year) were: TCHO 259 +/- 71, LDL 209 +/- 47, HDL 35 +/- 7 mg/dl. Coronary angiography (CA) performed in 1995 disclosed three vessel coronary heart disease with significant stenoses of the distal right coronary artery, multiple calcifications of the interventricularis artery and multiple plaques with significant stenoses in the ramus circumflexus. The woman underwent coronary by-pass surgery. Thereafter the patient was treated for six years with HELP in biweekly intervals, in combination with statins. TCHO, LDL, HDL and fibrinogen (fb) levels were measured before and after each treatment. Their mean values for an amount of 120 sessions were: TCHO pre 216 +/- 23, post 111 +/- 18 LDL pre 152 +/- 16 post 67 +/- 18, HDL pre 42 +/- 5 post 35 +/- 4 fb pre 306 +/- 48 post 125 +/- 31. In 2001 a new CA was performed. Calcifications disappeared and stenoses were identical to the previous CA or reduced. There were no further clinical manifestations of CHD. We trust that the clinical benefit of the HELP procedure will be substantial for those patients who have problems in clearing LDL from their plasma pool and who are at the same time sensitive to elevated LDL levels by the development of premature coronary sclerosis.
Rashbaum, I. G., M. Lacerte, et al. (2003). "Interventions in chronic pain management. 5. Disease-specific issues in chronic pain." Arch Phys Med Rehabil 84(3 Suppl 1): S57-62; quiz S63-8.
This self-directed learning module highlights the importance of applying principles described earlier in the Study Guide to specific diseases encountered by practitioners managing chronic pain in order to administer appropriate treatment. This chapter focuses on several challenging and increasingly common maladies and attempts to delineate rationales for holistic, comprehensive care. OVERALL ARTICLE OBJECTIVE: To explore diagnostic concepts and therapeutic strategies in fibromyalgia syndrome, central pain, multiple sclerosis, complex regional pain syndrome, and postherpetic neuralgia.
Redegeld, F. A. and F. P. Nijkamp (2003). "Immunoglobulin free light chains and mast cells: pivotal role in T-cell-mediated immune reactions?" Trends Immunol 24(4): 181-5.
Immunoglobulin (Ig) free light (L)-chains have long been considered as the meaningless remnants of a spillover in the regular Ig production by B cells. The recently discovered role for Ig free L-chains in mediating hypersensitivity-like responses sheds new light on their potential role in immune responses. Ig free L-chains can sensitize mast cells, such that a second encounter with the appropriate antigen results in mast-cell activation. The possible importance of this reaction for the induction of T-cell-mediated immune reactions, leading to contact sensitivity, multiple sclerosis and rheumatoid arthritis is discussed.
Reidel, M. A., C. Stippich, et al. (2003). "Differentiation of multiple sclerosis plaques, subacute cerebral ischaemic infarcts, focal vasogenic oedema and lesions of subcortical arteriosclerotic encephalopathy using magnetisation transfer measurements." Neuroradiology 45(5): 289-94.
Although multiple sclerosis (MS) plaques, subacute cerebral ischaemic infarcts, focal vasogenic brain oedema, and subcortical arteriosclerotic encephalopathy (SAE) often have typical radiological patterns, they are sometimes difficult to distinguish from each other. Our aim was to determine whether they can be differentiated by magnetisation transfer (MT) measurements. We measured MT ratios (MTR) in ten patients with plaques of MS, 11 with subacute ischaemic infarcts, 12 with focal vasogenic oedema, and ten with lesions of SAE and compared the mean MTRs statistically. The MTR of normal white matter was 47.3%; the lowest MTR was found in plaques of MS (mean 26.4%). With the exception of vasogenic oedema and subacute cerebral ischaemic infarcts the mean MTRs were significantly different between all groups. MT measurements can provide additional information for the differentiation of these conditions, but we could not distinguish vasogenic oedema from subacute cerebral ischaemic infarcts.
