HISTORICAL NEUROLOGY

The centennial lesson of encephalitis lethargica

Bart Lutters, BSc, Paul Foley, PhD, and Peter J. Koehler, MD, PhD Correspondence
Dr. Koehler
Neurology® 2018;90:563-567. doi:10.1212/WNL.0000000000005176 pkoehler@neurohistory.nl

Abstract
We commemorate the centenary of Constantin von Economo’s description of encephalitis
lethargica, a mysterious disease that had a significant effect on 20th-century neuroscience. In the
acute phase, encephalitis lethargica was marked by intractable somnolence, which von Econ-
omo attributed to lesions in the diencephalon, thereby paving the way for future efforts to
localize the regulation of sleep in the subcortical brain. At the same time, neuropathologic
findings in postencephalitic parkinsonism affirmed the role of the substantia nigra in the
pathophysiology of parkinsonism. The occurrence of psychiatric symptoms in patients with
encephalitis lethargica—such as mood disorders, obsessive-compulsive behavior, and
bradyphrenia—drew attention to the organic basis of mental illness.

From the Faculty of Medicine (B.L.), University Medical Center Utrecht, the Netherlands; Neuroscience Historian (P.F.), Sydney, Australia; and Department of Neurology (P.J.K.),
Zuyderland Medical Center, Heerlen, the Netherlands.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Copyright © 2018 American Academy of Neurology 563

Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 Glossary
DBS = deep brain stimulation; PD = Parkinson disease; PPN = pedunculo-pontine nucleus; RBD = REM sleep behavior
disorder.
In his celebrated “Essay on the shaking palsy,” James
Parkinson1 was the first to recognize that “sleep becomes
much disturbed” in patients with the debilitating disease that
would eventually bear his name. Over recent decades,
Parkinson disease (PD) and other synucleinopathies have
indeed been associated with a variety of sleep disorders, in-
cluding REM sleep behavior disorder (RBD), excessive day-
time sleepiness, and restless legs syndrome. In addition, the
high incidence of psychiatric symptoms in patients with PD
has been increasingly recognized, as reflected by recent deep
brain stimulation (DBS) studies targeting both motor and
nonmotor symptoms associated with PD.2–5
In 1917, the Viennese neuropsychiatrist Constantin von
Economo6 (1876–1931) described a mysterious sleeping
sickness that would have a profound effect on 20th-century
sleep and PD research and contemporary neuropsychiatry. In
the acute phase, encephalitis lethargica was marked by a pe-
culiar state of intractable somnolence, generally accompanied
by oculomotor palsies. Based on autopsy findings, von
Economo was able to attribute the somnolence to pathology
in the “interbrain,” prompting him to propose the existence of
a diencephalic “sleep-regulating center.” If a patient survived
the acute phase of encephalitis lethargica, it was often
followed by chronic sequelae, of which postencephalitic par-
kinsonism was the most common, and was associated with
lesions in the substantia nigra, thereby affirming its role in the
pathophysiology of parkinsonism. Moreover, the occurrence
of psychiatric derangements in patients with encephalitis
lethargica drew attention to the “organic” basis of similar
“functional” symptoms in other contexts. We commemorate
the centenary of von Economo’s description of encephalitis
lethargica, a disease that earned sleep, parkinsonism, and
mental illness a physical location in the brain.
Localization of sleep
During the winter of 1916/1917, a number of patients with
unusual symptoms were admitted to the psychiatric clinic in
Vienna. Constantin von Economo, who had recently returned
from service in the Austrian air force, quickly noticed that
these patients displayed a common set of symptoms that did
not fit any known diagnosis. Patients with this disease typi-
cally presented with headache and general discomfort, soon
followed by a state of persistent somnolence resembling
physiologic sleep. This excessive sleepiness—generally ac-
companied by oculomotor problems, such as partial or
complete eye muscle paralysis—could rapidly lead to death,
persist unchanged for weeks, or, in the mildest cases, swiftly
disappear. In May 1917, von Economo6 published his clinical
564 Neurology | Volume 90, Number 12 | March 20, 2018
Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
observations of his initial 7 cases of encephalitis lethargica in
the Wiener Klinische Wochenschrift, together with autopsy
findings from 2 patients who had died of the disease. Histo-
pathologic examination revealed acute inflammation of the
brainstem, marked by small cell infiltration of the gray matter
around the third ventricle and cerebral aqueduct, the area of
the oculomotor nuclei, and the floor of the fourth ventricle.
After ruling out many potential etiologies, von Economo
concluded that encephalitis lethargica was caused by an as yet
unknown virus with affinity for central nervous tissue, com-
parable to but not identical with the poliomyelitis virus.6
By the end of the 1920s, von Economo7,8 had published
dozens of articles on encephalitis lethargica, as well as 2 ex-
tensive monographs. In the meantime, the disease had spread
throughout Europe and North America (affecting about
1 million people worldwide), providing adequate material for
a host of histopathologic, microbiologic, and clinical inves-
tigations.9 The consistent pathology of the disorder allowed
von Economo10 to localize the lethargic symptoms of en-
cephalitis lethargica to the posterior wall of the third ventricle,
near the oculomotor nuclei. Further, he traced insomnia,
a disturbance paradoxically encountered in about 10% of en-
cephalitis lethargica cases, more anteriorly, to the lateral walls
of the third ventricle, near the corpus striatum. For von
Economo,10 these clinicopathologic findings confirmed the
existence of a subcortical sleep-regulating center (figure).
During sleep, this center would actively inhibit the cerebral
cortex, reducing the level of consciousness; following sensory
stimulation, the process was suddenly reversed, and con-
sciousness was swiftly restored.10 Interestingly, von Economo
accurately predicted his sleep-regulating center to be involved
in the pathogenesis of narcolepsy, which had first been de-
scribed by Westphal and Gélineau during the late 19th century.
During the 1930s, the rise of EEG caused a substantial para-
digm shift in the physiologic approach to investigating sleep
and wakefulness. The Belgian neurophysiologist Frédéric
Bremer (1892–1982) discovered that the EEG pattern
recorded from cat brain preparations dissected at the level of
the midbrain (and hence deprived of most sensory input)
resembled that of typical sleep, rather than wake activity.
From this, Bremer11 concluded that the brain was not, in fact,
put to sleep by an active inhibitory process as envisaged by
von Economo, but was instead actively kept awake or aroused
by sensory input. In 1949, Chicago physiologist Horace
Magoun (1907–1991) and visiting professor Giuseppe Mor-
uzzi (1910–1986) identified the reticular formation and as-
cending brainstem projections to the cerebral cortex (the
ascending reticular activating system) to be primarily
Neurology.org/N

