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

Statin therapy inhibits remyelination in the central nervous system

Remyelination of lesions in the central nervous system contributes to neural repair following clinical relapses in multiple sclerosis. Remyelination is initiated by recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. Simvastatin, a blood-brain barrier-permeable statin in multiple sclerosis clinical trials, has been shown to impact the in vitro processes that have been implicated in remyelination. Animals were fed a cuprizone-supplemented diet for 6 weeks to induce localized demyelination in the corpus callosum; subsequent return to normal diet for 3 weeks stimulated remyelination. Simvastatin was injected intraperitoneally during the period of coincident demyelination and OPC maturation (weeks 4 to 6), throughout the entire period of OPC responses (weeks 4 to 9), or during the remyelination-only phase (weeks 7 to 9). Simvastatin treatment (weeks 4 to 6) caused a decrease in myelin load and both Olig2(strong) and Nkx2.2(strong) OPC numbers. Simvastatin treatment (weeks 4 to 9 and 7 to 9) caused a decrease in myelin load, which was correlated with a reduction in Nkx2.2(strong) OPCs and an increase in Olig2(strong) cells, suggesting that OPCs were maintained in an immature state (Olig2(strong)/Nkx2.2(weak)). NogoA+ oligodendrocyte numbers were decreased during all simvastatin treatment regimens. Our findings suggest that simvastatin inhibits central nervous system remyelination by blocking progenitor differentiation, indicating the need to monitor effects of systemic immunotherapies that can access the central nervous system on brain tissue-repair processes

Aspartoacylase-LacZ Knockin Mice: An Engineered Model of Canavan Disease

Canavan Disease (CD) is a recessive leukodystrophy caused by loss of function mutations in the gene encoding aspartoacylase (ASPA), an oligodendrocyte-enriched enzyme that hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. The neurological phenotypes of different rodent models of CD vary considerably. Here we report on a novel targeted aspa mouse mutant expressing the bacterial β-Galactosidase (lacZ) gene under the control of the aspa regulatory elements. X-Gal staining in known ASPA expression domains confirms the integrity of the modified locus in heterozygous aspa lacZ-knockin (aspalacZ/+) mice. In addition, abundant ASPA expression was detected in Schwann cells. Homozygous (aspalacZ/lacZ) mutants are ASPA-deficient, show CD-like histopathology and moderate neurological impairment with behavioural deficits that are more pronounced in aspalacZ/lacZ males than females. Non-invasive ultrahigh field proton magnetic resonance spectroscopy revealed increased levels of NAA, myo-inositol and taurine in the aspalacZ/lacZ brain. Spongy degeneration was prominent in hippocampus, thalamus, brain stem, and cerebellum, whereas white matter of optic nerve and corpus callosum was spared. Intracellular vacuolisation in astrocytes coincides with axonal swellings in cerebellum and brain stem of aspalacZ/lacZ mutants indicating that astroglia may act as an osmolyte buffer in the aspa-deficient CNS. In summary, the aspalacZ mouse is an accurate model of CD and an important tool to identify novel aspects of its complex pathology

Differential expression of apoptotic markers in jimpy and in Plp overexpressors: evidence for different apoptotic pathways

Point mutations and duplications of proteolipid protein (PLP) gene in mammals cause dysmyelination and oligodendrocyte cell death. The jimpy mouse, which has a lethal Plp point mutation, is the best characterized of the mutants; transgenic mice, which have additional copies of Plp gene, are less characterized. While oligodendrocyte death is a prominent feature in jimpy, the pathways leading to death have not been investigated in jimpy and Plp overexpressors. Using immunohistochemistry and immunobloting, we examined expression of cleaved caspase-3, Poly (ADP-ribose) polymerase (PARP), caspase-12, and mitochondrial apoptotic markers in spinal cord in jimpy males and Plp overexpressors. Compared to controls, cleaved caspase-3 is increased 10x in jimpy white matter spinal cord, and 3x in Plp overexpressor. In jimpy, the number of cleaved caspase-3 cells far exceeds the number of TUNEL+ cells. The majority of cleaved caspase-3(+) cells were not TUNEL+ and these cells exhibited staining in perikarya and in processes. Only 30% of the cleaved caspase-3(+) cells were TUNEL+ and exhibited both nuclear and perinuclear staining. This observation suggests that activation of caspase-3 begins earlier and overlaps for a period of time with DNA fragmentation. In both Plp mutants, quantitative immunobloting of PARP showed a 45% increase in total as well as cleaved form, indicating that oligodendrocytes die via apoptosis. Most interestingly, cleavage of caspase-12, a caspase associated with unfolded protein response, is dramatically increased in jimpy but not at all in Plp overexpressors. Mitochondrial markers cytochrome c and Bcl-X-L are upregulated in both Plp mutants but levels of expression are different between mutants, suggesting that apoptosis in these two Plp mutants follows different pathways. In jimpy, mitochondrial apoptotic markers may play a role in amplifying the apoptotic signal. Our data shows for the first time, in vivo, that mutations in Plp gene increase oligodendrocyte death by activating the caspase cascade but the trigger to upregulate this cascade follows different pathways

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

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