Search

Misdiagnosis of multiple sclerosis (MS) (the incorrect assignment of a diagnosis of MS) remains a problem in contemporary clinical practice. Studies indicate that misdiagnosed patients are often exposed to prolonged unnecessary health care risks and morbidity. The recently published 2017 revision of the McDonald criteria for the diagnosis of MS provides an opportunity to consider the effect of these revisions on the problem of MS misdiagnosis. The 2017 McDonald criteria include several new recommendations to reduce potential for misdiagnoses. The criteria should be used for the types of patients in which validation studies were performed, specifically those patients who present with typical demyelinating syndromes. MRI lesion characteristics were defined for which McDonald criteria would be expected to perform with accuracy. However, 2017 revisions, which now include assessment for cortical lesions, and the inclusion of symptomatic lesions and positive oligoclonal bands for the fulfillment of diagnostic criteria, may have the potential to lead to misdiagnosis of MS if not applied appropriately. While the 2017 McDonald criteria integrate issues relating to MS misdiagnosis and incorporate specific recommendations for its prevention more prominently than prior criteria, the interpretation of clinical and radiologic assessments upon which these criteria depend will continue to allow misdiagnoses. In patients with atypical clinical presentations, the revised McDonald criteria may not be readily applied. In those situations, further evaluation or monitoring rather than immediate diagnosis of MS is prudent.

Background and ObjectiveTo describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).MethodsThe COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t-tests, Pearson χ2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity.ResultsAs of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%–75.5%]), whereas 15.6% (95% CI: 8.3%–25.6%) were hospitalized only, 9.1% (95% CI: 3.7%–17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%–19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79–19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated.DiscussionAmong the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size.

This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts.This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex.Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p0.0001). 25FTW was associated with RD and FA in PCs (p0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI.DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.

Objective: B cells and the humoral immune system have been implicated in the pathogenesis of multiple sclerosis (MS). This study sought to evaluate the efficacy, safety, and tolerability of add-on therapy with rituximab, a monoclonal antibody that depletes circulating B cells, in subjects with relapsing MS with breakthrough disease defined by clinical and MRI activity (Class III evidence). Methods: Thirty subjects with a relapse within the past 18 months despite use of an injectable disease-modifying agent, and with at least 1 gadolinium-enhancing (GdE) lesion on any of 3 pretreatment MRIs, received rituximab administered at 375 mg/m 2 weekly × 4 doses. Three monthly posttreatment brain MRI scans were obtained beginning 12 weeks after the first infusion. Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) were obtained at baseline and throughout the posttreatment follow-up. Results: GdE lesions were reduced after treatment with rituximab, with 74% of posttreatment MRI scans being free of GdE activity compared with 26% free of GdE activity at baseline ( p p = 0.02). EDSS remained stable. Conclusion: Rituximab add-on therapy was effective based upon blinded radiologic endpoints in this phase II study. In combination with standard injectable therapies, rituximab was well-tolerated with no serious adverse events. B-cell–modulating therapy remains a potential option for treatment of patients with relapsing MS with an inadequate response to standard injectable therapies. Classification of evidence: This study provides Class III evidence that add-on rituximab reduces gadolinium-enhancing brain lesions in multiple sclerosis.

Determine the utility of optical coherence tomography (OCT) to detect clinical and subclinical remote optic neuritis (ON), its relationship to clinical characteristics of ON and visual function, and whether the retinal nerve fiber layer (RNFL) thickness functions as a surrogate marker of global disease severity.Cross-sectional study of 65 subjects with at least 1 clinical ON episode at least 6 months prior. Measures included clinical characteristics, visual acuity (VA), contrast sensitivity (CS), OCT, and visual evoked potentials (VEP).Ninety-six clinically affected optic nerves were studied. The sensitivity of OCT RNFL after ON was 60%, decreasing further with mild onset and good recovery. VEP sensitivity was superior at 81% (p = 0.002). Subclinical ON in the unaffected eye was present in 32%. VEP identified 75% of all subclinically affected eyes, and OCT identified20%. RNFL thickness demonstrated linear correlations with VA (r = 0.65) and CS (r = 0.72) but was unable to distinguish visual categories20/50. RNFL was thinner with severe onset and disease recurrence but was unaffected by IV glucocorticoids. OCT measurements were not related to overall disability, ethnicity, sex, or age at onset. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye.Visual evoked potentials (VEP) remains the preferred test for detecting clinical and subclinical optic neuritis. Optical coherence tomography (OCT) measures were unrelated to disability and demographic features predicting a worse prognosis in multiple sclerosis. OCT may provide complementary information to VEP in select cases, and remains a valuable research tool for studying optic nerve disease in populations.

