Encephalitis lethargica

• 1. Introduction

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  Encephalitis lethargica left some of its victims in a statue-like condition, speechless and motionless. The disease attacks the brain. It goes by several names, including sleepy sickness and von Economo encephalitis. It should not be confused with the sleeping sickness spread by the tsetse fly. For roughly a decade it moved around the world, and then it stopped. Doctors of the time faced an illness with no single face, one that could look like a dozen other conditions. How was it finally recognized as a disease of its own? Why did so many survivors seem to recover, only to fall ill again in a different way? And what caused it at all? Researchers were still arguing about that question long after the last wave of cases had passed.

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• 2. A Winter Without a Name

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  In the winter of 1916-1917, a puzzling illness surfaced in Vienna and other cities. Reports had appeared across Europe as early as the winter before. But wartime made news slow and chaotic, and the symptoms varied so widely that no one saw a pattern. Doctors labeled the pieces they saw as botulism, toxic ophthalmoplegia, epidemic stupor, acute polioencephalitis, Heine-Medin disease, bulbar paralysis, hystero-epilepsy or acute dementia. Some reports settled for "an obscure disease with cerebral symptoms".

  In April 1917, the neurologist Constantin von Economo published a paper on cases he had met during the winter months. His patients carried different diagnoses. Yet they shared a pattern of symptoms, and that led him to propose a new disease, which he named Encephalitis Lethargica. He also found a distinctive pattern of damage in the brains of patients who had died. That gave the new name something solid to rest on.

  In France, the physician Jean-René Cruchet was meeting the same illness. Only 10 days before von Economo's breakthrough in Vienna, Cruchet had described 40 cases of what he called subacute encephalomyelitis. The disease was officially recognized as distinct in 1917. After these two reports, many more followed, first across Europe and then around the globe.

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• 3. Signs of Sleepy Sickness

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  High fever, sore throat and headache sound ordinary, yet they sit on the list beside far stranger signs. Patients also showed lethargy, double vision, delayed physical and mental responses and catatonia. Another sign was sleep inversion, a reversal of the normal sleep pattern. In severe cases a patient could slip into a coma-like state called akinetic mutism.

  Abnormal eye movements, known as oculogyric crises, could also occur. Some patients developed Parkinsonism, upper body weakness, muscular pains, tremors and neck rigidity. Behavioral changes, including psychosis, were reported as well.

  The German neurologist Felix Stern examined hundreds of patients during the 1920s and saw that the illness changed over time. The early symptoms were dominated by sleepiness or by wakefulness. A second symptom led to an oculogyric crisis. The third was recovery, followed by a Parkinson-like syndrome. Patients who followed that course were diagnosed by Stern with encephalitis lethargica. He wrote the definitive book on the subject, Die Epidemische Encephalitis.

  Klazomania, a vocal tic of compulsive screaming, is sometimes present.

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• 4. Behavior and Age

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  Approximately a third of affected children went through a change of behavior, and many were labeled "delinquents". Boys between the ages of 5 and 18 were the most affected. The changes included a new personality, restlessness, irregular sleeping habits and emotional instability. That instability showed up as irritability, crying spells and temper tantrums, along with impulsivity and unpredictability. Von Economo described the pattern as "moral insanity". The more extreme cases brought aggression and what the record calls "shameless sexual activity".

  Children under the age of 5 suffered severe developmental delays. Delays were also reported in children between 5 and 14, although those claims are controversial.

  Among adults, an estimated 25-90% suffered psychological problems. These included hysteria and abnormal behavior and movement. A large minority of patients described bradyphrenia, a slowing of thought.

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• 5. A Pandemic That Vanished

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  More than 1 million people are thought to have caught the disease during the ten years of the pandemic, and it directly caused more than 500,000 deaths. The exact number infected is unknown. A higher estimate for 1915-1927 puts the total at nearly 5 million people, with about 1.6 million deaths. Some authors date the outbreak instead from 1918 to 1930.

  Between October 1918 and January 1919, the disease took on its most virulent form. In the United States, the epidemic peaked from 1920 to 1924. As many as one million people there are estimated to have been diagnosed during that period.

  In 1927, the pandemic disappeared as abruptly and mysteriously as it had arrived. It had coincided with the 1918 influenza pandemic. The influenza virus likely boosted the effects of the cause of the encephalitis, or lowered resistance to it in a catastrophic way. Whether influenza played that role became one of the central arguments about the disease.

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• 6. The Unsolved Cause

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  For years it was believed that encephalitis lethargica was tied to the Spanish flu epidemic, but modern research argues against that claim. Parkinsonism after encephalitis was clearly documented following an outbreak after the 1918 influenza pandemic. Evidence for a viral cause is circumstantial, including epidemiologic patterns and influenza antigens found in patients. Evidence against it is of the negative sort, such as the absence of viral RNA in brain material from postencephalitic Parkinsonian patients.