Reindl, M., A. Lutterotti, et al. (2003). "Mutations in the gene for toll-like receptor 4 and multiple sclerosis." Tissue Antigens 61(1): 85-8.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with heterogeneous pathological features, disease courses and genetical backgrounds. In this study we determined whether genetic variants of toll-like receptor (TLR) 4, which confer substantial differences in the inflammation elicited by bacterial lipopolysaccharide, are related to the development of MS. We found no differences in the frequencies of the cosegregating TLR4 Asp299Gly and Thr399Ile polymorphisms between Austrian MS patients (11.6%) and age-matched controls (13.7%). Furthermore, we could not detect any influence of these mutations on clinical parameters and serum levels of soluble adhesion molecules of MS patients. Our data indicate that these TLR4 polymorphisms have no influence on the incidence, progression and inflammatory parameters of MS.
Renganathan, M., M. Gelderblom, et al. (2003). "Expression of Nav1.8 sodium channels perturbs the firing patterns of cerebellar Purkinje cells." Brain Res 959(2): 235-42.
The sensory neuron specific sodium channel Na(v)1.8/SNS exhibits depolarized voltage-dependence of inactivation, slow inactivation and rapid repriming, which differentiate it from other voltage-gated sodium channels. Na(v)1.8 is normally selectively expressed at high levels in sensory ganglion neurons, but not within the CNS. However, expression of Na(v)1.8 mRNA and protein are upregulated within cerebellar Purkinje cells in animal models of multiple sclerosis (MS), and in human MS. To examine the effect of expression of Na(v)1.8 on the activity pattern of Purkinje cells, we biolistically introduced Na(v)1.8 cDNA into these cells in vitro. We report here that Na(v)1.8 can be functionally expressed at physiological levels (similar to the levels in DRG neurons where Na(v)1.8 is normally expressed) within Purkinje cells, and that its expression alters the activity of these neurons in three ways: first, by increasing the amplitude and duration of action potentials; second, by decreasing the proportion of action potentials that are conglomerate and the number of spikes per conglomerate action potential; and third, by contributing to the production of sustained, pacemaker-like impulse trains in response to depolarization. These results provide support for the hypothesis that the expression of Na(v)1.8 channels within Purkinje cells, which occurs in MS, may perturb their function.
Repovic, P., K. Mi, et al. (2003). "Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: Synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide." Glia 42(4): 433-46.
Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis. GLIA 42:433-446, 2003. Copyright 2003 Wiley-Liss, Inc.
Riazi, A., J. C. Hobart, et al. (2003). "Using the SF-36 measure to compare the health impact of multiple sclerosis and Parkinson's disease with normal population health profiles." J Neurol Neurosurg Psychiatry 74(6): 710-4.
OBJECTIVE: To examine the relative impact of two chronic neurological disorders, multiple sclerosis and Parkinson's disease, by comparing patients' scores on the medical outcomes study 36-item short form health survey (SF-36) with the health profile of the United Kingdom population norms. METHODS: 638 people representing the full spectrum of multiple sclerosis and 227 patients with Parkinson's disease were studied. Health status was measured by the SF-36. Scores for the eight health domains were compared after controlling for age, sex, disease duration, mobility, social class, ethnicity, education, marital status, and employment status. RESULTS: People with multiple sclerosis and those with Parkinson's disease had significantly worse health than the general population on all eight domains measured by the SF-36. The relative impact of multiple sclerosis and Parkinson's disease were similar, but multiple sclerosis resulted in poorer scores on physical functioning and better scores in mental health. People with mild multiple sclerosis who walked without an aid also had significantly worse scores in all dimensions than the general UK population. CONCLUSIONS: The results highlight the need for further research into aspects of health measured by the SF-36. Nevertheless, generic measures that are applicable across multiple diseases may fail to address clinically important aspects of the impact of specific disorders.
Ribeiro, J. A., A. M. Sebastiao, et al. (2003). "Participation of adenosine receptors in neuroprotection." Drug News Perspect 16(2): 80-6.
Adenosine is released from most cells, including neurons and glial cells. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors. Interaction between adenosine receptors and other receptors for neuromodulators might contribute to a fine tuning of neuronal function, and therefore, to neuroprotection. Manipulation of adenosine receptors may influence sleep and arousal, cognition and memory, neuronal damage and degeneration and neuronal maturation. The therapeutic implications for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, epilepsy and multiple sclerosis are discussed.
