COVID-19 in multiple sclerosis patients and risk factors for severe infection

Multiple sclerosis (MS) patients have been considered a higher-risk population for COVID-19 due to the high prevalence of disability and disease-modifying therapy use; however, there is little data identifying clinical characteristics of MS associated with worse COVID-19 outcomes. Therefore, we conducted a multicenter prospective cohort study looking at the outcomes of 40 MS patients with confirmed COVID-19. Severity of COVID-19 infection was based on hospital course, where a mild course was defined as the patient not requiring hospital admission, moderate severity was defined as the patient requiring hospital admission to the general floor, and most severe was defined as requiring intensive care unit admission and/or death. 19/40(47.5%) had mild courses, 15/40(37.5%) had moderate courses, and 6/40(15%) had severe courses. Patients with moderate and severe courses were significantly older than those with a mild course (57[50-63] years old and 66[58.8-69.5] years old vs 48[40-51.5] years old, P = 0.0121, P = 0.0373). There was differing prevalence of progressive MS phenotype in those with more severe courses (severe:2/6[33.3%]primary-progressing and 0/6[0%]secondary-progressing, moderate:1/14[7.14%] and 5/14[35.7%] vs mild:0/19[0%] and 1/19[5.26%], P = 0.0075, 1 unknown). Significant disability was found in 1/19(5.26%) mild course-patients, but was in 9/15(60%, P = 0.00435) of moderate course-patients and 2/6(33.3%, P = 0.200) of severe course-patients. Disease-modifying therapy prevalence did not differ among courses (mild:17/19[89.5%], moderate:12/15[80%] and severe:3/6[50%], P = 0.123). MS patients with more severe COVID-19 courses tended to be older, were more likely to suffer from progressive phenotype, and had a higher degree of disability. However, disease-modifying therapy use was not different among courses

MRI findings in Neurosarcoidosis Patients with Headache as a Primary Presenting Symptom

Objective: To determine if there are MRI differences in patients with neurosarcoidosis, who present with headache as a primarily clinical symptom, compared with those who initially present with non-headache symptomatology. To the author’s knowledge, this has not been previously reported in the available literature. Background: Neurologic complications occur in approximately 5 to 10 percent of patients with sarcoidosis. Clinical manifestations include cranial nerve palsies, sensory and/or motor deficits, and, commonly, persistent headache. The typical work-up of these patients includes a contrast enhanced brain MRI. Design/Methods: This is an IRB-approved retrospective chart review conducted at an urban tertiary care center. 123 patients with Neurosarcoidosis were identified between the years 1980 and 2018, of whom 110 had a completed MRI at the time of diagnosis. These patients were then separated into two groups. Group A included patients who reported headache as their primary neurological complaint, while group B included patients whose presenting neurological symptom was other than headache. Available brain MRI reports were reviewed for each of these patients. Chi-square test was used for analysis. Results: Out of the 110 patients, headache was an initial presenting symptom in 33 patients (Group A), of whom 24, or 73%, had meningeal contrast enhancement on their initial MRI. Of the 77 patients who presented initially with other than headache (Group B), 59, or 77%, did not have meningeal enhancement on their initial MRI (p-value \u3c0.001). Conclusions: Patients with neurosarcoidosis who present with headache as an initial symptom are more likely to have meningeal contrast enhancement as compared to those who present with other symptomatology. This suggests a clinicoradiologic link between headache and meningeal disruption in patients with neurosarcoidosis

Efficacy and safety of fingolimod and dimethyl fumarate for management of multiple sclerosis: A single center retrospective study