Making the diagnosis of multiple sclerosis (MS) remains a challenging problem for clinicians. The foundation of diagnosis rests on demonstrating neurologic lesions, predominantly in the white matter, that are disseminated over space and time. Diagnostic criteria guide the clinician through applying clinical, radiologic, and laboratory evidence to secure the diagnosis. Complicating the process, however, is the existence of other conditions that may resemble MS and mislead the clinician to the wrong diagnosis. A familiarity with the differential diagnoses of symptoms commonly associated with MS permits the clinician to make the most accurate diagnosis. Continuum Lifelong Learning Neurol 2007;13(5):13–34.

MRI has revolutionized the diagnosis of multiple sclerosis (MS). In addition, use of MRI has provided a means to monitor disease and the response to therapy and has been used extensively as an adjunct means to evaluate new therapies. Despite its high sensitivity to detect MS lesions, its specificity for the underlying pathology is low. Furthermore, correlation of MS disability with the extent of abnormalities using several different methods of imaging has been modest at best. This chapter discusses the main imaging techniques used for MS diagnosis, MS management and treatment monitoring, and in clinical trials.

Background: African Americans (AAs) experience greater disability from multiple sclerosis (MS) compared with Caucasian Americans (CAs). Interethnic immunologic differences in MS and their relationship to disease-related disability have not been described. Objective: To compare measures of CSF humoral immunity between AAs and CAs with MS. Methods: Using a case–control design, all AA MS patients with CSF immune studies at the Washington University MS center were compared with randomly selected CAs with MS. Two CA controls were selected for every AA case. Immunoglobulin G (IgG) index and synthesis rates, oligoclonal band positivity, white blood cell count, and CSF protein were compared between groups. Survival analysis was conducted to compare times to ambulatory assistance. Results: Sixty-six AA cases and 132 CA controls were identified. Measures of CSF humoral activity were all higher in the AA group. The mean IgG index of AAs was 1.35 (SD 0.62), and that of CAs was 1.05 (SD 0.55), for a mean difference of 0.30 ( p = 0.001). The median IgG synthesis rate was also higher among AAs (13.55 vs 8.20 mg/day), for a median difference of 5.35 mg/day ( p = 0.010). Survival analysis confirmed previous reports of earlier ambulatory assistance requirement among AAs. Despite differences in both humoral immune response and times to ambulatory assistance, Cox proportional hazards modeling did not show IgG index as predictive of earlier ambulatory assistance. Conclusions: The CSF humoral immune response is more active among African Americans (AAs) than among Caucasian Americans (CAs) with multiple sclerosis. AAs also progress to ambulatory assistance earlier than CAs, but high immunoglobulin G index does not predict earlier progression to the disability endpoint.

Neuromyelitis optica (NMO) is an inflammatory and demyelinating disease characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM).1 NMO is associated with antibodies against the aquaporin-4 (AQP4) water channel.2 NMO–immunoglobulin G (IgG) predicts a relapsing course and is a supportive criterion for NMO.3–5 The high risk of relapse, sometimes with devastating effects, makes early diagnosis important. Early identification permits counseling and consideration for immunosuppressive therapy. The serum NMO-IgG assay, using indirect immunofluorescence, is 73% sensitive and 91% specific for clinically defined NMO.6 While helpful when positive, the sensitivity is insufficient to exclude the diagnosis. We describe 3 of 26 patients with NMO at our institution with NMO-IgG positivity restricted to CSF. ### Case reports. #### Case 1. A 25-year-old African American woman presented with leg numbness and mild tetraparesis that resolved over 1 month. Two months later, she developed a midthoracic sensory level, again with recovery. The next month, bilateral leg weakness impaired her ability to ambulate. MRI (figure, A–C) demonstrated T2 hyperintensities (T2H) and patchy enhancement spanning the medulla through C7 and T2–T11. Brain MRI revealed a single nonspecific T2H. Visual evoked potentials (VEPs) were normal. Serum NMO-IgG was negative but CSF NMO-IgG was positive. IgG index was elevated to 0.79, CSF leukocytes were 24/μL, but albumin index, IgG synthesis, and oligoclonal bands (OCBs) were normal. Serum antinuclear antibodies (ANA) were negative. Treatment included IV glucocorticoids and rituximab with no further exacerbations. After 8 months of disease, Expanded Disability Status Scale (EDSS) was 6.0. Figure Neuroimaging of CSF antibody-positive neuromyelitis optica Case 1: Sagittal T2-weighted STIR …

Elevated CSF free kappa light chains (FKLCs) may predict disability in multiple sclerosis (MS). We reviewed records of 57 patients with MS with 15-year median follow-up for correlations of disability and CSF FKLCs. Levelsor = 1.53 microg/mL predicted progression to need for ambulatory assistance during follow-up (specificity 87.5%, positive predictive value 88.9%) or within 10 years (specificity 78.6%, positive predictive value 66.7%).

