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.

Updated diagnostic criteria for neuromyelitis optica spectrum disorder: Similar outcomes of previously separate cohorts.

BACKGROUND: The specificity of the aquaporin-4 antibody to predict recurrent inflammatory central nervous system disease has led to the design of the 2015 neuromyelitis optica spectrum disorder criteria which capture all aquaporin-4 antibody seropositive patients. OBJECTIVE: The purpose of this study was to compare treatment outcomes in aquaporin-4 antibody seropositive patients who met the previous 2006 clinical criteria for neuromyelitis optica with patients who meet the 2015 neuromyelitis optica spectrum disorder criteria. METHODS: The study involved a three-center retrospective chart review of clinical outcomes among aquaporin-4 patients diagnosed with neuromyelitis optica and neuromyelitis optica spectrum disorder. RESULTS: Hazard ratios of relapse during immunosuppressive therapy, relative to pre-therapy, were not significantly different for patients who met the 2006 criteria of neuromyelitis optica versus the 2015 neuromyelitis optica spectrum disorder criteria among those treated with azathioprine ( p = 0.24), mycophenolate mofetil ( p = 0.63), or rituximab ( p = 0.97). CONCLUSION: Reductions in the hazard of relapse during treatment with immunosuppressive therapies, relative to average pre-treatment, were not different for aquaporin-4 antibody seropositive patients categorized using the 2006 criteria of neuromyelitis optica and the 2015 neuromyelitis optica spectrum disorder criteria. These therapeutic findings support the design of the 2015 neuromyelitis optica spectrum disorder criteria which capture all aquaporin-4 antibody seropositive patients.

The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.

The clinical features of relapses and progression largely define multiple sclerosis phenotypes. A relapsing course is followed by chronic progression in some 80% of cases within 2 decades. The relationship between these phases and long-term outcome remains uncertain. We have analysed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years. For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively. Among 824 attack-onset patients, the great majority entered a progressive phase with a mean time to progression of 10.4 years. The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less. Three subgroups allow for clarity of outcome comparison and they are (i) cases of primary progressive (PP) disease, (ii) attack-onset disease where only a single attack has occurred before onset of progression (SAP) and (iii) secondary progressive (SP) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins. Here we compare survival curves in these three groups. Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10. These findings demonstrate that the progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it. Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome. The site of the original attack was not usually where progression began. The relatively stereotyped nature of the progressive phase seen in all progressive phenotypes suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature. The highly prevalent distal corticospinal tract dysfunction in progressive disease and the pathologically demonstrated selective axonal loss seen in this tract raises the possibility of a dying back central axonopathy, at least in part independent of plaque location or burden. Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-DSS2 is similarly stereotyped in quality and pace and may entail mechanisms common to all forms of progressive multiple sclerosis. The possibility that this is the primary process in some cases must be considered.

Autonomic symptom burden is associated with MS-related fatigue and quality of life.

BACKGROUND: Nonspecific symptoms such as fatigue and dizziness are common in multiple sclerosis (MS), even in patients with normal exams. Little is known about the relationship of autonomic dysfunction with these symptoms and quality of life. OBJECTIVE: Assess the association of autonomic symptom burden with fatigue, clinical status and quality of life. METHODS: Subjects completed an autonomic symptom (COMPASS-31), quality of life (MSQOL-54) and fatigue (FSS) questionnaire at their routine MS clinic follow-up. Demographic and clinical data were collected from the medical record. Pearson correlations were assessed between autonomic symptoms and fatigue, quality of life, disability and disease duration. RESULTS: One-hundred subjects completed the study (mean age 48 years; 78% female; 84% relapsing-remitting), mean disease duration was 14.7 years and mean EDSS 2.5. MSQOL-54 composite scores were 58 physical and 65 mental. COMPASS-31 correlated with MSQOL-54 (Physical R= -0.60; Mental -0.54; p<0.001) and FSS (R=0.51; p<0.001). There was no relationship between COMPASS-31 and EDSS (R=0, p=0.97) or disease duration (R= -0.02, p=0.84). CONCLUSIONS: Autonomic symptom burden is correlated with decreased quality of life and increased fatigue. Autonomic symptoms are present early in the disease and at low disability and may reflect aspects of disease burden that are not well-captured by current disability measures.

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.

