COVID-19: can we learn from encephalitis lethargica?

In 1918, influenza caused one of the most severe pandemics in history. Encephalitis lethargica emerged at around the same time and affected more than one million individuals. It had a nonspecific prodromal phase, with influenza-like symptoms, and an acute phase, characterised by fever, sleepiness, ocular motility disturbances, and movement disorders. Months to years later, patients experienced subtle chronic neurological manifestations, mainly postencephalitic parkinsonism.¹

Whether 1918 influenza caused encephalitis lethargica is unclear. Von Economo, who first described encephalitis lethargica, proposed a viral cause, and spreading through nasal membranes.¹ Damage of the upper midbrain and substantia nigra has been reported in encephalitis lethargica, and brain atrophy and neurofibrillary tangles have been reported in postencephalitic parkinsonisms, suggesting a shared neurodegenerative component.¹

Up to 85% of patients with SARS-CoV-2 have minor neurological symptoms such as anosmia.² Translational models suggest coronaviruses can be neuroinvasive, with an olfactory route into the CNS,³ transport along axons,³ and neuron-to-neuron propagation towards the brainstem.⁴ Such transmission would fit with Von Economo's hypothesis and is reminiscent of spreading via neural connections in neurodegenerative conditions.⁵

We should take advantage of both historical and novel evidence. The prevalence of anosmia, combined with the neuroinvasive properties of coronaviruses, might support neuroinvasion by SARS-CoV-2. Whether the infection might trigger neurodegeneration, starting in the olfactory bulb, in predisposed patients is unknown. We should not underestimate the potential long-term neurological sequelae of this novel coronavirus.