U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

Cover of StatPearls

StatPearls [Internet].

Show details

Von Economo Encephalitis

; .

Author Information and Affiliations

Last Update: August 23, 2023.

Continuing Education Activity

Constantin Alexander von Economo, a psychiatrist and neurologist, reported in April 1917 about encephalitis lethargica in front of the Vienna Psychiatric Society. His primary description of the illness that raged in an epidemic in Europe and North America between 1916 and 1926 was named a von Economo encephalitis. This activity reviews the evaluation and management of von Economo encephalitis and highlights the interprofessional team's role in managing patients with this condition.


  • Identify the etiology of von Economo encephalitis.
  • Review the evaluation of von Economo encephalitis.
  • Summarize the management options available for von Economo encephalitis.
  • Outline some interprofessional strategies that will improve patient care and outcomes for individuals with von Economo encephalitis.
Access free multiple choice questions on this topic.


Constantin Alexander von Economo, a psychiatrist and neurologist, reported in 1917 about encephalitis lethargica in front of the Vienna Psychiatric Society.[1] Sporadic cases of this brain and brainstem encephalitis were reported in 1916 and 1917, and similar cases were reported around the world between 1919 and 1920.[2] His primary description of the illness that raged in an epidemic in Europe and North America between 1916 and 1927 was named von Economo encephalitis.[3][4] 

A few weeks before, Jean-Rene Cruchet presented his observations to the Paris Medical Society after treating military patients with neuropsychiatric disorders showing unusual neurological signs. Encephalitis lethargica or von Economo encephalitis is also known as sleeping sickness. Originally it was classified into three clinical forms: somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic. Currently, postencephalitic parkinsonism has a very close relationship with encephalitis lethargica, also called von Economo encephalitis.[3][5] 

Von Economo was nominated for the 1926, 1930, and 1932 Nobel Prize in Physiology or Medicine. Encephalitis lethargica came to light after the book “Awakening” written by an English neurologist, Oliver Sacks. A movie based on the book was released in 1990.[6]


The specific cause of von Economo encephalitis is unknown but is most likely related to an autoimmune reaction against neuronal proteins. The prevalence of encephalitis lethargica occurred during the Spanish influenza pandemic, and several reports attributed the etiology to the influenza virus.[7] However, recent studies using old brain samples do not confirm the association with the influenza virus.[8][9][10] 

Von Economo ruled out external sources such as sausage poisoning and gas poison. As there was no contact with another individual, meningitis, and polio were also ruled out. Discussions related to the etiology of influenza were still mentioned. However, his cases and a few other reports concluded that the encephalitis lethargica is a separate disorder than directly caused by the influenza infection. Still, influenza as a prodromal phase was not ruled out by von Economo.[11] 

The archival tissues of the encephalitis lethargica patients were RT-PCR tested in 2001 but failed to show evidence of the influenza virus. This disease was recently described as associated with streptococcal infection and included in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).[6]


The spread of the disease is thought to have been facilitated by the military troops' movement during World War I across Europe. Although the exact amount of affected individuals was never recorded, it is estimated more than one million were affected.[7][12]

The condition was more prevalent in individuals between the ages of 10 and 45 without gender predominance. In the somnolent-ophthalmoplegic form, the mortality exceeded 50%.[12] Children, the elderly, and people with existing respiratory diseases are more susceptible.[13] No other epidemics have occurred after the epidemic of 1916, but occasional cases are still reported.


Von Economo encephalitis is a disorder of possible autoimmune origin that affects the midbrain, pons, basal ganglia, and substantial nigra. It is believed that this autoimmune reaction follows an initial viral (influenza) or bacterial (streptococcal) infection.[1] The damage to these areas manifests with a wide variety of symptoms, the most common of which are sleep disorders, abnormal movements (especially parkinsonism), and neuropsychiatric disorder.[13] The pathophysiology for hypersomnolence is attributed to inflammation of the reticular activating system, ophthalmoplegia to the involvement of cranial nerve nuclei and tracts, and parkinsonism-like features to basal ganglia involvement.[6]

Postencephalitic parkinsonism is based on the hypothesis that dopamine depletion and hypersensitive dopamine receptors result in dopamine neurotransmission imbalance.[5] In encephalitis lethargica, the parkinsonism syndrome affecting dopamine neurotransmission shows significant improvement with dopamine agonists.

Von Economo described three clinical forms of encephalitis lethargica:[1][4][6][11][13][14]

  1. Somnolent-ophthalmologic form characterized by excessive sleepiness followed by progressive confusion, stupor, and coma. It was associated with internal ophthalmoplegia, oculogyric crisis, nystagmus, dyskinesia, pyramidal, and cerebellar signs.
  2. Amyostatic-akinetic form characterized by acute parkinsonism, catatonia, or mutism.
  3. The hyperkinetic form presented restlessness, mania, visual hallucination, chorea, hemichorea, myoclonic twitches, troublesome sleeplessness, and dyskinesia.


