key: cord-0873899-8tephu2f authors: Finsterer, Josef title: Putative mechanisms explaining neuro-COVID date: 2020-12-02 journal: J Neuroimmunol DOI: 10.1016/j.jneuroim.2020.577453 sha: fbd3579b74789e2754b12deb8bca3d1bcaf16e6c doc_id: 873899 cord_uid: 8tephu2f • Mechanisms underlying neuro-COVID are more variable than anticipated. • Neuro-COVID may be due to side effects of the treatment applied against the viral infection. • Affection of organs other than the nervous system may secondarily lead to neuro-COVD. With interest we read the article by Kayhanian et al. about the presumed neuro-immunological mechanisms underlying the involvement of the central nervous system (CNS) and the peripheral nervous system (PNS) (neuro-COVID), about the neuro-immunological responses to the viral infection, and about the therapeutic approaches for neuro-COVID [1] . Proposed mechanisms explaining neuro-COVID were direct attack of the virus, neuro-inflammation, autoimmune responses to the infection, hypercoagulability, metabolic injury, or hypoxic injury [1] . Treatment relies on targeting the virus (antivirals, neutralizing antibodies, convalescent plasma therapy), targeting the inflammatory response (immune-modulatory medications, cytokine inhibitors), and on vaccines (put in promising by BionTech, Moderna, AstraZenica) [1] . We have the following comments and concerns. A mechanism responsible for neuro-COVID not considered by the authors is the damage of the CNS/PNS by the empiric treatment applied to COVIDpatients. Most of the COVID-19 patients receive antivirals, antibiotics, chloroquine, steroids, and biologicals (e.g. tocilizumab (IL-6 blocker). From remdesivir, ritonavir, and lopinavir it is known that they occasionally trigger rhabdomyolysis [2] . From chloroquine it is well known that it may cause toxic myopathy [3] . Known side effects of tocilizumab include arterial hypertension, hyperlipidemia, obesity, infections, bowel ulceration, and heart failure [4] , which may secondarily cause cerebrovascular disease. From azithromycin and meropenem, and linezolid it is well known that they are myotoxic. In a single COVID-19 patient chloroquine triggered the development of a myasthenic syndrome [5] . A second mechanism responsible for neuro-COVID not considered by the authors is secondary CNS/PNS damage through affection by the virus of other organs. These other organs particularly include the heart and the arteries. Ischemic stroke in COVID-19 may not only result from thrombus formation due to hyper-coagulability directly in the brain but also from thrombus formation in distant veins from where thrombi may embolise via a patent foramen (PFO) to the CNS. There is also evidence that SARS-CoV-2 may cause myocarditis [6] which may lead to intra-ventricular thrombus formation and secondarily to ischemic stroke. Myocarditis may also go along with heart failure, which may lead to low output failure and consecutively cerebral watershed infarctions. Myocarditis may be also complicated by supra-or ventricular arrhythmias, which may secondarily lead to intra-ventricular thrombus formation and eventually ischemic stroke. Severe COVID-19 may J o u r n a l P r e -p r o o f Journal Pre-proof be complicated by arterial hypertension, which may eventually cause ischemic stroke or intra-cerebral bleeding (ICB). Arterial hypertension may also result from affection of the kidneys by the viral infection, which may be complicated by renal hypertension and secondarily by stroke or ICB. The authors propose hypoxic injury as a possible mechanism underlying CNS/PNS involvement in COVID-19 [1] . Cerebral hypoxia usually results from near drowning, asphyxia, cardiac arrest, or respiratory failure. Whether cerebral hypoxia may result from extra-corporal membrane oxygenation (ECMO) therapy, frequently required for COVID-19 patients with severe acute respiratory distress syndrome (ARDS), remains unproven. Supposing that global CNS hypoxia is responsible for neuro-COVID, typical features on cerebral imaging should be present. First, primarily the grey matter, such as the cortex, basal ganglia (BG), thalami, the cerebellum, and hypocampi should be affected. Second, lesions at these locations should show up as diffuse edema, loss of grey/white matter differentiation, BG hypodensity, reversal sign, white cerebellum sign, linear hyperdensity outlining the cortex, and pseudo-subarachnoid bleeding on cerebral computed tomography (CCT), and as cytotoxic edema on multimodal magnetic resonance imaging (MRI) within the first 24h after hypoxia [7] . MRI lesions are hyperintens on T2-imaging. These lesions are followed by pseudo-normalisation after about 1 week [7] . After 1-2 weeks T1-hyperintensity indicating cortical laminar necrosis becomes evident [7] . However, such dynamic lesions have not described in patients with neuro-COVID, why it is unlikely that cerebral hypoxia plays a crucial role in the development of neuro-COVID. Additionally, most patients with COVID-19 develop respiratory failure subacutely, why most of them are intubated and ventilated in due time and thus not hypoxic. Neurological manifestations of COVID-19 not addressed in the review were movement disorders (e.g. myoclonic ataxia syndrome) [8] , cerebellitis [9] , acute necrotising encephalitis [10] , limbic encephalitis [11] , cerebral vasculitis [12] , pituitary apoplexia [13] , posterior reversible encephalopathy syndrome (PRES) [14] , and dermatomyositis [15] . Overall, the valuable review by Kayhanian et al. has some limitations which should be met before the conclusions drawn can be justified. Mechanisms leading to neuro-COVID may be more variable than anticipated. Treatment may occasionally be more harmful than beneficial. SARS-CoV-2 and nervous system: From pathogenesis to clinical manifestation Major Neurologic Adverse Drug Reactions, Potential Drug-Drug Interactions and Pharmacokinetic Aspects of Drugs Used in COVID-19 Patients with Stroke: A Narrative Review Side Effects of Chloroquine and Hydroxychloroquine on Skeletal Muscle: a Narrative Review Tocilizumab monotherapy for large vessel vasculitis: results of 104-week treatment of a prospective, single-centre, open study. 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Posterior Reversible Encephalopathy Syndrome in Patients with Coronavirus Disease 2019: Two Cases and A Review of The Literature Dermatomyositis during COVID-19 Pandemic (A Case Series): Is there a Cause Effect Relationship?