46 Encephalitis Lethargica

Foremost among recorded encephalitis epidemics was the global pandemic of encephalitis Iethargica that emerged in and from Europe during the last years of the Great War and occurred in successive waves throughout the world during the following decade.

Clinical Manifestations and Pathology

Clinically, encephalitis Iethargica was characterized by diffuse involvement of the brain and spinal cord, producing practically the entire range of the signs and symptoms of neurological disease. Sometimes occurring in close conjunction with respiratory- spread influenza, but more often after a long interval, encephalitis patients developed an illness usually characterized by the triad signs of fever, lethargy, and disturbances of eye movement, along with a broad range of other signs and symptoms. These included headache, tremor, weakness, depression, delirium, convulsions, the inability to articulate ideas, coordi­nate movements, or recognize the importance of sen­sory stimuli, as well as psychosis and stupor. Oculogyric crisis (eyeballs fixed in one position for a period of time) and other disorders of eye movement, the most frequent sign of localized damage to the nervous system, were present in three-fourths of the cases. Lethargy, another common symptom, in some patients lasted only a few days, but in others it per­sisted for weeks and months or until death from coma­tose respiratory failure. Not infrequently, spasmodic twitching and severe psychic and behavior changes persisted long after the acute illness. Approximately a third of encephalitis Iethargica patients died of their acute illness, and a large proportion (80 per­cent) of survivors developed parkinsonism during en­suing decades.

The main pathological findings during the acute encephalitic illness were a diffuse inflammatory re­action in the meninges and around the blood vessels of the brain and the spinal cord; degenerative changes were found in the neurones, especially in the brainstem, basal ganglia, and cerebellum, but

_χ ENCEPHALITIS LETHARGICA DEATHS

c By Month of Onset of Illness

O

∑

Figure VIIL46.1. Encephalitis lethargica, influenza­pneumonia, other pneumonia/bronchitis deaths in Seattle-King County, Washington, 1918-26. (From

Ravenholt and Foege. 1981. 1918 influenza, encephalitis lethargica, parkinsonism. Lancet 2: 860-4, by permis­sion of The Lancet.)

also including the cortex and the subcortical white matter. In the spinal cord, both the white and gray matter were involved in the inflammatory, degenera­tive disease process.

Epidemiology

The dominant epidemiological feature of encephalitis Iethargica was its unique time distribution. Al­though epidemics of encephalitic disease had oc­curred in conjunction with many previous influenza epidemics - 1580,1658,1673-5,1711-2,1729,1767, 1780-2, 1830-3, 1847-8, and especially 1889-92 - the global pandemic of encephalitis accompanying and following the 1918 influenza pandemic was in a class by itself with respect to virulence and sequelae. Along with its unique time distribution, 1917—26, the encephalitis Iethargica epidemic, as Figure VIIL46.1 indicates, also had a pronounced seasonal predilection for the winter months. Encephalitis cases often occurred in such close conjunction with individual and community attacks of influenza that many professional and laypersons initially believed the disease to be caused by the devastatingly virulent influenza. But the fact that many cases and epidem­ics of encephalitis subsequently occurred at times when, and in places where, there was no discernible influenza activity generated confusion and skepti­cism that influenza could be the principal cause.

Earliest reports of epidemic encephalitis in 1917 by Constantin Economo in Vienna and by French observers differed little in substance; but Economo’s provocative title, encephalitis Iethargica - giving unique emphasis to one sign in the broad spectrum of clinical manifestations - gained him lasting recognition while generating ongoing diagnostic confusion.

Although these reports of encephalitis preceded the explosive general global dissemination of influ­enza in 1918, influenza was active in war-torn Eu­rope during the winter of 1916-17. In 1918, in close association with the initial massive waves of influ­enza, encephalitis was reported in Britain, Scandina­via, Germany, the United States, and many other countries; but the greatest epidemic peaks of en­cephalitis occurred in 1919-20 and during subse­quent winters - as shown for Seattle in Figure VΠI.46.1.

Typically, encephalitis Iethargica was generally distributed by age, sex, race, occupation, education, economic status, and geographic location. Ages of cases ranged from infancy to old age, with the high­est attack rates among young adults; and the sexes were equally represented. Rarely was there discern­ible clustering of encephalitic cases within families and neighborhoods; and where such was reported, it is retrospectively apparent that the clustering arose as a result of diagnostic confusion with other causes of central nervous system disease - for example, botulism.

Attack rates for encephalitis Iethargica during the pandemic years 1918-26 approached 1 case per 1,000 general population in the United States and in European countries where fairly complete records were maintained.

