View source for Medicine:Encephalitis lethargica

{{Short description|Form of encephalitis (sleeping sickness)}}
{{Infobox medical condition (new)
| name = Encephalitis lethargica
| synonyms = Economo's disease; von Economo's encephalitis<ref name=Berger2014>{{cite book |vauthors=Berger JR, Vilensky JA |title=Neurovirology |chapter=Encephalitis lethargica (von Economo's encephalitis) |series=Handbook of Clinical Neurology |volume=123 |pages=745–761 |date=2014 |pmid=25015515 |doi=10.1016/B978-0-444-53488-0.00036-5|isbn=978-0444534880 }}</ref>
| image = Economo1918h.PNG
| caption = An illustration from von Economo's ''Die Encephalitis lethargica'' (1918) showing brain tissue of a monkey affected by Encephalitis lethargica, as seen under a microscope
| causes = Unknown
| frequency = Unknown
}}

'''Encephalitis lethargica''' is an atypical form of [[Medicine:Encephalitis|encephalitis]]. Also known as "'''sleeping sickness'''" or "'''sleepy sickness'''" (distinct from [[Biology:Tsetse fly|tsetse fly]]–transmitted [[Medicine:African trypanosomiasis|sleeping sickness]]), it was first described in 1917 by neurologist Constantin von Economo<ref>{{WhoNamedIt|synd|3356|Economo's disease}}</ref><ref>{{cite journal |first=K. |last=von Economo |journal=Wiener klinische Wochenschrift |trans-journal=Vienna clinical weekly |date=May 10, 1917 |volume=30 |pages=581–585 |language=de |title=Die Encephalitis lethargica. |location=Leipzig and Vienna |publisher=Franz Deuticke 1918}}</ref> and pathologist Jean-René Cruchet.<ref>{{cite journal |last1=Cruchet |first1=R |last2= Moutier |first2=J |last3= Calmettes |first3=A |title= Quarante cas d'encéphalomyélite subaiguë |trans-title=Forty cases of (subacute) encephalitis lethargica |journal=Bull Soc Med Hôp |location=Paris |year=1917 |volume=41 |pages=614–616 |language=fr}}</ref> The disease attacks the brain, leaving some victims in a statue-like condition, speechless and motionless.<ref name=Dale_2004>{{cite journal |author=Dale, Russell C. |author2=Church, Andrew J. |author3=Surtees, Robert A.H. |author4=Lees, Andrew J. |author5=Adcock, Jane E. |author6=Harding, Brian |author7=Neville, Brian G. R. |author8=Giovannoni, Gavin |title = Encephalitis Lethargica Syndrome: 20 New Cases and Evidence of Basal Ganglia Autoimmunity |journal = Brain |volume = 127 |issue = 1 |pages = 21–33 |year = 2004 |pmid = 14570817 |doi = 10.1093/brain/awh008 |doi-access = free }}</ref> Between 1915 and 1926,<ref>{{DorlandsDict|nine/000952335|Encephalitis lethargica}}</ref> an [[Medicine:Epidemic|epidemic]] of encephalitis lethargica spread around the world. The exact number of people infected is unknown, but it is estimated that more than one million people contracted the disease during the epidemic, which directly caused more than 500,000 deaths.<ref name=":2">{{Cite journal |last1=Ravenholt |first1=R. T. |last2=Foege |first2=William H |title=1918 Influenza, Encephalitis Lethargica, Parkinsonism |date=1982-10-16 |url=http://www.sciencedirect.com/science/article/pii/S0140673682908200 |journal=The Lancet |series=Originally published as Volume 2, Issue 8303 |language=en |volume=320 |issue=8303 |pages=860–864 |doi=10.1016/S0140-6736(82)90820-0 |pmid=6126720 |s2cid=45138249 |issn=0140-6736 |access-date=2020-12-23 |archive-date=2021-07-12 |archive-url=https://web.archive.org/web/20210712225718/https://www.sciencedirect.com/science/article/abs/pii/S0140673682908200 |url-status=live }}</ref><ref name=":3">{{Cite journal |last1=McCall |first1=Sherman |last2=Vilensky |first2=Joel A |last3=Gilman |first3=Sid |last4=Taubenberger|first4=Jeffery K|date=May 2008|title=The relationship between encephalitis lethargica and influenza: A critical analysis |journal=Journal of Neurovirology |volume=14 |issue=3 |pages=177–185 |doi=10.1080/13550280801995445 |issn=1355-0284 |pmc=2778472 |pmid=18569452}}</ref><ref name=":4">{{Cite journal |last1=Hoffman |first1=Leslie A. |last2=Vilensky |first2=Joel A. |date=2017-08-01 |title=Encephalitis lethargica: 100 years after the epidemic |url=https://academic.oup.com/brain/article/140/8/2246/3970828 |journal=Brain |language=en |volume=140 |issue=8 |pages=2246–2251 |doi=10.1093/brain/awx177 |pmid=28899018 |issn=0006-8950 |doi-access=free |access-date=2020-12-23 |archive-date=2021-03-04 |archive-url=https://web.archive.org/web/20210304022143/https://academic.oup.com/brain/article/140/8/2246/3970828 |url-status=live }}</ref> Most of those who survived never returned to their pre-morbid vigour.