Rigby, S. A., C. Domenech, et al. (2003). "Development and validation of a self-efficacy measure for people with multiple sclerosis: the Multiple Sclerosis Self-efficacy Scale." Mult Scler 9(1): 73-81.
The aim of this study is to develop and validate a brief measure of self-efficacy specifically for use with people with multiple sclerosis (MS). Self-efficacy is the subjective belief that one can overcome challenges that one is faced with. In order to incorporate the subjective experiences of individuals with MS, a 'patient-focused' methodology has been adopted. Open-ended interviews were used to generate potential scale items. Items were piloted on an initial sample of individuals with MS and reduced to 14 items on the basis of their perceived relevance to this patient group. The final 14-item scale was then used with a further 142 individuals in order to assess its psychometric properties. The scale demonstrated high internal consistency (Cronbach's alpha = 0.81) and test-retest reliability (r = 0.81, P < 0.001) and acceptable validity. Issues concerning the assessment of validity are discussed in terms of the scale's relevancy to individuals with MS and the theoretical issues around the construct of self-efficacy. The scale has shown sensitivity to detect change following a brief therapeutic intervention, with an effect size of 0.502. This MS Self-efficacy Scale could, therefore, be a useful tool in the assessment of psychological adjustment and quality-of-life of individuals with MS.
Riise, T. (2003). "Can we contract multiple sclerosis from our working environment?" Mult Scler 9(3): 217-8.
Rivera, V. M. (2003). "[Deciding on treatment in Multiple Sclerosis]." Rev Neurol 36: 80-5.
The modern history of the treatment of multiple sclerosis is reflected during the last years with the advent of controlled clinical trials design to produce measurable outcomes utilizing MRI techniques and statistical analysis. Addressing in this form the use of disease modifying medications: immunomodulation with interferons and glatiramer acetate in the relapsing/remitting type, and combination therapies or immunosuppression in the progressive forms, these studies based on evidence provide to the clinician direction in the process to decide the most appropriate treatment for the individual patient.
Robbie-Ryan, M., M. B. Tanzola, et al. (2003). "Cutting edge: both activating and inhibitory Fc receptors expressed on mast cells regulate experimental allergic encephalomyelitis disease severity." J Immunol 170(4): 1630-4.
Mast cell-deficient mice (W/W(v)) exhibit significantly reduced severity of experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. In this study, the contribution of FcR-mediated mast cell activation to disease was examined. W/W(v) mice were reconstituted i.v. with bone marrow-derived mast cells (BMMCs) from wild-type mice or those lacking functional FcRs. Eight weeks later, EAE was induced by immunization with the myelin oligodendrocyte glycoprotein 35-55 peptide. Disease scores were analyzed in reconstituted mice and compared with age-matched W/W(v) mice and wild-type littermates. Mice reconstituted with FcRgamma(-/-) BMMCs or FcgammaRIII(-/-) BMMCs exhibited less severe clinical symptoms similar to W/W(v) controls, while reconstitution with FcRIIB(-/-) BMMCs resulted in disease significantly more severe than wild-type controls. Notably, mice reconstituted with FcgammaRIII(-/-) BMMC exhibit a relapsing-remitting course of disease. These data demonstrate that both activating and inhibitory FcRs expressed on mast cells influence the course of EAE.
Rocca, M. A., D. M. Mezzapesa, et al. (2003). "Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis." Neuroimage 18(4): 847-55.