Multifocal brain MRI artifacts secondary to embolic metal fragments.

We report a patient with unusual MRI abnormalities that had the physical characteristics of ferromagnetic artifact. We believe that the MRI artifacts were due to microscopic embolic metal fragments, most likely from a mechanical heart valve prosthesis. Potential sources of metal emboli should be considered in patients with MRI abnormalities compatible with ferromagnetic artifact.

Paraneoplastic encephalomyelitis and seminoma: importance of testicular ultrasonography.

We report two patients with paraneoplastic limbic and brainstem encephalitis associated with occult nonmetastatic testicular seminoma. In each patient, the neoplasm was detectable only by testicular ultrasonography. Male patients with this syndrome in whom lung cancer is not found should undergo testicular ultrasonography as part of the search for an extrapulmonary neoplasm. A normal clinical testicular examination is insufficient to exclude an occult seminoma.

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.

Genetic variation in the tumor necrosis factor alpha gene and the outcome of multiple sclerosis.

The objective of this study was to determine whether sequence variation in the tumor necrosis factor alpha (TNF alpha) gene is associated with MS course and severity in Olmsted County, MN. The severity and temporal course of MS are heterogeneous. Genetic factors may play a role in determining the course of MS. TNF alpha expression is temporally associated with exacerbations of MS and is increased in individuals with progressive disease. The entire TNF alpha gene was amplified by polymerase chain reaction in 78 MS patients and in 39 patients with schizophrenia. Denaturation finger-printing, a modification of direct sequencing that detects virtually all genetic polymorphisms, was performed for four regions spanning the functionally significant portions of the gene, including the promoter region. Polymorphisms were confirmed by complete sequencing. The severity and temporal course of MS were compared in those with wild-type versus variant alleles. Four sequence changes were detected, three of which occurred in MS patients. None occurred in a protein-encoding sequence. Neither of the two most common sequence variants were associated with disease severity or temporal course. Genetic variation of the TNF alpha gene is not associated with variation in the course or long-term outcome of MS in this population-based sample.

Genetic variants in the tumor necrosis factor receptor 1 gene in patients with MS.

We scanned for all genetic variants in functionally important regions of the tumor necrosis factor receptor 1 gene (TNF-R1) in 100 to 111 MS patients from Olmsted County, MN, and analyzed selected variants for an association with disease course and severity. Ten genetic variants were uncovered. Only one variant, a silent substitution, was found in coding sequence. One intronic variant may generate a novel splice-junction sequence. We did not find an association between either this intronic variant or another common promoter variant and the course or severity of MS.

Is there a neurologist on this flight?

OBJECTIVE: To analyze the frequency of neurologic events during commercial airline flights and to assess whether onboard emergency medical kits are adequate for in-flight neurologic emergencies. METHODS: Collaboration of the Mayo Clinic's Departments of Emergency Medicine and Medical Transportation Service and the Division of Aerospace Medicine to provide real-time in-flight consultation to a major US airline that flies approximately 10% of all US passengers. We analyzed all medical events reported from 1995 to 2000 in a database that catalogs the air-to-ground medical consultations. All cases with potential neurologic symptoms were reviewed and classified into various neurologic symptom categories. The cost of diversion for each neurologic symptom was calculated and then extrapolated to assess the cost of neurologic symptoms to the US airline industry. RESULTS: A total of 2,042 medical incidents led to 312 diversions. Neurologic symptoms were the single largest category of medical incidents, prompting 626 air-to-ground medical calls (31%). They caused 34% of all diversions. Dizziness/vertigo was the most common neurologic symptom followed by seizures, headaches, pain, and cerebrovascular symptoms. Whereas seizures and dizziness/vertigo were the most common reasons for diversion, loss of consciousness/syncope was the complaint most likely to lead to a diversion. The estimated annual cost of diversions due to neurologic events is almost 9,000,000 dollars. CONCLUSION: Neurologic symptoms are the most common medical complaint requiring air-to-ground medical support and are second only to cardiovascular problems for emergency diversions and their resultant costs to the US airline industry. Adding antiepileptic drugs to the onboard medical kit and greater emergency medical training for in-flight personnel could potentially reduce the number of diversions for in-flight neurologic incidents.

A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis.