The pathology often shows changes in the upper midbrain, substantia nigra, basal ganglia, pons, thalamus, and medulla that correlate with the illness's clinical features. Perivascular lymphocyte infiltration, especially plasma cells, activated astrocytes, and macrophages were usually seen. No viral inclusion bodies, presence of amyloid or complement in basal ganglia were found.[14]

In a large percentage of patients, oligoclonal bands, and antibodies against the basal ganglia were detected. In 65% of patients, antibodies against beta-hemolytic streptococci were detected.[13] Autopsy findings revealed meningeal involvement with brain vessel engorgement. Red spots on the cerebral cortex, medulla oblongata, ventral and dorsal horns of the cervical spinal cord showed petechial hemorrhage.[1] Microscopic examination showed inflammation of the gray matter, especially at the midbrain.[2][11]

History and Physical

Von Economo encephalitis involves acute and chronic phases.[12] The acute phase can have flu-like prodromal symptoms followed later by neurological sequelae, including hemiplegia and death in several cases. There is an initial manic phase in the hyperkinetic form, followed by chorea, vocalization, myorhythmia of ocular and masticatory muscles, and myoclonic twitches. In the amyostatic-akinetic form, rigidity and lack of movements may be observed, without noticeable weakness. In the somnolent ophthalmoplegic form, patients exhibit meningeal irritation with cranial nerve III, IV, and VI palsies leading to ophthalmoplegia. Amblyopia due to the oculomotor nerve was most common but paresis related to trigeminal, abducens, and facial nerves were also noted. Most patients experience an overwhelming desire to sleep and sleep for abnormally long hours; however, they were easily awakened.[2][3] 

Parkinsonism with extrapyramidal signs due to basal ganglia involvement can be seen as an early or late complication. Patients will present stiffness and bradykinesia involving the upper extremities more than the lower. They can also show chorea, myoclonus, torsion spasms, and facial tics, including the tongue and palate.[1] Von Economo encephalitis can present with high fever, headache, double vision, vertigo, vomiting, catatonia, confusion, and increased tone in all four extremities. Catatonia presents with immobility, staring, negativism, stupor, and echolalia. Characteristic symptoms of hypersomnolence, easy arousable, ophthalmoplegia, and extrapyramidal signs following a recent upper respiratory tract infection suggest the development of autoimmune encephalitis.[3][12]

The chronic phase of encephalitis lethargica can immediately follow the acute phase; however, it usually starts one to five years later. This phase was typified by parkinsonism. Several other symptoms occurred concomitantly, including oculomotor abnormalities, sleep disturbances, psychiatric disorders, and involuntary movements. Psychiatric manifestations consisted of mood changes, euphoria, increased sexual drive, and hallucinations. Post paresis phase had presentations of increased reflexes, including positive Babinski’s signs and spasms for a prolonged time even after the recovery from ocular muscle paralysis and somnolence.[1][3]


Brain magnetic resonance imaging will reveal hyperintense lesions in the midbrain tegmentum, thalamus, and basal ganglia. The changes resolve when recovery from the disease is complete.[14]

Cerebrospinal fluid (CSF) analysis:[1][2][3][15]

  • sometimes show increased CSF protein
  • negative for bacteria or virus
  • oligoclonal IgG bands present
  • mild/moderate lymphocytic pleocytosis
  • normal glucose

Electroencephalography and evoked potentials: may present diffuse unilateral or bilateral slowing, with occasional focal sharp waves and altered evoked potential.[1][4][13]

Treatment / Management

Treatment for encephalitis is supportive. Methylprednisolone 1 gram intravenously daily for three days produces significant improvement. The first-line treatment for catatonia is benzodiazepines, followed by electroconvulsive therapy. In treatment-resistant cases, bromocriptine, memantine, zolpidem, and valproate can also be used.[5] However, in encephalitis with parkinsonism, dopamine agonists played a pivotal role. Few reports showed that simultaneous administration of levodopa and carbidopa has a better outcome than levodopa alone.[5][16] The use of immunoglobulin and plasmapheresis has not been well established yet.[14] Acyclovir has not proven any benefits.

Differential Diagnosis

  • Parkinson disease
  • Psychiatric illness
  • Limbic encephalitis
  • Herpes simplex encephalitis
  • Bickerstaff brainstem encephalitis
  • Rasmussen encephalitis
  • Hashimoto encephalopathy
  • Anti-N-methyl-D-aspartate receptor encephalitis


One-third of the patients died during the acute phase, while another third recovered without sequelae and another third suffered chronic neurological sequelae.[1][14]


  • Hemiplegia
  • Stupor
  • Coma
  • Ophthalmoplegia
  • Oculogyric crisis 
  • Chorea
  • Hemichorea
  • Dyskinesia
  • Acute parkinsonism
  • Mood changes
  • Catatonia
  • Mutism
  • Visual hallucination
  • Mania
  • Euphoria
  • Troublesome sleepiness


  • Neurologist
  • Psychiatrist
  • Movement disorder specialist
  • Neuroophthalmologist
  • Neuroradiologist

Deterrence and Patient Education

Cases of von Economo encephalitis are sporadic. In the past, many patients who survive were significantly hindered due to chronic neurological sequelae. Dopamine agonists played a pivotal role in the treatment. Recent studies had found no association with the influenza virus.