Previous work has suggested that functional reorganization of cortical areas might have a role in limiting the clinical impact of axonal pathology in patients with established multiple sclerosis (MS). Since there is evidence for irreversible tissue damage even in patients with early MS, we assessed, using functional MRI (fMRI) and a general search method, the brain pattern of movement-associated cortical activations in patients at presentation with clinically isolated syndromes (CIS) suggestive of MS. To elucidate the role of cortical reorganization in these patients, we also investigated the extent to which the fMRI changes correlated with the extent of overall axonal injury of the brain. From 16 right-handed patients at presentation with CIS and 15 right-handed, age- and sex-matched healthy volunteers, we obtained: (1). fMRI (repetitive flexion-extension of the last four fingers of the right hand), (2). conventional MRI scans, and (3). a new, unlocalized proton MR spectroscopy ((1)HMRS) sequence to measure the concentration of N-acetylaspartate of the whole brain (WBNAA). Compared to controls, patients with CIS had more significant activations of the contralateral primary somatomotor cortex (SMC), secondary somatosensory cortex, and inferior frontal gyrus. They also had significant decreased WBNAA concentration. Relative activation of the contralateral primary SMC was strongly correlated with WBNAA levels (r = -0.78, P < 0.001). This study shows that axonal pathology and functional cortical changes over a rather distributed sensorimotor network occur in patients at presentation with CIS suggestive of MS and that these two aspects of the disease are strictly correlated. This suggests that the increased functional recruitment of the cortex in these patients might have an adaptive role in limiting the clinical impact of irreversible tissue damage.
Rocca, M. A., G. Iannucci, et al. (2003). "Occult tissue damage in patients with primary progressive multiple sclerosis is independent of T2-visible lesions--a diffusion tensor MR study." J Neurol 250(4): 456-60.
Although quantitative magnetic resonance (MR) studies have shown that primary progressive multiple sclerosis (PPMS) patients have subtle and diffuse changes of the normal-appearing brain tissue (NABT), the nature of these changes is still poorly understood. The aim of this study was to improve our understanding of the NABT damage in PPMS patients by comparing diffusion tensor magnetic resonance (DT MR) quantities of a large portion of the brain from these patients with those from healthy subjects with and without T2-visible lesions. Dual-echo and DT MR images of the brain were obtained from 20 patients with PPMS, 20 age- and gender-matched healthy volunteers with normal conventional MR scans of the brain, and 20 age-, gender- and T2 lesion volume-matched healthy subjects. Mean diffusivity (MD) and fractional anisotropy (FA) histograms of the NABT were derived from all the individuals. Average lesion MD and FA were calculated in PPMS patients and healthy controls with T2-visible lesions. MD and FA histogram-derived metrics of the NABT from PPMS patients differed significantly from the corresponding quantities from healthy volunteers with no brain T2-visible lesions and from those from healthy volunteers with overt brain MR abnormalities (p values ranging from < 0.0001 to 0.01). Average lesion MD was also significantly higher in PPMS patients than in healthy volunteers with T2-visible lesions (p = 0.03). In PPMS patients, no significant correlation was found between any of the DT MR quantities of NABT damage and a) the T2 lesion volume, b) the average lesion MD, and c) the normalized brain volume. This study shows that in PPMS patients there is a significant microscopic damage of the NABT which is independent of the extent of T2-visible abnormalities. This suggests that Wallerian degeneration of fibers passing through macroscopic abnormalities is not a major factor contributing to diffuse NABT pathology of these patients.
Rode, G., E. Maupas, et al. (2003). "[Medical treatment of spasticity]." Neurochirurgie 49(2-3 Pt 2): 247-55.
Spasticity is one of the clinical signs observed after a lesion of the pyramidal tract. Clinical manifestations are polymorphous and depend on the location of the lesion on the pre-motoneuron. Functional consequences are also variable. Only negative effects such as painful spasms, stiffness, distortions, are to be treated. Three different categories of drugs are available: GABA-like (baclofen, benzodiazepine), central alpha 2 agonists (tizanidine, clonidine) and peripheral anti-spastics (dantrolene). Baclofen remains the most commonly used anti-spastic. The preferential indication is spasticity from spinal cord disease, especially when the aetiology is multiple sclerosis. Efficacy of benzodiazepines (diazepam, tetrazepam, clonazepam) is comparable with baclofen; however, side effects (drowsiness) are more frequent. Benzodiazepines are indicated when spasticity is associated with anxiety. Tizanidine is an efficient and well tolerated antispastic. In France, prescription requires a temporary authorization of use. Dantrolen has a peripheral mechanism of action and can be prescribed in the different forms of spasticity. There are other compounds with anti-spastic properties (gabapentine, cyproheptadine, piracetam). Their advantage is rather limited when used alone. Generally, they are administrated in combinaison with usual anti-spastic drugs.
