With interest we read the review article by Brouwer et al. about the neurological complications of a SARS-CoV-2 infection [1]. The authors concluded that headache and taste/smell disturbances are the most frequent neurological symptoms in SARS-CoV-2 infected patients [1] We have the following comments and concerns.

We do not agree that neuro-COVID manifests only with ischemic stroke, headache, acute, hemorrhaghic, necrotising encephalopathy (AHNE), hyposmia, hypogeusia, cerebral hypoxia, and Guillain Barre syndrome (GBS) but also with several other abnormalities of the central or peripheral nervous system (CNS, PNS). CNS disorders associated with COVID-19 other than the ones described in the review include acute disseminated encephalomyelitis (ADEM), transverse myelitis, viral encephalitis, cerebellitis, immune encephalitis, epilepsy, delirium, psychosis, cytokine release syndrome, myoclonus ataxia syndrome, sinus venous thrombosis, sleep disorders, and cerebral vasculitis [Finsterer, submitted]. PNS disorders not addressed in the review are myositis, dermatomyositis, myasthenia, and mononeuropathies of cranial nerves. Additionally, the authors did not mention neurological complications of the treatment applied to COVID-19 patients such as critical ill neuropathy/myopathy, rhabdomyolysis, myasthenic syndrome, or neuroleptic malignant syndrome [Finsterer, submitted].   

We do not agree that only a single patient with AHNE due to COVID-19 has been reported [1]. According to a literature search in PubMed at least 6 further cases with AHNE due to a COVID-19 infection as per November 2020 have been reported.

We do not agree that headache in COVID-19 can be explained by hypoxia, metabolic disturbances, or systemic inflammation alone. Due to the pro-coagulatory state headache could be also due to recurrent thrombosis. Since SARS-CoV-2 affects also the endothelium of arteries it is conceivable that headache may be due to vasculitis in some cases [2]. Headache can be also associated with cerebral vasoconstriction syndrome. Since COVID-19 may also lead to posterior reversible encephalopathy syndrome (PRES) [3], it can be assumed that in some cases PRES is responsible for headache. Since SARS-CoV-2 may cause myositis of skeletal muscle, headache may be attributable to involvement of head muscles in the inflammatory process. Last but not least the infection may be associated with fear and uncertainty, which may secondary to hypertension of muscle and in particular tension headache. 

We do not agree that direct infection of the central nervous system (CNS) by SARS-CoV-2 is unlikely [1]. The authors themselves propose the invasion of the CNS by retrograde axonal migration [1]. Additionally, there is evidence that the virus disrupts the blood brain barrier (BBB) and enters the CNS via the hematogenic pathway. Further evidence for the presence of the virus in the CNS comes from pathoanatomic studies showing the intraneuronal presence of the virus [4]. There are also a number of cases with encephalitis, in which the virus could be documented in the cerebro-spinal fluid (CSF) [5].

Overall, the review by Brewer et al. has several limitations as outlined above which should be met before drawing final conclusions. Neurological manifestations of SARS-CoV-2 are much more widespread than described, the frequency of several manifestations, such as AHNE and GBS, is higher than anticipated, the pathogenesis of headache in COVID-19 is highly variable, and the virus definitively invades the CNS.