Enhancing Healthcare Team Outcomes

Von Economo encephalitis occurred as an epidemic in Europe and North America between 1916 and 1927. Fortunately, no other epidemic occurred afterward. Only rare cases are still described in the scientific literature. The general physician treated patients with von Economo encephalitis in consultation with an interprofessional team of specialists, including a neurologist and a psychiatrist. The condition became even more complicated when the patients developed chronic parkinsonism, which required treatment with pharmacotherapy. Knowledge of this disease is essential for the healthcare team.

Review Questions


da Mota Gomes M. Encephalitis lethargica epidemic milestones in early sleep neurobiology researches. Sleep Med. 2020 Oct;74:349-356. [PMC free article: PMC7448964] [PubMed: 32957006]
Davis LE, Koster F, Cawthon A. Neurologic aspects of influenza viruses. Handb Clin Neurol. 2014;123:619-45. [PMC free article: PMC7152431] [PubMed: 25015508]
Pearce JM. Baron Constantin von Economo and encephalitis lethargica. J Neurol Neurosurg Psychiatry. 1996 Feb;60(2):167. [PMC free article: PMC1073797] [PubMed: 8708646]
Howard RS, Lees AJ. Encephalitis lethargica. A report of four recent cases. Brain. 1987 Feb;110 ( Pt 1):19-33. [PubMed: 3801849]
Bigman DY, Bobrin BD. Von Economo's disease and postencephalitic parkinsonism responsive to carbidopa and levodopa. Neuropsychiatr Dis Treat. 2018;14:927-931. [PMC free article: PMC5894716] [PubMed: 29670352]
Sak J, Grzybowski A. Brain and aviation: on the 80th anniversary of Constantin von Economo's (1876-1931) death. Neurol Sci. 2013 Mar;34(3):387-91. [PMC free article: PMC3586395] [PubMed: 22569570]
Ravenholt RT, Foege WH. 1918 influenza, encephalitis lethargica, parkinsonism. Lancet. 1982 Oct 16;2(8303):860-4. [PubMed: 6126720]
McCall S, Vilensky JA, Gilman S, Taubenberger JK. The relationship between encephalitis lethargica and influenza: a critical analysis. J Neurovirol. 2008 May;14(3):177-85. [PMC free article: PMC2778472] [PubMed: 18569452]
McCall S, Henry JM, Reid AH, Taubenberger JK. Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases. J Neuropathol Exp Neurol. 2001 Jul;60(7):696-704. [PubMed: 11444798]
Reid AH, McCall S, Henry JM, Taubenberger JK. Experimenting on the past: the enigma of von Economo's encephalitis lethargica. J Neuropathol Exp Neurol. 2001 Jul;60(7):663-70. [PubMed: 11444794]
Jang H, Boltz DA, Webster RG, Smeyne RJ. Viral parkinsonism. Biochim Biophys Acta. 2009 Jul;1792(7):714-21. [PMC free article: PMC4642437] [PubMed: 18760350]
Hoffman LA, Vilensky JA. Encephalitis lethargica: 100 years after the epidemic. Brain. 2017 Aug 01;140(8):2246-2251. [PubMed: 28899018]
Uribe CS, González AL, González P. La Von Economo’s encephalitis lethargica and the Spanish flu pandemic in Bogotá and Medellín (Colombia): An historic review one hundred years after. Biomedica. 2019 Mar 31;39(1):8-16. [PubMed: 31021542]
Vadalá SF, Pellegrini D, Silva ED, Miñarro D, Finn BC, Bruetman JE, Nápoli G, Young P. [Lethargic encephalitis. Report of one case]. Rev Med Chil. 2013 Apr;141(4):531-4. [PubMed: 23900376]
Bale JF. Emerging viral infections. Semin Pediatr Neurol. 2012 Sep;19(3):152-7. [PMC free article: PMC7111197] [PubMed: 22889544]
Kim R, Shin CW, Kim HJ, Jeon BS. Postencephalitic parkinsonism responsive to a dopamine agonist: A case report. Parkinsonism Relat Disord. 2015 Jun;21(6):667-8. [PubMed: 25899543]

Disclosure: Ankit Vyas declares no relevant financial relationships with ineligible companies.

Disclosure: Orlando De Jesus declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK567791PMID: 33620860


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...