We previously reported elevations of interleukin 2 (IL-2) in the serum of patients with chronic progressive MS. Using gel chromatography, protein A sepharose affinity chromatography, and ELISAs for IL-2 and the IL-2 soluble receptor, we now demonstrate that this cytokine is bound to serum proteins. These serum proteins include antibodies to IL-2, soluble IL-2 receptors, and high-molecular-weight proteins. Using a CTLL cell assay, a serum fraction corresponding to IgG antibodies to IL-2 inhibited the activity of this cytokine. Thus, we present evidence for potential immunomodulation of a pivotal cytokine in MS by serum proteins.

Celiac disease (celiac sprue or gluten-sensitive enteropathy) is an inflammatory autoimmune disease of the small intestine that occurs in genetically susceptible (HLA DQ2+ or DQ8+) individuals upon exposure to dietary gluten.1 Gluten (gliadin and glutenin, found in wheat, rye, and barley) comprises a family of proline- and glutamine-rich proteins. Celiac disease is common, affecting 0.5 to 1% of the Caucasian population, but incidence varies in different races. Classic symptoms, including chronic diarrhea and malabsorption, may occur in children or adults, but patients may be completely asymptomatic despite positive antibody and biopsy tests. Treatment with a strict, gluten-free diet results in cessation of gastrointestinal symptoms and normalization of antibody titers. The strong HLA DQ2 or DQ8 haplotype association in celiac disease implicates a CD4+ T-cell–mediated process because HLA DQ molecules present processed peptide antigens to CD4+ T cells. CD4+ T cells extracted from celiac disease-affected intestine respond to transglutaminase modified gluten peptides presented by HLA DQ2 or DQ8. Patients’ peripheral blood T cells do not display such restriction. T cells in the gut are typically Th1 in phenotype, secreting large amounts of IFNγ. Both HLA-restricted CD4+ T cells with αβ T cell receptors and T cells bearing γδ T cell receptors (presumably not HLA DQ–restricted) infiltrate the small intestine.2 While IgA and IgG anti-gliadin antibodies are found in the blood of celiac disease patients upon exposure to gluten-containing foods, they can be also found in many “normal” individuals (5–12%). Only a minority of gluten-sensitive patients (defined by presence of antigliadin antibodies) have classic celiac disease. This is distinct from autoantibodies to tissue transglutaminase (tTG), which are present in a high proportion of patients with active celiac disease (and rarely in “normal” individuals). tTG, an enzyme found naturally in gut endomysium, deamidates gluten peptides, …

Molecularly engineered therapeutics can provide the advantage of promoting specific biologic effects. Moreover, disease treatments with few or no “off-target” effects have great potential to improve safety and side effect profiles. Monoclonal antibodies represent one category of engineered therapeutics that is increasingly utilized in many different disorders, often offering enhanced efficacy compared to therapies with more generalized and nonspecific mechanisms of action. Despite the success of many monoclonal antibody therapies, concerns remain with regard to safety, dosing, neutralizing antibody formation, and CNS penetration.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Beta-interferon (β-IFN) has become an accepted treatment for patients with relapsing-remitting multiple sclerosis (MS). Physicians in the United States now have two FDA-approved β-IFNs, Betaseron (Berlex Laboratories; Wayne, NJ) and Avonex (Biogen; Cambridge, MA), to offer their patients.1,2 Treatment with either agent decreases the relapse rate and the severity of individual relapses. β-IFNs are proteins administered by injection and, as with other parenterally administered proteins such as insulin, IFN injections can induce the development of antibodies. Not all antibodies are the same. Some antibodies may merely bind to the protein, whereas others may neutralize the action of the protein. In the case of insulin, antibodies that block its desired treatment effects (referred to as neutralizing antibodies [NAB]) are relatively easy to monitor. In the case of the β-IFNs, the issue of whether antibodies truly neutralize the efficacy of β-IFN for the MS disease process is more complex. The article by Rudick et al.3 in this issue of Neurology focuses on the questions "To what extent are antibodies formed to β-IFN 1a in patients with MS?" and "Do these antibodies interfere with the clinical efficacy of the drug?" In a selected, well-studied cohort of patients being treated with β-IFN 1a, Rudick et al. report that a minority of patients develop antibodies that may neutralizeβ-IFN function. There was no correlation between progression of disability or relapse rate and the presence of NAB. However, a trend was noted of increased MS disease activity as measured by MRI. Patients with a single NAB titer greater than 20 were considered positive. Patients with NAB displayed suggestively more contrast-enhancing brain lesions on MRI at the end of the second year than did NAB-negative patients ( p = 0.062). β-IFN induces many genes. Rudick et al. report that the presence of NAB correlated with decreased levels …

