Monday, June 08, 2020

PrePrint: Cytokine Release Syndrome-Associated Encephalopathy in Patients with COVID-19














#15,311

Two months ago, in JAMA: Neurologic Manifestations Of Patients With Severe Coronavirus Disease, we looked at reports that more than 1/3rd of a study group of 214 patients hospitalized with COVID-19 in Wuhan, China showed signs of neurological involvement.
Neurological manifestations ranged from relatively mild (headaches, dizziness, anosmia, mild confusion, etc.) to more profound (seizures, stupor, loss of consciousness, etc.) to potentially fatal (ischemic stroke, cerebral hemorrhage, muscle injury (rhabdomyolysis), etc.). 
While this early report from Wuhan indicated an unusually high percentage of patients with neurological symptoms, it isn't unheard of that a severe respiratory infection can cause neurological complications. 

Two years ago, in Neuroinfluenza: A Review Of Recently Published Studies, we looked at rare instances or neurological manifestations associated with with seasonal (and avian) influenza infection.

Credit CDC 2018 COCA Call On Severe Influenza
The exact mechanisms behind these neurological symptoms are unknown, as seasonal flu viruses are generally not regarded as being neurotropic. But some researchers have suggested that these neurological symptoms may be due to neuroinflammation induced by the host's immune response.
Along the same lines, we have a preprint (not-yet-peer-reviewed) article that describes 5 COVID-19 patients admitted to a renal unit at the Strasbourg University Hospital (in Strasbourg, France) between early March and early April, all presenting with neurological symptoms. 
While none of these patient's cerebrospinal fluid showed signs of the SARS-CoV-2 virus, all showed blood markers suggestive of a Cytokine Release Syndrome (CRS), including high levels of  IL-6,
C-reactive protein, and ferritin.

A link, and the abstract, to the study (the full 25-page PDF is available) follow:

Cytokine Release Syndrome-Associated Encephalopathy in Patients with COVID-19
Peggy Perrin * , Nicolas Collongues , Seyyid Baloglu , Dimitri Bedo , Xavier Bassand , Thomas Lavaux , Gabriela Gautier , Nicolas Keller , Stephane Kremer , Samira Fafi-Kremer , Bruno Moulin , Ilies Benotmane , Sophie Caillard
Version 1 : Received: 5 June 2020 / Approved: 7 June 2020 / Online: 7 June 2020 (15:50:37 CEST)

How to cite: Perrin, P.; Collongues, N.; Baloglu, S.; Bedo, D.; Bassand, X.; Lavaux, T.; Gautier, G.; Keller, N.; Kremer, S.; Fafi-Kremer, S.; Moulin, B.; Benotmane, I.; Caillard, S. Cytokine Release Syndrome-Associated Encephalopathy in Patients with COVID-19. Preprints 2020, 2020060103 (doi: 10.20944/preprints202006.0103.v1). 
Abstract
Severe disease and uremia are risk factors for neurological complications of coronavirus disease-2019 (COVID-19). An in-depth analysis of a case series was conducted to describe the neurological manifestations of patients with COVID-19 and gain pathophysiological insights that may guide clinical decision-making – especially with respect to the cytokine release syndrome (CRS). 
Extensive clinical, laboratory, and imaging phenotyping was performed in five patients. Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Neurological disturbances were remarkably accompanied by laboratory evidence of CRS. 
SARS-CoV-2 was undetectable in the cerebrospinal fluid. Hyperalbuminorachy and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain MRI findings comprised evidence of acute leukoencephalitis (n = 3, of whom one with a hemorrhagic form), cytotoxic edema mimicking ischemic stroke (n = 1), or normal results (n = 2).
Treatment with corticosteroids and/or intravenous immunoglobulins was attempted – resulting in rapid recovery from neurological disturbances in two cases. Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory, and imaging similarities with those of chimeric antigen receptor-T cell-related encephalopathy. 
The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.
          (SNIP)
Our findings need to be interpreted in the context of some limitations. Notably, this is a case series and some neurological manifestations occurring in patients with COVID-19 – especially related to neurovascular dysfunction – might have been absent in our patients.

In conclusion, we provide a pilot description of the peculiar clinical, laboratory, and imaging  findings of COVID-19-associated neurological disturbances. The clinical manifestations were  chiefly driven by peripheral CRS, absent direct CNS invasion by SARS-CoV-2. Pending future  confirmation, our data indicate that corticosteroids aimed at tackling CRS [28] and IVIg may be effective to control severe neurological disturbances in patients with COVID-19.
          (Continue . . . )

This study - along with others, like . . . 
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