Encephalitis lethargica is characterized by high fever, sore throat, headache, lethargy, double vision, delayed physical and mental response, sleep inversion and catatonia.

[citation needed] Patients may also experience abnormal eye movements ("oculogyric crises"),[11] Parkinsonism, upper body weakness, muscular pains, tremors, neck rigidity, and behavioral changes including psychosis.

[15] 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 (for example, lack of viral RNA in postencephalitic Parkinsonian brain material).

[17] In 2010, in a substantial compendium[18] reviewing the historic and contemporary views on EL, it quotes a researcher, writing in 1930, who stated, "we must confess that etiology is still obscure, the causative agent still unknown, the pathological riddle still unsolved", and went 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?

[19] In 2012, Oliver Sacks, the author of the book Awakenings, about institutionalized survivors, acknowledged this virus as the probable cause of the disease.

Another diagnostic criterion, suggested more recently, says that the diagnosis of encephalitis lethargica "may be considered if the patient's condition cannot be attributed to any other known neurological condition and that they show the following signs: influenza-like signs; hypersomnolence (hypersomnia), wakeability, ophthalmoplegia (paralysis of the muscles that control the movement of the eye), and psychiatric changes".

[27][28] Retrospective diagnosis tentatively suggests various historical outbreaks of encephalitis lethargica: In the winter of 1916–1917, a "new" illness suddenly appeared in Vienna and other cities, and rapidly spread world-wide over the next three years.

[31] Neurologist Constantin von Economo published a paper in April 1917 describing some of the cases he encountered in the winter months of 1916–1917.

[14] These patients, despite varying diagnoses, had a similar pattern of symptoms which led von Economo to suggest a novel disease, which he called Encephalitis Lethargica.

[30] Just 10 days before von Economo's breakthrough in Vienna, Jean-René Cruchet described 40 cases of "subacute encephalomyelitis" in France.

However, the majority of survivors subsequently developed neurological or psychiatric disorders, often after years or decades of seemingly perfect health.