==Signs and symptoms==
Encephalitis lethargica is characterized by high [[Medicine:Fever|fever]], sore throat, [[Medicine:Headache|headache]], lethargy, [[Medicine:Diplopia|double vision]], delayed physical and mental response, [[Medicine:Sleep inversion|sleep inversion]] and [[Medicine:Catatonia|catatonia]].<ref name=Dale_2004/><ref>{{Cite journal |last=Koch |first=Christof |date=March–April 2016 |title=Sleep without End |journal=Scientific American Mind |volume=27 |issue=2 |pages=22–25 |doi=10.1038/scientificamericanmind0316-22}}</ref> In severe cases, patients may enter a [[Medicine:Coma|coma]]-like state (akinetic mutism).{{citation needed|date=December 2015}} Patients may also experience abnormal [[Biology:Human eye|eye]] movements ("oculogyric crises"),<ref name="pmid16200538">{{cite journal |author1=Vilensky, J.A. |author2=Goetz, C.G. |author3=Gilman, S. |title=Movement Disorders Associated with Encephalitis Lethargica: A Video Compilation |journal = Mov. Disord. |volume=21 |issue=1, January |pages=1–8 |year = 2006 |pmid=16200538 |doi=10.1002/mds.20722|s2cid=34382398 }}</ref> Parkinsonism, upper body weakness, muscular pains, tremors, neck rigidity, and behavioral changes including [[Medicine:Psychosis|psychosis]].{{citation needed|date=December 2015}} Klazomania, a vocal tic involving compulsive screaming, is sometimes present.<ref name=Jankovic>{{cite journal |author1=Jankovic, J. |author2=Mejia, N.I. |title= Tics Associated with Other Disorders |journal = Adv. Neurol. |year=2006 |volume=99 |pages=61–68 |pmid= 16536352}}</ref>