OBJECTIVE: To determine whether IV immunoglobulin (IVIg) reverses chronic visual impairment in MS patients with optic neuritis (ON). METHODS: In this double-blind, placebo-controlled Phase II trial, 55 patients with persistent acuity loss after ON were randomized to receive either IVIg 0.4 g/kg daily for 5 days followed by three single infusions monthly for 3 months, or placebo. RESULTS: The trial was terminated by the National Eye Institute because of negative results when 55 of the planned 60 patients had been enrolled. Fifty-two patients completed the scheduled infusions, and 53 patients completed 12 months of follow-up. Analysis of this data indicated that a difference between treatment groups was not observed for the primary outcome measure, improvement in logMAR visual scores at 6 months (p = 0.766). Exploratory secondary analyses suggested that IVIg treatment was associated with improvement in visual function (including logMAR visual scores at 6 months and visual fields at 6 and 12 months) in patients with clinically stable MS during the trial. CONCLUSIONS: IVIg administration does not reverse persistent visual loss from ON to a degree that merits general use.

Denaturation fingerprinting: two related mutation detection methods especially advantageous for high G + C regions.

Two versions of denaturation fingerprinting (dnF2R and dnF1R are described for detecting mutations. DnF2R is a sensitive screening method in which fingerprints are generated by performing denaturing gel electrophoresis on bidirectional "cycle-sequencing" reactions with each of two dideoxy terminators, e.g. ddATP and ddCTP. When the fingerprints generated by ddATP and ddCTP are combined, all sequence changes are expected to result in one extra and one absent segment. DnF2R was performed on 246- and 318-bp segments of the human factor IX gene, and the products were electrophoresed through a 6% Long Ranger gel with 7 M urea. All 32 single-base mutations were detected in hemizygous males with hemophilia B. DnF2R has been applied to detect a total of seven heterozygous sequence changes in large-scale screening and was found to be especially suitable for high G+C regions. In a blinded analysis, all of twenty-four additional single-base mutations were detected, but 7 of 31 heterozygous mutations were missed (23%). To reduce the effort of dnF2R by almost twofold while retaining the ability to detect all types of single-base changes, one fingerprint (dnF1R) was generated by performing a single reaction with ddATP and a second chemically modified terminator (e.g., ROX-conjugated ddCTP), which retards the mobility of the same termination products. The sensitivity and specificity of dnF1R equaled that of dnF2R, with the exception that the blinded analysis of heterozygotes in the 318-bp segment, which revealed the presence of an additional mutation. DnF under partially denaturing conditions may have optimal sensitivity for the detection of heterozygotes.

Clinical outcome measures and rating scales in multiple sclerosis trials.

In this review, we analyzed clinical outcome measures used in multiple sclerosis (MS) clinical trials in which the primary goal is to slow or arrest progression of disease. In addition, we examined rating scales that quantify symptomatic complications of MS (for example, spasticity) and the current role of magnetic resonance imaging in MS treatment trials. Each proposed scale has advantages and deficiencies, and none meets all the criteria for an ideal outcome measure. The validity of trial design may be improved by using combinations of selected components of current scales as well as new instruments targeted to specific variables (such as motor strength). Symptom-specific rating scales are most appropriately used in trials of symptomatic therapeutic strategies for MS. Until serial magnetic resonance imaging changes are definitely known to predict long-term impairment and disability in patients with MS, clinical outcome measures will remain the primary means of assessing therapeutic efficacy in phase III clinical trials.

Early versus late antiepileptic drug withdrawal for people with epilepsy in remission.

