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Alain Buguet1, Manny W. Radomski2, Jacques Reis3, Raymond Cespuglio4, Peter S. Spencer5, Gustavo C. Román6
• UMR 5246 CNRS, Claude-Bernard Lyon-1 University, Villeurbanne, France
• Physiology, Faculty of Medicine, University of Toronto, Canada
• Faculté de Médecine, Université de Strasbourg, Strasbourg, France
• Neurocampus Michel Jouvet, Claude-Bernard Lyon-1 University, Lyon, France
• Department of Neurology, School of Medicine, Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, USA
• Department of Neurology, Neurological Institute, Houston Methodist Hospital, USA, and Weill Cornell Medical College, Cornell University, New York, NY, USA
• Correspondence to Prof. Alain Buguet, Malaria Research Unit, UMR 5246 CNRS, Claude-Bernard Lyon-1 University, 69622 Villeurbanne, France; firstname.lastname@example.org
We read with interest the Post-Script comment by Liu et al. highlighting the neurological manifestations of SARS-CoV-2 infection. We would like to contribute additional information on the neurology of COVID-19, as recently published by our group at the World Federation of Neurology.1 In addition to the reported disorders affecting central and peripheral nervous system as well as muscle, we add sleep-wake disorders to the list of conditions that may be associated with COVID-19 both during and fol...
We read with interest the Post-Script comment by Liu et al. highlighting the neurological manifestations of SARS-CoV-2 infection. We would like to contribute additional information on the neurology of COVID-19, as recently published by our group at the World Federation of Neurology.1 In addition to the reported disorders affecting central and peripheral nervous system as well as muscle, we add sleep-wake disorders to the list of conditions that may be associated with COVID-19 both during and following SARS-CoV-2 infection.
Sleep disorders and influenza pandemics
The Spanish flu pandemic caused by the H1N1 influenza virus of avian origin spread worldwide during the years 1918-1919. Throughout World War I, between 1915 and 1917, Jean-René Cruchet and Constantin von Economo described the occurrence of sleep-wake disorders following the initial pharyngitis. von Economo coined the name encephalitis lethargica for this condition characterized by an initial phase of hypersomnia (“somnolent ophthalmoplegia” or “sopor”).2 He also observed insomnia associated with basal ganglia “choreatic” dysfunction, circadian sleep disruption (“inversion of sleep”), sleep paralysis (“dissociation of cerebral and body sleep” and “akinetic cases”), and “somnambulism.” Identification of the clinical and neuropathological features of these disorders by von Economo launched the search for sleep-wake regulatory networks. He described the “centre for regulation of sleep” in the anterior hypothalamus and the “wake centre” in the posterior hypothalamus.2
During more recent pandemics such as the H2N2 influenza type A 1957-1958 Asian flu, or the influenza B in Japan,3 sporadic cases of Kleine-Levin syndrome were reported. This is a rare disorder characterized by recurrent episodes of excessive daytime sleepiness (hypersomnia) along with cognitive and behavioural changes. However, sleep reports were lacking after the subsequent re-emergence in 1968-1969 of the Hong-Kong flu pandemic attributed to H3N2 influenza type A virus. Four to six months after the 2009-2010 H1N1 influenza epidemic, narcoleptic syndromes were reported in Chinese children, 4 and seasonal distribution of narcoleptic syndromes was suspected after winter upper respiratory infections.
Pathways used by neurotropic influenza viruses and coronaviruses
The probable transmission pathway of H1N1 was elucidated in intranasally-infected mice that developed narcolepsy-like syndromes. 5 The virus infected the olfactory nerves (CN I) crossed the olfactory epithelium and cribriform plate (day 0 post-infection), olfactory bulb glomerular layer (day 14), and mitral and granular cells (day 28). From the olfactory bulb, the virus progressed retrogradely to orexin- and melanin-concentrating-hormone nuclei located in the lateral hypothalamus (day 28). The virus then spread to the pontine dorsal raphe and locus coeruleus nuclei.
