COVID-19 associated myelitis: early insights from a multi-center study

Introduction: Neurologic complications of Coronavirus Infectious Disease 2019 (COVID-19) are well recognized and may affect both the central and peripheral nervous system.Cases of acute myelitis in close temporal relationship withCOVID-19 are increasingly reported in the literature but may underly a reporting bias. Aim(s): This study aimed to provide insights into acute myelitis associated with COVID-19 by analyzing cases treated at four tertiary care neurology centers. Patients and Methods: The retrospective observational study was conducted at the University Hospital Centre Zagreb in Croatia, University Medical Centre Ljubljana in Slovenia, University Clinical Centre of Serbia in Serbia, and Landesklinikum Mistelbach- Ganserndorf in Austria.We searched foracute myelitis cases that occurred during or after COVID-19. Demographic data, clinical course, magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) analysis, treatment, and outcome were analyzed. Result(s): We identified ten patients (70% male). The mean age was 49.2 years (standard deviation 17.9). In five patients COVID- 19 presented with upper respiratory symptoms. Five patients suffered from COVID-19 pneumonia, but none required mechanical ventilation. Neurological disturbances caused by acute myelitis occurred after a median of 13 days (range 5 to 76 days following the onset of systemic or respiratory COVID-19 symptoms. Spinal cord lesions were identified in eight patients on MRI. CSF examination was performed in eight patients and oligoclonal bands were detected in one patient. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were present in one patient. Eight patients were treated with corticosteroids, and three of them received intravenous immunoglobulins. One patient received mycophenolate mofetil. The outcome was good, with partial or complete recovery in nine patients and only one patient experiencing no significant improvement. Conclusion(s): Our study raises awareness for this potential neurological complication of COVID-19. While the time lag of COVID-19 and clinical signs of myelitis point at either post- or parainfectious mechanisms, causality needs to be corroborated. Moreover, further studies need to define the diagnostic approach and clarify the optimal standards of care.

Top-line results of emphasis, a phase 2 clinical trial of vidofludimus calcium (IMU-838) in relapsing-remitting multiple sclerosis

Background: Dihydroorotate dehydrogenase (DHODH) inhibition is an established mode of action for disease-modifying treatment of relapsing-remitting multiple sclerosis (RRMS). Vidofludimus calcium (IMU-838) is a selective and potent second- generation DHODH oral immunomodulator being developed for the treatment of several immune-mediated diseases including MS and COVID-19. The inhibition of the DHODH enzyme leads to metabolic stress in stimulated lymphocytes with subsequent reduction of pro-inflammatory cytokines and induction of apoptosis. Due to IMU-838's pharmacological selectivity and lack of relevant off-target effects on kinases, increased rates of typical antiproliferative effects (neutropenia, alopecia and gastrointestinal disturbances) have not been observed in clinical trials. The serum half-life of approximately 30 hours allows quick on- and off-dosing. Objectives: To report topline efficacy, safety, and tolerability of IMU-838 in the relapsing MS EMPhASIS trial (NCT03846219), the first trial of IMU-838 in MS. Methods: EMPhASIS is a phase 2 multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to assess the efficacy and safety of two once-daily oral doses of IMU-838 (30 and 45 mg/day) in patients with RRMS. Inclusion criteria are age 18-55 years, active RRMS defined by the evidence of clinical and radiological disease activity, and Expanded Disability Status Scale (EDSS) 0-4. The primary endpoint is the cumulative number of combined unique active MRI lesions over 24 weeks. Secondary endpoints include efficacy, safety and tolerability parameters. The study also includes a subsequent optional, open-label treatment period to evaluate long-term safety and tolerability. Results: 210 subjects (65% women) were enrolled in 36 centers across four European countries. The mean age at baseline was 36.8 years (SD 8.8). 198 subjects (94%) completed the 24-week main treatment period, with the last follow-up visit in April 2020. Database lock will be in July 2020 and top-line data will be available shortly thereafter. Primary outcome and several secondary outcomes (including safety data) will be presented. Conclusions: IMU-838 is an orally available, next-generation selective immunomodulator with a potentially more favorable profile than first-generation DHODH inhibitors. Top-line results of IMU-838 on primary and several secondary endpoints in patients with RRMS in the EMPhASIS trial will be presented.

The international European Academy of Neurology survey on neurological symptoms in patients with COVID-19 infection.

