Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up

Vardan Nersesjan ,Michael E Benros ,Sigurður Þór Sigurðsson ,Marie Norsker Folke ,Moshgan Amiri ,Eva Løbner Lund ,Bo Jespersen ,Klaus Hansen ,Pernille Martens ,Annika Reynberg Langkilde ,Helene Mens ,Per Meden ,Christian Wamberg ,Anne‐Mette Lebech ,Jonathan Frederik Carlsen ,Marianne Berntsen ,Lene Russell ,Casper Roed ,Lise Fonsmark ,Anne‐Mette Hejl ,Daniel Kondziella

doi:10.1007/s00415-020-10380-x

Abstract

ObjectiveTo systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients.MethodsWe conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related.ResultsFrom April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated.ConclusionCNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.

Highlights

Central (CNS) and peripheral (PNS) nervous system manifestations can occur during and after coronavirus disease 2019 (COVID-19) [1,2,3,4,5,6], but the underlying mechanisms, the semiology and the frequency of these complications remain poorly understood [7, 8].Limited postmortem studies have shown signs of hypoxic brain injury [9] and neuro-inflammatory changes in the brainstem [10], while neuropathological data from the PNS are so far almost non-existent
Neurological complications are common in hospitalized COVID-19 patients, occur mainly in severely affected patients in the ICU and can often be attributed to critical illness
In cases in which neurological disease was likely directly associated with COVID-19, we did not find signs of viral invasion of SARS-CoV-2 into the CNS or PNS, but laboratory inflammatory changes suggested autoimmunemediated para- and post-infectious mechanisms

Summary

Introduction

Central (CNS) and peripheral (PNS) nervous system manifestations can occur during and after coronavirus disease 2019 (COVID-19) [1,2,3,4,5,6], but the underlying mechanisms, the semiology and the frequency of these complications remain poorly understood [7, 8].Limited postmortem studies have shown signs of hypoxic brain injury [9] and neuro-inflammatory changes in the brainstem [10], while neuropathological data from the PNS are so far almost non-existent. Journal of Neurology (2021) 268:3086–3104 invasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into neuronal tissue has been suggested in a few cases [11, 12], but autoimmune-mediated injury and neurological complications related to intensive care management are recognized [7, 8]. The contribution of these mechanisms to the overall burden of COVID-19 CNS and PNS complications is unknown. Most reports include convenience samples, lack follow-up and do not attempt to determine if COVID-19 complications are caused by direct viral invasion of the nervous system, by para/post-infectious immune-mediated mechanisms or by treatment-related injury [7, 16]

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