==Cause==
[[Image:Encephalitis-livre.png|thumb|''Encephalitis lethargica. Its sequelae and treatment'' – Constantin von Economo, 1931: front page]]
The causes of encephalitis lethargica are uncertain.<ref name= "pmid18569452">{{cite journal |last1=McCall |first1=S. |last2=Vilensky |first2=J. A. |last3=Gilman |first3=S. |last4=Taubenberger |first4=J. K. |title=The Relationship Between Encephalitis Lethargica and Influenza: A Critical Analysis |journal=Journal of Neurovirology |volume=14 |issue=3, May |pages=177–185 |year = 2008 |pmid=18569452 |doi=10.1080/13550280801995445 |pmc=2778472}}</ref><ref name=":1a">{{Cite web|title=Encephalitis Lethargica|url=https://www.encephalitis.info/encephalitis-lethargica|access-date=2021-06-12|website=The Encephalitis Society|date=27 June 2017|language=en|archive-date=2017-12-28|archive-url=https://web.archive.org/web/20171228054011/https://www.encephalitis.info/encephalitis-lethargica|url-status=live}}</ref> Though it used to be believed that it was connected to the Spanish flu epidemic, modern research provides arguments against this claim.<ref name=":2a">{{Cite journal|last1=Reid|first1=Ann H.|last2=McCall|first2=Sherman|last3=Henry|first3=James M.|last4=Taubenberger|first4=Jeffery K.|date=2001-07-01|title=Experimenting on the Past: The Enigma of von Economo's Encephalitis Lethargica|journal=Journal of Neuropathology & Experimental Neurology|volume=60|issue=7|pages=663–670|doi=10.1093/jnen/60.7.663|pmid=11444794 |issn=0022-3069|doi-access=free}}</ref> Some studies have explored its origins in an autoimmune response,<ref name=Dale_2004/> and, separately or in relation to an immune response, links to pathologies of infectious disease—viral and bacterial,<ref name=Dale_2004/> such as in the case of influenza, where a link with encephalitis is clear.<ref name= "Haeman">{{Cite journal |doi=10.1073/pnas.0900096106 |last1=Haeman |first1=Jang |last2=Boltz |first2=D. |last3=Sturm-Ramirez |first3=K. |last4=Shepherd |first4=K. R. |last5=Jiao |first5=Y. |last6=Webster |first6=R. |author7-link=Richard Smeyne |last7=Smeyne |first7=Richard J. |title=Highly Pathogenic H5N1 Influenza Virus Can Enter the Central Nervous System and Induce Neuroinflammation and Neurodegeneration |access-date=8 December 2015 |year=2009 |url=http://www.pnas.org/content/early/2009/08/07/0900096106.full.pdf+html |journal=Proceedings of the National Academy of Sciences |volume=106 |pages=14063–14068 |pmid=19667183 |issue=33, August 10 |pmc=2729020 |doi-access=free |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828073617/https://www.pnas.org/content/early/2009/08/07/0900096106 |url-status=live }}</ref> 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 ([[Social:Epidemiology|epidemiologic]], and finding influenza [[Biology:Antigen|antigen]]s in encephalitis lethargica patients), while evidence arguing against this cause is of the [[Philosophy:Argument from ignorance#Distinguishing absence of evidence from evidence of absence|negative sort]] (for example, lack of [[Biology:RNA virus|viral RNA]] in postencephalitic Parkinsonian brain material).<ref name="Haeman"/> In reviewing the relationship between influenza and encephalitis lethargica (EL), McCall and coauthors conclude, as of 2008, that "the case against influenza [is] less decisive than currently perceived&nbsp;... 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."<ref name=Reid_2001>{{cite journal |last1=Reid |first1=A. H. |last2=McCall |first2=S. |last3=Henry |first3=J. M. |last4=Taubenberger |first4=J. K. |title = Experimenting on the Past: The Enigma of von Economo's Encephalitis Lethargica |journal = Journal of Neuropathology and Experimental Neurology |volume = 60 |issue = 7 |pages = 663–670 |year = 2001 |pmid = 11444794 |doi = 10.1093/jnen/60.7.663 |doi-access = free }}</ref> Hence, while opinions on the relationship of encephalitis lethargica to influenza remain divided, the preponderance of literature appears skeptical.<ref name= Reid_2001/><ref name="pmid17675021">{{cite journal |last1=Vilensky |first1=J.A. |last2=Foley |first2=P. |last3=Gilman |first3=S. |date=August 2007 |title=Children and Encephalitis Lethargica: A Historical Review |journal=Pediatric Neurology |volume=37 |issue=2 |pages=79–84 |pmid=17675021 |doi=10.1016/j.pediatrneurol.2007.04.012 |url=http://www.pedneur.com/article/S0887-8994(07)00194-4/abstract |access-date=8 December 2015 |archive-date=17 April 2020 |archive-url=https://web.archive.org/web/20200417064629/https://www.pedneur.com/article/S0887-8994(07)00194-4/abstract |url-status=live }}</ref>