BACKGROUND: Antiepileptic drugs ( AEDs) are used to prevent seizures but are associated with both short and long term adverse effects. When epilepsy is in remission, it may be in the patient's best interest to discontinue medication. However, the optimal timing of AED discontinuation is not known. OBJECTIVES: To quantify seizure relapse risk after early (less than two seizure free years) versus late (more than two seizure free years) AED withdrawal in adult and pediatric epilepsy patients. To assess which variables modify the risk of seizure recurrence. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, the Cochrane Controlled trials register (Cochrane Library Issue 4, 2000), MEDLINE (January 1996 to January 2001), EMBASE, Index Medicus, CINAHL, as well as hand-searching of journals. SELECTION CRITERIA: Randomized controlled trials that evaluate withdrawal of AEDs after varying periods of seizure remission in adult and pediatric epilepsy patients with or without blinding were included. Included studies compared an early versus late AED discontinuation. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Relative risks with 95% confidence intervals were calculated for each trial. Summary relative risks and 95% confidence intervals for dichotomous data were calculated using a random effects model. A test of statistical heterogeneity was conducted for each pooled relative risk calculation. MAIN RESULTS: Seven eligible controlled trials were included in the analysis representing 924 randomized pediatric patients. There were no eligible trials evaluating adult seizure free patients. The pooled relative risk for seizure relapse in early versus late AED withdrawal was 1.32 (95% confidence interval 1.02 to 1.70). On the basis of this estimate, the number needed to harm, that is expose an individual to a higher risk of seizure relapse because of early withdrawal of AED, is 10. Early discontinuation was associated with greater relapse rates in patients with partial seizures[pooled RR = 1.52; 95% confidence interval 0.95 to 2.41] or an abnormal EEG [pooled RR=1.67; 95% confidence interval 0.93 to 3.00]. REVIEWER'S CONCLUSIONS: There is evidence to support waiting for at least two or more seizure free years before discontinuing AEDs in children, particularly if individuals have an abnormal EEG and partial seizures. There is insufficient evidence to establish when to withdraw AEDs in pediatric patients with generalized seizures. There is no evidence to guide the timing of withdrawal of AEDs in adult seizure free patients. Further blinded randomized controlled trials are needed to identify the optimal timing of AED withdrawal and risk factors predictive of relapse.

Multiple sclerosis: epidemiology, genetics, classification, natural history, and clinical outcome measures.

Advances in MR imaging and randomized controlled-trial methodology have fundamentally altered the diagnosis and investigation of multiple sclerosis (MS). Further progress in epidemiology and classification will provide clues toward identification of the genetic and environmental factors that predispose to MS and dictate its course. More detailed understanding of the descriptive natural (untreated) history of the disease and development of intermediate and surrogate outcome measures, with better validity and reliability, will increase the likelihood that future clinical trials will identify beneficial treatments to reduce disability. This article reviews the current state of knowledge of MS epidemiology, genetics, disease classification, natural history, and outcome measures.

AQP4 autoantibody assay performance in clinical laboratory service.

OBJECTIVE: To compare performance of contemporary aquaporin-4-immunoglobulin (Ig) G assays in clinical service. METHODS: Sera from neurologic patients (4 groups) and controls were tested initially by service ELISA (recombinant human aquaporin-4, M1 isoform) and then by cell-based fluorescence assays: fixed (CBA, M1-aquaporin-4, observer-scored) and live (fluorescence-activated cell sorting [FACS], M1 and M23 aquaporin-4 isoforms). Group 1: all Mayo Clinic patients tested from January to May 2012; group 2: consecutive aquaporin-4-IgG-positive patients from September 2011 (Mayo and non-Mayo); group 3: suspected ELISA false-negatives from 2011 to 2013 (physician-reported, high likelihood of neuromyelitis optica spectrum disorders [NMOSDs] clinically); group 4: suspected ELISA false-positives (physician-reported, not NMOSD clinically). RESULTS: Group 1 (n = 388): M1-FACS assay performed optimally (areas under the curves: M1 = 0.64; M23 = 0.57 [p = 0.02]). Group 2 (n = 30): NMOSD clinical diagnosis was confirmed by: M23-FACS, 24; M1-FACS, 23; M1-CBA, 20; and M1-ELISA, 18. Six results were suspected false-positive: M23-FACS, 2; M1-ELISA, 2; and M23-FACS, M1-FACS, and M1-CBA, 2. Group 3 (n = 31, suspected M1-ELISA false-negatives): results were positive for 5 sera: M1-FACS, 5; M23-FACS, 3; and M1-CBA, 2. Group 4 (n = 41, suspected M1-ELISA false-positives): all negative except 1 (positive only by M1-CBA). M1/M23-cotransfected cells expressing smaller membrane arrays of aquaporin-4 yielded fewer false- positive FACS results than M23-transfected cells. CONCLUSION: Aquaporin-4-transfected CBAs, particularly M1-FACS, perform optimally in aiding NMOSD serologic diagnosis. High-order arrays of M23-aquaporin-4 may yield false-positive results by binding IgG nonspecifically.