Encephalitis lethargica

Encephalitis lethargica is an atypical form of encephalitis. Also known as "sleeping sickness" or "sleepy sickness" (distinct from tsetse fly-transmitted sleeping sickness), it was first described in 1917 by the neurologist Constantin von Economo and the pathologist Jean-René Cruchet.

The disease attacks the brain, leaving some victims in a statue-like condition, speechless and motionless. Between 1915 and 1926, an epidemic of encephalitis lethargica spread around the world. Nearly five million people were affected, a third of whom died in the acute stages. Many of those who survived never returned to their pre-existing "aliveness".

They would be conscious and aware – yet not fully awake; they would sit motionless and speechless all day in their chairs, totally lacking energy, impetus, initiative, motive, appetite, affect or desire; they registered what went on about them without active attention, and with profound indifference. They neither conveyed nor felt the feeling of life; they were as insubstantial as ghosts, and as passive as zombies.

No recurrence of the epidemic has since been reported, though isolated cases continue to occur.

Signs and symptoms

Encephalitis lethargica is characterized by high fever, sore throat, headache, lethargy, double vision, delayed physical and mental response, sleep inversion and catatonia. In severe cases, patients may enter a coma-like state (akinetic mutism).

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

Klazomania (a vocal tic) is sometimes present.

Cause

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Encephalitis lethargica. Its sequelae and treatment – Constantin Von Economo, 1931: front page

The causes of encephalitis lethargica are uncertain.

Some studies have explored its origins in an autoimmune response, and, separately or in relation to an immune response, links to pathologies of infectious disease — viral and bacterial, e.g., in the case of influenza, where a link with encephalitis is clear. 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 (e.g., lack of viral RNA in postencephalitic parkinsonian brain material). In reviewing the relationship between influenza and encephalitis lethargica (EL), McCall and coworkers conclude, as of 2008, that while "the case against influenza [is] less decisive than currently perceived… 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." Hence, while opinions on the relationship of encephalitis lethargica to influenza remain divided, the preponderance of literature appears skeptical.

German neurologist Felix Stern, who examined hundreds of encephalitis lethargica patients during the 1920s, pointed out that the encephalitis lethargica typically evolved over time. The early symptom 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 symptom. If patients of Stern followed this course of disease, he diagnosed them with encephalitis lethargica. Stern suspected encephalitis lethargica to be close to polio without evidence. Nevertheless, he experimented with the convalescent serum of survivors of the first acute symptom. He vaccinated patients with early stage symptoms and told them that it might be successful. Stern is author of the 1920s definitive book Die Epidemische Encephalitis (1920 and 2nd ed. 1928). Stern was driven to suicide during the Holocaust by the German state, his research forgotten.

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 Pool, 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:

Does the present volume solve the "riddle" of EL, which… 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."

Subsequent to publication of this compendium, an enterovirus was discovered in encephalitis lethargica cases from the epidemic. In 2012, Oliver Sacks acknowledged this virus as the probable cause of the disease. Other sources have suggested Diplococcus as a cause.

History

Occurrences

Retrospective diagnosis tentatively suggests numerous accounts of encephalitis lethargica throughout history:

• In 1580, Europe was swept by a serious febrile and lethargic illness, which led to Parkinsonian and other neurological sequelae.
• In 1673–1675, a similar serious epidemic occurred in London, which Thomas Sydenham described as "febris comatosa."
• In 1695, a 20-year-old woman in Germany experienced oculogyric crises, Parkinsonism, diplopia, strabismus, and other symptoms following an attack of somnolent brain fever, as described by Dr. Albrecht of Hildesheim.
• In 1712–1713, a severe epidemic of Schlafkrankheit (encephalitis lethargica) occurred in Tübingen, Germany, followed in many cases by persistent slowness of movement and lack of initiative (aboulia).
• Between 1750 and 1800, France and Germany experienced minor epidemics of "coma somnolentum" with Parkinsonian features, includig hyperkinetic hiccough, myoclonus, chorea, and tics.
• Between 1848 and 1882, Paris-based neurologist Jean-Martin Charcot documented many isolated cases of juvenile Parkinsonism, associated with diplopia, oculogyria, tachypnoea (hyperventilation), retropulsion, tics, and obsessional disorders, which were almost certainly post-encephalitic in origin.
• 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.
• Between 1915 and 1926, a world-wide encephalitis lethargica pandemic occurred, impacting nearly 5 million people and killing an estimated 1.6 million people.

The encephalitis lethargica pandemic of 1915–1926

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. 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. 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: 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." Just ten days before von Economo's breakthrough in Vienna, Jean-René Cruchet described forty cases of "subacute encephalomyelitis" in France.

In the ten years that the pandemic raged, nearly five million people's lives were taken or ravaged. Encephalitis lethargica assumed its most virulent form between October 1918 and January 1919. The pandemic disappeared in 1927 as abruptly and mysteriously as it first appeared. The great encephalitis pandemic coincided with the 1918 influenza pandemic, and it is likely that the influenza virus potentiated the effects of the encephalitis virus or lowered resistance to it in a catastrophic way.

Aftermath of the pandemic (postencephalitic syndromes)

Many surviving patients of the 1915–1926 encephalitis lethargica 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. Postencephaltic Parkinsonism is perhaps the most widely recognized of such syndromes.

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: Influenza-like signs; hypersomnolence (hypersomnia), wakeability, ophthalmoplegia (paralysis of the muscles that control the movement of the eye), and psychiatric changes."

Treatment

L-DOPA

Modern treatment approaches to encephalitis lethargica include immunomodulating therapies, and treatments to remediate specific symptoms.

There is little evidence so far of a consistent effective treatment for the initial stages, though some patients given steroids have seen improvement. The disease becomes progressive, with evidence of brain damage similar to Parkinson's disease.

Treatment is then symptomatic. Levodopa (L-DOPA) and other anti-Parkinson drugs often produce dramatic responses; however, most people given L-DOPA experience improvements that are short lived.

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.
• 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).
• 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 Lewy body dementia.
• Rosita Renard (1894–1949), Chilean pianist, contemporary of Claudio Arrau and student of Martin Krause.
• Those described in the book Awakenings by the British neurologist Oliver Sacks.

Further reading

Describes the history of the disease, and the epidemic of the 1920s.

External links

Classification	ICD-10: A85.8 ICD-9-CM: 049.8 DiseasesDB: 32498

• National Institute of Neurological Disorders and Stroke
• Mystery of the Forgotten Plague: BBC news item about the tracing of the infectious agent in encephalitis lethargica