Objective: To observe the efficacy and safety of fingolimod and dimethyl fumarate (DMF) in patients with relapsing multiple sclerosis (RMS). Background: Fingolimod was the very first oral disease modifying therapy (oDMT) approved by FDA in 2010 for treatment of RMS. It has changed the therapeutic paradigm of the disease. ODMT are now commonly used as a first line of treatment. Design/Methods: Retrospective chart review of patient’s with multiple sclerosis (MS), treated with fingolimod and DMF was performed. Patients demographics, duration of disease, type of MS, side effects of medications, clinical and radiographic data were recorded. We performed a survival analysis using Kaplan-Meier methods and cox proportional hazards modeling and report hazard ratio of relapse and MRI lesions. Results: Our study population consisted of 141 patients: 111(79%) on DMT and 30(21%) on Fingolimod. Median(IQR) age was 50(42–56), 76% female, and 59% White. Median(IQR) disease duration was 12(8–19) years and time on oDMT was 2.8 (1.2–3.9) years. The percentage of patients who experienced side-effects was 40%; with flushing common in DMF(23% vs 0%, p\u3c0.01) and bradycardia common in Fingolimod(10% vs 1%, p\u3c0.01). Median(IQR) time to first relapse post-oDMT initiation was 1.2 (0.2–2.9) years with no statistically significant difference between the two groups. Median (IQR) time to new/enhanced brain T2 MRI lesion post-oDMT initiation was shorter for DMF compared to Fingolimod: 0.9(0.2–1.5) vs 1.4(0.7–2.3), respectively(p\u3c0.01). Conclusions: The interesting finding of our study is a shorter median (IQR) time to new or enhanced Brain MRI lesions in DMF group compared to Fingolimod group. The time to first relapse was not significantly different between groups. The limitation of our study is a small sample size and retrospective design. The complete data analysis of over 300 patients will be presented at AAN 2020

Clinical, diagnostic and therapeutic spectrum of seropositive and seronegative autoimmune encephalitis: Single center cohort study of 51 cases

Abstract Objective: In this retrospective study, we compared the clinical characteristics, diagnostic and treatment paradigm of seropositive and seronegative autoimmune encephalitis (AE). Background: AEs are severe inflammatory disorders of central nervous system. The diagnosis remain challenging and relies on the clinical manifestations, finding biomarkers and therapy response. However, this can be problematic given that antibody testing results are not readily available and negative testing does not exclude the diagnosis. Design/Methods: Retrospective chart review of patients diagnosed with AE in the last 6 years was performed. Demographic, clinical presentation, laboratory, imaging, electrophysiologic and treatment data were recorded. The patients were divided into two groups, autoantibody positive AE (AE+) and autoantibody negative AE (AE−). Two sample two-tailed t-tests and Fisher exact tests were used to compare AE+ and AE− patients. All statistical analyses were conducted using STATA 14.2 for Mac. Results: 51 patients with the diagnosis of AE were included, AE + (n=36) and AE− (n=15). Psychiatric symptoms at onset were more frequently seen in AE+ compared to AE− (38% vs 13%), while autonomic disorders were found only in AE+ (9%). CSF findings were similar between the two groups with exception of oligoclonal bands which were significantly abnormal in AE− (82% vs 40%, p= 0.03). Demographic data, MRI findings and EEG findings were similar between groups. Steroids were used more frequently in AE− compared to AE+ patients (87% vs 55%, p=0.03). PLEX more commonly in AE+ (30% vs 20%) while long term immunosuppressant more commonly in AE− (40% vs 18%). Conclusions: In our cohort psychiatric manifestations and autonomic dysfunction at onset were more frequently seen in AE+. Positive oligoclonal bands in AE− patients may represent immunological response and guide clinicians to consider immunotherapy when clinical suspicion for AE is high. Early recognition of highly suggestive presentation despite negative autoantibodies is important for this potentially treatable disorders

Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination

The metabolic needs of the premature/premyelinating oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation from the pre-OLs to the OLs is not fully understood. Here, we show that the terminal maturation and higher mitochondrial respiration in the OLs is an integrated process controlled through pyruvate dehydrogenase complex (Pdh). Combined bioenergetics and metabolic studies show that OLs show elevated mitochondrial respiration than the pre-OLs. Our signaling studies show that the increased mitochondrial respiration activity in the OLs is mediated by the activation of Pdh due to inhibition of the pyruvate dehydrogenase kinase-1 (Pdhk1) that phosphorylates and inhibits Pdh activity. Accordingly, when Pdhk1 is directly expressed in the pre-OLs, they fail to mature into the OLs. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh-dependent acetyl-CoA generation from pyruvate contributes to the acetylation of the bHLH family transcription factor, oligodendrocyte transcription factor 1 (Olig1) which is known to be involved in the OL maturation. Pdh inhibition via direct expression of Pdhk1 in the pre-OLs blocks the Olig1-acetylation and OL maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is however reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status in the cuprizone model. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications in the development of therapies for a variety of demyelinating disorders including multiple sclerosis

Disease course and treatment of neurosarcoidosis in a single center cohort study of 113 cases

