The causes of encephalitis lethargica are uncertain.

Some studies have explored its origins in an autoimmune response, and, separately or in relation to an immune response, links to pathologies of infectious disease — viral and bacterial, e.g., in the case of influenza, where a link with encephalitis is clear.
Postencephalitic parkinsonism was clearly documented to have followed an outbreak of encephalitis lethargica following the 1918 influenza pandemic; evidence for viral causation of the Parkinson's symptoms is circumstantial (epidemiologic, and finding influenza antigens in encephalitis lethargica patients), while evidence arguing against this cause is of the negative sort (e.g., lack of viral RNA in postencephalitic parkinsonian brain material).

In reviewing the relationship between influenza and encephalitis lethargica (EL), McCall and coworkers conclude, as of 2008, that while "the case against influenza [is] less decisive than currently perceived… there is little direct evidence supporting influenza in the etiology of EL," and that "[a]lmost 100 years after the EL epidemic, its etiology remains enigmatic."
Hence, while opinions on the relationship of encephalitis lethargica to influenza remain divided, the preponderance of literature appears skeptical.

German neurologist Felix Stern, who examined hundreds of encephalitis lethargica patients during the 1920s, pointed out that the encephalitis lethargica typically evolved over time.
The early symptom would be dominated by sleepiness or wakefulness.
A second symptom would lead to an oculogyric crisis.
The third symptom would be recovery, followed by a Parkinson-like symptom.
If patients of Stern followed this course of disease, he diagnosed them with encephalitis lethargica.
Stern suspected encephalitis lethargica to be close to polio without evidence.
Nevertheless, he experimented with the convalescent serum of survivors of the first acute symptom.
He vaccinated patients with early stage symptoms and told them that it might be successful.
Stern is author of the 1920s definitive book Die Epidemische Encephalitis (1920 and 2nd ed.
1928).
Stern was driven to suicide during the Holocaust by the German state, his research forgotten.


In 2010, in a substantial Oxford University Press compendium reviewing the historic and contemporary views on EL, its editor, Joel Vilensky of the Indiana University School of Medicine, quotes Pool, writing in 1930, who states, "we must confess that etiology is still obscure, the causative agent still unknown, the pathological riddle still unsolved…", and goes on to offer the following conclusion, as of that publication date:
Does the present volume solve the "riddle" of EL, which… has been referred to as the greatest medical mystery of the 20th century?
Unfortunately, no: but inroads are certainly made here pertaining to diagnosis, pathology, and even treatment."

Subsequent to publication of this compendium, an enterovirus was discovered in encephalitis lethargica cases from the epidemic.
 In 2012, Oliver Sacks acknowledged this virus as the probable cause of the disease.
Other sources have suggested Diplococcus as a cause.
The causes of encephalitis lethargica are uncertain.
Some studies have explored its origins in an autoimmune response, and, separately or in relation to an immune response, links to pathologies of infectious disease — viral and bacterial, e.g., in the case of influenza, where a link with encephalitis is clear. Postencephalitic parkinsonism was clearly documented to have followed an outbreak of encephalitis lethargica following the 1918 influenza pandemic; evidence for viral causation of the Parkinson's symptoms is circumstantial (epidemiologic, and finding influenza antigens in encephalitis lethargica patients), while evidence arguing against this cause is of the negative sort (e.g., lack of viral RNA in postencephalitic parkinsonian brain material).
In reviewing the relationship between influenza and encephalitis lethargica (EL), McCall and coworkers conclude, as of 2008, that while "the case against influenza [is] less decisive than currently perceived… there is little direct evidence supporting influenza in the etiology of EL," and that "[a]lmost 100 years after the EL epidemic, its etiology remains enigmatic." Hence, while opinions on the relationship of encephalitis lethargica to influenza remain divided, the preponderance of literature appears skeptical.
German neurologist Felix Stern, who examined hundreds of encephalitis lethargica patients during the 1920s, pointed out that the encephalitis lethargica typically evolved over time. The early symptom would be dominated by sleepiness or wakefulness. A second symptom would lead to an oculogyric crisis. The third symptom would be recovery, followed by a Parkinson-like symptom. If patients of Stern followed this course of disease, he diagnosed them with encephalitis lethargica. Stern suspected encephalitis lethargica to be close to polio without evidence. Nevertheless, he experimented with the convalescent serum of survivors of the first acute symptom. He vaccinated patients with early stage symptoms and told them that it might be successful. Stern is author of the 1920s definitive book Die Epidemische Encephalitis (1920 and 2nd ed. 1928). Stern was driven to suicide during the Holocaust by the German state, his research forgotten.

In 2010, in a substantial Oxford University Press compendium reviewing the historic and contemporary views on EL, its editor, Joel Vilensky of the Indiana University School of Medicine, quotes Pool, writing in 1930, who states, "we must confess that etiology is still obscure, the causative agent still unknown, the pathological riddle still unsolved…", and goes on to offer the following conclusion, as of that publication date:
Does the present volume solve the "riddle" of EL, which… has been referred to as the greatest medical mystery of the 20th century? Unfortunately, no: but inroads are certainly made here pertaining to diagnosis, pathology, and even treatment."
Subsequent to publication of this compendium, an enterovirus was discovered in encephalitis lethargica cases from the epidemic.  In 2012, Oliver Sacks acknowledged this virus as the probable cause of the disease. Other sources have suggested Diplococcus as a cause.
Encephalitis lethargica