Encephalitis Lethargica: The Still Unexplained Sleeping Sickness

The encephalitis lethargica epidemic of 1916-1930 is estimated to have affected at least half a million of people in Europe and still remains a mystery.

The encephalitis lethargica epidemic of 1916-1930 is estimated to have affected at least half a million of people in Europe. The disease is documented to have spread throughout the world to afflict hundreds of thousands more. The cause of the strange illness still remains a mystery today. Since the initial outbreak, there have been sporadic reports of patients who had what seemed to be similar symptoms, but it is not completely clear whether the more recently described patients suffered from encephalitis lethargica or from something else. 

The Widespread Outbreak

According to accounts in the literature, the symptoms of the disease did not seem to immediately suggest a unified diagnosis. Strange neuropsychiatric behaviors and an overwhelming lethargic sleepiness, which induced a coma like state, as well as muscle rigidity, were cornerstones of the illness.

But not every patient had all of the characteristic symptoms and not all of them experienced the same disease severity. According to the medical literature, about a third of the patients died from respiratory failure caused by neurological dysfunction. And, while at least hundreds thousands of patients died, there were at least as many who survived. Some of the survivors exhibited residual Parkinsonian or neuropsychiatric sequelae.

A group of patients who survived the outbreak had substantial lethargy, remaining in a sleep like state for years. Many in this group, described in great detail by Oliver Sacks, MD, were noted to have muscle rigidity at rest. Some of them responded to L-dopa, which was a new medication for Parkinson’s disease at the time. That symptomatic response points to the possibly that the illness, like Parkinson disease (PD), may involve the substantial nigra in some way. 

Because there was an influenza outbreak at the same time as the encephalitis lethargica epidemic, some researchers who study this disease consider an infectious cause to be a possibility--although some others suggest that the two outbreaks may have been coincidental and that an unrelated trigger could have caused the sleeping sickness. 

Imaging and Pathological Clues

One interesting series1 of 20 patients with a symptomatology similar to that of encephalitis lethargica identified autoantibodies reactive against human basal ganglia antigens in 95% of the patient population using western immunoblotting (in comparison to 2-4% of child and adult controls.) The researchers reported that these antibodies were also present in the CSF in four of the patients tested.

Yet, reports2 from the original outbreak document more widespread abnormalities in the brain, including in the cerebral cortex. These abnormalities also appeared to have autoimmune characteristics. 

New Cases of Encephalitis Lethargica?

There are very few modern day case reports describing patients who have symptoms suggestive of possible encephalitis lethargica. One of these3 describes a young child with HIV who was reported to have somnolence, akinetic mutism, and ophthalmoplegia. His symptoms began after he had experienced an intermittent fever, which, along with his symptoms, placed encephalitis lethargica on the list of possible diagnoses.  His CSF fluid showed pleocytosis and positive oligoclonal bands, and he responded to steroids and immunoglobilins, which supports the possibility that there was an autoimmune component to his illness. His imaging studies showed evidence of disease only in the substantia nigra, consistent with the series of 20 patients, but unlike what would have been expected of patients who were part of the last century’s widespread outbreak. 

Unanswered Questions About Sleeping Sickness

The rare neurological disease that was so widespread for a relatively brief period of time and has not recurred beyond some possible sporadic cases still remains a mystery. At the tail end of the illness, some patients improved with levodopa, at a time when it was the only available medication for PD and symptoms of Parkinsonism.  Perhaps we will never know if the encephalitis lethargica epidemic was caused by an infection, an unusual response to a microbial agent, a neurotoxic pollutant or some other extraordinary trigger. 


1. Dale RC, Church AJ, Surtees RA, et al. Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity.Brain. 2004 Jan;127(Pt 1):21-33. Epub 2003 Oct 21.

2. Anderson LL, Vilensky JA, Duvoisin RC. Review: neuropathology of acute phase encephalitis lethargica: a review of cases from the epidemic period,  Neuropathol Appl Neurobiol. 2009 Oct;35(5):462-72. doi: 10.1111/j.1365-2990.2009.01024.x.

3. Yang L, Jia G, Li B, et al. Encephalitis Lethargica With Isolated Substantia Nigra Lesions Followed by a Second Encephalitis in a Child With Humoral Immunodeficiency. Pediatr Neurol. 2015 Dec;53(6):519-22. doi: 10.1016/j.pediatrneurol.2015.03.030. Epub 2015 Jun 18.