Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in immune-mediated optic neuritis at long-term follow-up.

OBJECTIVES: To re-evaluate serum samples from our 2007 cohort of patients with single-episode isolated ON (SION), recurrent isolated ON (RION), chronic relapsing inflammatory optic neuropathy (CRION), multiple sclerosis-associated ON (MSON) and neuromyelitis optica (NMO). METHODS: We re-screened 103/114 patients with available serum on live cell-based assays (CBA) for aquaporin-4 (AQP4)-M23-IgG and myelin-oligodendrocyte glycoprotein (MOG)-α1-IgG. Further testing included oligoclonal bands, serum levels of glial fibrillar acidic and neurofilament proteins and S100B. We show the impact of updated serology on these patients. RESULTS: Reanalysis of our original cohort revealed that AQP4-IgG seropositivity increased from 56% to 75% for NMO, 5% to 22% for CRION, 6% to 7% for RION, 0% to 7% for MSON and 5% to 6% for SION. MOG-IgG1 was identified in 25% of RION, 25% of CRION, 10% of SION, 0% of MSON and 0% of NMO. As a result, patients have been reclassified incorporating their autoantibody status. Presenting visual acuity was significantly worse in patients who were AQP4-IgG seropositive (p=0.034), but there was no relationship between antibody seropositivity and either ON relapse rate or visual acuity outcome. CONCLUSIONS: The number of patients with seronegative CRION and RION has decreased due to improved detection of autoantibodies over the past decade. It remains essential that the clinical phenotype guides both antibody testing and clinical management. Careful monitoring of the disease course is key when considering whether to treat with prophylactic immune suppression.

MOG encephalomyelitis: international recommendations on diagnosis and antibody testing.

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM ("red flags") that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.

[MOG encephalomyelitis: international recommendations on diagnosis and antibody testing]. / MOG-Enzephalomyelitis: Internationale Empfehlungen zu Diagnose und Antikörpertestung.

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM ("red flags") that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation, and propose for the first time diagnostic criteria for MOG-EM.

A population-based prospective study of optic neuritis.

BACKGROUND: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. OBJECTIVE: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. METHOD: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. RESULTS: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16-66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44-4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. CONCLUSION: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

A point mutation in PTPRC is associated with the development of multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis. Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown. Here we investigated the role of a point mutation in the gene (PTPRC) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families.

Neuromyelitis optica-IgG (aquaporin-4) autoantibodies in immune mediated optic neuritis.

The clinical course of immune mediated optic neuritis (ON) will depend on the specific underlying inflammatory disease. These disorders have traditionally been classified according to clinical and MRI findings. Aquaporin-4 (AQP4) autoantibodies (neuromyelitis optica-IgG (NMO-IgG)) may have diagnostic and prognostic value in patients who present with isolated ON. In this prospective study, NMO-IgG was evaluated in 114 patients with ON in the following contexts: neuromyelitis optica (NMO), multiple sclerosis (MSON), chronic relapsing inflammatory ON (CRION), relapsing isolated ON (RION) and single isolated ON (SION). The proportion seropositive was 56% for NMO (n = 9), 0% for MSON (n = 28) and 5% for the remaining diagnostic categories (CRION (n = 19), RION (n = 17) and SION (n = 41)). Testing for NMO-IgG in patients with recurrent or severe ON who lack convincing evidence of MS may identify patients who would benefit from immunosuppression rather than MS directed immunomodulatory therapies.

Treatment of MOG antibody associated disorders: results of an international survey.

INTRODUCTION: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. OBJECTIVE: To survey the current global clinical practice of clinicians treating MOGAD. METHOD: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019). RESULTS: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. CONCLUSION: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

Neuromyelitis optica: clinical syndrome and the NMO-IgG autoantibody marker.

Neuromyelitis optica (NMO) is a severe demyelinating disease of the CNS that preferentially affects the optic nerves and spinal cord, tends to relapse, and results in early permanent disability for most affected patients. A new autoantibody marker called neuromyelitis optica immunoglobulin G (NMO-IgG), which targets the water channel protein aquaporin-4, is highly specific for NMO. The marker has demonstrated that the NMO spectrum of disorders is wider than previously known and includes some patients with single-episode or recurrent longitudinally extensive myelitis, recurrent isolated optic neuritis, Asian optic-spinal multiple sclerosis, and patients with co-existing systemic autoimmune diseases such as lupus erythematosus or Sjögren's syndrome. We review the place of NMO within the nosology of CNS demyelinating diseases, the discovery of NMO-IgG and its impact on the definition of NMO and its spectrum, implications for understanding NMO pathogenesis, and informing treatment decisions.

Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG.