Figure von Economo’s sleep-regulating center: First
published in 1926
28
The sleep-regulating center is located at the transition between the di-
encephalon and mesencephalon (dotted line). The horizontal lines indicate
the location of lesions resulting in somnolence. The diagonal lines denote
the location of lesions resulting in insomnia.
responsible for this arousal mechanism. Even though this
system was modulated by sensory input, it was not considered
to be as dependent upon it as Bremer had supposed. In fact,
Moruzzi and Magoun argued that clinicopathologic findings
from encephalitis lethargica provided evidence of the disso-
ciation between arousal and sensory input:
Prolonged somnolence has followed chronic lesions in the basal
diencephalon and anterior midbrain which did not involve afferent
pathways to the cortex […] and similar results have followed injury
to this region from tumors or encephalitis [lethargica] in man.12
Localization of parkinsonism
In 1924, Danish neuropsychiatrist August Wimmer13
(1872–1937) noted in the preface to his chronic encephalitic
lethargica monograph that postencephalitic parkinsonism, the
typical state of chronic encephalitis lethargica patients, was
well known to the medical community. Patients with post-
encephalitic parkinsonism typically developed bradykinesia,
rigidity, tremor, masked facies, and speech disturbances,
thereby closely mimicking the symptomatology of
PD—except that the patients could be as young as teenagers.8
These symptoms could directly precede the acute phase, or
develop months to years after apparent recovery (similar to
the variable time of onset that was later observed in 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine–induced parkinsonism).14
Parkinsonism could be accompanied by other extrapyramidal
Neurology.org/N
Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
disorders—such as dystonia, chorea, and athetosis—
respiratory disturbances, and oculomotor crises. The striking
resemblance between postencephalitic and idiopathic par-
kinsonism prompted the notion that it was not so much the
causative agent but rather the anatomic localization of the
disease process that ultimately explained parkinsonian
symptoms.15
The Russian neurologist Constantin Trétiakoff (1892–1958),
who had trained with Pierre Marie and collaborated with
Bremer in Paris, was the first to attribute the rigidity and
tremor of encephalitic lethargica and parkinsonism to lesions
in the substantia nigra.16 Elaborating on the “nigral hypoth-
esis” first raised by Marie’s predecessor Édouard Brissaud in
1895, Trétiakoff16 set out to investigate the pathologic alter-
ations of the substantia nigra in 54 patients who had died of
various neurologic conditions, including 13 cases of PD and 3
of encephalitis lethargica–associated parkinsonism (at this
point, postencephalitic parkinsonism was not yet recognized
as a chronic syndrome). He concluded that both PD and the
rigidity and tremor of encephalitic lethargica were essentially
associated with lesions of the substantia nigra.
The significance of the nigral lesion was, however, not uni-
versally accepted until the late 1930s. Throughout the 19th
century, the anatomic substrate of parkinsonism had been the
subject of speculation, with a range of theories implicating
the muscles, spinal cord, brainstem, cerebellum, and even the
cerebral cortex.9 During the first decades of the 20th century,
the focus was on disturbances of the corpus striatum, partic-
ularly the globus pallidus, with the American neurologist
Ramsay Hunt, pathologists Friedrich Lewy and Cécile and
Oskar Vogt, and French neurologist Jean Lhermitte among
the major proponents of the lenticular hypothesis. With
growing awareness of the work of Trétiakoff and of the typical
pathology of encephalitic lethargica, attention gradually shif-
ted to the substantia nigra. For some time, however, both
anatomic structures were thought to be involved in parkin-
sonism; whereas PD was attributed to lesions in the globus
pallidus, postencephalitic parkinsonism was linked with the
substantia nigra.9 Eventually, the publications by students
Rolf Hassler17 (1938) and Rudolf Klaue18 (1940) established
the importance of the substantia nigra for both forms of
parkinsonism beyond dispute.
Localization of psychiatric symptoms
Besides sleep disturbances and parkinsonism, psychiatric
phenomena were common in encephalitis lethargica. During
the acute phase, typical symptoms included altered
personality, lability of mood, hallucinations, delirium, and
catatonia-like states, while marked personality changes,
obsessive–compulsive behaviors, mood disorders, and
bradyphrenia could emerge during the chronic phase.
Particularly fascinating were the oculomotor crises of the
chronic phase, then regarded as unique to encephalitis leth-
argica, which seemingly combined complex psychiatric,
Neurology | Volume 90, Number 12 | March 20, 2018 565
 motor, and sleep features. Children, on the other hand, often
had negative personality changes combined with extreme
impulsiveness and behavioral abnormalities that ranged from
conditions resembling attention-deficit/hyperactivity disor-
der to criminal behavior (theft, assault, rape, murder). The