Neurotropic coronaviruses may reach their central nervous system targets by transynaptic transmission, as shown in porcine HEV 67N coronavirus and avian bronchitis virus infections. 5 Another route is the trigeminal pathway, either from collateral nerve endings in the nasal mucosa or directly from the buccal mucosa to the cranial nerve V (CN V) nucleus. 5
Do coronaviruses behave in a similar manner? In humans, a shortcut for influenza and other viruses is considered to be through the olfactory pathway to the brain. Following SARS-CoV-1 infection patients suffered from nonrestorative sleep related to sleep instability. Sleep alterations may relate to the reported presence of cytoplasmic viral particles and viral genome sequences in hypothalamic neurons.1 Transit of viruses can occur from blood by crossing the blood-brain barrier (BBB) or via the weaker BBB of the median eminence, but neural pathways appear to be more direct.
Anosmia and ageusia represent two clinical symptoms that support the diagnosis of COVID-19. These two manifestations may occur in 86% to 88% of the cases before the appearance of the general symptoms associated with COVID-19 infection.1 The neurotropic potential of SARS-CoV-2 infection is enhanced by the presence of angiotensin-converting enzyme 2 (ACE2) receptors in neurons and glial cells. ACE2 receptors are the main attachment point for the spike S glycoprotein that mediates coronavirus entry into the host. Therefore, the above clinical symptoms in the absence of nasal congestion and rhinorrhoea implicate involvement of the olfactory nerve (CN I) and gustatory nerves. The latter nerve tracts come from the tongue and the oral cavity (CN VII and IX) and from the pharynx (CN X). Most probably, the virus may use cranial nerve tracts to enter the CNS, reaching preferentially some specific neuronal networks, notably basal ganglia, hypothalamic regulatory networks of hunger, thirst or body temperature, and sleep-wake networks (anterior and posterior hypothalamus, and mesencephalon-pontine nuclei).6 Neural invasion from infected lungs via CNs IX-X has also been postulated. Involvement of brainstem respiratory centres may be responsible for the extremely high case-fatality rate (49%) of COVID-19 patients in critical condition requiring respiratory support.1
Based on the foregoing observations, we propose that sleep specialists around the world remain aware of the possibility of COVID-19-related sleep disorders now and into the future. We also propose that patients exhibiting symptoms suggestive of cerebral invasion undergo sleep investigation. Such information should provide a better understanding of the impact of COVID-19 on the brain and assist in the clinical evaluation and the development of treatment strategies.
1. Román CG, Spencer PS, Reis J, et al. The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries. J Neurol Sci [published online 2020 May 6]. doi: 10.1016/j.jns.2020.116884
2. Von Economo C. Sleep as a problem of localization. J Nerv Ment Dis 1930;71:249-259. doi: 10.1097/00005053-193003000-00001
3. Kodaira M, Yamamoto K. First attack of Kleine-Levin syndrome triggered by influenza B mimicking influenza-associated encephalopathy. Intern Med 2012;51:1605-8. doi: 10.2169/internalmedicine.51.7051
4. Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 pandemic in China. Ann Neurol 2011;70:410-417. doi: 10.1002/ana.22587
5. Tesoriero C, Codita A, Zhang M-D, et al. H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice. Proc Natl Acad Sci U S A 2016;113:E368-E377. doi: 10.1073/pnas.1521463112
6. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol.2020;92(6) [published online 2020 Feb 27]. doi: 10.1002/jmv.25728
Contributors: All authors are lead authors. AB proposed and drafted the manuscript for intellectual concept; AB, MWR, JR, RC, PSS, GCR: conceptualisation, literature search and analysis; AB, MWR, JR, RC, PSS, GCR: writing and revision of the manuscript for intellectual content. GCR is Chair, Environmental Neurology Specialty Group of the World Federation of Neurology of which AB, JR and PSS are members.
Funding: GCR’s research is funded by the Wareing Family Fund, Houston Texas, USA.
Competing Interests: None declared.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.