  In 2008, McCall and co-authors reviewed the question. They concluded that "the case against influenza is less decisive than currently perceived... yet there is little direct evidence supporting influenza in the etiology of EL." They added that "almost 100 years after the EL epidemic, its etiology remains enigmatic." Opinion on influenza remains divided, though the literature leans skeptical. Other studies have explored an autoimmune response, alone or alongside viral and bacterial infection.

  Stern suspected that the disease was close to poliomyelitis, but he had no evidence. He experimented with convalescent serum taken from survivors of the first acute syndrome. He also vaccinated patients with early-stage symptoms, telling them it might be successful.

  A 2010 compendium reviewing historic and contemporary views quotes a researcher writing in 1930. That researcher said "we must confess that etiology is still obscure, the causative agent still unknown, the pathological riddle still unsolved". The compendium itself asks whether it solves the riddle of a disease called the greatest medical mystery of the 20th century. Its answer is "Unfortunately, no". After its publication, an enterovirus was discovered in cases from the epidemic. In 2012, Oliver Sacks, author of Awakenings, a book about institutionalized survivors, acknowledged this virus as the probable cause. Other sources have suggested Streptococcus pneumoniae.

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• 7. Older Outbreaks

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  In 1580, Europe was swept by a serious febrile and lethargic illness that led to Parkinsonism and other neurological aftereffects. Retrospective diagnosis tentatively suggests that this was an early outbreak of encephalitis lethargica. The same reading is offered for several later episodes.

  From 1673 to 1675, a similar epidemic struck London. Thomas Sydenham described it as "febris comatosa". In 1695, Albrecht of Hildesheim described a 20-year-old woman in Germany. She had oculogyric crises, Parkinsonism, double vision and strabismus after an attack of somnolent brain fever.

  In 1712-1713, a severe epidemic of Schlafkrankheit, meaning sleep sickness, broke out in Tübingen. In many cases it was followed by persistent slowness of movement and a lack of initiative called aboulia. Between 1750 and 1800, France and Germany saw minor epidemics of "coma somnolentum". These carried features of Parkinsonism, including hyperkinetic hiccup, myoclonus, chorea and tics.

  Between 1848 and 1882, the Paris neurologist Jean-Martin Charcot documented many isolated cases of juvenile Parkinsonism. They involved double vision, abnormal eye movements, rapid breathing and obsessional disorders. They were almost certainly post-encephalitic in origin.

  In Italy in 1890, after the influenza epidemic of 1889-1890, a severe epidemic of somnolent illnesses appeared, nicknamed the "Nona". In almost every one of the few survivors, Parkinsonism and other aftereffects developed.

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• 8. Aftermath and Treatment

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  Years or even decades of seemingly perfect health could follow recovery, and still the majority of survivors later developed neurological or psychiatric disorders. Many people from the 1915-1927 pandemic appeared to recover completely and return to normal life. Most, though, never regained their former vigor. The later syndromes varied widely. Some progressed rapidly to profound disability or death. Others advanced very slowly, or reached a certain point and stayed there for years or decades. Some remitted and disappeared. The disease can also cause postencephalitic parkinsonism. Though often thought of as a disease of the past, it is still seen in occasional cases today.

  One widely accepted diagnostic criterion requires an acute or subacute encephalitic illness from which all other known causes of encephalitis have been excluded. A more recent proposal allows the diagnosis when the condition cannot be attributed to any other known neurological condition. It also requires influenza-like signs, hypersomnolence, wakeability, ophthalmoplegia and psychiatric changes. Ophthalmoplegia is paralysis of the muscles that control eye movement. Others describe lethargy, "mask-like faces" and excess blood in the meninges.

  Steroids brought improvement to some patients in the initial stages, though there is little evidence of a consistently effective treatment for that phase. Modern approaches include immunomodulating therapies and treatments aimed at specific symptoms. The disease then becomes progressive, with brain damage similar to that of Parkinson's disease. Treatment is symptomatic from that point. L-DOPA, also called Levodopa, and other anti-Parkinson drugs often produce dramatic responses. For most people given L-DOPA, however, the improvement is short-lived.

  Muriel "Kit" Richardson, born Muriel Hewitt, was the first wife of the actor Sir Ralph Richardson. She first showed symptoms in 1927-1928 and died of the condition in October 1942. There is speculation that Adolf Hitler may have had encephalitis lethargica as a young adult. The author Mervyn Peake, who lived from 1911 to 1968 and wrote the Gormenghast books, began a decline that was initially attributed to the disease, with Parkinson's disease-like symptoms. Others have since suggested that Lewy body dementia caused his decline and death.

  In 1925, Jane Norton Grew Morgan, wife of J. P. Morgan Jr., died of encephalitis lethargica. Doctors at the time attributed her illness to influenza she had caught during the 1918 pandemic.

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