Neuromyelitis optica: Clinical course and potential prognostic indicators.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neurological disorder associated with antibodies to aquaporin-4 (AQP4). NMOSD has been thought to follow a progressive disease course, with step-wise accumulation of disability over time, even in patients undergoing immunosuppressive/immunomodulatory therapy. The influence of factors such as AQP4 seropositivity, AQP4 serum titer levels, and administration of plasmapheresis on NMOSD prognosis is, as yet, unclear. METHODS: We performed a retrospective chart review of 53 persons with NMOSD at Duke University Hospital-collecting data on longitudinal disease course, imaging, demographics, and serum AQP4 titers (measured using the ELISA or FACS method). Most patients in our cohort were treated with high-dose corticosteroids and, following diagnosis, received maintenance immunosuppressive/immunomodulatory therapies. Longitudinal data on EDSS scores were used to calculate the slope of disability over time for each participant. We additionally investigated the correlation between initial AQP4 seropositivity, initial AQP4 serum titer levels, and treatment with plasmapheresis on disability progression for each participant. RESULTS: Contrary to current views on NMOSD disease course, the majority of our participants showed either no change (31.9%) or improvement (27.1%) in disability over time. Our results additionally revealed no significant association between clinical prognosis and initial AQP4 seropositivity (p = 0.830), initial AQP4 serum titer levels (p = 0.338), or administration of plasmapheresis (p = 0.1149). CONCLUSIONS: Our study presents a contemporary view of the clinical course of NMOSD and shows a more favorable view of its disease course than prior studies (performed before high-efficacy disease modifying therapies became widely-used for this patient population). Most patients in this study received treatment with high-dose corticosteroids following NMOSD flares, as well as a variety of maintenance immunosuppressive therapies. The results of this study cannot shed light on the disease course of untreated NMOSD. Our findings additionally challenge the theory that AQP4 seropositivity or serum titer levels at time of diagnosis may be used to effectively predict NMOSD prognosis. While we were unable to find evidence supporting a favorable effect of plasmapheresis administration on disease outcomes, further research is needed to determine the role plasmapheresis ought to play in the treatment of NMOSD.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease: Presentation and outcomes of adults at a single center.

BACKGROUND/INTRODUCTION: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a chronic demyelinating disorder that has been increasingly recognized since the serum antibody became commercially available in 2017. The most common clinical presentation is optic neuritis, and first line acute treatment is intravenous (IV) steroids. However, there are many questions that remain unanswered. For clinicians and patients, the primary question is whether relapses will occur and whether to treat with chronic therapy. METHODS: This retrospective chart review examined characteristics of thirty-three known adult MOGAD cases at a single institute. Data was collected on patient demographics, clinical presentation, objective diagnosis with MRI and serum antibody levels, acute and chronic treatment and disease outcomes. RESULTS: Our MOGAD cases revealed a slight female to male predominance of 1.5:1. No racial groups were affected disproportionately, and age of symptom onset spanned a large range with a median of 40 years. The most common clinical and radiologic presentation was optic neuritis followed by transverse myelitis and brainstem symptoms/lesions. IV methylprednisolone was used in the vast majority of cases for acute treatment. 83.3% of our patients were treated with chronic therapy at some point during their disease course. Therapies include rituximab, IVIG, ocrelizumab, mycophenolate mofetil and ofatumumab. The majority of our patients were treated with rituximab and we did not see a significant benefit of yearly relapse reduction for rituximab versus other therapies. Our cohort had a higher-than- expected percentage of cases with relapsing disease (56.3%) compared to monophasic (43.8%). DISCUSSION/CONCLUSION: Our study confirms prior data regarding the demographics, clinical presentation and radiologic presentation of MOGAD. There is no consensus on whether maintenance therapy should be started for MOGAD cases with a single clinical event. Our cohort showed a higher relapse rate than has been reported previously and all known relapses occurred within one year of diagnosis. More data is necessary to confirm risk of relapse in the years following diagnosis. In addition, further data on biomarkers are needed to predict the disease course could help guide management.

Changing Paradigms and Unmet Needs in Multiple Sclerosis: The Role of Clinical Neurophysiology.

SUMMARY: Our increasing understanding of the immunopathogenesis of multiple sclerosis has led to the development of many disease-modifying therapies that have revolutionized the care of patients with relapsing forms of the disease. Our understanding of the pathophysiologic basis of progressive forms of the disease is much more limited but has dramatically changed over the past several decades. We are now on the verge of developing therapies that promote remyelination, reduce axonal loss, and restore axonal function. This progress is challenged by inadequate animal models of progressive disease and incomplete biomarkers of progression. In measuring central nervous system function, evoked potentials may have an advantage over biomarkers, which measure only pathologic change. Monitoring multifocal visual evoked potential amplitude may be one possible means of monitoring disease progression in multiple sclerosis. Additional clinical studies are required to document whether evoked potentials can adequately serve as effective biomarkers of progression.