The German neurologist Felix Stern, who examined hundreds of encephalitis lethargica patients during the 1920s, noted that their encephalitis lethargica typically evolved over time. The early symptoms 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 syndrome. If patients of Stern followed this course of disease, he diagnosed them with encephalitis lethargica. Stern suspected encephalitis lethargica to be close to [[Medicine:Poliomyelitis|poliomyelitis]], without evidence. Nevertheless, he experimented with the [[Biology:Antiserum|convalescent serum]] of survivors of the first acute syndrome. He vaccinated patients with early-stage symptoms, telling them that it might be successful. Stern is author of the definitive 1920s book, {{lang|de|Die Epidemische Encephalitis}}.<ref>{{cite web|title=Auf der Spur der Schlaf-Epidemie|periodical=Spektrum.de|url=https://www.spektrum.de/news/felix-stern-der-arzt-der-das-geheimnis-der-encephalitis-lethargica-lueften-wollte/1618214|access-date=2019-01-28|date=2019-01-25|language=de|archive-date=2019-01-26|archive-url=https://web.archive.org/web/20190126014426/https://www.spektrum.de/news/felix-stern-der-arzt-der-das-geheimnis-der-encephalitis-lethargica-lueften-wollte/1618214|url-status=live}}</ref>

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 another researcher, 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:

{{quote|Does the present volume solve the "riddle" of EL, which&nbsp;... 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"<ref>{{cite book |last1=Vilensky |first1=J. A. |last2=Gilman |first2=S. |year = 2010 |chapter = Introduction |title = Encephalitis Lethargica: During and After the Epidemic |editor-last = Vilensky |editor-first=Joel A. |location = Oxford |publisher = Oxford University Press |isbn = 978-0190452209 |chapter-url = https://books.google.com/books?isbn=019045220X |access-date = 8 December 2015 |pages = 3–7, esp. 6f }}</ref>}}

Subsequent to publication of this compendium, an [[Biology:Enterovirus|enterovirus]] was discovered in encephalitis lethargica cases from the epidemic.<ref>{{Cite journal |last1=Dourmashkin |first1= Robert R. |last2=Dunn |first2=Glynis |last3=Castano |first3=Victor |last4=McCall |first4=Sherman A. |date=2012-01-01 |title=Evidence for an enterovirus as the cause of encephalitis lethargica |journal=BMC Infectious Diseases |volume=12 |pages=136 |doi= 10.1186/1471-2334-12-136 |issn=1471-2334 |pmc=3448500 |pmid=22715890 |doi-access= free }}</ref> In 2012, Oliver Sacks, the author of the book ''Awakenings'', about institutionalized survivors, acknowledged this virus as the probable cause of the disease.<ref>Letter from Oliver Sacks to Professor Joel A. Vilensky, 9 September 2012.</ref>{{verify inline|reason=Sources must be verifiable, which a private letter is not. Was this published? If so, cite the publication instead|date=August 2023}} Other sources have suggested ''[[Biology:Streptococcus pneumoniae|Streptococcus pneumoniae]]'' as a cause.<ref>{{cite news |url=http://news.bbc.co.uk/1/hi/health/3930727.stm |title=Mystery of the forgotten plague |date=27 July 2004 |website=BBC News |access-date=28 July 2004 |archive-date=13 May 2008 |archive-url=https://web.archive.org/web/20080513005052/http://news.bbc.co.uk/1/hi/health/3930727.stm |url-status=live }}</ref>

== Diagnosis ==
There have been several proposed diagnostic criteria for encephalitis lethargica. One, which has been widely accepted, includes an acute or subacute encephalitic illness where all other known causes of encephalitis have been excluded. 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: [[Medicine:Influenza|influenza]]-like signs; hypersomnolence ([[Medicine:Hypersomnia|hypersomnia]]), wakeability, ophthalmoplegia (paralysis of the muscles that control the movement of the eye), and psychiatric changes".<ref>{{cite web|url=https://www.encephalitis.info/encephalitis-lethargica|title=Encephalitis Lethargica|last1=Easton|first1=Ava|website=The Encephalitis Society|date=27 June 2017|access-date=27 December 2017|archive-date=28 December 2017|archive-url=https://web.archive.org/web/20171228054011/https://www.encephalitis.info/encephalitis-lethargica|url-status=live}}</ref> Others describe lethargy, "mask-like faces", excess blood in the meninges, and other general neurological symptoms.<ref name=":3a">{{Cite journal|last1=Hoffman|first1=Leslie A|last2=Vilensky|first2=Joel A|date=2017-08-01|title=Encephalitis lethargica: 100 years after the epidemic|journal=Brain|volume=140|issue=8|pages=2246–2251|doi=10.1093/brain/awx177|pmid=28899018 |issn=0006-8950|doi-access=free}}</ref>

