We read with interest the review article by Wan et al. about the neurological complications of COVID-19 and its mechanisms of infection by SARS-CoV-2 [1]. It was concluded that SARS-CoV-2 may enter the brain via pathways other than invasion of the olfactory nerve, inflammatory responses disrupting the blood-brain-barrier (BBB), or infection of vascular endothelial cells [1]. The study is appealing but raises concerns and comments. The main shortcoming of the review is that the number of neurological complications after SARS-CoV-2 infections is incomplete. The authors did not consider various central nervous system (CNS) disorders, such as cerebellitis, ventriculitis, cerebral vasculitis, giant cell arteritis, transverse myelitis, optic neuritis, hypophysitis, cerebral vasoconstriction syndrome, pontine myelinolysis, and venous sinus thrombosis (VST) as manifestations of neuro-COVID. Missing are also some manifestations of neuro-COVID in the peripheral nervous system (PNS), such as cranial neuritis, myasthenia, myasthenic syndrome, and Parsonage-Turner syndrome. The various pathophysiological models according to which the virus allegedly enters the brain are nice but unsupported by real world data. For example, in almost all patients with SARS-CoV-2 associated GBS, SARS-CoV-2 could not be detected within the cerebro-spinal fluid (CSF) [2], suggesting that the virus not necessarily needs to invade the CNS to cause CNS damage. We do not agree with the statement that “cerebro-vascular disease is characterised by damage to brain tissue due to intra-cranial blood circulation disturbances” [1]. Cerebro-vascular disease may also derive from damage to extra-cranial arteries, from cardiac abnormalities, and even from disease of the peripheral veins in case of a patent foramen ovale. The cardiac origin of cerebro-vascular disease is crucial to encounter as the heart can be affected by the SARS-CoV-2 infection as well and may secondarily lead to cerebro-vascular disease. Cardiac abnormalities that have been reported in SARS-CoV-2 infected so far include endocarditis, which is usually secondary due to infectious agents other than SARS-CoV-2, myocarditis, which is usually immune-mediated and responds to immune-suppressive treatment [3], and Takotsubo syndrome, a stress-related transient heart failure. All these conditions may be complicated by intra-ventricular thrombus formation and thus a risk of cardio-embolism.
We also do not agree with the cartoon in figure 1, distinguishing between Guillain-Barre syndrome (GBS) and Miller-Fisher syndrome (MFS). MFS is one of several subtypes of GBS, which can be associated with other subtypes of GBS.
Table 1 is misleading as it lists cerebro-vascular disease, ischemic stroke and others under the header “neurological symptoms of SARS-CoV-2” [1]. Cerebro-vascular disease and ischemic stroke, posterior reversible encephalopathy syndrome (PRES), acute, hemorrhagic, necrotising encephalitis (AHNE), cerebral edema, multiple sclerosis, NMO-spectrum disorders, GBS, MFS, rhabdomyolysis are neither symptoms nor signs of a neurological disease but in fact neurological disorders.
A stroke mechanism not discussed in the review is dissection of the internal carotid artery which has been repeatedly reported in SARS-CoV-2 infected [4].
Missing is a discussion about neurotoxic side effects of anti-COVID-19 drugs frequently applied to patients with severe COVID-19.
Overall, the interesting review has some limitations which challenge the results and their interpretation. A number of SARS-CoV-2 associated neurological disorders are missing, cardiac involvement in SARS-CoV-2 infections should be considered as a pathophysiological mechanisms of neuro-COVID. Though neuro-COVID is increasingly recognised as a complication of COVID-19, there is a need to elucidate the pathophysiological background in order to develop the most appropriate treatment for patients with neuro-COVID.
Ethical Approval
Ethical approval and consent to participate: not applicable
Consent for Publication:
Not applicable
Availability of Data and Material:
All data reported are available from the corresponding author
Competing Interests:
None
Funding
None received
Acknowledgements:
None
Author Contribution:
JF: design, literature search, discussion, first draft, critical comments, FS: literature search, discussion, critical comments, final approval
Wan, D. et al. "Neurological complications and infection mechanism of SARS-COV-2." Signal Transduction and Targeted Therapy, vol. 6, no. 1, 2021, pp. 406. doi:10.1038/s41392-021-00818-7.
Finsterer, J. and Scorza, F.A. "Guillain-Barre syndrome in 220 patients with COVID-19." Egyptian Journal of Neurology, Psychiatry and Neurosurgery, vol. 57, no. 1, 2021, pp. 55. doi:10.1186/s41983-021-00310-7.
Kwon, S. et al. "COVID-19 myocarditis: A case report, overview of diagnosis and treatment." Infectious Diseases in Clinical Practice (Baltimore, Md.), vol. 29, no. 6, 2021, pp. e414–e417. doi:10.1097/IPC.0000000000001016.
Gencler, O.S. et al. "Unilateral common carotid artery dissection in a patient with recent COVID-19: An association or a coincidence?" Journal of Clinical Neuroscience, vol. 87, no. 1, 2021, pp. 26–28. doi:10.1016/j.jocn.2021.02.010.
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