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Review 1: "Neurological manifestations associated with COVID-19: a nationwide registry"

Study finds broad spectrum of neurological manifestations associated with SARS-CoV-2 infection. Findings are informative for future intervention studies. Decision-makers should consider the claims in this study actionable with limitations to some methods and data.

Published onAug 11, 2020
Review 1: "Neurological manifestations associated with COVID-19: a nationwide registry"
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Neurological manifestations associated with COVID-19: a nationwide registry
Description

Background: The clinical description of the neurological manifestations in COVID-19 patients is still underway. This study aims to provide an overview of the spectrum, characteristics and outcomes of neurological manifestations associated with SARS-CoV-2 infection. Methods: We conducted a nationwide, multicentric, retrospective study during the French COVID-19 epidemic in March-April 2020. All COVID-19 patients with de novo neurological manifestations were eligible. Results: We included 222 COVID-19 patients with neurological manifestations from 46 centers throughout the country. Median age was 65 years (IQR 53-72), and 136 patients (61.3%) were male. COVID-19 was severe or critical in almost half of the patients (102, 45.2%). The most common neurological diseases were COVID-19 associated encephalopathy (67/222, 30.2%), acute ischemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%), and Guillain-Barre Syndrome (15/222, 6.8%). Neurological manifestations appeared after first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19 associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barre Syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 MRI (70.7%). Brain MRI of encephalitis patients showed heterogeneous acute non vascular lesion in 14/21 patients (66.7%) with associated small ischemic lesion or microhemorrhages in 4 patients. Among patients with acute ischemic cerebrovascular syndrome, 13/57 (22.8%) had multi territory ischemic strokes, with large vessel thrombosis in 16/57 (28.1%). Cerebrospinal fluid was analyzed in 97 patients (43.7%), with pleocytosis in 18 patients (18.6%). A SARS-CoV-2 PCR was performed in 75 patients and was positive only in 2 encephalitis patients. Among patients with encephalitis, ten out of 21 (47.6%) fully recovered, 3 of whom received corticosteroids (CS). Less common neurological manifestations included isolated seizure (8/222, 3.6%), critical illness neuropathy (8/222, 3.6%), transient alteration of consciousness (5/222, 2.3%), intracranial hemorrhage (5/222, 2.3%), acute benign lymphocytic meningitis (3/222, 1.4%), cranial neuropathy (3/222, 1.4%), single acute demyelinating lesion (2/222, 0.9%), Tapia syndrome (2/222, 0.9%), cerebral venous thrombosis (1/222, 0.5%), sudden paraparesis (1/222, 0.5%), generalized myoclonus and cerebellar ataxia (1/222, 0.5%), bilateral fibular palsy (1/222, 0.5%) and isolated neurological symptoms (headache, anosmia, dizziness, sensitive or auditive symptoms, hiccups, 15/222, 6.8%). The median (IQR) follow-up of the 222 patients was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). Conclusion: Neurological manifestations associated with COVID-19 mainly included CAE, AICS, encephalitis and GBS. Clinical spectrum and outcomes were broad and heterogeneous, suggesting different underlying pathogenic processes.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

This is a timely and important report on the neurological manifestations associated with COVID-19 based on data from a nationwide registry in France. The current retrospective study included 222 COVID-19 patients with de novo neurological manifestations from 46 centers.

The main findings included the broad spectrum of neurological manifestations associated with SARS-CoV-2 infection including COVID-19 associated encephalopathy (CAE), acute ischemic cerebrovascular syndrome (AICS), encephalitis, Guillain-Barré Syndrome (GBS), etc. The investigation was conducted by the brain imaging, CSF profiling and clinical course analyses. The authors also reported the effect of corticosteroid in patients with encephalitis and CAE, and the effect of IVIG in patients with GBS. Taken as a while, this is informative for future intervention studies.  The following are some minor suggestions:

1) It would be meaningful if the authors could compare the clinical characteristics of their patient cohort with patient cohorts from other regions, such as in China and USA, to check whether different SARS-CoV-2 variants are associated with different clinical manifestations.

2) It will be more useful for the community if the authors provide more information about the patients who received treatment of steroid, IVIG or other specific treatment, including dosage, clinical course after treatment, and the effect of treatment on both neurological deficits and respiratory manifestations.

3) The authors reported that the median age of included patients was 65 years (IQR 53-72), while they reported three young patients with a median age of 20 years (IQR 19-35) in the section “Acute benign lymphocytic meningitis”. Are the three young patients from the same retrospective cohort?

4) In the section “Clinical course (table 2)”, the authors reported that “Eleven out of 15 patients (73.3%) with GBS had progressive weakness in both arms and legs that could be associated with sensory symptoms.” By “associated with sensory symptoms”, could the authors clarify whether they mean that the weakness in limbs is accompanied by sensory symptoms, or partially caused by sensory symptoms?

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