Neurological consequences of Covid-19

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There is as yet very little in the published literature on the neurological consequences of Covid-19 (the disease caused by infection with SARS-Cov-2). The first extensive report – a retrospective consecutive case series of 214 patients from Wuhan, China, with either moderate or severe COVID-19, was published in JAMA Neurology in early April 2020.(1) Of these patients, 36.4% had neurological symptoms, some specific to the central or peripheral nervous systems (e.g. anosmia, dysgeusia, stroke, myopathy), and others less so (headache, depressed level of consciousness, dizziness, seizures). In the case of the latter symptoms, it is difficult to know whether they are due to the disease itself, or to the body’s reaction to it. More severe neurological symptoms were generally seen in patients with more severe respiratory involvement, but again it is difficult to be certain whether this reflects direct neurological involvement, or the presence of common co-morbidities such as hypertension, diabetes, or obesity.

In addition to this, isolated case reports of more serious neurological conditions associated with Covid-19 are starting to appear, including potential cases of encephalitis or encephalopathy,(2,3) acute disseminated necrotising encephalomyelitis,(4) and Guillain-Barré syndrome.(5)

How might SARS-Cov-2 affect neurological function? We know, from experience with SARS and MERS, that in rare cases coronavirus infection can be associated with conditions that affect the peripheral neurological system (PNS). Patients with SARS have been reported to develop axonal neuropathy or myopathy, possibly due to a virally-induced vasculitis in these tissues.(6) A handful of such cases have been reported following MERS infection, though it is again unclear whether these were due to the infection itself, or to the consequences of critical illness and/or some of the antiviral treatments given.(7) Reports of parasthesiae and skeletal muscle injury in Covid-19 patients are intriguing, but further neurophysiological and histological studies are needed to understand the pathophysiological processes behind these observations.

There is no doubt that coronaviruses can potentially enter the central nervous system (CNS). Post-mortem examination of the brains of patients dying of SARS showed histological changes in cortex and diencephalic neurons.(8) There is now good evidence that SARS-Cov-2 invades target cells by binding of its surface spike protein to the ACE2 receptor, which is distributed widely in human body tissues, including the central nervous system.(9) The most likely portal of entry is ACE2-expressing cells in the olfactory epithelium, whence axons and dendrites extend to the olfactory bulb, and on towards the olfactory nucleus in the pyriform cortex. In rodents exposed to SARS-CoV by inhalation, the virus was found in the olfactory bulb, and within four days it could be detected in the pyriform cortex, and in dorsal nucleus of the raphe in the brainstem.(10) It is likely that the high prevalence of anosmia and dysgeusia in patients with Covid-19 is due to viral olfactory neuropathy, but whether this risk is increased by nicotine exposure through smoking (including e-cigarettes, or vaping) because of functional interactions between the nicotinic receptor and ACE2, is not clear.(11) Some authorities to speculate that respiratory distress in Covid-19 patients may be due to virally-induced dysfunction in central respiratory control centres, though this is disputed.(12,13)

Finally, because of the effects that SARS-Cov-2 has on the blood and endothelium – in severe cases hypertension, hypercoagulability, microthrombi, and disseminated intravascular coagulation (DIC) are all reported, as well as the risk of embolism from cardiac injury – patients with Covid-19 may be at risk of cerebrovascular complications, such as ischaemic stroke, cerebral haemorrhage, or cerebral venous thrombosis. At present only one such case has been reported in which a direct link between Covid-19 infection and intracranial haemorrhage is postulated.(14)

All neurologists should be on the lookout for cases of neurological disease associated with SARS-Cov-2 infection. It will be difficult in many instances to be certain about the exact pathophysiology of the association. In the last two weeks I have seen a case of facial palsy following on from an (untested) illness, very likely to have been Covid-19, and a patient in whom a previous tendency to migraine was reactivated halfway through a proven bout of Covid-19, and outlasted the resolution of other systemic features by a couple of weeks: are these direct effects of the virus, or consequences of the body’s immune reaction to it? Time – and more research – will tell.

In an forthcoming blog, I will look at the indirect neurological consequences of Covid-19: what effect is the pandemic having on neurological services in the UK and beyond?

References

  1. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020. Published online April 10, 2020. doi:10.1001/jamaneurol.2020.1127
  2. Zhou L, Zhang M, Gao J, Wang J. Sars-Cov-2: underestimated damage to nervous system, Travel Med Infect Dis [Internet] 2020 101642. doi.org/10.1016/j.tmaid.2020.101642
  3. Filatov A, Sharma P, Hindi H, Espinosa P. Neurological complications of Coronavirus disease (COVID-19). Encephalopathy 2020. 12: 3.
  4. Poyiadji N, Shahin G, Noujaim D, et al. COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology [Internet] 2020. 31. 201187. doi.org/10. 1148/radiol.2020201187.
  5. Zhao H, Shen D, Zhou H, et al. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurology 2020. Published online April 1, 2020 doi.org/10.1016/ S1474-4422(20)30109-5
  6. Tsai L-K, Hsieh S-T, Chao C-C, et al. Neuromuscular disorders in severe acute respiratory syndrome. Arch Neurol 2004. 61: 1669-1673. doi:10.1001/archneur.61.11.1669
  7. Kim J, Heo J, Kim H et al. Neurological complications during treatment of Middle East respiratory syndrome. J Clin Neurol 2017. 13: 227-33.
  8. Gu J, Gong E, Zhang B, et al., Multiple organ infection and the pathogenesis of SARS, J Exp Med 2005. 202: 415-24.
  9. Walls A, Park Y-J, Tortorici M, et al. Structure, function, and antigenicity of the SARS-Cov-2 spike glycoprotein. Cell 2020. Published online March 09, 2020. doi.org/10.1016/j.cell.2020.02.058
  10. Netland J, Meyerholz D, Moore S, et al. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 2008. 82: 7264-75
  11. Kabbani N, Olds J. Does COVID19 infect the brain? If so, smokers may be at higher risk. Molecular Pharmacology Fast Forward. Published online April 1, 2020. doi.10.1124/molpharm.120.000014
  12. Li Y-C, Bai W-Z , Hashikawa T. The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020. doi:10.1002/jmv.25728
  13. Turtle L. Respiratory failure alone does not suggest central nervous system invasion by SARS-CoV-2. J Med Virol 2020.  doi: 10.1002/jmv.25828
  14. Karimi N, Rouhani N. COVID 19 and intra cerebral hemorrhage: causative or coincidental, New Microb New Infect [Internet] 2020. 100669. doi.org/10.1016/j.nmni.2020.100669