association between psychiatric symptoms and the diffuse
subcortical lesions encountered in encephalitis lethargica
drew attention to the role of the subcortical brain, particularly
the basal ganglia, in the pathogenesis of mood changes,
obsessional disorders, and psychosis. By showing that
psychiatric symptoms could be caused by physical brain
lesions in previously healthy people, encephalitis lethargica
narrowed the divide between organic and functional
illnesses.14 von Economo19 considered this one of the most
valuable lessons taught by the disease:
Future scientific generations will hardly be able to appreciate our pre-
encephalitic neurological and psychiatric conceptions […]. Now we can
[…] describe encephalitis lethargica as a functional affection, but on an
organic basis. The apparent contradiction which this would have
constituted in the past exists no longer.
Sleep dysfunction and psychiatric
symptoms in PD
During the second half of the 20th century, the introduction
of levodopa further drew attention to the pathophysiologic
relationship between sleep dysfunction, psychiatric symp-
toms, and parkinsonism, and to the role of dopamine in these
derangements. In the early 1970s, various groups reported on
the effects of levodopa on sleep architecture in patients with
PD, thereby elucidating the effects of dopamine on sleep in
humans.20–23 Levodopa also drew attention to the role of
dopamine in the pathophysiology of psychiatric symptoms, as
patients with PD treated with the drug frequently exhibited
psychiatric side effects, including depression, psychosis, and
delirium.24 Whether these symptoms were a direct effect of
levodopa, or secondary to the disease process, remained
disputed.24
During the 1980s, increased public and medical awareness of
sleep medicine attributed to the definition of a variety of sleep
disorders, most notably RBD, characterized by dream-
enacting behavior with preservation of muscular tone during
REM sleep.25 Interestingly, it was found that about 1 in 3
patients diagnosed with RBD eventually developed a parkin-
sonian disorder, and that the pedunculo-pontine nucleus
(PPN) was implicated in this linked RBD parkinsonism.26 It is
now recognized that the nonmotor symptoms of parkinson-
ism can precede the motor symptoms by many years,27 and
high-frequency DBS of the PPN has been reported as effec-
tively ameliorating both the motor and nonmotor symptoms
of PD (including sleep and psychiatric symptoms),5 an ex-
citing development that von Economo10 seems to have
foreseen when he discussed the implications of his sleep
theory:
566 Neurology | Volume 90, Number 12 | March 20, 2018
Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Imagine we once had an effective method of influencing deep lying centers
[by electricity or diathermia]. In this case, the exact knowledge of the
localization of the center for sleep regulation, which I have attempted to
give you, would make it possible to treat insomnia and other sleep
disturbances in a better and more active way than by drugs or by the
roundabout way of hydrotherapy or psychotherapy.
Discussion
Constantin von Economo’s description of encephalitis
lethargica clearly had an important effect on 20th-century
neuroscience. By tracing its most characteristic symptom,
somnolence, to the diencephalon, von Economo paved the
way for efforts to localize the regulation of sleep in the sub-
cortical brain. Simultaneously, neuropathologic findings in
postencephalitic parkinsonism drew attention to the role of
the substantia nigra in the pathophysiology of parkinsonism.
The occurrence of psychiatric symptoms in patients with
encephalitis lethargica drew attention to the organic basis of
mental illness.
Author contributions
Bart Lutters: study conception and design, drafting the
manuscript for intellectual content. Paul Foley: revising the
manuscript for intellectual content. Peter Koehler: study
conception and design, revising the manuscript for intellectual
content.
Acknowledgment
Joel Vilensky (Indiana University) provided intellectual
suggestions and source material.
Study funding
No targeted funding reported.
Disclosure
The authors report no disclosures relevant to the manuscript.
Go to Neurology.org/N for full disclosures.
Received August 12, 2017. Accepted in final form December 8, 2017.
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 The centennial lesson of encephalitis lethargica
Bart Lutters, Paul Foley and Peter J. Koehler
Neurology 2018;90;563-567
DOI 10.1212/WNL.0000000000005176

This information is current as of March 19, 2018

Updated Information & including high resolution figures, can be found at:
Services http://n.neurology.org/content/90/12/563.full.html

References This article cites 19 articles, 2 of which you can access for free at:
http://n.neurology.org/content/90/12/563.full.html##ref-list-1
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
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http://n.neurology.org//cgi/collection/all_sleep_disorders
History of Neurology
http://n.neurology.org//cgi/collection/history_of_neurology
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http://n.neurology.org//cgi/collection/parkinsons_disease_parkinsonism

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