== Treatment ==
[[Image:Levodopa.png|thumb|L-DOPA]]
Modern treatment approaches to encephalitis lethargica include immunomodulating therapies, and treatments to remediate specific symptoms.<ref>{{cite journal |author1=Lopez-Alberola, R. |author2=Georgiou, M. |author3=Sfakianakis, G.N. |author4=Singer, C. |author5=Papapetropoulos, S. |year = 2009 |journal = J. Neurol. |volume = 256 |issue = 3, March |pages = 396–404 |doi = 10.1007/s00415-009-0074-4 |title = Contemporary Encephalitis Lethargica: Phenotype, Laboratory Findings and Treatment Outcomes |pmid=19412724|s2cid=38388333 }}</ref>

There is little evidence so far of a consistent effective treatment for the initial stages, though some patients given steroids have seen improvement.<ref name=Blunt_1997>{{cite journal |author1=Blunt, S.B. |author2=Lane, R.J. |author3=Turjanski, N. |author4=Perkin, G.D. |title = Clinical Features and Management of Two Cases of Encephalitis Lethargica |journal = Mov. Disord. |volume = 12 |issue = 3 |pages = 354–359 |year = 1997 |pmid = 9159730 |doi = 10.1002/mds.870120314 |s2cid=14741885 }}</ref> The disease becomes progressive, with evidence of brain damage similar to that of [[Medicine:Parkinson's disease|Parkinson's disease]].<ref>{{cite journal |last=Kohnstamm |first=P. |year=1934 |title=Über die Beteiligung der beiden Schichten der Substantia nigra am Prozeß der Encephalitis epidemica |journal=J Psychol Neurol |volume=46 |issue=1 |pages=22–37 |language=de}}</ref>{{update after|2015|12|9}}

Treatment is then symptomatic. [[Chemistry:L-DOPA|L-DOPA]] (Levodopa) and other anti-Parkinson drugs often produce dramatic responses; however, most people given <small>L</small>-DOPA experience improvements that are short-lived.<ref>{{Cite web |url=https://www.ninds.nih.gov/Disorders/All-Disorders/Encephalitis-Lethargica-Information-Page |title=Encephalitis Lethargica Information Page |date=August 9, 2018 |website=National Institute of Neurological Disorders and Stroke |access-date=February 15, 2019 |archive-date=January 4, 2017 |archive-url=https://web.archive.org/web/20170104195107/https://www.ninds.nih.gov/Disorders/All-Disorders/Encephalitis-Lethargica-Information-Page |url-status=live }}</ref><ref name=sacksnp>{{harv|Sacks|1990|p=}}{{page needed|date=June 2021}}</ref>

