sleeping princes and princesses: the encephalitis lethargica epidemic of the 1920s and a...
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Sleeping Princes and Princesses:
The Encephalitis Lethargica Epidemic of the 1920s and a Contemporary
Evaluation of the Disease
Joel A. Vilensky Ph.D. Indiana University School of Medicine Fort Wayne
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Encephalitis Lethargica (EL)
• Epidemic disease 1917-1930– Described by Constantin von
Economo in 1917
• More than 1 million cases, approx 500,000 deaths, worldwide
• Extremely polymorphic symptoms and signs
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Constantin von Economo
• Vienna Psychiatric and Neurological Clinic, Austria
• Observed an Epidemic outbreak of a “sleeping sickness” in winter of 1916-1917
Constantin von Economo (1876-1931)
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Constantin von Economo’sWritten Account of Encephalitis
Lethargica• Series of cases that
did not fit any usual diagnoses– Similarity in onset
and symptoms – Grouped them into
one clinical disease picture
• Described as “a kind of sleeping sickness” and gave name
Encephalitis lethargica v. Economo C. 1917 Encephalitis Lethargica, Wien Klin Wschr 30:581-585
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Progression of EL Epidemic
• 1916-17 Vienna (v. Economo)• 1918 Influenza Epidemic spreads• 1918-1919 Germany• 1918 London • 1918-1919 North America
19161918
Progression of Reported Cases Of EL
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• High incidence reached in 1920
• Reached low levels 1922-23
• A second high peak occurred in 1924
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Encephalitis Lethargica: Its Sequelae and
Treatment
By Constantin von Economo (1929)
Oxford University Press (1931)
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Character of Infection
• Transmission – Direct (person to person) rare – Possibly airborne – Possible non-affected carriers– Potential for contagion reduces once localized in CNS
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Character of Infection
• Incubation– Almost impossible to predict – Reported as a minimum of one day, average
of ten days, and a maximum of 2 months
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Predisposition • Concentrated
populations
• General hardship
• Afflicted with another pathogen
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Etiology• No known cause • Different pathogens
possibly associated with EL
• Pathogens not found consistently through out EL brain tissue samples
• Unable to replicate experimental results
streptococcus
globuli
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Etiology• von Economo “due to the nature of the
disease a virus specific for the mid-brain and lower brain must be the causing agent though it can not be found”
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Pathology
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Pathology
Substantia nigra
Putamen
Caudate nucleus
Globus pallidus
Basal
ganglia
Mesencephalon
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von Economo’s Types of EL
• Common Prodromal Stage
• Three described types–Somnolent-Ophthalmoplegic
–Hyperkinetic
–Amyostatic-Akinetic
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Common Prodromal Stage • Almost always of
short length• General discomfort • Lassitude, Seediness
(Weariness, Lethargy)
• Shivering• Headache• Vertigo and
Vomiting• Slight fever • Mild Pharyngitis
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Somnolent-Ophthalmoplegic
• Somnolence–falls asleep, even
during activity–if aroused wakes up
quickly and completely
–Can be present with no rise in temperature or CSF pressure
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Somnolent-Ophthalmoplegic
• Ocular Palsies– Lateral rectus muscle
paralysis (outward movement of the eye)
– Ptosis (Drooping eyelids)
– Impairment of accommodation (focusing the lens for near vision)
– Conjugate deviation palsy (Both eyes moving together)
– Vertical palsy (paralysis of movement up or down)
– Nystagmus (rapid involuntary movements of the eyes )
– Strabismus (cross eyed)
Bilateral Ptosis
Lateral Rectus Palsy
Strabismus
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Somnolent-Ophthalmoplegic
• Intraocular muscle paralysis – Anisocoria (pupils are different sizes)
– Myosis (constriction of the pupil)
– Mydriasis (dilation of the pupils) – Argyll Robertson’s sign (The pupils are small and irregular, they do
not react to light but react for accommodation)
AnisocoriaMydriasisMyosis
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Somnolent-Ophthalmoplegic
Other Signs and Symptoms • Dream like deliria• Sight Disturbances