This study investigates the relation between the serological status of NMO (neuromyelitis optica)-IgG and the clinical and MRI features in Japanese patients with multiple sclerosis. Serum NMO-IgG was tested in 35 Japanese patients diagnosed with multiple sclerosis, including 19 with the optic-spinal form of multiple sclerosis (OSMS), three with the spinal form of multiple sclerosis (SMS), and 13 with the conventional form of multiple sclerosis (CMS), which affects the brain. NMO-IgG was detected in 14 patients, 12 with OSMS and 2 with CMS. In these patients, longitudinally extensive (> 3 vertebral segments) spinal cord lesions (93% v 57%) and permanent, complete blindness (no perception of light) in at least one eye (50% v 0%) were the noticeable features as compared with NMO-IgG-negative OSMS. The two patients having CMS with NMO-IgG had unusual brain lesions, but in other respects had features suggesting OSMS. NMO-IgG was detected in more than half the number of patients with OSMS and in some patients with CMS. This newly discovered serum autoantibody was markedly associated with longitudinally extensive spinal cord lesions and with complete blindness, suggesting severe optic-spinal disease.

Stopping immunomodulatory medications in MS: Frequency, reasons and consequences.

Prolonged periods of disease quiescence during long term treatment of patients with clinically isolated syndrome and MS may prompt consideration of discontinuing disease-modifying therapy (DMT). We reviewed pertinent studies to identify the frequency and reasons for discontinuation of DMT.

Long-term and short-term outcome of multiple sclerosis: a 3-year follow-up study.

BACKGROUND: The anticipated rate of short-term worsening of disability scores is the basis of power estimations in clinical trials of progressive multiple sclerosis (MS). While the clinician is most concerned in modifying the long-term outcome (eg, time to reach the Expanded Disability Status Scale [EDSS]6), the end points studied in clinical trials are those describing short-term outcome (eg, worsening of EDSS scores over 1 to 3 years). However, short-term outcome of MS may not be correlated with long-term outcome. OBJECTIVES: To validate previously published models predicting time to EDSS 6. To establish predictors of short-term outcome of MS. SETTING: The Ottawa, Ontario, Regional Multiple Sclerosis Clinic. PATIENTS: Two hundred fifty-nine patients were followed up prospectively by a single neurologist. MAIN OUTCOME MEASURES: Actuarial analysis of time to reach EDSS 6 and change in EDSS scores over a follow-up period of 1 to 3 years. RESULTS: The long-term outcome in the Ottawa population was more favorable than published data from London, Ontario. Predictions of time to EDSS 6 were not strongly correlated with the degree of short-term worsening over the follow-up period. Parameters associated with a higher probability of short-term worsening were proximity of the baseline EDSS score to 4.5 and duration of MS less than 20 years. CONCLUSION: Baseline EDSS and duration of MS must be considered in the design of clinical trials of progressive MS.

Meta-analysis of the placebo-treated groups in clinical trials of progressive MS.

The behavior of the control groups can substantially affect the power and outcome of a clinical trial. We report a meta-analysis of the control groups of four large, double-blind, placebo-controlled clinical trials of immuno-suppressive treatment of progressive MS to address the sensitivity of five hypothetical definitions of treatment failure (TF). The rate of TF in the aggregate control groups (n = 427) was 31% when a confirmed increase of 1.0 expanded disability status scale (EDSS) point was required at the end of the trial; it was 51% when confirmation was not required and TF was allowed at the first point where the criteria for TF were met. The rate of confirmed TF was 45% when the TF criteria were indexed to baseline EDSS, accounting for the observed differences in staying times at different EDSS levels. We developed models predicting TF in progressive MS. In addition to baseline EDSS, the pyramidal functional score and, for one definition, brainstem functional score were associated with probability of TF.

Retroviruses and multiple sclerosis. I. Analysis of seroreactivity by western blot and radioimmune assay.

We were unable to identify an antibody to either HTLV-I or HIV-1 in patients with multiple sclerosis (MS) by ELISA, by radioimmune assay, or by radioimmune precipitation techniques. Immunoblot studies for HTLV-I-specific antibodies revealed faintly reactive bands in 2 of 44 MS patients but not in patients with other neurologic diseases. We did not find seroreactivity to HIV-1 or to the distantly related retrovirus, caprine arthritis encephalitis virus (CAEV). These findings suggest that MS is not related to infection by human retroviruses with antigenic similarity to HTLV-I, HIV-1, or CAEV.

A population-based case-control study of the tumor necrosis factor alpha-308 polymorphism in multiple sclerosis.