Multiple sclerosis (MS) affects 1–2 per 1,000 people in North America and has a complex etiology that is not fully understood (www.nmss.org), though the immune system plays a major role. Rapidly accumulating studies have identified several genes related to MS susceptibility; most of these encode proteins with immune functions. Furthermore, environmental factors affect both risk for MS development and MS activity. Perhaps the most well-known environmental factor affecting MS is geographic latitude.1 However, the latitudinal gradient appears to be decreasing with time, a finding that may be due to changing environmental factors.2 Interestingly, several regions of the world report an increasing female to male ratio, which has also been attributed to changing environmental factors that affect women differently than men. Environmental factors purported to play a role in risk of MS development or progression include viruses such as Epstein-Barr virus (EBV), vitamin D levels, and smoking, as well as diet, obesity, pregnancy, hormones, and stress. Of these, vitamin D and infections have the clearest seasonality. Vitamin D levels fluctuate along with ultraviolet light exposure, which changes with season.3 Regarding infections, Sibley and colleagues4 reported that the frequency of MS relapses is 3 times higher in periods related to viral infections. Such observations are in accord with the finding that interferon-γ, …

Alemtuzumab, a humanized monoclonal antibody, depletes CD52+ circulating leukocytes. In humans, this includes most mononuclear leukocytes. Exciting results from 2 phase III trials established the superiority of alemtuzumab in reducing multiple sclerosis (MS) relapse rate compared with high-dose interferon-β.1 Increased mild to moderate infections occurred in both trials in the alemtuzumab compared to interferon-β arms. Also noteworthy, secondary autoimmune diseases develop in a sizeable proportion of alemtuzumab-treated patients.

The road to universal immunization against hepatitis B has been bumpy.1 The hepatitis B vaccine (HBV) has been anecdotally linked to multiple sclerosis (MS), systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus, leukemia, and chronic fatigue syndrome. The possibility that the vaccine could induce MS prompted temporary halting of the universal HBV program in France in 1998 based on surveillance reports. In 2000, a French court awarded damages to three people with MS who had received the HBV, in a decision that was later highly criticized.2–5⇓⇓⇓ Subsequently, numerous studies, commissions, and hearings have not corroborated the association. The report by Hernan et al.6 in this issue of Neurology has potential to reopen the debate. The Hernan paper used the General Practice Research Database (GPRD) of the United Kingdom to ascertain 163 cases of confirmed MS, and performed a case-controlled analysis for the association of first MS symptoms with HBV. The authors identified 11 people who developed first symptoms of MS within 3 years of the vaccine, producing an odds …

Objective: Determine whether pain frequency, use of pain-relief medications, and pain level control differed between subjects with NMO versus MS. Background Pain is a frequent and disabling symptom among demyelinating diseases. Neuromyelitis optica (NMO) is associated with severe inflammatory lesions of the spinal cord and optic nerve, with potential for chronic pain. Design/Methods: Cross-sectional study (NMO=29, MS=66) included McGill Pain Score (MPS), Short Form 36 Scale (SF36), Center for Epidemiologic Studies Depression Scale (CES-D), Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC). Involved T2 spinal segments were counted. CNS pain medications use was quantified. Results: Current pain was noted in 86% in NMO subjects, compared to 41% in MS. Severe current pain was present in 52% with NMO vs. 11% with MS. Painful tonic spasms were present in 90% with NMO vs. 39% with MS. McGill Pain Score had a positive correlation with involved spinal cord segments for NMO (r=0.45, p=0.02). Current pain on a 10 point scale was correlated with the physical component of the SF36 (r= -0.49, p Conclusions: Pain is very common in NMO, and is severe in the majority. Pain magnitude has a deleterious effect on quality of life. Although medications are often used to help relieve pain, many patients continue to suffer. Our pain medications may be contributing to side effects such as slowed cognition and fatigue. Supported by: NIH funding T32NS007205 to PQ. NIH funding K23NS052430 to RTN. Disclosure: Dr. Qian has received personal compensation for activities with Teva Neuroscience as an employee. Dr. Cross has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Teva Neuroscience, Eli Lilly & Company, Hoffman-La Roche, and Genentech, Inc. Dr. Naismith has received personal compensation for activities with Acorda Therapeutics, Bayer Pharmaceuticals Corporation, and Biogen Idec as a consultant and/or speaker. Dr. Naismith has received personal compensation in an editorial capacity for Journal Watch Neurology. Dr. Naismith has received research from Acorda Therapeutics.

