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.

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.

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.

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.

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.