Objective: To describe treatment and outcomes in a cohort of patients with neurosarcoidosis. Background: Neurosarcoidosis (NS) is estimated to be in present in up to 25% of patients with systemic sarcoidosis. Current treatment of NS, including steroids, immunosuppressants, relies on case reports as there are no controlled trials. Design/Methods: The study setting was a large, integrated health care system serving southeastern Michigan. Electronic medical records for 113 patients who met the criteria for NS (Zajicek, 1999) were reviewed. Data on medication usage and outcomes were analyzed by observing clinical response, imaging and modified Rankin score (mRS). Good response was defined as improvement or no progression in disease activity. Poor response was defined as worsening of symptoms, imaging or relapses. Chi-squared tests were used to compare the outcomes for most recent MRI. Nonparametric tests were used to test the associations. All testing was done at the 0.05 level. SAS version 9.4 was used for data analyses. Results: Of 113 patients, 58% were female and 73% African American. The average duration of follow up was 7.6 years. 61.5% had a monophasic disease, 31.5% had relapses and 11.5% died. Of the 113 patients, 107 (94%) received glucocorticosteroids. Additional immunosuppressant agents were used in 72%. Good response was noted with TNFa (59%), methotrexate (52%), azathioprine (32%). Poor response was noted with mycophenolate mofetil (44%), hydroxycholoroquine (24%). Out of 65 patients with MRI outcomes, 11% had resolution, 8% improved, 35% remained stable. mRS remained stable in 65% but worsen in in 13%. Abstract Conclusions: We present the largest case series of NS treatment and outcomes. Most patients had response to glucocorticosteroids. TNFa and methotrexate provided the highest good outcomes when combination therapy was used. Treatment remains challenging and prospective studies as well as clinical trials are needed to improve outcome in NS

Clinical presentation and treatment of autoimmune encephalitis: Single center cohort study of 47 cases

Objective: In this retrospective cohort study, we aim to identify the distinctive clinical, laboratory and radiological presentation of autoimmune encephalitis and the response to treatment. Background: Autoimmune encephalitis are severe inflammatory disorders of central nervous system and diagnosis in clinical practice remains challenging despite recent advances in identification of new syndromes and autoantibodies. The diagnosis relies on the clinical manifestations, finding biomarkers and therapy response. However, this can be problematic given that antibody testing results are not readily available and negative testing does not exclude the diagnosis. Design/Methods: The study setting was a southeastern Michigan large health system. Electronic Medical Record was queried for diagnosis of autoimmune/paraneoplastic conditions using ICD 10 diagnostic code. Neurological symptoms, sociodemographic, laboratory, radiographic, treatment and outcomes data using modified Rankin scale (mRS) were collected. Two sample t-tests and Fisher\u27s exact tests were used. SAS version 9.4 was used for data analyses. Results: Of 47, 64% were female, 51% were white. The mean age at diagnosis was 56.9 years. The most common presentation was cognitive impairment (34%), followed by psychosis (30%). 69% had antibody to cell surface and 33% had normal MRI. 68% of 41 patients with mRS data had a mRS ≤ 2 and 32% had a mRS \u3e2. Patients with mRS ≤ 2 were younger (p=0.046), less likely to have abnormal protein (p=0.031) or elevated IgG index (p=0.09), but higher rate of elevated WBC in CSF (p=0.097). PLEX treatment was less likely to be required for patients with mRS ≤ 2 (p=0.069). Steroid treatment was used in 62%, PLEX 28%, IVIG 19%. 23% remained on long term immunosuppression Conclusions: Autoimmune encephalitis is increasingly recognized as a heterogeneous group presenting with acute/subacute symptoms, but a diagnosis test is still yet to be found. Early recognition is important for this potentially treatable disorders as it may improve the prognosis