Biomarkers and Surrogate End points in Multiple Sclerosis Trials: Regulatory Issues.

SUMMARY: Evoked potentials have assisted in the diagnosis of multiple sclerosis for years, but the potential to demonstrate pathophysiologic change has prompted a reconsideration of their potential role as outcome measures in clinical trials of multiple sclerosis. The use of any surrogate end point or biomarker in clinical trials requires a thorough understanding of that end point's performance characteristics and utility in a particular setting. This article explores regulatory issues regarding the use of biomarkers and surrogate end points in clinical trials of multiple sclerosis with particular emphasis on challenges faced by evoked potential studies.

Is Easier Better Than Harder? An Experiment on Choice Experiments for Benefit-Risk Tradeoff Preferences.

OBJECTIVES: To test the convergent validity of simple and more complex study designs in a discrete-choice experiment (DCE) of multiple sclerosis (MS) treatment preferences. METHODS: Five hundred US adults with MS completed an online DCE survey. Respondents answered 8 choice questions with pairs of constructed MS treatment profiles defined by delays in problems with walking, delays in problems with cognition, thyroid disorders, and 10-y risks of kidney failure and serious brain infection (i.e., progressive multifocal leukoencephalopathy [PML]). Four hundred respondents completed choice questions using 4 levels for all attributes, except thyroid disorders with 3 levels. One hundred respondents completed choice questions using only the 2 extreme attribute levels of the 4-level version. Random-parameters logit models were used to estimate choice-model parameters. RESULTS: Respondents viewing the 4-level and 2-level versions agreed on the relative importance of the 3 most important attributes: cognition, walking, and PML. Respondents viewing the 4-level version indicated much stronger disutility for a 0% to 0.5% increase in kidney-failure risk than those viewing the 2-level version where the risk for kidney failure increased from 0% to 3%. Otherwise, utilities for other 4-level attributes were approximately linear but with significantly steeper slopes (except for cognition) than the 2-level estimates, indicating that attributes were perceived as more important as the number of levels increased. CONCLUSIONS: Although the relative importance of some attributes was similar, the 2-level and 4-level versions generally failed to demonstrate convergent validity. If the study goal is attribute rankings, a 2-level version could be adequate. If goals include quantifying tradeoffs among attribute levels, more complex designs can help respondents discriminate among attribute levels. Reductions in measurement error using fewer attribute levels appear to have come at the expense of less discriminating evaluations.

Rapid transfer of knowledge for multiple sclerosis clinical care during COVID-19: ECHO MS.

BACKGROUND: Healthcare providers caring for people with multiple sclerosis (MS) have had significant concerns about the intersection of MS and COVID-19. As a result, there has been an urgency to understand and share information about how to best provide MS clinical care during COVID-19. The Project ECHO model is well-suited for this challenge, as it provides a uniquely efficient and effective approach to sharing information in real-time using real cases. We report on the translation of the Project ECHO model for the rapid sharing of knowledge among MS clinical providers during COVID-19. METHODS: The ECHO MS COVID-19 Response Clinic was a videoconference-based education and case consultation program offered to providers in the U.S. who care for individuals with MS. The Response Clinic was offered as four sessions, each delivered by three regional hubs. Data were collected on participation and the self-reported impact of the program. RESULTS: A total of 132 unique providers participated in the Response Clinic, which consisted of 11 didactic modules and 43 case consultations. Participant providers overwhelmingly indicated that the program improved their knowledge, attitude, and skills for providing healthcare for people with MS during the COVID-19 pandemic. DISCUSSION: The Project ECHO model was successfully adapted to serve the needs of the MS community during COVID-19, suggesting the program could be continued or could be expanded to other disease areas for a similar purpose. More research is needed to objectively measure the impact of the program on patient outcomes.

The clinical presentation and treatment of MOG antibody disease at a single academic center: A case series.

OBJECTIVES: To describe the clinical presentation of MOG antibody disease (MOG-AD) in a series of patients at a single academic center. METHODS: We performed a retrospective review of patients with MOG antibodies. RESULTS: We review the clinical presentation of 11 patients with MOG antibodies. In patients seen at Duke University Health System with MOG antibodies, the most common presentation was optic neuritis. Rituximab was the most used treatment for long-term management. CONCLUSIONS: Our case series highlights the common presentation of MOG antibody disease (MOG-AD) at a single academic medical center.

Recurrent disseminated encephalomyelitis: A case report and literature review.