Tumor necrosis factor alpha (TNF alpha) expression is enhanced in patients with active MS and other inflammatory diseases. A guanine-to-adenine polymorphism at position -308 of the TNF alpha promoter region (the TNF2 allele) is associated with increased TNF alpha expression. We evaluated 110 MS patients derived from an Olmsted County, MN, prevalence study. Three other patient cohorts (autoimmune, serious infectious illness, and other neurologic diseases) and matched controls were derived from a Mayo Clinic DNA bank. We used polymerase chain reaction amplification of specific alleles to screen for the TNF2 allele and to determine zygosity. We found one homozygote and 29 heterozygotes in the MS patients. There was no association between the presence of the TNF2 allele and MS or the other disease categories by matched-pair and group analyses.

Complete ophthalmoplegia as a complication of acute corticosteroid- and pancuronium-associated myopathy.

We report acute complete external ophthalmoplegia and severe myopathy in a patient treated with high doses of IV methylprednisolone and pancuronium. Awareness of this rare syndrome in a common clinical setting can lead to prompt recognition and avoid confusion with other causes of acute weakness and ophthalmoparesis.

A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis.

Fatigue occurs in a majority of patients with MS and is generally independent of measurable neurologic disability. Few options for treatment are available. We conducted a double-blind, placebo-controlled, crossover trial for each of two 4-week treatment periods. Forty-six eligible patients entered and five dropped out due to concurrent exacerbations. Nineteen patients (46.3%) experienced excellent or good relief of fatigue with pemoline, and eight patients (19.5%) with placebo (p = 0.06, Fisher's exact test). One-fourth of patients did not tolerate the drug well, and 7% had to discontinue pemoline during the study due to side effects. The most common side effects were anorexia, irritability, and insomnia. Pemoline may be an effective short-term treatment for fatigue associated with MS, but its adverse effects are not well tolerated by many patients.

A comparison of sporadic and familial multiple sclerosis.

We compared demographic and clinical features, including outcome defined by a failure time analysis of disability, in 143 patients with a family history of multiple sclerosis (familial MS) compared with 956 patients without such a history (sporadic MS). Patients with familial MS did not differ from those with sporadic MS even when patients with 1st-degree relatives or multiple relatives with MS were considered separately. An intraclass correlation analysis of 13 pairs of affected 1st-degree relatives, both members of which were followed in our clinic, failed to reveal heterogeneity among different families. We were unable to find any support for differences between familial and sporadic MS.

An open trial of OKT3 in patients with multiple sclerosis.

We report our experience with treatment with Muromonab-CD3 (Orthoclone OKT3) of 16 patients with multiple sclerosis (MS) who were in a progressive phase of their disease (n = 13) or in an acute severe attack lasting longer than 1 month without recovery (n = 3). We induced acute severe T-cytopenia with OKT3. Fifteen patients completed treatment for 10 days. Side effects were common and severe and included hypotension, nausea and vomiting, diarrhea, fever, and myalgia. In two of two patients tested, there was a transient though major rise in the levels of interferon gamma and tumor necrosis factor in the first 12 hours of treatment. Nonetheless, we did not detect new clinical or MRI activity of MS during the period of treatment, although many patients deteriorated transiently in disability scores. At the conclusion of follow-up, only four patients had deteriorated by 1.0 or more points on the Expanded Disability Status Scale of Kurtzke (EDSS) (73% stabilization rate). Of those patients who deteriorated, two died of complications of MS (EDSS 10). Only two patients had clinical improvement at 1 year follow-up. The attendant toxicity of OKT3 makes it unlikely that it will play a major role in the treatment of MS.

The clinical course of neuromyelitis optica (Devic's syndrome).

OBJECTIVES: To evaluate the spectrum of neuromyelitis optica (NMO), including characteristics of the index events (optic neuritis [ON]) and myelitis), neuroimaging, CSF, and serologic studies, and to evaluate the long-term course. METHODS: Review of 71 patients with NMO evaluated at the Mayo Clinic between 1950 and 1997. RESULTS: NMO was either monophasic or relapsing. Patients with a monophasic course (n = 23) usually presented with rapidly sequential index events (median 5 days) with moderate recovery. Most with a relapsing course (n = 48) had an extended interval between index events (median 166 days) followed within 3 years by clusters of severe relapses isolated to the optic nerves and spinal cord. Most relapsing patients developed severe disability in a stepwise manner, and one-third died because of respiratory failure. Features of NMO distinct from "typical" MS included >50 cells/mm3 in CSF (often polymorphonuclear), normal initial brain MRI, and lesions extending over three or more vertebral segments on spinal cord MRI. CONCLUSIONS: Clinical, laboratory, and imaging features generally distinguish neuromyelitis optica from MS. Patients with relapsing optic neuritis and myelitis may have neuromyelitis optica rather than MS. Patients with a relapsing course of neuromyelitis optica have a poor prognosis and frequently develop respiratory failure during attacks of cervical myelitis.