John L. Trotter, MD, died unexpectedly on July 12, 2001, at age 58. John was one of the United States’ first neuroimmunologists, having trained in both clinical neurology and immunology. He was a dedicated “fixture” at Washington University School of Medicine as student, intern, neurology resident, graduate trainee, and professor of neurology. Also very important was his extended research experience at the National Institute of Neurological Disorders and Stroke with Drs. Dale McFarlin and King Engel. Notorious for his hospital rounds uniform of shirt sleeves, wrinkled tie, and suspenders, John was respected and adored by patients with MS in the St. Louis area. He founded the Multiple Sclerosis Clinic at Washington University and Barnes–Jewish Hospital in 1978. A long-time board member of the Gateway Chapter of the National MS Society, he …

“All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.” Arthur Schopenhauer (1788–1860) Associations of environmental agents and MS have gone through the first and second stages of Schopenhauer’s “truth” but have not yet attained the stage of acceptance. For more than 50 years environmental triggers, typically viruses, have been implicated in the etiology of MS.1,2⇓ The epidemiology of MS supports an environmental agent. There is evidence of MS clustering,3 and MS increases in incidence with distance in either direction from the equator. Migration away from high prevalence areas before adulthood decreases the likelihood of developing MS. In addition, genetic factors alone are insufficient to cause MS. Despite a clear genetic influence in MS (the rate of concordance is eight times greater in monozygotic than dizygotic twins),4,5⇓ the concordance rate among monozygotic twins remains only 25%. An increased risk of MS has also been observed in persons developing childhood infections as adults.1 Demyelinating animal models exist in which viruses with long incubation periods cause relapsing neurologic disorders,1,6⇓ some of which are immune-mediated. Similar immune reactivities to a number of viruses have been reported in patients with MS.7 Increased antibody titers to a variety of infectious agents …

Molecules of the tumor necrosis factor (TNF) receptor superfamily could both suppress and promote MS disease activity. These molecules, including Fas (CD95), TRAIL receptor 2 (TRAIL R2), and TNF receptors p55 and p75, contain a “death sequence” in their cytoplasmic tail linking them to caspases—a series of potentially destructive cysteine proteases. Signaling activates a caspase cascade, culminating in the fragmentation of nuclear DNA and ultimately, self-destruction by programmed cell death or “apoptosis.” MS remissions could be triggered by the elimination of CNS-infiltrating inflammatory cells through Fas, TRAIL R2, or TNF p55/p75 receptor pathways. Conversely, MS exacerbations could result from the killing of oligodendrocytes via stimulation through Fas receptors. The articles by Huang et al.1 and Comi et al.2 in this issue of Neurology support a role for TNF family receptors in the regulation of …

The single most consistent laboratory abnormality found in patients with MS is increased intrathecal production of oligoclonal immunoglobulin (Ig), present in >90% of persons with definite MS.1 The increased Ig in MS CSF, described by Kabat in 1942,2 prompted a search to identify its antigenic target. However, the search for a target proved frustrating, with no infectious or autoimmune antigen being consistently identified. This frustration, together with the failure of B cells or antibody alone to induce CNS pathology in animals, led to diminished interest in B cells in MS. In the 1980s, when T lymphocytes were identified in MS plaques, T cell subset alterations were observed in MS blood, and T cells were shown to transfer the experimental allergic encephalomyelitis (EAE) animal model for MS, the role of T cells became the focus of investigation. Yet today, 150 years after the first clinico-pathologic descriptions of MS, its etiology and pathogenesis remain unknown. The pendulum is swinging back. New data are implicating B cells and Ig in MS. In this issue, Smith-Jensen and colleagues present evidence that the …

Reply from the Authors: We appreciate Dr. Poser's comments and agree with his approach of using a drug holiday to maximize efficacy. We found that weekend holidays can be quite useful, allowing the patient to take the medication during the busier work week, in effect 5 of 7 days each week. Drs. Dulli and Schutta question whether the study confirms that amantadine is the first-line drug therapy for fatigue in MS. They note that the changes in fatigue as measured by the FSS and the MS-FS are no more than one-half point for each scale and that there is a difference at …