Rodriguez, M. (2003). "A function of myelin is to protect axons from subsequent injury: implications for deficits in multiple sclerosis." Brain 126(Pt 4): 751-2.
Rodriguez Rodriguez, Y. and I. Suarez Luis (2003). "[Activation of T cells in experimental autoimmune encephalomyelitis and multiple sclerosis]." Rev Neurol 36(7): 649-52.
AIMS. In this study we describe the main findings from research into the autoreactive process triggered by activated T lymphocytes, which are generated in the peripheral compartment and then migrate towards the central nervous system (CNS) in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) its animal model. METHOD. The different strategies that have been developed to date for the immunological treatment of MS have been designed to intervene in the pathogenic process of the disease by blocking the activation of T cells and B cells with specific antigens, interfering with immunological effector mechanisms and inhibiting the migration of lymphocytes towards the CNS. The cause of the inflammatory response in MS has still not been defined, but the findings from EAE studies and in patients with MS suggest that the disease has an autoimmune aetiology involving autoreactive T cells which are specific for antigens in the myelin membrane. To activate these cells at least two cues are needed during antigen recognition and later the T CD4+ lymphocytes are differentiated in two subpopulations, Th1 and Th2, which differ in the pattern of secretion of cytosines depending on the stage of the disease process. The progressions of EAE and MS give rise to changes in the primary and secondary self reactive responses of the T cells during the progression of the disease. CONCLUSION. The pathological immune mechanisms mediated by activated myelin specific T lymphocytes play a key role in the progression and recuperation, as well as the mediation, of tissue damage during the course of MS and EAE.
Rodriguez-Casero, M. V., L. K. Shield, et al. (2003). "Childhood chronic inflammatory demyelinating polyneuropathy with central nervous system demyelination resembling multiple sclerosis." Neuromuscul Disord 13(2): 158-61.
Central nervous system demyelination has been described in adults but not in children with chronic inflammatory demyelinating polyneuropathy. We describe a patient with clinical and electrophysiological features consistent with chronic inflammatory demyelinating polyneuropathy who presented at age 5 with an intramedullary spinal cord tumor-like lesion and at age 8, represented with cerebral and spinal demyelinating lesions. Her clinical course and magnetic resonance imaging features were atypical for multiphasic disseminated encephalomyelitis and indistinguishable from multiple sclerosis. To our knowledge, this association has not been previously described in the English literature in childhood.
Roscoe, L. A., J. E. Malphurs, et al. (2003). "Antecedents of euthanasia and suicide among older women." J Am Med Womens Assoc 58(1): 44-8.
OBJECTIVES: To identify the characteristics of older women who sought Jack Kevorkian's assistance in dying and to compare them with those of an age-matched sample who committed suicide. METHOD: This retrospective case-control study compared all 18 women age 55 and older who died with the assistance of Jack Kevorkian and whose deaths were investigated in Oakland County, Michigan from 1995 to 1997 with all 15 women age 55 and older who committed suicide in the same county during the same time period. We coded 203 variables in 7 domains from medical examiner files, including autopsy findings. RESULTS: Significantly more of Kevorkian's cases had amyotrophic lateral sclerosis or multiple sclerosis (p = .018), a recent decline in health (p = .031), or inadequately controlled pain (p = .041). Women who committed suicide had more prevalent chronic illnesses and were more likely to have been diagnosed with clinically significant depression or other psychiatric disorders (p = .023). Both groups were significantly less likely to be married (p < .001) and more likely to be divorced (p < .001) than US Census data would predict. CONCLUSIONS: The different vulnerabilities of older women who want to die and either commit suicide or seek assistance deserve continued careful research. Poorly controlled pain was a factor in seeking assistance in dying, and depression and psychiatric disorders characterized older women who committed suicide in our study. Not having a spouse may increase isolation and reinforce the hopelessness of women who are living with catastrophic illness.
Rosenbluth, J. and D. Moon (2003). "Dysmyelination induced in vitro by IgM antisulfatide and antigalactocerebroside monoclonal antibodies." J Neurosci Res 71(1): 104-9.
