Indirect impact of the COVID-19 pandemic on the care and outcomes of people with MS: A combined survey and insurance claims study.

BACKGROUND: In the context of the COVID-19 pandemic, people with multiple sclerosis (pwMS) have been particularly vulnerable to adverse outcomes due to increased risk of severe infection and/or widespread disruptions in care. The CopeMS study led by The University of Texas at Austin and the MS Association of America investigates the long-term impact of the COVID-19 pandemic on healthcare access, disease modifying therapy (DMT) utilization and outcomes of pwMS. METHODS: This retrospective cohort analysis used Optum's de-identified Clinformatics® Data Mart Database (CDM), a large de-identified administrative healthcare claims database to identify pwMS who were continuously enrolled from 01/01/2019 to 12/31/2020 and assessed changes in the utilization of DMTs and healthcare services during the COVID-19 pandemic compared to the year prior. Additionally, a national survey of pwMS and healthcare providers (HCPs) was conducted to further understand the indirect impact of the pandemic on healthcare resource utilization (HCRU), outcomes and prescription patterns. RESULTS: Out of 529 pwMS in our national survey, over 47 % reported that their overall health and neurologic symptoms had deteriorated during the COVID-19 pandemic, with increased anxiety, and inability to maintain exercise habits as leading perceived causes for worsening. Survey respondents reported widespread disruption of MS-related services during the pandemic. In the Optum database, we identified 39,209 pwMS validating inclusion criteria. We observed a decrease in the utilization of MS-related services in 2020 compared to 2019. Significantly fewer pwMS had visits with their neurologist, primary care provider, physical or occupational therapist despite an increased utilization of telemedicine services. Fewer pwMS had magnetic resonance imaging (MRI) studies of the brain or spinal cord during the pandemic. Only 22.2 % of HCPs surveyed agreed that the perceived risk of more severe COVID-19 infection on a specific DMT influenced their therapeutic decisions. In the Optum database, individuals with an established diagnosis of MS prior to 2019 saw decreases in utilization of platform and moderate efficacy DMTs. In this group, those over the age of 55 saw a decrease in utilization of B-cell therapies (rate ratio 0.79, CI 0.75-0.83), whereas individuals under the age of 55 saw an increase in utilization of B-cell therapies (rate ratio 1.10, CI 1.03-1.17). We did not see any difference in rates of starting DMTs in persons diagnosed in 2019 prior to the pandemic and those diagnosed in 2020. Compared to 2019, B-cell therapies were prescribed more frequently in pwMS diagnosed in 2020 who were younger than 55 or commercially insured (rate ratio 1.35, CI 1.11-1.63). CONCLUSION: The COVID-19 pandemic was associated with perceived worsening of neurological symptoms in pwMS. Despite the expansion of telemedicine, we observed decreased access to healthcare services important to the comprehensive care of pwMS. Additionally, we observed changes in DMT utilization in pwMS during the pandemic, particularly in older adults with an established diagnosis of MS.

Does GPT-4 have neurophobia? Localization and diagnostic accuracy of an artificial intelligence-powered chatbot in clinical vignettes.

BACKGROUND AND OBJECTIVES: This is an observational study of the performance of an artificial intelligence-powered chatbot tasked with solving unknown neurologic case vignettes. The primary objective of the study is to assess the current capabilities of widely-accessible artificial intelligence within the field of clinical neurology in order to determine how this technology can be deployed in clinical practice, and what insights can be learned from its performance and translated to clinical education. METHODS: This observational study tested the accuracy of GPT-4, an artificial intelligence-powered chatbot, at appropriately localizing and generating a differential diagnosis for a series of 29 clinical case vignettes. The cases were from previously published educational material prepared for learners. No cases required more than text input, a current limitation of GPT-4. The primary outcome measures were ranked accuracy of localization and differential diagnosis based on clinical history and exam alone and after ancillary clinical data was provided. Secondary outcome measures included a comparison of accuracy by case difficulty. RESULTS: GPT-4 identified the correct localization less than 50% of the time and performed worse when provided ancillary testing. GPT-4 was more accurate with localization and diagnosis of easier versus harder cases. Diagnostic accuracy was independent of its ability to localize the lesion. DISCUSSION: GPT-4 did not perform as well on neurology clinical vignettes as compared to reported accuracy when provided other medical clinical vignettes. Incorporation of an AI chatbot into the practice of clinical neurology will require neurology-focused teaching.