The effect of race on clinical presentation and outcomes in neurosarcoidosis

BACKGROUND: Nervous system is affected in 25% of patients with sarcoidosis. Current literature is largely limited to case reports with disproportionate Caucasian population. We aim to evaluate differences in presentation, management and outcomes by race in neurosarcoidosis. METHODS: Clinical and demographic data on consecutive patients fulfilling Zajicek criteria for neurosarcoidosis from 1995 to 2016 at Henry Ford Hospital were extracted. Disparities in clinical presentation, laboratory values, radiological features, treatment and outcomes, were compared between two groups: African Americans (AA) and non-AA using chi-squared tests, two sample t-test for age and Wilcoxon two sample tests. RESULTS: A total of 118 patients were included, of which 58% were female and 73% were AA. The diagnosis of neurosarcoidosis was noted to be definite (25%), probable (64%) and possible (11%). AA patients had a significantly higher rate of elevated erythrocyte sedimentation rate (62% vs 24%, P = .005) and had lower resolution of abnormalities on follow-up imaging (14% vs 41%, P = .017). There was no difference in disability on follow-up (25% vs 33%, P = .43) or mortality (13% vs 9%, P = .6). CONCLUSIONS: There were no differences in presentation, management and outcomes by race. Discordance in the clinical and radiological data by race has clinical implications and needs further investigation

Clinical and diagnostic spectrum of optic neuritis: A single-center retrospective study of disorders associated with multiple sclerosis, anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies

OBJECTIVE: Optic neuritis (ON) is an immune-mediated optic neuropathy associated with multiple immune-mediated neurological conditions. Our aim was to characterize the clinical and diagnostic features of first or initial episodes of ON associated with multiple sclerosis (MS)-associated (typical) and antibody-related (atypical) ON. METHODS: Retrospective, single institution, medical record review. We analyzed demographic, clinical, laboratory, and radiographic findings of 139 patients who presented with first episodes of MS-associated ON (MS-ON), aquaporin 4 antibody-associated ON (AQP4-ON), and myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON) between January 2015 and October 2019 without preceding diagnosis. Simple hypothesis testing assessed differences between groups were performed. RESULTS: Of 139 patients (109 [79 %] women; 29 [21 %] men; mean age 47 [SD, 14] years), 106 had MS-ON, 25 had AQP4-ON, and 8 had MOG-ON. Patients with MOG-ON had the highest recurrence rate (88 %) relative to MS-ON (28 %) and AQP4-ON (56 %) patients (P \u3c .001). Patients with AQP4-ON had the highest mean visual functional system scores (4.3 [SD, 1.8]) relative to MS-ON (2.0 [SD, 1.9]) and MOG-ON patients (2.8 [SD, 2.0]) (P \u3c .001). CONCLUSION: Patients presenting with initial episodes of ON exhibit a range radiographic and laboratory feature depending on the underlying associated disease. Understanding the variable characteristics of typical (MS-associated) and atypical (antibody-associated) ON may help physicians accurately diagnose and effectively treat ON

A blood-based, six metabolite signature for relapsing-remitting multiple sclerosis

Background: Multiple sclerosis (MS) is a serious debilitating health problem. Monitoring of the disease more closely with a non-invasive marker in the clinic will be of immense benefit. Metabolomics provides a new powerful approach to discover diagnostic and therapeutic biomarkers by analyzing global changes in an individual\u27s metabolic profile. Objectives: The aim of this study was to identify serum metabolites as disease biomarker(s) for relapsing-remitting multiple sclerosis (RRMS) using untargeted metabolomics approach. Methods: Using ultra-performance liquid chromatography linked to gas chromatography and tandem mass spectrometry (Metabolon, Durham, NC), we measured serum metabolites from 35 RRMS subjects without any drug treatment (mean age: 45 years and mean duration of disease 18.2 years; 64% female) and 14 healthy subjects with no disease (mean age: 40 years; 64% female). Results: A total of 621 known metabolites were detected with significance changes observed in 60 metabolites (53 up-regulated and 7 down-regulated) in the serum of RRMS compared to HS. Partial least-squares discriminant analysis of the metabolites reveals a separation of these groups. Bioinformatics analysis revealed 4 metabolic pathways being impacted and altered in RRMS including glycerophospholipid metabolism, citrate cycle (TCA), taurine and hypotaurine and pyruvate metabolism. Casual Network Analysis in IPA identified sphingosine and transforming growth factor beta as a master regulator of altered metabolites in RRMS. Further to identify the potential biomarker specific for RRMS, we identified 14 metabolites, which were selected for prediction model creation. Six out of 14 metabolites were validated in an independent cohort (HS=34, RRMS=40), which could be predicted as potential biomarker for RRMS. Conclusion: Identified and validated 6 metabolites signature have potential to be developed into a clinically useful diagnostic or biomarker tool, that could also contribute to further understanding of disease mechanisms