== History ==
=== Occurrences ===
Retrospective diagnosis tentatively suggests various historical outbreaks of encephalitis lethargica:
* In 1580, Europe was swept by a serious febrile and lethargic illness that led to Parkinsonism and other neurological sequelae.<ref name=":1">{{harv|Sacks|1990|pp=319–321}}</ref>
* In 1673–1675, a similar serious epidemic occurred in [[Place:London|London]], which Thomas Sydenham described as {{lang|la|"febris comatosa"}}.<ref name=":1" />
* In 1695, a 20-year-old woman in {{wipe|Germany}} experienced oculogyric crises, Parkinsonism, [[Medicine:Diplopia|diplopia]], [[Medicine:Strabismus|strabismus]], and other symptoms following an attack of [[Medicine:Somnolence|somnolent]] brain fever, as described by Albrecht of Hildesheim.<ref name=":1" />
* In 1712–1713, a severe epidemic of {{lang|de|Schlafkrankheit}} ('sleep sickness') occurred in Tübingen, Germany, followed in many cases by persistent slowness of movement and lack of initiative ([[Philosophy:Aboulia|aboulia]]).<ref name=":1" />
* Between 1750 and 1800, {{wipe|France}} and Germany experienced minor epidemics of {{lang|la|"coma somnolentum"}} with features of Parkinsonism, including hyperkinetic [[Medicine:Hiccup|hiccup]], [[Medicine:Myoclonus|myoclonus]], chorea, and tics.
* Between 1848 and 1882, [[Place:Paris|Paris]]-based neurologist Jean-Martin Charcot documented many isolated cases of juvenile Parkinsonism, associated with [[Medicine:Diplopia|diplopia]], oculogyria, tachypnoea, retropulsion, and obsessional disorders, which were almost certainly post-encephalitic in origin.<ref name=":1" />
* In 1890 in Italy, following the influenza epidemic of 1889–1890, a severe epidemic of somnolent illnesses (nicknamed the ''"Nona"'') appeared. For the few survivors of the ''Nona'', Parkinsonism and other sequelae developed in almost all cases.<ref name=":1" />
* Between 1915 and 1926, a world-wide encephalitis lethargica pandemic occurred, impacting nearly 5 million people and killing an estimated 1.6 million people.<ref name=":1" />

=== Pandemic of 1915–1926 ===
In the winter of 1916–1917, a "new" illness suddenly appeared in [[Place:Vienna|Vienna]] and other cities, and rapidly spread world-wide over the next three years. Earlier reports appeared throughout Europe as early as the winter of 1915–1916, but communication about the disease was slow and chaotic, given the varied manifestation of symptoms and difficulties disseminating information in wartime;<ref name=":0">{{harv|Sacks|1990|pp=12–19}}</ref> it was officially recognized as its own disease in 1917.<ref name=":3a" /> Some authors define the span of the outbreak as being from 1918 to 1930.<ref name=":0a">{{Cite journal|last=Dourmashkin|first=R R|date=September 1997|title=What caused the 1918–30 Epidemic of Encephalitis Lethargica?|journal=Journal of the Royal Society of Medicine|language=en|volume=90|issue=9|pages=515–520|doi=10.1177/014107689709000916|issn=0141-0768|pmc=1296535|pmid=9370993}}</ref>

Neurologist Constantin von Economo published a paper in April 1917 describing some of the cases he encountered in the winter months of 1916–1917.<ref name=":2a" /> 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.<ref name=":2a" /> In France, physician Jean-René Cruchet was experiencing something similar, and he published his findings within a few days of von Economo.<ref name=":2a" />After these two, many more reports began being released about the disease, starting in Europe before moving around the globe.<ref name=":3a" />

Until Constantin von Economo identified a unique pattern of damage among the brains of deceased patients and introduced the unifying name ''encephalitis lethargica,'' reports of the protean disease came in under a range of names: [[Medicine:Botulism|botulism]], toxic ophthalmoplegia, epidemic stupor, epidemic lethargic encephalitis, acute polioencephalitis, Heine-Medin disease, bulbar paralysis, hystero-epilepsy, acute dementia, and sometimes just "an obscure disease with cerebral symptoms".<ref name=":0" /> Just 10 days before von Economo's breakthrough in Vienna, Jean-René Cruchet described 40 cases of "subacute encephalomyelitis" in France.<ref name=":0" />

The number of people infected during the ten years of the pandemic is unknown, but it is estimated that more than 1 million people contracted the disease, which directly caused more than 500,000 deaths.<ref name=":2" /><ref name=":3" /><ref name=":4" /> Encephalitis lethargica assumed its most virulent form between October 1918 and January 1919.

