We appreciated to read the review article by Al‐Sarraj [1] about the pathophysiology of neurological impairment in SARS-CoV-2 infected patients with COVID-19 (neuro-COVID [1]. The authors proposed four mechanisms to explain involvement of the Central Nervous System (CNS) or the Peripheral Nervous System (PNS) in COVID-19 and concluded that cerebral abnormalities probably represent a combination of direct cytopathic effects mediated by SARS-CoV-2 replication or indirect effects due to respiratory failure, injurious cytokine reaction, reduced immune response, or cerebrovascular accidents induced by coagulopathy due to viral infection [1]. Pathways via which the virus may enter the CNS include taste buds and olfactory epithelial cells, the hematogenous route, or via immune cells originating from the respiratory tract [1]. We have the following comments and concerns.

The authors do not consider side effects of drugs as causative for various neurological abnormalities. It is well known that steroids, chloroquine, protease-inhibitors (lopinavir/ritonavir), remdesivir, azithromycin, toclizumab, or cromstat can trigger neurological adverse reactions. Steroids can cause mitochondrial myopathy. Protease-inhibitors carry the risk of triggering sensory neuropathy [2]. Azithromycin is known to trigger rhabdomyolysis [3]. Toclizumab has been reported to cause facial palsy and diplopia [4]. Chloroquine may cause toxic myopathy [5] or even a myasthenic syndrome [6].

Since many COVID-19 patients with severe pulmonary compromise require mechanical ventilation and long-term stay on the ICU, it is conceivable that at least some of them may develop critical ill neuropathy or critical ill myopathy. Critical ill neuropathy/myopathy may strongly determine the duration of rehabilitation and outcome of COVID-19 patients [7]. 

Unfortunately, there is no mentioning of myasthenia [8] or myasthenic syndrome [6] as a neurological complication of COVID-19. Though MG has been reported as a manifestation of COVID-19 in three patients as of 18^th September [8], it is conceivable that MG induced by COVID-19 is more frequent but neglected, particularly in patients on the Intensive Care Unit (ICU), where pulmonary compromise may dominate the clinical presentation. In a recent mini-review it has been found that exacerbation of MG in 50% of the MG patients with COVID-19 MG   and   SARS-CoV-2 triggered a myasthenic crisis in 20% of these cases [9]. There is also no discussion of mononeuropathies of cranial nerves associated with SARS-CoV-2.

Though it is conceivable that SARS-CoV-2 enters the CNS via taste buds or olfactory epithelial cells, presence of the virus has been only rarely documented within neurons, glial cells, endothelial cells, or the Cerebrospinal Fluid (CSF). In a mini-review about Guillain Barre Syndrome (GBS) in 62 COVID-19 patients the virus respectively virus-RNA was not detected in any of the 62 included patients [10]. In a mini-review about 48 patients with infectious or immune-mediated CNS disease, the CSF was positive for the virus in only 4 cases [11]. From these preliminary results it can be concluded that the virus is present only temporarily in the CSF, resides in a hibernated form within cells of the CNS, or is not directly involved in the pathogenesis of neuro-COVID. More likely than a direct viral attack is a secondary reaction of the CNS or PNS to the immunological reaction against the virus. It has been postulated that antibodies against the virus may cross-react with receptors in the CNS/PNS and that a storm of cytokines may secondarily affect neurons, glial cells, vascular smooth muscle cells, or endothelial cells [12]. 

In conclusion, we definitively need more CSF investigations and autopsy studies for virus RNA during all stages of COVID-19. Only if a systematic and prospective study of COVID-19 patients for the presence of the virus-RNA is carried out, the pathophysiological role of the virus for neurological disease can be settled. 

Author Contribution

JF: Design, literature search, discussion, first draft, critical comments. JF, FS, CS and AF: literature search, discussion, critical comments. All authors have read the journal’s position on issues involved in ethical publication.

1. Al‐Sarraj, S. et al. “The spectrum of neuropathology in COVID-19.” Neuropathology and Applied Neurobiology, 2020, doi:10.1111/nan.12667.

2. Ellis, R.J. et al. “Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy.” Annals of Neurology, vol. 64, no. 5, 2008, pp. 566–72. doi:10.1002/ana.21484.

3. Teng, C. et al. “Rhabdomyolysis associations with antibiotics: A pharmacovigilance study of the FDA Adverse Event Reporting System (FAERS).” International Journal of Medical Sciences, vol. 16, no. 11, 2019, pp. 1504–9. doi:10.7150/ijms.38605.

4. Dastan, F. et al. “Promising effects of tocilizumab in COVID-19: A non-controlled, prospective clinical trial.” International Immunopharmacology, vol. 88, 2020, 106869. doi:10.1016/j.intimp.2020.106869.

5. Shukla, S. et al. “Pearls & oy-sters: Hydroxychloroquine-induced toxic myopathy mimics Pompe disease: Critical role of genetic test.” Neurology, vol. 92, no. 7, 2019, e742–e745. doi: 10.1212/WNL.0000000000006914.

6. Koc, G. et al. “Myasthenic syndrome caused by hydroxychloroquine used for COVID-19 prophylaxis.” Journal of Clinical Neuromuscular Disease, vol. 22, no. 1, 2020, pp. 60–62. DOI: 10.1097/CND.0000000000000316.

7. Lin, Y.H. “Intensive care during a global epidemic.” Hu Li Za Zhi, vol. 67, no. 3, 2020, pp. 4–5. doi:10.6224/JN.202006_67(3).01.

8. Restivo, D.A. et al. “Myasthenia gravis associated with SARS-CoV-2 infection.” Annals of Internal Medicine, 2020, doi: 10.7326/L20-0845.

9. Finsterer, J. et al. “SARS-CoV-2 and myasthenia.” Journal of Medical Virology, 2020, doi:10.1002/jmv.26501.

10. Finsterer, J. et al. “SARS‐CoV‐2 associated Guillain‐Barre syndrome in 62 patients.” European Journal of Neurology, 2020.

11. Finsterer, J. and F.A. Scorza. “Infectious/parainfectious, nonvascular, nonhypoxic central nervous system disease in 48 COVID-19 patients.” Journal of Medical Virology, 2020, doi:10.1002/jmv.26399.

12. Yamamoto, V. et al. “COVID-19: Review of a 21st century pandemic from etiology to neuro-psychiatric implications.” Journal of Alzheimer’s Disease, vol. 77, no. 2, 2020, pp. 459–504. doi: 10.3233/JAD-200831.