Disease associations of excessive daytime sleepiness in multiple sclerosis: A prospective study.

Background: Excessive daytime sleepiness (EDS) in multiple sclerosis (MS) can be a significant source of disability. Despite this, its prevalence as a patient-reported outcome in this condition has not been well established, and its causes are not well understood. Methods: We prospectively assessed EDS as part of an observational study for patients referred for diagnostic neuro-ophthalmological testing. EDS was evaluated by the Epworth Sleepiness Scale (ESS), and visual data were also collected as part of a research protocol. Analysis with patient data was performed following the exclusion of patients with known primary sleep disorders. Results: A total of 69 patients with MS were included in the analysis. The mean ESS was 6.5 with a SD of 4.3. ESS ≥ 10 was present in 23% of the cohort even in the presence of minimal mean neurological disability (Patient Determined Disease Steps (PDDS) = 1.5). The ESS score was not associated with age, sex, disease-related disability, retinal nerve fiber layer (RNFL), or optic neuritis (ON), but displayed an association with visual dysfunction. Conclusions: There is an increased prevalence of EDS in MS. The increased values of the ESS are not explained by other sleep disorders, suggesting separate mechanisms. Further study of the underlying mechanisms is warranted.

Enrollment of Non-White Participants and Reporting of Race and Ethnicity in Phase III Trials of Multiple Sclerosis DMTs: A Systematic Review.

BACKGROUND AND OBJECTIVES: Black and Hispanic people with multiple sclerosis (MS) (pMS) have been found to have different disease courses or worse outcomes associated with MS compared to White pMS. They are also more likely to be negatively affected by social determinants of health, further worsening disparities in outcomes. As these disparities may affect treatment response, non-White pMS must be included in trials for greater generalizability of research and therefore more inclusive treatment plans. In this study, we aimed to evaluate how representation of non-White groups in phase III trials of approved disease-modifying therapies (DMTs) has evolved over time and how race and ethnicity are reported in medical journals and on manufacturer websites. METHODS: We conducted a systematic review of the PubMed database from 1995 to June 2020 to identify manufacturer-sponsored phase III trials for Food and Drug Administration-approved MS DMTs. We explored how race and ethnicity were reported in trial publications. Using studies where information was available, we analyzed the representation of non-White pMS over time and compared to multinational census data. We reviewed patient- and health care provider (HCP)-facing websites of available DMTs to assess the dissemination of information on racial and ethnic representation in trials. RESULTS: A total of 44 phase III trial publications were reviewed, representing 45 trials, among which 17 (37.8%) did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities. When compared to multinational census data, non-White pMS were significantly underrepresented in MS trials. Due to lack of data, trends in representation of other races and ethnicities could not be assessed. No patient- or HCP-facing DMT websites reported data on race and ethnicity in pivotal trials. Study results are available on our study dashboard. CONCLUSION: Race and ethnicity are underreported in MS DMT trial publications and race and ethnic representation are omitted from manufacturer websites. When available, data show that non-White pMS are significantly underrepresented in MS trials. The availability of this information is crucial for patients, together with their HCPs, to make informed decisions about their care.

Neuromyelitis Optica Spectrum Disorders (NMOSD) and Connective Tissue Disease (CTD): an Update for the Rheumatologist.