In the United States the epidemic peaked from 1920 to 1924.<ref name=":0a" /> It is estimated that as many as one million people were diagnosed with encephalitis lethargica during the epidemic period.<ref name=":3a" />

The pandemic disappeared in 1927, as abruptly and mysteriously as it first appeared.<ref name=":0" /> The great encephalitis pandemic coincided with the 1918 influenza pandemic, and it is likely that the influenza virus potentiated the effects of the causative agent of the encephalitis or lowered resistance to it in a catastrophic way.<ref name=":0" />

====Aftermath====
Many surviving patients of the 1915–1926 pandemic seemed to make a complete recovery and return to their normal lives. However, the majority of survivors subsequently developed neurological or psychiatric disorders, often after years or decades of seemingly perfect health. Post-encephalitic syndromes varied widely: sometimes they proceeded rapidly, leading to profound disability or death; sometimes very slowly; sometimes they progressed to a certain point and then stayed at this point for years or decades; and sometimes, following their initial onslaught, they remitted and disappeared.<ref>{{harv|Sacks|1990|pp=20–21}}</ref> It is also known to cause postencephalitic parkinsonism (PEP).<ref name=":2a" /> Though often thought of as a disease of the past, it is still seen in occasional cases today.<ref name=":1a" />

==Notable cases==
Notable cases include:
* Muriel "Kit" Richardson (née Hewitt), first wife of actor Sir Ralph Richardson, died of the condition in October 1942, having first shown symptoms in 1927–28.{{Citation needed|date=October 2020}}
* There is speculation that Adolf Hitler may have had encephalitis lethargica when he was a young adult (in addition to the more substantial case for Parkinsonism in his later years).<ref>{{cite journal|title= Adolf Hitler Had Post-Encephalitic Parkinsonism |journal= Parkinsonism Relat Disord. |date= April 1996 |volume= 2 |number= 2 |pages= 95–103 |last= Lieberman |first= A |pmid=18591024 |doi=10.1016/1353-8020(96)00005-3}}</ref><ref>{{ cite journal |author1=Boettcher, L.B. |author2=Bonney, P.A. |author3=Smitherman A.D. |author4=Sughrue, M.E. |year = 2015 |journal = Neurosurg Focus |volume = 39 |issue = 1, July |page = E8 |doi = 10.3171/2015.4.FOCUS1563 |title = Hitler's Parkinsonism |pmid=26126407 |doi-access =  }}</ref><ref>{{cite journal|title= Understanding the Influence of Parkinson's Disease on Adolf Hitler's Decision-Making During World War II |journal= World Neurosurg. |year = 2015 |author=Gupta, R |author2=Kim, C |author3=Agarwal, N |author4=Lieber, B |author5=Monaco, E.A. |pmid=26093359 |volume = 84 |issue = 5, November |pages= 1447–1452 |doi= 10.1016/j.wneu.2015.06.014}}</ref><ref>{{cite journal |author = Rosen, Denis |year = 2010 |title = Review: "Asleep: the Forgotten Epidemic That Remains One of Medicine's Greatest Mysteries" [Molly Caldwell Crosby |journal= J. Clin. Sleep Med. |volume= 6 |number= 3, 15 June |page= 299 |pmc= 2883045 |doi = 10.5664/jcsm.27831 }}</ref>
* Mervyn Peake (1911–1968), author of the ''Gormenghast'' books, began his decline towards death which was initially attributed to encephalitis lethargica with Parkinson's disease–like symptoms, although others have later suggested his decline in health and eventual death may have been due to [[Medicine:Lewy body dementia|Lewy body dementia]].<ref name="dlb">{{cite journal|author=Demetrios J. Sahlas|year=2003|title=Dementia With Lewy Bodies and the Neurobehavioral Decline of Mervyn Peake|journal=Arch. Neurol.|volume=60|issue=6|pages=889–892|doi=10.1001/archneur.60.6.889|pmid=12810496|doi-access=free}}</ref><ref>{{Cite book|url=http://download.audible.com/product_related_docs/BK_NAXO_000663.pdf|title=Publisher's Liner Notes on Mervyn Peake for 'Titus Alone'|last1=McMillan|first1=Roy|last2=Peake|date=20 July 2011|editor-last=Butcher Sara|via=Audible.com|publisher=Naxos Audiobooks|location=Germany|page=7|language=en|type=Liner Notes|format=Liner Notes/ Reference Guide for Abridged Audiobook of Titus Alone|orig-date=1959 |isbn=978-184-379-542-1|access-date=2 May 2018|quote=But the plays were not the financial winners he had hoped for, and he suffered another nervous breakdown in 1957. This led to the more evident display of the symptoms of a type of Parkinson's Disease which, alongside the effects of encephalitis lethargica that he contracted in childhood, was slowly to kill him over more than a decade.|edition=Abridged, Audio}}{{Dead link|date=February 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>
* Those described in the book ''Awakenings'' by the British neurologist Oliver Sacks.<ref name=sacksnp />
* Jane Norton Grew Morgan, wife of J. P. Morgan Jr., died of encephalitis lethargica in 1925. At the time, doctors attributed her encephalitis to having contracted influenza during the 1918 pandemic.<ref>{{Cite book |last=Chernow |first=Ron |year=1990 |title=The House of Morgan: An American Banking Dynasty and the Rise of Modern Finance |location=New York |publisher=Atlantic Monthly Press |isbn=0-87113-338-5}}</ref>