Etiology

Despite the assertions of F. G. Crookshank (1919), RudolfvonJaksch (1923), and others that 1918 influ­enza was the principal cause of encephalitis lethar­gica, leading researchers of the 1920s, such as E. O. Jordan (1927) and A. J. Hall (1924), judged the rela­tionship between influenza and encephalitis to be so inconsistent and confusing that they stated the etiol­ogy of encephalitis Iethargica to be “unknown.” But now, 60 and more years after the pandemic, from research done in Seattle and Samoa by R. T. Ra­venholt and W. H. Foege (1982), the etiology of en­cephalitis Iethargica seems clear. Death records in Seattle show a characteristic modal lag of approxi­mately a year from influenza-pneumonia death peaks to onset of encephalitis Iethargica clusters terminating in death (Figure VIII.46.1), providing strong evidence that encephalitis cases previously thought to have occurred independently of influenza were actually late sequelae.

The Samoan Islands were chosen as another site for study because the sharply contrasting experience of Western and American Samoa with respect to the 1918 influenza epidemic provided a unique basis for study of its pathological effects. As stated by Jordan:

In no part of the world did influenza exact a more crushing toll than in the islands of the South Sea. In Western Samoa the steamer Talune from Auckland introduced the disease on November 7,1918, into the islands of Upolu and Savaii.

Meanwhile, American Samoa, just 70 kilometers away, and inhabited by the same racial stock, man­aged to exclude the infection with strict quarantine measures and good fortune.

During May 1982, American Samoa records stored in the National Archives and Records, in San Bruno, California, along with death records for American Samoa maintained by the Lyndon B. Johnson Tropi­cal Medicine Center on Tutuila, and death records for Western Samoa available in the Registrar’s Office at Apia were analyzed. Although the rudimentary na­ture of the death records in Western Samoa limited the comparative studies that could be made of mortal­ity patterns in American and Western Samoa during the 1920s, it was clear that whereas Western Samoa suffered heavily from both influenza-pneumonia and encephalitis Iethargica during the years 1918-22, American Samoa was remarkably free of both these diseases during those years. The evidence, then, is compelling that the pandemic of influenza beginning in 1918 and the pandemic of encephalitis Iethargica generally beginning the following year had a com­mon etiology. Both pandemics were globally distrib­uted and were closely related in time, and only one etiologic agent (swine influenza virus) has been reli­ably identified.

Local, regional, and national influenza-pneumonia epidemics ordinarily (perhaps invariably) preceded local, regional, and national epidemics of encephali­tis lethargica. A large proportion of individual en­cephalitis Iethargica cases during the early years of the pandemic had had clinical influenza. Later, as influenza and encephalitis occurrence patterns shifted from massive epidemic to sporadic endemic, the relationship between these two diseases became progressively obscured.

Seasonal and global occurrence patterns of en­cephalitis Iethargica rule out the possibility that this pandemic was caused by an arbovirus or any known nonrespiratorily spread infection.

Analogous pandemics of encephalitis have been recorded in close association with other influenza epidemics, although none as severe as that in asso­ciation with the 1918 influenza pandemic. Guillain- Barr6^,s disease following inoculation with swine in­fluenza antigen suggests a neurotoxic effect of this organism, even in the killed state. Likewise occur­rence of parkinsonism during convalescence from influenza and/or encephalitis and during many years and decades thereafter demonstrates the extra­ordinary neuropathogenic qualities of the causative agent - now identified as the 1918 (swine) influenza virus.

Immunology

The immunologic findings of E. T Gamboa and col­leagues in 1974 support the contention that the 1918 influenza (swine, type A) and encephalitis lethar­gica epidemics had a common etiology: They found deceased patients with well-documented postenceph­alitic parkinsonism to have intranuclear fluorescent antibody to neurotropic influenza A strain antigen in hypothalamic and midbrain sections, whereas no such fluorescence was observed in similar sections Table VIΠ.46.1. Time interval from encephalitis to parkinsonism to death in six patients

Source: Gamboa et al. (1974).

from brains of persons with idiopathic (not posten­cephalitic) parkinsonism. The long intervals be­tween the several manifestations of 1918 (swine) influenza virus - pneumonia, encephalitis lethar­gica, parkinsonism - must be kept in mind when seeking to understand the interrelated epidemiology of these diseases (see Table VΠI.46.1).