PURPOSE OF REVIEW: To review the pathophysiology, presentation, and treatment of neuromyelitis optica spectrum disorder (NMOSD) and its association with systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). RECENT FINDINGS: NMOSD is an autoimmune disorder of the central nervous system that primarily targets astrocytes. Although the prevalence is unknown, the coexistence of NMOSD and SLE/SS is well-recognized. Patients with both NMOSD and SLE or SS require may require unique approaches to diagnosis and management. Coexistence of NMOSD and SLE/SS is important for the rheumatologist and neurologist to be able to recognize. For the rheumatologist, NMOSD and its neurologic symptoms represent a distinct disease process from neurologic complications of the patient's underlying connective tissue disease, and it requires distinct acute and chronic management. For the neurologist, the coexistence of SLE and SS can help to establish a diagnosis of NMOSD, or in some situations, the development of neurologic symptoms secondary to NMOSD can lead to the diagnosis of connective tissue disease.

Mitigating alemtuzumab-associated autoimmunity in MS: A "whack-a-mole" B-cell depletion strategy.

OBJECTIVE: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity. METHODS: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy. RESULTS: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed. CONCLUSIONS: An anti-CD20 "whack-a-mole" B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.

Paraneoplastic PRES from lymphoma induced hypercalcemia: Case report and review of the literature.

Hypercalcemia from tumors has been associated with Posterior Reversible Encephalopathy Syndrome (PRES) but the mechanism remains unclear. In this article, we describe a case of PRES caused by hypercalcemia from lymphoma. We summarize the available scientific evidence linking hypercalcemia to failure of cerebral autoregulation and potentially PRES. A major link is the hypomagnesemia induced by hypercalcemia. While this concept requires further clinical testing and validation, it is clinically significant for the management of PRES, even when not directly caused by hypercalcemia.

Updates and Controversies in the Management of Acute Optic Neuritis.

Optic neuritis remains a common diagnosis with controversial management. Although typical optic neuritis is often associated with "good" recovery of visual acuity, patients are often left with persistent impairments of contrast sensitivity, color vision, and visual field. These permanent visual deficits correlate with structural injury to the anterior visual pathway and are closely linked to visual quality of life. High dose corticosteroids are commonly used for patients with acute optic neuritis. However, even several decades after the initial clinical trials, there remains significant controversy regarding the efficacy and utility of this treatment. There is a need for more effective treatments, and many new immunomodulatory and neuroprotective agents have been investigated recently. Atypical optic neuritis, such as that seen with neuromyelitis optica spectrum disorder, often requires more aggressive initial treatment. Thus, it is important for clinicians to have a framework for rapid diagnosis and triage of patients who present with typical or atypical optic neuritis. Lastly, optic neuritis is associated with an elevated long-term risk of developing multiple sclerosis. Some patients may benefit from initiation of medications targeting multiple sclerosis at the time of initial presentation of optic neuritis. Appropriate identification and treatment of patients at highest risk of developing multiple sclerosis may help impact their disease course, while limiting exposure to potential adverse effects in patients who are at lower risk and do not require disease-modifying treatment.

Identification and treatment of the visual processing asymmetry in MS patients with optic neuritis: The Pulfrich phenomenon.