– Diplopia (double vision), Dazzling (Impaired vision in bright light), Indistinct vision
• Facial Paralysis, Soft palate paralysis
• Disturbances in swallowing and chewing
• Hypotonus (decreased muscle tone)
• Ataxia (incoordination of muscle movements)
• Hyperhidrosis (Excessive Sweating)
Diplopia
Facial Paralysis
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Hyperkinetic• Motor unrest
– Myoclonic twitches (involuntary twitching of a muscle or a group of muscles)
• Frequently accompanied by stabbing pains
– Clonus (involuntary muscular contractions causes large motions)
– Chorea (involuntary quick movements of the feet or hands)
– Athetosis (continuous stream of slow, sinuous, twisting movements that distort posture, typically the hands and feet)
– Derailments of movement (Stopping an action in the middle of completion)
Athetosis
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Hyperkinetic
• Psychomotor unrest– Anxiety– Frenzy– Apprehension– Hallucinations – Panic– Hypomania
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Hyperkinetic Sleep Disturbances
• Sleep Disturbances– Insomnia
• Not responsive to drugs
– Sleep Inversion• Night time motor
unrest • Daytime
Somnolence
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HyperkineticOther Signs and Symptoms
• Speech disturbances• Severe headache • Pain
– Facial, Arms and legs, Abdominal (often mistaken for appendicitis)
• Vomiting• Facial swelling• Delirium and confusion• Pupillary disturbances• Respiratory disturbances• Seizures
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Amyostatic-Akinetic
• Rigidity (inflexibility)
– Common in chronic cases
• Asthenia (weakness without actual loss of strength)
• Bradykinesia (slowness in the
execution of movement) • Flexibilitas cerea (characteristic
rigidity that holds the limb in position)
• Masked facial expression (face lacks expression and animation)
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Amyostatic-Akinetic• Sleep
disturbance–somnolence–inversion–insomnia–disassociated
body sleep and brain sleep
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Amyostatic-Akinetic:Other Signs and Symptoms
• Festinating (progressively more rapid)
and slouching gait (pattern of walking)
• Propulsion and/or retro propulsion (compulsory movement forward or backward)
• Hypersialisis (excessive salivation)
• Hyperhidrosis (excessive sweating)
• Hypertonus (increased muscle tone)
• Speech disturbances• Swallowing disturbances• Eye muscle paresis
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Types of EL• Any number and combination of symptoms may
be seen in a single case • Clinicians began dividing the disease into
additional types
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Prognosis • Varied course
– Symptoms may appear suddenly– Sometimes show a dramatic turn (for better or
worse) without warning
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Prognosis• Death
– In acute cases 40% die– In all cases (acute and subacute)
15% die – Frequently nonspecific modes of
death occur• e.g. pneumonia
• Recovery and Sequelae – Of all surviving cases
• 22% complete recovery • 44% recovery with slight defect• 34% chronic invalids
New York Times Sep. 29, 1937
New York Times March 9, 1923
New York Times June 19, 1931
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Sequelae• Residual Symptoms and Signs
– Ocular paralysis – Spastic muscle paralysis – Sensory disturbances– Vegetative disturbances
• Protracted States– Relapsing cases – Intermittent progression
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Sequelae• Post Encephalitic Diseases
–Psychosis
–Parkinsonism
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Psychosis• Mostly in Children • Juvenile pseudo-
psychopathia – Erethic imbecility (abnormal
irritable foolishness)
– Hypomania– Insomnia – Lack of inhibitions– Sexually inappropriate– Able to know they are doing
wrong but unable to stop themselves
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Post-encephalitic Parkinsonism
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Post-encephalitic Parkinsonism
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1973 1990
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EL’s relevance to the Present• Sporadic Cases
– 230 cases of EL cited in the literature throughout the world since 1940 (unpublished observation)
– 29 of those occurred in the last 10 years
• Possible relationship to Influenza - Many reports of EL like diseases occurred with influenza pandemics in world
history - Some evidence suggest a relationship - Researchers have yet to conclusively say
that EL is not caused by or associated with EL
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Sporadic Case of EL• In 1999
diagnosed with EL
• Unconscious for three months.