Antiglycolipid antibodies cause a distinctive form of dysmyelination in vivo characterized by marked widening of the myelin period. Such "expanded" or "wide-spaced" myelin occurs in peripheral nerves in certain paraproteinemias and in the CNS in multiple sclerosis. We have used an in vitro system to reproduce this pathology under controlled conditions to assess the role of antibody specificity and class and the need for cofactors in generating this kind of lesion in peripheral myelin. Schwann cell myelin formed in vitro around dorsal root ganglion cell axons was exposed for 3-14 days to hybridoma cells that produce specific monoclonal antibodies. Typical wide-spaced myelin developed after exposure to either O4, which produces an IgM antisulfatide antibody, or O1, which produces an IgM antigalactocerebroside antibody. In both cases, the effect was apparent by three days in paranodal as well as internodal myelin, especially in the outer lamellae. This change did not depend on the presence of complement or macrophages in the cultures. Exposure to anti-GalC hybridoma cells, which produce an IgG3 antiglycolipid antibody, did not produce wide-spaced myelin, nor did exposure to hybridoma cells that secrete IgM antibodies directed against a non-myelin antigen. The location and rapidity of the pathologic changes seen after O4 or O1 are consistent with penetration of the antibodies through the external mesaxon of already formed myelin and then between compact lamellae, progressively spreading them apart in the centripetal direction. This in vitro model shows that either of two specific monoclonal IgM antiglycolipid antibodies can alone reproduce a well known form of myelin pathology under defined conditions.
Rovaris, M. and M. Filippi (2003). "Interventions for the prevention of brain atrophy in multiple sclerosis : current status." CNS Drugs 17(8): 563-75.
The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of the neurodegenerative component of multiple sclerosis (MS) pathology. Results from placebo-controlled and crossover clinical trials indicate that immunomodulating (e.g. recombinant interferon-beta [IFNbeta]-1a [Rebif] and IFNbeta-1b [Betaferon] and glatiramer acetate [Copaxone]) and immunosuppressive (e.g. cladribine and alemtuzumab) treatments for relapsing-remitting (RR) and secondary progressive MS lack substantial efficacy in preventing the development of brain atrophy, despite the marked effects of these treatments on clinical and MRI outcomes of disease activity. A modest but significant treatment effect on brain atrophy has been reported for patients with RRMS only in one trial of IFNbeta-1a (Avonex) and in another study of long-term corticosteroid therapy.Failure to find a significant treatment benefit in preventing brain atrophy might be the result of inadequate trial designs, including their relatively short durations, which may not be adequate to reveal beneficial effects in a chronic disease like MS. Alternatively, such a failure might indicate that treatments proven to be effective in reducing MS-related inflammation are unable to act with the same efficacy on the most severe and disabling pathological substrates of the disease. The modest correlation between MRI enhancement frequency and brain atrophy observed in the placebo groups of several trials also fits with the concept that the suppression of inflammatory activity in MS is not fully and rapidly associated with a similar effect on the global neurodegenerative process of the disease.
Rovaris, M., M. A. Rocca, et al. (2003). "Magnetic resonance-based techniques for the study and management of multiple sclerosis." Br Med Bull 65: 133-44.
Conventional magnetic resonance imaging (cMRI) is widely used for diagnosing multiple sclerosis (MS) and for monitoring its activity and evolution. However, the correlation between cMRI and clinical findings of MS is limited, possibly due to the low pathological specificity of the abnormalities seen on cMRI scans and to the inability of cMRI to quantify the extent of the damage of the normal-appearing tissues. Magnetization transfer and diffusion-weighted MRI can quantify the extent and pathological severity of structural changes occurring within and outside cMRI-visible MS lesions. Proton MR spectroscopy can add information on the biochemical nature of such changes. Finally, functional MRI can provide new insights into the role of cortical adaptive changes in limiting the clinical consequences of MS structural damage. The application of quantitative MR-based techniques is changing dramatically our understanding of how MS causes irreversible disability and there is increasing perception that these methodologies should be more extensively employed in clinical trials to derive innovative information.
