Encephalitis Lethargica During and After the Epidemic. Edited by Joel A. Vilensky. 336 Pages. Oxford University Press 2010.
Asleep: The Forgotten Epidemic That Remains One of Medicine's Greatest Mysteries. By Molly Caldwell Crosby. 304 Pages. Berkley Publishing Group 2010.
1918 was a good year and a bad year. World War I was coming to an end but a worldwide pandemic of influenza was killing, maiming, or transiently incapacitating millions of people, especially in Europe and the United States. The disease was rampant but difficult to diagnosis clinically. Objective measures were not yet available to differentiate the signs and symptoms from other diseases. No “biomarkers” such as cultures of blood or other body fluids could differentiate the flu from other infections. That came later, decades later.
Worse still was the train of conditions. The accompanying brain disease had first been called “epidemic encephalitis” by Constantin von Economo, and his name became the eponym; other names were “encephalitis lethargica” (EL) or “sleeping sickness.” However, the clinical diagnosis of EL was not reliable, depending on the constellation of- symptoms and signs. First came the influenza, then “wakable” hypersomnolence with ophthalmoplegia and, especially severe in children, behavioral disorders.
EL was lethal in about 40 percent of those affected but some people survived and recovered completely. Months or years after the onset of symptoms, some developed signs of slowed movement, limb stiffness, tremor of the hands, bent posture, slow gait and poor balance that led to falls. These were the signs of “postencephalitic parkinsonism.”
No social group was spared. Some medical historians made a retrospective diagnosis of ELS from records about poet Robert Frost, US President Woodrow Wilson, and Jessie Morgan, wife of financier J. P. Morgan. An episode of EL has been blamed for the change in Wilson's attitude from benevolence to harsh punishment for a defeated Germany, a change that could have contributed to the rise of Adolph Hitler.
In 2010, two books appeared to document these events. In Asleep: The Forgotten Epidemic That Remains One of Medicine's Greatest Mysteries, science writer Molly Caldwell Crosby cites as a mystery the failure of later investigators to explain the etiology of EL after 92 years. Although a French physician, Cruchet, also claimed priority for publication, von Economo even postulated that the somnolence could have originated from hypothalamic dysfunction.
Crosby has a knack for making medical verbiage accessible to the general reader. She provides vivid descriptions of the personalities involved, including Frederick Tilney, an important neuro-logist of the day who raised the money needed for construction of the Neurological Institute in New York. Another influential New Yorker was William Matheson, a wealthy chemical manufacturer who developed the EL himself and became a major backer of disease-related research. He established a commission to investigate possible causes of epidemic encephalitis. Their study findings were published in three reports.
The second book, Encephalitis Lethargica, is written for neurologists and historians. Joel Vilensky, PhD, a neuroscientist at the University of Indiana, edited and wrote most of the chapters, with the participation of Drs. Sid Gilman, Roger Duvoisin, Paul Foley, Keith Josephs, and others. These expert authors have provided detailed descriptions of the history of EL and answers to some, but not all, pertinent questions. For instance, the influenza agent has proved to be the H1N1 virus, but it is not clear whether contemporary cases now have been caused by the same strain of virus as the one responsible for the 1917 and 1918 epidemics.
However, the relationship of influenza virus to EL remains uncertain. Modern immunological and molecular techniques were applied to brain samples from patients who had died with EL or postencephalitic parkinsonism (PEP) but even these sophisticated studies came up empty, showing no trace of influenza virus RNA. Alternate possibilities theories suppose that the flu infection prepares for subsequent invasion by an EL virus.
In 1960, Dr. Oleh Hornykiewicz reported depletion of dopamine in samples of the caudate from the brain of a patient with PEP. This chemical, a neurotransmitter, is found in part of the brain that controls normal limb movements and the loss of dopamine results in a tremor of the hands.
The next year, a colleague of Hornykiewicz's gave dopamine in the form of levodopa to a PEP patient with “dramatic improvement.”
In 1968, a front-page article in the New York Times announced a coming report from biochemist Dr. George Cotzias, describing the benefits of levodopa therapy and scheduled to appear in the New England Journal of Medicine. For the first time, symptoms of an age-related and seemingly irreversible neurodegenerative disease could be ameliorated by drug therapy.
A few years later, in 1973, Awakenings, the bestseller by Dr. Oliver Sacks made medical history part of American culture and had a major influence in establishing the story as one of historical import. A popular 1990 movie based on the book starred Robert De Niro and Robin Williams. The exhilaration continued as Dr. Sacks pronounced the effects of treatment with levodopa in patients he encountered in a chronic care facility; he thought they appeared to be “extinct volcanoes” that erupted into life. In those days, no one used the term “translational research” to mean the benefit conferred on humans by applying results of basic laboratory research, but there can be no better example of that term than the levodopa story, as told here by Vilensky.
Other theories of causation have been proposed. A toxic agent in the environment has been suggested by studies in Guam, where indigenous people have an unusually high incidence of a syndrome of parkinsonism combined with dementia and amyotrophic lateral sclerosis (ALS). Some Americans serving in Guam have also developed ALS. However, the environmental agent has not been identified.
Yet another theory involves PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection). This view draws a parallel between EL, PEP, and another constellation of problems that follow an episode of streptococcal sore throat; after the infection joint pains and swelling precede the coming of rheumatic heart disease. Sore throat is also common among the early symptoms of patients who develop EL and PEP, which affect areas of the body far away from the infection and in a pattern consistent with an autoimmune disorder.
Mystery or not, the documentation of EL and PEP in both of these books warrants thought and appreciation for clear and informative writing.
Dr. Rowland, chief editor emeritus of Neurology Today, is professor of neurology at the Columbia University College of Physicians & Surgeons Neurological Institute.