BACKGROUND: Acute disseminated encephalomyelitis has been understood as a monophasic, often post-infectious illness that predominantly affects the pediatric population. Though that describes the majority of cases, exceptions do exist. In this case report, we present an adult case of recurrent disseminated encephalomyelitis (DEM) and review the available literature on this clinical entity. METHODS: PubMed search performed using the terms "MDEM" and "Recurrent ADEM" in April 2018. A total of 23 items resulted for the first search and another 142 for the second. We selected articles that described cases of recurrent ADEM with a preference for those publications describing adult cases and those written in English language. CONCLUSION: Recurrent disseminated encephalomyelitis is a distinct clinical entity that has features which overlap with multiple sclerosis, making it imperative to distinguish the two. Our case presentation and accompanying literature review highlights the limited scope of data available on recurrent DEM and the need for further study.

Nivolumab-Induced Autoimmune Encephalitis in Two Patients with Lung Adenocarcinoma.

Immune checkpoint inhibitors have improved patient survival outcomes in a variety of advanced malignancies. However, they can cause a number of immune-related adverse effects (irAEs) through lymphocyte dysregulation. Central nervous system (CNS) irAEs are rare, but as the number of indications for checkpoint inhibitors increases, there has been emergence of CNS immune-mediated disease among cancer patients. Given the relatively recent recognition of checkpoint inhibitor CNS irAEs, there is no standard treatment, and prognosis is variable. Therefore, there is a great need for further study of checkpoint inhibitor-induced CNS irAEs. Here, we present two unique cases of nivolumab-induced autoimmune encephalitis in patients with non-small cell lung cancer and review the available literature.

Subacute combined degeneration due to copper deficiency.

There is growing clinical evidence supporting a connection between copper deficiency and subacute combined degeneration. While nearly half of patients with copper deficiency myelopathy exhibit MRI abnormalities, signal changes are often ill-defined in distribution. We report a patient with sensory ataxia and spastic paraplegia from copper deficiency whose MRI demonstrates abnormal signal restricted to the dorsal and lateral columns, providing clear radiological support of an association between hypocupremia and combined system degeneration.

Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. METHODS: This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. FINDINGS: The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3·5 ms (17·3 vs 20·8 [95% CI -10·6 to 3·7]; 17%; p=0·33) in the ITT population, and -7·6 ms in the PP population (14·7 vs 22·2 [-15·1 to 0·0]; 34%; p=0·050) at week 24 and -6·1 ms (15·1 vs 21·2 [-12·7 to 0·5]; 29%; p=0·071) in the ITT population and -9·1 ms (13·2 vs 22·4 [-16·1 to -2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. INTERPRETATION: Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. FUNDING: Biogen.

Neurologic manifestations of gastrointestinal disease.

Although previously considered rare, neurologic manifestations of gastrointestinal diseases are increasingly recognized. Understanding of Whipple disease and gluten sensitivity is in transition and these conditions are becoming the province of neurologists. Recent improvements in diagnostic testing have improved our understanding and case finding for vitamin B12 deficiency. Many patients with these conditions present with neurologic manifestations alone. Therefore, these conditions are becoming the province of neurologists, and neurologic manifestations of gastrointestinal disease are becoming a more common part of neurologic practice.

Electroencephalography leads placed by nontechnologists using a template system produce signals equal in quality to technologist-applied, collodion disk leads.

The purpose of this study was to compare the quality of the electroencephalographic (EEG) data obtained with a BraiNet template in a practical use setting, to that obtained with standard 10/20 spaced, technologist-applied, collodion-based disk leads. Pairs of 8-hour blocks of EEG data were prospectively collected from 32 patients with a Glasgow coma score of ≤9 and clinical concern for underlying nonconvulsive status epilepticus over a 6-month period in the Neurocritical Care Unit at the Duke University Medical Center. The studies were initiated with the BraiNet template system applied by critical care nurse practitioners or physicians, followed by standard, collodion leads applied by registered technologists using the 10/20 system of placement. Impedances were measured at the beginning and end of each block recorded and variance in impedance, mean impedance, and the largest differences in impedances found within a given lead set were compared. Physicians experienced in reading EEG performed a masked review of the EEG segments obtained to assess the subjective quality of the recordings obtained with the templates. We found no clinically significant differences in the impedance measures. There was a 3-hour reduction in the time required to initiate EEG recording using the templates (P < 0.001). There was no difference in the overall subjective quality distributions for template-applied versus technologist-applied EEG leads. The templates were also found to be well accepted by the primary users in the intensive care unit. The findings suggest that the EEG data obtained with this approach are comparable with that obtained by registered technologist-applied leads and represents a possible solution to the growing clinical need for continuous EEG recording availability in the critical care setting.

Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.

BACKGROUND: Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. METHODS: 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. FINDINGS: All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001). INTERPRETATION: GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. FUNDING: National Institutes of Health.