Rovaris, M., G. Comi, et al. (2003). "Short-term correlations between clinical and MR imaging findings in relapsing-remitting multiple sclerosis." AJNR Am J Neuroradiol 24(1): 75-81.
BACKGROUND AND PURPOSE: Despite extensive use of MR imaging to provide markers of multiple sclerosis (MS) activity and accumulated disease burden, the magnitude of the relationship between clinical and MR findings is still debated. Using data from the European/Canadian glatiramer acetate (GA) trial, we investigated short-term correlations between clinical and MR measures of disease activity in patients with relapsing-remitting MS (RRMS). METHODS: In a 9-month, double-blinded, placebo-controlled study, 239 patients with RRMS were randomly assigned to receive 20 mg GA (n = 119) or placebo (n = 120). Clinical assessment included monthly neurologic examinations with Expanded Disability Status Scale scoring and visits for symptoms suggestive of relapse. Dual-echo T2-weighted and pre- and postcontrast T1-weighted brain MR images were obtained at baseline and monthly during follow-up. Contrast-enhancing and new T2-hyperintense lesions were counted, and total T2-hyperintense and T1-hypointense lesion volumes were measured. RESULTS: Significant univariate correlations were found between the number of relapses during the study period and the number of enhancing lesions at baseline (r = 0.25) and during follow-up (r = 0.30) in the study population as a whole. Multivariable analysis showed that two independent factors were more strongly correlated with relapse frequency: the number of relapses during the 2 years before entry and the number of on-trial enhancing lesions, in the whole study population and in the placebo group. CONCLUSION: In RRMS, MR imaging measures of inflammatory activity are modestly but significantly correlated with the occurrence of clinical attacks over the short term. Clinical and MR imaging assessment can provide complementary outcome measures for RRMS trials.
Rubio Terres, C., I. Aristegui Ruiz, et al. (2003). "[Cost Utility analisys of multiple sclerosis treatment with glatiramer acetate or interferon beta in Spain]." Farm Hosp 27(3): 159-65.
OBJECTIVE: To carry out a cost-utility analysis of the treatment of relapsing-remitting multiple sclerosis (RRMS) with glatiramer acetate (copaxone) or interferon beta (all, avonex, rebif and betaferon). METHODS: A pharmacoeconomic Markov model was used to compare treatment options by simulating the life of a hypothetical cohort of women aged 30, from the societal perspective. The transition probabilities, utilities, resource utilisation and costs (direct and indirect) were obtained from Spanish sources and from bibliography. Univariant sensitivity analyses of the base case were performed. RESULTS: In the base case analysis, the average cost per patient (euro in 2001) for a lifetime treatment, considering a life expectancy of 53 years, would be 1,243,906 euros (euro), 1,818,149 euros, 1,763,263 euros, 1,987,153 euros and 1,704,031 euros with copaxone, all interferons, avonex, rebif and betaferon, respectively. Therefore, the saving with copaxone would range between 460,000 and 737,000 euros approximately. The quality-adjusted life years (QALY) obtained with copaxone or interferons would be 10.977 and 6.917, respectively, with an average gain of 4.060 QALY patient with copaxone. The sensitivity analyses confirmed the robustness of the base case. The interferons would only be superior to copaxone in the unlikely hypothetical case that they delay the progression of the illness by 20% more than that actually observed in clinical trials. CONCLUSIONS: For a typical patient with RRMS, treatment with copaxone would be more efficient than interferons and would dominate (would be more efficacious with lower costs) interferon beta.
Rudick, R. A., D. L. Cookfair, et al. (2003). "Interferons in relapsing remitting multiple sclerosis." Lancet 361(9371): 1824; author reply 1824-5.
Rudick, R. (2003). "Mechanisms of disability progression in primary progressive multiple sclerosis: are they different from secondary progressive multiple sclerosis?" Mult Scler 9(2): 210-2.
Rudy, C. A. (2003). "Case presentations. Double vision and numb hand." J Pediatr Health Care 17(2): 91, 106.
Ryle, A. (2003). "Supporting individuals with disabling multiple sclerosis." J R Soc Med 96(2): 104.