== See also ==

* [[Medicine:Idiopathic disease|Idiopathic disease]]
* Idiopathic chronic fatigue
* [[Medicine:Chronic fatigue syndrome|Chronic fatigue syndrome]]
* [[Medicine:Fever of unknown origin|Fever of unknown origin]]

==References==
{{Reflist|35em}}

==Further reading==
* {{Cite book |author = Crosby, Molly Caldwell |year = 2010 |title = 'Asleep: The Forgotten Epidemic that Remains One of Medicine's Greatest Mysteries |location = New York|publisher = Penguin/Berkley|isbn= }}{{ISBN?}}{{snd}}Describes the history of the disease, and the epidemic of the 1920s.
* {{Cite journal |author1=Reid, A.H. |author2=McCall, S. |author3=Henry, J.M. |author4=Taubenberger, J.K. |title = Experimenting on the Past: The Enigma of von Economo's Encephalitis Lethargica |journal = J. Neuropathol. Exp. Neurol. |volume = 60 |issue = 7 |pages = 663–670 |year = 2001 |pmid = 11444794 |doi = 10.1093/jnen/60.7.663 |doi-access = free }}
* {{Cite book|last=Sacks|first=Oliver|title=Awakenings|year=1990|publisher=Vintage Books|isbn=978-0-375-70405-5|oclc=21910570}}
* {{Cite journal |author = Sacks O |year = 1983 |title = The origin of 'Awakenings' |journal = Br. Med. J. (Clin. Res. Ed.) |volume = 287 |issue = 6409 |pages = 1968–1969 |doi=10.1136/bmj.287.6409.1968 |pmid = 6418286 |pmc = 1550182 }}
* {{Cite journal |author1=Vilensky, J.A. |author2=Foley, P. |author3=Gilman, S. |year = 2007 |title=Children and Encephalitis Lethargica: A Historical Review |journal=Pediatr. Neurol. |volume=37 |issue=2, August |pages=79–84 |pmid=17675021 |doi=10.1016/j.pediatrneurol.2007.04.012}}
* {{Cite book |year = 2010 | editor = Vilensky, Joel A. |title = Encephalitis Lethargica: During and After the Epidemic |location = Oxford, UK |publisher = Oxford University Press |isbn = 978-0190452209}}

== External links ==
* [http://www.ninds.nih.gov/health_and_medical/disorders/encephalitis_lethargica.htm National Institute of Neurological Disorders and Stroke] {{Webarchive|url=https://web.archive.org/web/20081203201518/http://www.ninds.nih.gov/health_and_medical/disorders/encephalitis_lethargica.htm |date=2008-12-03 }}
* [http://news.bbc.co.uk/1/hi/health/3930727.stm Mystery of the Forgotten Plague]: BBC news item about the tracing of the infectious agent in encephalitis lethargica

{{Medical resources
| DiseasesDB = 32498
| ICD10 = {{ICD10|A|85|8|a|80}}
| ICD9 = {{ICD9|049.8}}
| ICDO =
| OMIM =
| MedlinePlus =
| eMedicineSubj =
| eMedicineTopic =
| MeshID =
}}
{{Viral diseases}}
{{CNS diseases of the nervous system}}

[[Category:Unsolved problems in neuroscience]]

{{Sourceattribution|Encephalitis lethargica}}