BACKGROUND AND PURPOSE: Although the main clinical features of COVID-19 infection are pulmonary, several associated neurological signs, symptoms and diseases are emerging. The incidence and characteristics of neurological complications are unclear. For this reason, the European Academy of Neurology (EAN) core COVID-19 Task Force initiated a survey on neurological symptoms observed in patients with COVID-19 infection. METHODS: A 17-question online survey was made available on the EAN website and distributed to EAN members and other worldwide physicians starting on 9 April 2020. RESULTS: By 27 April 2020, proper data were collected from 2343 responders (out of 4199), of whom 82.0% were neurologists, mostly from Europe. Most responders (74.7%) consulted patients with COVID-19 mainly in emergency rooms and in COVID-19 units. The majority (67.0%) had evaluated fewer than 10 patients with neurological manifestations of COVID-19 (neuro COVID-19). The most frequently reported neurological findings were headache (61.9%), myalgia (50.4%), anosmia (49.2%), ageusia (39.8%), impaired consciousness (29.3%) and psychomotor agitation (26.7%). Encephalopathy and acute cerebrovascular disorders were reported at 21.0%. Neurological manifestations were generally interpreted as being possibly related to COVID-19; they were most commonly recognized in patients with multiple general symptoms and occurred at any time during infection. CONCLUSION: Neurologists are currently and actively involved in the management of neurological issues related to the COVID-19 pandemic. This survey justifies setting up a prospective registry to better capture the prevalence of patients with neuro COVID-19, neurological disease characteristics and the contribution of neurological manifestations to outcome.

EAN consensus statement for management of patients with neurological diseases during the COVID-19 pandemic.

BACKGROUND AND PURPOSE: The recent SARS-CoV-2 pandemic has posed multiple challenges to the practice of clinical neurology including recognition of emerging neurological complications and management of coexistent neurological diseases. In a fast-evolving pandemic, evidence-based studies are lacking in many areas. This paper presents European Academy of Neurology (EAN) expert consensus statements to guide neurologists caring for patients with COVID-19. METHODS: A refined Delphi methodology was applied. In round 1, statements were provided by EAN scientific panels (SPs). In round 2, these statements were circulated to SP members not involved in writing them, asking for agreement/disagreement. Items with agreement >70% were retained for round 3, in which SP co-chairs rated importance on a five-point Likert scale. Results were graded by importance and reported as consensus statements. RESULTS: In round one, 70 statements were provided by 23 SPs. In round two, 259/1061 SP member responses were received. Fifty-nine statements obtained >70% agreement and were retained. In round three, responses were received from 55 co-chairs of 29 SPs. Whilst general recommendations related to prevention of COVID-19 transmission had high levels of agreement and importance, opinion was more varied concerning statements related to therapy. CONCLUSION: This is the first structured consensus statement on good clinical practice in patients with neurological disease during the COVID-19 pandemic that provides immediate guidance for neurologists. In this fast-evolving pandemic, a rapid response using refined Delphi methodology is possible, but guidance may be subject to change as further evidence emerges.

A systematic review of neurological manifestations of SARS-CoV-2 infection: the devil is hidden in the details.

BACKGROUND AND PURPOSE: We systematically reviewed available evidence for reports of neurological signs and symptoms in patients with COVID-19 to identify cases with severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection or immune-mediated reaction in the nervous system. METHODS: We followed PRISMA guidelines and used the MEDLINE, EMBASE, Google Scholar, MedRxiv and ChinaXiv databases to search for articles on COVID-19 and nervous system involvement that were published from 1 January to 24 April 2020. Data on design, sample size, neurological assessment and related work-up were extracted. Biases were assessed with the Newcastle-Ottawa scale. RESULTS: We analysed 27 publications on potential neuroinvasive or parainfectious neurological complications of COVID-19. The reports focused on smell and taste (n = 5) and evaluation of neurological symptoms and signs in cohorts (n = 5). There were cases of Guillain-Barré syndrome/Miller-Fisher syndrome/cranial neuropathy (seven cases), meningitis/encephalitis (nine cases) and various other conditions (five cases). The number of patients with examination of cerebrospinal fluid and, in particular, SARS-CoV-2 polymerase chain reaction was negligible. Two had a positive SARS-CoV-2 polymerase chain reaction examination of cerebrospinal fluid specimen. Study of potential parenchymal involvement with magnetic resonance imaging was rare. Only four reports received a rating of the highest quality standards. CONCLUSIONS: This systematic review failed to establish comprehensive insights into nervous system manifestations of COVID-19 beyond immune-mediated complications in the aftermath of respiratory symptoms. The authors therefore provide guidance for more careful clinical, diagnostic and epidemiological studies to characterize the manifestations and burden of neurological disease caused by SARS-CoV-2 on behalf of the Infectious Disease Panel of the European Academy of Neurology.