key: cord-325296-zrvykzof
authors: Zuhorn, Frédéric; Omaimen, Hassan; Ruprecht, Bertram; Stellbrink, Christoph; Rauch, Michael; Rogalewski, Andreas; Klingebiel, Randolf; Schäbitz, Wolf-Rüdiger
title: Parainfectious encephalitis in COVID-19: “The Claustrum Sign”
date: 2020-09-03
journal: J Neurol
DOI: 10.1007/s00415-020-10185-y
sha: 
doc_id: 325296
cord_uid: zrvykzof

nan

included positive serum antibody indices for SARS-CoV-2. On day 4, respiratory deterioration required endotracheal intubation and treatment of bacterial superinfection was started according to antibiogram. Eight days later, the patient could be extubated and PCR tests were negative for SARS-CoV-2. Yet, the patient continued to show concentration difficulties and delirious behavior. Subsequent MRI (Fig. 1a c) revealed signal alterations within the claustrum/external capsule region, showing reduced diffusion. Cerebrospinal fluid (CSF) analysis disclosed a mild lymphocytic pleocytosis with negative test results for common neurotropic viruses. Tests in serum and CSF were also negative for various antineuronal antibodies. The patient recovered and was discharged with only mild cognitive impairment.

Follow-up has been carried out four months later showing a normalization in cell count of CSF and improvement of MRI findings, although the claustrum lesions persisted. Clinically, his neurological and cognitive status was normal.

Our case is characterized by evidence of parainfectious autoimmune encephalitis in the context of severe COVID-19 pneumonia. Clinically, the patient presented with various neuropsychiatric symptoms, which were reported before in other COVID-19 patients with encephalopathy [1] . Neither SARS-CoV-2 itself nor antibodies against the virus were found positive in the CSF, precluding direct viral CNS infection. Comprehensive laboratory tests ruled out antineuronal antibodies as well as common infectious causes of encephalitis, altogether supporting the diagnosis of parainfectious autoimmune encephalitis. In addition, the diagnostic criteria for possible autoimmune encephalitis as proposed by Gaus et al. were met [2] .

While immunological markers remained unspecific and imaging findings of acute necrotizing encephalitis were absent in our patient, brain MRI disclosed a unique pattern, a.k.a. the claustrum sign. Previously, this sign has been coined in MRI studies of autoimmune epilepsy, where an immune-inflammatory-mediated encephalopathy is suspected [3] . The claustrum is known to play a crucial role in regulating consciousness [6] correlating well to the Randolf Klingebiel and Wolf-Rüdiger Schäbitz both authors contributed equally to this work. clinical findings of impaired levels of consciousness in the presented case.

In autoimmune epilepsy, the claustrum signals normalized in the majority but not in all patients [4] , suggesting a varying severity of claustrum damage. This is confirmed by reduced diffusion in the first MRI scan of our patient, heralding irreversible tissue damage (as proven by the 4-month MRI follow-up). At no point in time, there was evidence for other causes of diffusion reduction, i.e., hypoxemia or status epilepticus. Comparable claustrum lesions have also been reported in the context of autoimmune encephalitis without epileptic or anoxic episodes, supporting inflammation as a decisive factor [5] .

A particular vulnerability of claustral neurons to hypoxic stress has been shown [7] , without relating to the inflammatory pathogenesis of our MRI findings. Yet, astrocyte proliferations and microglia/macrophage infiltrations of the claustrum have been observed in non-herpetic encephalitis [8] . To which extent other pathomechanisms, such as encephalitic hypermetabolism as known from the striatum [9] . Additionally, compromise the claustrum remains speculative.

Common MRI findings in a recent study of COVID-19 encephalopathy were cortical signal abnormalities on FLAIR images (37%), accompanied by diffusion reduction, leptomeningeal enhancement and cortical blooming artifacts in some cases. These imaging findings, termed by the authors themselves as "rather unspecific", did not allow [10] . MRI findings in COVID-19 encephalitis, especially when suggesting autoimmune encephalopathy may imply therapeutic interventions, such as immunosuppressive therapy. Recently, progressive clinical improvement along with a reduction of inflammatory CSF parameters has been observed in COVID-19 encephalitis, following high-dose steroid treatment [11] .

In summary, a previously undescribed imaging pattern in parainfectious COVID-19 encephalitis is presented that bears a strong resemblance to MRI findings in autoimmune encephalitic syndromes, such as known from epileptic or encephalitis caused by antineuronal antibodies. This claustrum sign should be added to the still limited knowledge of encephalitic imaging patterns in COVID-19, as it most probably represents an autoimmune phenomenon that might progress from reversible signal changes to permanent tissue damage and thus may trigger appropriate as well as timely therapy.

Author contributions FZ is lead author, analyzed and interpreted the collected data and literature, designed and wrote the manuscript. HO&AR participated in the design and coordination of the manuscript. BR&CS helped in drafting the manuscript. MR&RK provided figures and data and revised the manuscript for important intellectual content. imaging (d-e), the FLAIR-hyperintensities persist (d) whereas tissue diffusion has normalized (e). CSF-cytology (f) showed a slightly elevated cell count (9/µl) with a lymphocytic predominance (88% lymphocytes, 12% monocytes). A meaningful plasmacytic transformation was not observed, the monocytes being only slightly activated

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