History

From among all causes of encephalitis - structural, chemical, and microbiological - it was a difficult task sorting out the many infectious causes of encephalitis by specific causative organism and route of transmis­sion. But with the explosion of scientific knowledge in the late nineteenth and twentieth centuries, many important agents and vectors of encephalitis were identified, among them, the spirochete of syphilis, and the trypanosome of African sleeping sickness, transmitted by sexual contact and tsetse flies, repectively; the bacterial toxin of botulism, from ingested food; the viruses of yellow fever, Japa­nese B encephalitis, equine encephalitis, trans­mitted by mosquitoes; the virus of rabies, trans­mitted by the bite of rabid animals; the viruses of influenza, mumps, and measles, transmitted by the respiratory route; the enteroviruses, trans­mitted by the fecal-oral route; and, most recently, the human immunodeficiency virus, transmitted by sexual contact and blood.

Adding to the diagnostic confusion generated by these numerous encephalitic microorganisms were the many cases and deaths from stuporous encepha­litic reactions to various toxins and drugs, especially Reye’s syndrome following the use of aspirin (intro­duced in 1899) to control the fever and discomfort of influenza, varicella, and other childhood diseases. The role of aspirin in the production of Reye’s syn­drome has become known only in the last decade.

But the main causative agent of epidemic encepha­litis during the pandemic years 1917—26 was the respiratorily spread influenza virus. Successive peaks of encephalitis occurred in European, Asian, African, and American countries from 1918 to about 1926. In the United States, encephalitis Iethargica progressed across the country from the east to the west in 1919, just as influenza had the previous year, reaching peak occurrence in New York during Janu­ary 1919, in Virginia during February, and in Illi­nois, Louisiana, and Texas during March; whereas in California more cases were reported in April than in any other month, and in Seattle the first encepha­litis Iethargica cases were reported in October 1919. Although Britain reported its peak number of cases in 1924, this was apparently a reporting artifact - as judged from the mortality pattern during the 1920s.

For too long, medical science has tended to rele­gate the 1918 influenza-encephalitis Iethargica- parkinsonism puzzle to an intellectual ash heap, apparently on the assumption that these epidemics are past history and of little or at least dwindling importance to current and future health. But fail­ure to identify influenza virus as the cause of en­cephalitis Iethargica and parkinsonism has crippled progress toward the understanding of influenza pa­thology and epidemiology needed to fuel and guide prevention of these elusive but exceedingly impor­tant diseases.

According to William Osler, Karl Menninger, and August Wimmer, almost every disease of the cen­tral nervous system (CNS) may follow influenza. Thus we should look to the diminutions of CNS structures caused by influenza attacks during ear­lier life when seeking the keys to prevention of much serious CNS disease, especially senile demen­tia (Alzheimer’s disease).

R. T. Ravenholt

Bibliography

Collins, S. D., and J. Lehmann. 1953. Excess deaths from important chronic diseases during epidemic periods, 1918-51. Public Health Monographs. U.S.P.H.S. Pub­lication No. 213.

Crosby, A. W. 1976. Epidemic and peace: 1918. Westport, Conn.

Crookshank, F. G. 1919. Epidemic encephalomyelitis and influenza. Lancet 1: 79—80.

Economo, C. 1931. Encephalitis lethargica: Its sequelae and treatment, trans. K. O. Newman. London.

Gamboa, E. T., et al. 1974. Influenza virus antigen in postencephalitic parkinsonism brain. Archives of Neu­rology 31: 228—32.

Hall, A. J. 1924. Epidemic encephalitis (encephalitis lethar­gica). New York.

Jaksch, Rudolf von. 1923. Influenza encephalitis. Acta Medica Scandinavica 58: 557-84.

Jordan, E. O. 1927. Epidemic influenza: A survey. Chicago. Matheson Commission Reports I, II, III. 1929, 1932, 1939.

Epidemic encephalitis: Etiology, epidemiology, and treatment. New York.

Menninger, K. A. 1926. Influenza and schizophrenia: An analysis of post-influenzal “dementia praecox” as of 1918, and five years later: Further studies of the psy­chiatric aspects of influenza. American Journal of Psy­chiatry 5: 469-529.

Merritt, H. H. 1967. A textbook of neurology, 4th edition. Philadelphia.

Ministry of Health. 1924. Memorandum on encephalitis lethargica. HMSO, London.

Ravenholt, R. T., and W. H. Foege. 1982. 1918 influenza, encephalitis lethargica, parkinsonism. Lancet 2: 860­4.

Shope, R. E. 1931. Swine influenza I: Experimental trans­mission and pathology. Journal OfExperimental Biol­ogy 54: 373-85.

Wimmer, A. 1924. Chronic epidemic encephalitis. London.

Winternitz, M. D., L. M. Wasson, and F. P. McNamara. 1920. The pathology of influenza. New Haven.