Viruses & nervous system disorders: insights from other pandemics

Everyone knows about the terrible Spanish flu that killed an estimated toll of 17 to 50 million people worldwide after the First World War. However, much less is known about the “Encephalitis Lethargica” pandemic that spread at the same time. That is in the late 1916s that Baron Constantin von Economo, soon followed by a French physician, René Cruchet, examined at the Psychiatric- Neurological Clinic of the University of Vienna several patients who presented unusual neurological symptoms. Diagnosed with disorders as varied as meningitis, multiple sclerosis or delirium, the signs and symptoms of these patients did however not really match the usual clinical picture of these diseases. Many patients in particular exhibited marked lethargy, which led Von Economo to design this set as a distinct disease entity, which he called Encephalitis Lethargica. Beginning in the winter 1916–17, this neurological syndrome spread across Europe and then the world, up into the 1930s. Although the exact number of victims of Encephalitis Lethargica (E.L.) during the pandemic is unknown, it has been estimated to reach more than one million worldwide (Hoffman and Vilensky 2017). After the number of acute cases decreased, many patients suffered chronic sequelaes that rendered them nearly akinetic. Despite a lack of recurrence of this epidemic, some putative sporadic cases continue to be observed. After more than a century of research, the aetiology of E.L. is still unknown but the hypothesis of a viral infection remains quite prevalent. Despite some similarity of the initial phase of E.L. to a flu prodrome (with features typical of an upper respiratory tract infection), it was soon obvious, from the signs and symptoms of affected patients, that the nervous system was involved. Interestingly, von Economo noticed some degree of epidemiological connection between influenza and E.L. which transiently led him to question a possible influenza aetiology to E.L. However, the existence of neuropathological differences in the brains of patients affected by either disease led clinicians to suggest that E.L. and influenza were distinct entities, but that influenza might predispose a person to infection with E.L. Interestingly, such a potential interrelationship has also been suggested to underlie the link that was made between narcolepsy and the H1N1 Pandemrix vaccine developed during the 2009 (H1N1) influenza pandemic. Indeed, the risk associated with Pandemrix vaccination (relative risk of developing narcolepsy of 12.7) seemed reduced when wild-type infection had been contracted farther back in time from vaccine administration, raising questions on a potential interaction between wild-type influenza infection and vaccination. A case-control study has reported an increased risk for narcolepsy in individuals who carried flu infections in the year before the onset of their disease (Picchioni, Hope et al. 2007). The pathogenesis of nervous system disturbances induced by influenza viral infections has been proposed to include both some effects of cytokines storms and some primary lesions due to viral invasion of the nervous system. Certain influenza strains are able to invade the brain through retrograde axonal transport to the brain, in particular through the olfactory and trigeminal nerve (Tesoriero, Codita et al. 2016).

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