• Passed away on 30th May 2006
Sophie Cameronwww.thesophiecamerontrust.org.uk
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Historical Accountsof Sleepy Sicknesses and
Influenza• 1580 Europe
• 1673-75 London
• 1763 France
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Historical Accountsof Sleepy Sicknesses and
Influenza • 1780-82 Paris
• 1830-33 Paris
• 1890-91 Italy
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EL and Influenza
Self-portrait after the Spanish Influenza Edvard Munch (1919)
• Among Contemporary Observers of EL…– Few believed EL and
influenza were from same organism
– Many believed influenza predispose for encephalitis lethargica
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Circumstantial Support for a Relationship Between EL and
Influenza• EL Cases in children
largely preceded by Influenza (Neal 1920)
• 37% of EL cases from
Belarus preceded by
Influenza (1918-1928)
• EL either led or followed the flu for the years 1918-19, 20, and 23 (Chasanow 1930)
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Circumstantial Support for a Relationship Between EL and
InfluenzaHardest hit U.S. city with both influenza & EL:
Philadelphia.
Least affected population by both influenza & EL:
Blacks.
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Circumstantial Support for a Relationship Between EL and
Influenza• 1918 Influenza
epidemic on Western Samoa– followed by EL for
several subsequent years
• Strict quarantine in American Samoa – No 1918 influenza
epidemic– No EL deaths
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Evidence Against an EL and Influenza
Relationship • v. Economo’s first case of EL preceded the earliest influenza cases
• Opposing geographical proliferations of Influenza and EL
Influenza
EL
Possible explanations…• Variant influenza virus • Spanish influenza began earlier in Europe • EL in North America prior to its recognition
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Evidence Against an EL and Influenza
Relationship• EL and influenza had notable medical differences:
– Prevalence, Clinical features, Infectivity
• Other diseases have different stages with very different signs and symptoms (Maurizi 1989)
Primary Syphilis effects genitals 10-90 day incubation period
NeuroSyphilis effects CNS occurs some time after original infection
Measles effects general body 4-12 day incubation
Subacute SclerosingPanencephalitis (SSPE) effects CNS 6-15 years after initial infection
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Evidence Against an EL and Influenza
Relationship• Modern Studies
of Preserved EL/ PEP Brain Tissue
• McCall et al., 2001– Influenza RNA not
detected
• Lo et al., 2003– Influenza RNA not
detected
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Limitations Of EL-Influenza Studies
• Failed to test non-CNS tissues
• RNA sequence mismatch
circular chromosome of Haemophilus influenzae
1918 Influenza, Bronchopneumonia. Inter-lobar pleurisy. Credit: National Museum Of Health And Medicine.
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Limitations Of EL-Influenza Studies
• EL material rare
• Tissue Prep and Handling not reliable
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Is EL caused by an Autoimmune Response?
• 20 putative modern cases of EL (Dale et al. 2003) – Significant increase in recent
streptococcus infections in EL vs. control patients
– 95% had basal ganglia autoantibodies
• Group A Streptococcal infections may cause latent neurological effects– Sydenham’s chorea– Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcal Infections (P.A.N.D.A.S)
streptococcus
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Vincent’s (2004) Problems with
Dale et al. (2003)• 60% normal MRI
findings • 35% no anti-
streptolysin-O elevation• No data for disease
duration vs. control • No data for the cross
reactivity of antibody
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Why EL-Influenza Studies may have false negatives
• Hypothesis by Hayase and Tobita (1997): How influenza can cause encephalitis by:
– Molecular mimicry– Cerebrovascular endothelial cell
infections– Alteration of normal blood-brain barrier
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The EL and Influenza Relationship
• Case of 2 Vietnamese siblings, 4 & 9 year old (deJong et. al. 2005)– Probable encephalitis associated with
H5N1 bird influenza virus– No respiratory symptoms presented
Raises the possibility that the avian H1N1 influenza virus of 1918 may also have had unusual manifestations (i.e. EL)
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If EL is Related to Influenza
• Waking to a New Flu Threat (Sacks and Vilensky 2005)
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Conclusions• Encephalitis lethargica produces
variable symptoms and signs • Encephalitis lethargica effects patients
long after initial sickness is over in the form of sequelae
• Understanding how encephalitis lethargica is diagnosed is critical because a new epidemic is possible and sporadic cases still occur
• Research into encephalitis lethargica causative agent is still needed to better understand this disease
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• Economo wrote in 1929 – “One thing is certain: whoever has observed
without bias the many forms of encephalitis lethargica… must of necessity have quite considerably altered his outlook on neurological and psychological phenomena…. Encephalitis lethargica can scarcely again be forgotten.”