key: cord-288484-qy619tfg
authors: Bernard‐Valnet, R.; Pizzarotti, B.; Anichini, A.; Demars, Y.; Russo, E.; Schmidhauser, M.; Cerutti‐Sola, J.; Rossetti, A. O.; Du Pasquier, R.
title: Two patients with acute meningoencephalitis concomitant with SARS‐CoV‐2 infection
date: 2020-05-30
journal: Eur J Neurol
DOI: 10.1111/ene.14298
sha: 
doc_id: 288484
cord_uid: qy619tfg

In December 2019, a cluster of patients with pneumonia of unknown cause led to the identification of a new strain of pandemic coronavirus called Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first SARS-CoV outbreak, human coronaviruses are known for their neurological tropism. If respiratory complications are at the forefront of clinical presentation of SARS-CoV-2, neurological involvement remains poorly described and understood. We report here two patients infected with SARS-CoV-2 who presented with neurological symptoms and signs.

In December 2019, a cluster of patients with pneumonia of unknown cause led to the identification of a new strain of pandemic coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] . Since the first SARS-CoV outbreak, human coronaviruses have been known for their neurological tropism [2, 3] . Respiratory complications are at the forefront of the clinical presentation of SARS-CoV-2 and neurological involvement remains poorly described and understood. We report here two patients infected with SARS-CoV-2 who presented with neurological symptoms and signs.

The clinical and ancillary test descriptions were personally retrieved by the authors, who examined the patients. This report was conducted in compliance with the Swiss Federal Act on Research involving Human Beings, which waives ethical approval for case reports of less than five patients. Both patients gave written informed consent for clinical and biological data to be used for this report. Viral/bacterial detection was performed using the FilmArray Meningitis/ Encephalitis Panel (BioFire Diagnostics, Salt Lake City, UT, USA) and confirmed by traditional polymerase chain reaction.

Patient 1 was a 64-year-old woman without psychiatric history, known to have had contact with SARS-CoV-2 (her husband tested positive 15 days before) and presenting for 5 days with flu-like symptoms (mild asthenia, myalgia, cough) without fever, acutely developed psychotic symptoms. She was first admitted to a psychiatric ward, but presented a tonico-clonic seizure motivating her admission to an external hospital. A routine electroencephalogram revealed nonconvulsive, focal status epilepticus (abundant bursts of anterior low-to mediumvoltage irregular spike and waves superimposed on an irregularly slowed theta background) that was managed with intravenous clonazepam and valproate. She was immediately referred to our center. The patient appeared disoriented, with strong attention deficit, verbal and motor perseverations and bilateral grasping, alternating with psychotic symptoms (hyper-religiosity with mystic delusions, visual hallucinations). There was no neck stiffness or focal signs on neurological examination. Cerebral magnetic resonance imaging was normal, but her lumbar puncture was compatible with viral meningoencephalitis (Table 1) and SARS-CoV-2 was detected in her nasopharyngeal swab. However, neither SARS-CoV-2 nor classic viral/bacterial pathogens were detected in the cerebrospinal fluid (CSF) ( Table 1. ). Anti-Nmethyl-D-aspartate antibodies were tested negative in CSF. Treatment by acyclovir was transiently administered until herpes simplex/varicella zoster virus polymerase chain reaction results came back negative. A follow-up electroencephalogram 24 h after admission showed a moderate theta background slowing, without epileptiform features. The patient markedly improved 96 h after admission with resolution of her symptoms.

A 67-year-old woman, already diagnosed with SARS-CoV-2 infection for 17 days with mild respiratory symptoms, presented an intense wake-up headache. A few hours later, she was found drowsy and confused, lying on the floor of her bathroom. She was referred to our hospital. On neurological evaluation, she was disoriented with motor perseverations, bilateral grasping, aggressiveness and left hemianopia and sensory hemineglect; there was no neck stiffness. SARS-CoV-2 pneumonia was diagnosed by a positive nasopharyngeal swab and an ultrasound showing subpleural condensation. Brain magnetic resonance imaging was normal and her lumbar puncture revealed lymphocytic pleocytosis (Table 1) . However, CSF SARS-CoV-2 and viral/bacterial pathogen polymerase chain reaction tests were negative (Table 1 ). The patient transiently received ceftriaxone, amoxicillin and acyclovir. Neurological symptoms resolved within 24 h, except for a mild headache. The patient was discharged 72 h after admission with no symptoms.

We report on two patients who developed meningoencephalitis a few days after a diagnosis of SARS-CoV-2 infection. Both had a 'benign' form with only mild respiratory and general symptoms. However, they suddenly developed severe neuropsychological symptoms and one developed a status epilepticus. The CSF *These authors contributed equally to the article.

profiles being compatible with viral meningoencephalitis, a large screening for the usual pathogens, including SARS-CoV-2, was performed but was negative. Although proof of a direct involvement of SARS-CoV-2 is missing, we hypothesize that it was responsible for this neurological presentation. Firstly, the usual pathogens that cause viral meningoencephalitis were negative. Second, the neurological picture occurred in the wake of proven SARS-CoV-2 infection. Third, coronaviruses are known for their neurological tropism and for inducing encephalitis. It is of note that CSF detection of coronavirus RNA seems infrequent [3] . A possible mechanism accounting for the encephalitic presentation in these patients may be a para-infectious one, somewhat reminiscent of the association of coronaviruses with acute disseminated encephalomyelitis and (for SARS-CoV-2) Guillain-Barr e syndrome [4, 5] . Such a mechanism would explain the rapid clinical recovery of both patients and the absence of magnetic resonance imaging lesions, suggesting a limited viral process, contrary to a previous report showing severe encephalitis and viral RNA in the CSF, although, in this case, herpes simplex virus encephalitis was not formally excluded [6] .

To conclude, we report the first temporal association between acute SARS-CoV-2 infection and aseptic encephalitis with focal neurological symptoms and signs. Further studies are needed to identify the spectrum of neurological complications of this pandemic outbreak and the underlying pathophysiological mechanisms.

A novel coronavirus from patients with pneumonia in China

Multiple organ infection and the pathogenesis of SARS

Neurologic alterations due to respiratory virus infections

Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis

Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence?

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

We would like to thank Prof. Pierre-Alexandre Bart, Dr David Gachoud, Dr Jan Novy, Dr Nicola Marchi and Dr Sergiu Vijala for taking care of these patients at different steps during their hospitalization. We would also like to acknowledge the work of Dr Onya Opota, Dr Katia Jaton and Prof. Gilbert Greub in molecular biology diagnostic testing. 

anti-N-methyl-D-aspartate receptor, anti-contactin-associated protein-like 2, anti-Leucine-rich glioma-inactivated 1, anti-dipeptidyl-peptidaselike protein 6, anti-gamma aminobutyric acid B receptor, anti-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, anti-immunoglobulin-like cell adhesion molecule 5, anti-metabotropic glutamate receptor 5 and anti-glycine receptor.