Medical and molecular perspectives into a forgotten epidemic: encephalitis lethargica, viruses, and high-throughput sequencing.

The emergence of encephalitis lethargica (EL), an acute-onset polioencephalitis of unknown etiology as an epidemic in the years 1917-1925 is still unexplainable today. Questioned by the first descriptor of EL himself, Constantin von Economo, there has been much debate shrouding a possible role of the "Spanish" H1N1 influenza A pandemic virus in the development of EL. Previous molecular studies employing conventional PCR for the detection of influenza A virus RNA in archived human brain samples from patients who died of acute EL were negative. However, the clinical and laboratory characteristics of EL and its epidemiology are consistent with an infectious disease, and recently a possible enterovirus cause was investigated. With the rapid development of high-throughput sequencing, new information about a possible viral etiology can be obtained if sufficient specimens for analysis were still available today. Here, we discuss the implications of these technologies for the investigation of a possible infectious cause of EL from archived material, as well as a prospectus for future work for acquiring viral nucleic acids from these sources.

[Modern Egypt and the history of microbiology. The campaign of Bonaparte]. / Egypte moderne et histoire de la microbiologie: De i'expédition de Bonaparte à nos jours.

The history of microbiology and parasitology in Egypt started with Bonaparte's campaign and the contemporary clinical reports from the physicians of the "Armee d'Orient" (1798-1903). Later, basic discoveries in parasitology and bacteriology have been the facts of German scientists such as Theodor Bilharz, Robert Koch and Arthur Looss. At the beginning of the First World War German physicians were evicted from Cairo and British parasitologists took over as Robert Leiper succeeded in clarifying the life cycle of schistosomiasis. Virology studies on poliomyelitis in Egypt started in 1942-1943 but British virologists were quickly supplanted by the Americans as the U.S. NAMRU-3 laboratory opened in Cairo in the 50s. Many basic contributions to the epidemiology of the viral diseases in the Nile valley have been established during the past forty years, concerning enteroviruses, mosquito and tick-borne arboviruses as well as hepatitis C virus.

The signalling contributions of Constantin von Economo to basic, clinical and evolutionary neuroscience.

The study, and the companion article that follows, reviews the entire spectrum of the epoch-making contributions of Constantin von Economo (1876-1931) to basic, clinical and evolutionary Neuroscience. An astute observer and avid writer, von Economo left marks of brilliance on fundamental areas of brain research through an exuberant record of publications dating from 1899 to 1932. His ingenious medical career began with the histological study of the developing pigeon and chick hypophysis, and culminated with bold propositions about the neuroanatomy of talent and the future evolution of the human brain. On the way, he made the seminal discovery of encephalitis lethargica ('von Economo disease'), and produced, with Georg N. Koskinas (1885-1975), one of the masterpieces of brain science, the 1925 Cytoarchitectonics of the Adult Human Cerebral Cortex, defining 107 cortical areas on the basis of cytoarchitectonic criteria. His untimely death at age 55, barely 5.5 months after inaugurating his new Brain Research Institute in Vienna, deprived the Neuroscience world of one of its brightest protagonists during the 20th century. An annotated total of 139 scientific works by von Economo have been identified. The present study covers the 76 works on brain structure, evolution and intelligence, and general works on nervous and mental pathology, with the complete bibliographic information. The companion article covers the remaining 63 works on encephalitis lethargica and sleep regulation.

The percipient observations of Constantin von Economo on encephalitis lethargica and sleep disruption and their lasting impact on contemporary sleep research.

The study, and the preceding companion article, reviews the pioneering contributions of Constantin von Economo (1876-1931) to Neuroscience in a modern context. The neurological studies of von Economo include the discovery of a new nosological entity, encephalitis lethargica, with which his name is forever linked ('von Economo disease'). Based on a percipient analysis of pathoanatomical material from patients with encephalitis lethargica who manifested with either insomnia or somnolence, von Economo deduced the existence of distinct centres in the brain for the regulation of sleep and wakefulness. He presented a synthesis of his ideas in a series of lectures in New York in 1929 and at the First International Neurological Congress held in Berne in 1931. Constantin von Economo was nominated three times for the Nobel Prize in Physiology or Medicine for the discovery of encephalitis lethargica. As those studies have exerted and continue to exert the highest impact among von Economo's publications, the present article examines the spectrum of his observations on encephalitis lethargica and the cerebral control of sleep, documented in 63 published works--including post-humous translations into French and English of original German texts; complete bibliographic information is given. His remaining 76 works of an annotated total of 139 scientific publications deal with brain structure, evolution and intelligence, as well as general works on nervous and mental pathology and form the focus of the preceding article.

Epidemic encephalitis and American neurology, 1919-1940.

