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Can narcolepsy research help solve one of the greatest medical mysteries of the 20th century?

In late 1916, while the world was entrenched in the Great War, two physicians on opposing sides of the conflict started to encounter patients who presented with bizarre neurological signs. Most notably, the patients experienced profound lethargy, and would sleep for abnormally long periods of time. One of the physicians, Constantin von Economo, was at the Psychiatric-Neurological Clinic at the University of Vienna. The other, René Cruchet, was a French physician in a military hospital for neuropsychiatric disorders. Both physicians were perplexed by the strange constellation of neurological signs and symptoms they observed in their patients, but because of their positions on opposing sides of the war, there was no way either of them could have known that these were not isolated cases, but the beginning of a worldwide epidemic that would claim over a million lives over the next decade, and leave many survivors permanently disabled.

Over 100 years later, the cause of encephalitis is still unknown. A recent article by Hoffman and Vilensky reviewed the previous and current hypotheses regarding the aetiology of encephalitis lethargica. Some of the most promising research into the possible cause of this bizarre disease comes from studies of narcolepsy. Like encephalitis lethargica, narcolepsy causes excessive sleepiness, often accompanied by paralysis or cataplexy. Narcolepsy was a recognized condition in 1916, and when von Economo encountered his first encephalitis lethargica patients, he immediately recognized the similarities between the two disorders. By examining the brains of encephalitis lethargica victims, von Economo was the first to correctly associate the hypothalamus with sleep regulation. Brains from patients who experienced pathological sleepiness consistently exhibited lesions in the posterior hypothalamus. Conversely, patients who experienced insomnia had brain lesions in the preoptic area of the anterior hypothalamus, an area now known as the “sleep center.”

So how can narcolepsy research help to answer the question that has been plaguing scientists for a century? It turns out that encephalitis lethargica and narcolepsy have more in common than just sleepiness. Both have a complex, yet undeniable relationship with the flu. Encephalitis lethargica appeared around the same time as the Spanish flu epidemic, and most encephalitis lethargica patients initially presented with influenza-like symptoms, including fever, fatigue, and pharyngitis. Although a causative relationship has never been proven, there appears to be an epidemiological connection between influenza and encephalitis lethargica. Similarly, many European countries reported an increase in narcolepsy cases following influenza vaccination or infection with influenza during the 2009 H1N1 influenza pandemic.

It turns out that encephalitis lethargica and narcolepsy have more in common than just sleepiness.

The exact cause of narcolepsy is unclear, but it is associated with lower levels of hypocretin in the cerebrospinal fluid. Hypocretin (also known as orexin) is a neuropeptide produced in the hypothalamus that regulates wakefulness and appetite. Most narcoleptics have a reduced number of hypocretin-producing neurons in the hypothalamus. While the cause of neuronal loss is not entirely clear, it has been hypothesized that an autoimmune mechanism may be to blame. Vaccine-associated narcolepsy, appears to be the result of a cross-reaction between hypocretin receptor 2 antibodies and a fragment of influenza protein used to create the vaccine. Individuals who develop narcolepsy following flu vaccination may already have a genetic predisposition for narcolepsy, coupled with an overactive immune system that is triggered by the vaccine, leading to the development of narcolepsy.

Von Economo hypothesized that infection with influenza might predispose a person to infection with encephalitis lethargica by increasing the permeability of the mucous membranes. The concept of autoimmunity was not discovered until the 1950s. Since then, a few hypotheses have pointed to an autoimmune mechanism as the cause of encephalitis lethargica. A 2004 study by Dale and colleagues suggested that encephalitis lethargica was a paediatric autoimmune neuropsychiaric disorder associated with streptococcal infection (PANDAS) disease. The same investigators later proposed that it was caused by autoimmunity against NMDA receptors.

Current research on the aetiology of encephalitis lethargica is severely limited by the scarcity and poor quality of existing specimens from the epidemic period, and the rarity of new cases. Barring another epidemic, we might never learn the cause of this mysterious illness, and why it essentially disappeared by the late 1920s. However, given the similarities between the two illnesses, ongoing research on narcolepsy could provide clues to help unravel what has been called the greatest medical mystery of the 20th century.

Featured image credit: Neurons by geralt. CC0 public domain via Pixabay.

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