BACKGROUND: The Pulfrich phenomenon (PF) is the illusory perception that an object moving linearly along a 2-D plane appears to instead follow an elliptical 3-D trajectory, a consequence of inter-eye asymmetry in the timing of visual object identification in the visual cortex; with optic neuritis as a common etiology. OBJECTIVE: We have designed an objective method to identify the presence and magnitude of the PF, in conjunction with a cooresponding strategy by which to abolish the effect; with monocular application of neutral density filters to the less affected fellow eye, in patients with MS and a history of optic neuropathy (e.g. related to acute optic neuritis or subclinical optic neuropathy). METHODS: Twenty-three MS patients with a history of acute unilateral or bilateral optic neuritis, and ten healthy control subjects (HC) were recruited to participate in a pilot study to assess our strategy. Subjects were asked to indicate whether a linearly moving pendulum ball followed a linear 2-D path versus an illusory 3-D elliptical object-motion trajectory, by reporting the ball's approximation to one of nine horizontally-oriented colored wires that were positioned parallel to one another and horizontal to the linear pendulum path. Perceived motion of the bob that moved along wires behind or in front (along the 'Z' plane) of the middle reference wire indicated an illusory elliptical trajectory of ball motion consistent with the PF. RESULTS: When the neutral density filter titration was applied to the fellow eye the severity of the PF decreased, eventually being fully abolished in all but one patient. The magnitude of neutral density filtering required correlated to the severity of the patient's initial PF magnitude (p < 0.001). CONCLUSIONS: We ascertained the magnitude of the visual illusion associated with the PF, and the corresponding magnitude of neutral density filtering necessary to abolish it.

New Ways of "Seeing" the Mechanistic Heterogeneity of Multiple Sclerosis Plaque Pathogenesis.

BACKGROUND: Over the past few decades, we have witnessed a transformation with respect to the principles and pathobiological underpinnings of multiple sclerosis (MS). From the traditional rubric of MS as an inflammatory and demyelinating disorder restricted to central nervous system (CNS) white matter, our contemporary view has evolved to encompass a broader understanding of the variable mechanisms that contribute to tissue injury, in a disorder now recognized to affect white and grey matter compartments. EVIDENCE ACQUISITION: A constellation of inflammation, ion channel derangements, bioenergetic supply: demand mismatches within the intra-axonal compartment, and alterations in the dynamics and oximetry of blood flow in CNS tissue compartments are observed in MS. These findings have raised questions regarding how histopathologic heterogeneity may influence the diverse clinical spectrum of MS; and, accordingly, how individual treatment needs vary from 1 patient to the next. RESULTS: We are now on new scaffolding in MS; one that promises to translate key clinical and laboratory observations to the application of emerging patient-centered therapies. CONCLUSIONS: This review highlights our current knowledge of the underlying disease mechanisms in MS, explores the inflammatory and neurodegenerative consequences of tissue damage, and examines physiologic factors that contribute to bioenergetic homeostasis within the CNS of affected patients.

Retinal Architecture and Melanopsin-Mediated Pupillary Response Characteristics: A Putative Pathophysiologic Signature for the Retino-Hypothalamic Tract in Multiple Sclerosis.

Importance: A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflex may represent a surrogate biomarker for the integrity of the retinohypothalamic tract, with potential utility for investigating alterations in homeostatic mechanisms associated with brain disorders and implications for identifying new treatments. Objective: To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. Design, Setting, and Participants: The case-control study was an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center for MS from September 6, 2012, to February 2015. Twenty-four patients with MS (48 eyes) and 15 individuals serving as controls (30 eyes) participated. The melanopsin-mediated, sustained pupillary constriction phase response following cessation of a blue light stimulus was compared with the photoreceptor-mediated pupillary constriction phase response following cessation of a red light stimulus. Optical coherence tomography was used to characterize the association between pupillary response characteristics and alterations in retinal architecture, specifically, the thickness of the retinal ganglion cell layer and inner plexiform layer (GCL + IPL). Main Outcomes and Measures: Association of pupillary response characteristics with alterations in retinal architecture. Results: Of 24 patients with MS included in the analysis, 17 were women (71%); mean (SD) age was 47 (11) years. Compared with eyes from individuals with MS who had normal optical coherence tomography-derived measures of retinal GCL + IPL thickness, eyes of patients who had GCL + IPL thickness reductions to less than the first percentile exhibited a correspondingly significant attenuation of the melanopsin-mediated sustained pupillary response (mean [SD] pupillary diameter ratios at a point in time, 0.18 [0.1] vs 0.33 [0.09]; P < .001, generalized estimating equation models accounting for age and within-patient intereye correlations). Conclusions and Relevance: In this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.