Encephalitis lethargica, also known as epidemic encephalitis, emerged as a new infectious disease near the end of the First World War. Bacteriologic, epidemiologic, and clinical investigation produced no clear consensus regarding the nature of the disease, even as several other experimentally demonstrable "encephalitides" appeared on the scene. By 1940, new encephalitis lethargica cases had almost entirely disappeared, and neurologists renamed this once-novel infection as an amorphous syndrome of marginal interest. A variety of forces influencing the fate of encephalitis lethargica's epidemic status can be seen at work in the Matheson Commission, whose members hoped to use encephalitis as a model disease that might supplant their reliance on clinical phenomenology with a causal analysis of nervous disease grounded in the laboratory. When it failed to live up to these expectations, the model was abandoned. Epidemic encephalitis was soon forgotten.

Stephan Környey's contribution to the study of encephalitides.

A considerable part of Környey's work deals with the problem of encephalitides. HIs interest in this topic was roused by Heinrich Pette and in collaboration they studied the histopathology and pathogenesis of experimental and human poliomyelitis. On the basis of their findings they advocated the neural spread of the poliomyelitis virus. THey described the distribution of the poliovirus within the nervous system, its close affinity to the voluntary motor system and analysed the influence of the portal of entry and special neurotropism on the development of the distribution pattern of the process. THe encephalitic process changes as a function of time; the significance of this observation was expressed in the concept of the time factor. Környey designated the affinity of the poliovirus towards the neurons among the cellular components of the nervous tissue as gangliocytotropism. Based on his observation, he characterized the features of neural spread of virsuses and the selective character of this spread within the central nervous system. THe study of two other polioencephalitides with predilectional involvement of the brain stem, Borna disease and tickborne encephalitis, allowed him further pathogenetic assessments. Környey described the first manifestation of subacute panencephalitis in the Carpathian basin. He devoted special attention to the clinical and neuropathological analysis of various forms of leukoencephalomyelitides and closely followed the development of the principle of neuro-allergy (Pette) and the change in the pathogenetic view of these diseases. His excellent synthesising ability enabled him to write comprehensive review articles and textbook chapters on the various aspects of encephalitides.

The control of mosquito-borne diseases in New York City.

Mosquito control began in New York City in 1901. Large-scale efforts to drain marshlands occurred through the 1930s, and aerial application of pesticide occurred as early as 1956. Components of early mosquito-borne disease control were reimplemented in 1999-2000 in response to an outbreak of West Nile virus, and included promoting public and health professional awareness regarding disease causation and prevention, providing free government laboratory testing, case reporting, mapping of mosquito breeding sites and their elimination or application of larvicide to them, and adult mosquito control. Because a potential for various mosquito-borne diseases in New York City persists, continued efforts are warranted to limit mosquito breeding, to monitor adult mosquito populations for the presence of human pathogens, and to establish protocols and capacity for adult mosquito control.

Australian X disease, Murray Valley encephalitis and the French connection.

Epidemics of a severe encephalitis occurred in eastern Australia between 1917 and 1925, in which over 280 cases were reported with a fatality rate of 68%. The disease had not been described previously and was called Australian X disease. The next epidemic occurred in south-east Australia in the summer of 1950-51. The disease was given its name of Murray Valley encephalitis as this was the area from which most cases were reported. A virus was isolated by Eric French in Victoria, and about the same time by John Miles and colleagues in South Australia. The virus Murray Valley encephalitis (MVE) virus, was shown to be a Group B arbovirus (flavivirus) which was related to, but distinct from, Japanese encephalitis virus. Early seroepidemiological studies showed that the most likely vertebrate hosts were water birds. MVE virus was first isolated from Culex annulirostris mosquitoes in 1960. The most recent epidemic of Murray Valley encephalitis occurred in 1974, at which time it was renamed Australian encephalitis. Since 1974, however, all cases have been confined to northern Australia, particularly the north of Western Australia. Indeed, the Kimberley region of Western Australia contains the only confirmed enzootic foci of virus activity. A closely related flavivirus, Kunjin virus, has also been shown to be an aetiological agent of Australian encephalitis. Since the first isolation of MVE and Kunjin viruses, considerable information has been accumulated on their ecology and epidemiology, some aspects of which are briefly described.

Reductionism and encephalitis lethargica, 1916-1939.

This paper is the 1992 winner of the Annual Stephen Wickes Prize in Medicine, presented by the Medical History Society of New Jersey. The history of encephalitis lethargica reflects a complex interaction between research-oriented science and clinical medicine.

William C. Reeves and arbovirus research in Australia.

William C. Reeves was invited to Australia in 1952 to take part in field studies of Murray Valley encephalitis. The results of his work led to various hypotheses which directed arbovirus research in Australia for a generation. That and the people he influenced in Australia made him a major figure in the development of Australian arbovirus research.