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Encephalitis lethargica may be defined as a subacute infectious disease of the sensory nervous system, occurring sporadically in man, characterized clinically by the triad syndrome, lethargy, cranial nerve palsies, and a febrile state, and pathologically by multiple inflammatory foci most commonly in the brain stem, subthalamic region, about the third ventricle, iter, and mesencephalon.
The World War period marks the origin of the term "encephalitis lethargica" and the beginning of our present conception of this disease. Profound and prolonged sleep, however, has been observed in connection with many epidemics of influenza since early times.
In 1917, von Economo1 described 13 cases that had been admitted to his clinic with headache, lethargy, and cranial palsies. He differentiated between the somnolence of brain pressure and that of encephalitis, remarking that in the light cases it is striking how similar the somnolence is to physiological sleep, since the patients are easily awakened. Von Economo described the cases and designated the disease "encephalitis lethargica."
While outbreaks of encephalitis lethargica (Schlafkrankheit) and "nona" have been connected with epidemics of influenza, the exact etiological relationship has not been satisfactorily explained. The World War occurrence, referred to by von Economo, appeared first in central Europe, thence spread into Germany, France, and England, in early 1918, and to the United States in the fall of the same year. Siemerling2 reported 15 cases. The cases occurred in or in the neighborhood of Kiel, between the end of November, 1918, and April, 1919. This author observed the same symptoms noted by von Economo, and considered his cases to be the same disease.
In the spring of 1918 it appeared in France and England. Netter,3 working in France, confirmed von Economo's findings, giving a detailed history of the disease in 10 adults and 10 children. He expressed the opinion that it is a maladie autonome, the specific agent of which is endowed with an affinity for the nerve centers, stating further that the epidemic began simultaneously in France and England late in January. In England the disease was confused with botulism and poliomyelitis. References were made to the disease as "Acute infective ophthalmophlegia, or botulism" by Harris,4 and as "toxic ophthalmophlegia associated with acute asthenia and other nervous manifestations" by Hall.5 Some 107 cases were reported in England and 121 in the provinces, mostly in March, April, and May, 1918. The subject was eventually taken in hand by the British Government and a complete investigation made.6 Evidence was brought forward establishing the disease as a distinct entity and differentiating it from poliomyelitis.
As further evidence of distribution, Morguio7 described an occurrence in Uruguay, and Arden-Delteil8 in Algeria.
The first case of encephalitis lethargica in the United States on which any data are available occurred in the city of New York on September 4, 1918.9 Three additional cases were reported there during the following month. The portal of entry into North America is not known. However, during the latter half of 1918 the disease spread rapidly throughout the United States, and by May, 1919, cases had been reported from 20 States, the largest numbers occurring in Illinois, New York, Louisiana, Virginia, and Ohio. During that time 255 cases were reported.
Encephalitis lethargica is not a reportable disease in many of the States and reports of its prevalence received by the United States Public Health Service are fragmentary. Some States do not report cases, while others record the cases which come to the attention of the State health officers. The United States Public Health Service has not considered it worth while to collect these fragmentary reports and tabulate them, since they would not show the real prevalence of the disease; therefore, the total incidence in the United States for the World War period can not be given. Because the disease is not found separately in the lists of disease published prior to 1920, the Bureau of the Census reports no deaths due to this cause; however, during that year, 1,070 deaths were reported in the registration area of the United States.10
The first cases, so far as could be ascertained, among American troops in the United States occurred at Camp Lee, Va., early in November, 1918. These cases, 8 in number, 2 among officers and 6 among enlisted men, were later reported by Pothier.11 Since the diagnosis encephalitis lethargica did not appear on the list of diagnoses as published by the Surgeon General until 1920, the statistical tables for the World War do not include the disease under this designation. Therefore, it is not possible to give the total occurrence in the Army during that time; however, among the clinical records of World War patients it is found that there were a number of primary admissions with the diagnosis encephalitis lethargica, later classified under encephalitis. Examination of these clinical records shows 20 to have been encephalitis lethargica; 8 occurred in the United States and 12 in the American Expeditionary Forces. The cases occurring in the American Expeditionary Forces were 11 white and 1 colored, and in the United States, 7 white and 1 colored. Of these 20 cases, 4 died, 7 were returned to duty, 7 were discharged on account of disability; the disposition of the remaining 2 could not be determined. Of the deaths, 2 occurred in the United States and 2 abroad.
Several theories have been advanced to explain the cause of encephalitis lethargica. In England it was first thought to be botulism or, perhaps, due to a poison, as solanin accumulating in the sprouts of potatoes and other vegetables. This theory was exploded by the findings of the British Government Local Board.12 It has been suggested to be a form of poliomyelitis.
Encephalitis lethargica belongs to the class of polyencephalitic diseases and it has been suggested that the relationship to anterior poliomyelitis may be similar to that of paratyphoid to typhoid fever.6 The influence of lowered resistance, due to war conditions, and, as a result, the possibility of saprophytic organisms becoming pathogenic, was stressed.6 Breinl,13 reporting upon the
"mysterious disease" in Australia, expressed the opinion that it was an aberrant form of acute poliomyelitis. Neal,14 on the other hand, thought it improbable that encephalitis lethargica is a form of poliomyelitis.
The only epidemics of encephalitis lethargica of the past have been in connection with epidemics of influenza. The association of these diseases formed the basis of many recent investigations. Siemerling2 attempted to associate his cases with the 1918 epidemic of influenza. Most of the cases gave a previous history of influenza. Smith9 remarked that almost all outbreaks have been preceded by influenza. Bassoe12 suggested that encephalitis may be a cerebral form of influenza, that the infection is akin to the virus of poliomyelitis, but not identical with it, and that nearly all cases are seen in persons more or less in a run-down state or exhausted. Hershfield15 reported 15 cases, 3 of which gave a distinct history of previous influenza attack. Twenty-five of Neal's 38 cases14 and half of Pothier's cases11 gave a history of a previous attack of influenza.
It must be acknowledged that the relationship of these two diseases has not been definitely determined. According to Zinsser16 the relationship to influenza is vague; but it is to be seriously considered, in view of the recent researches with influenza and filterable viruses in encephalitis.
In one of von Economo's cases, an emulsion of the brain and cord was injected subdurally into a monkey by von Wiesner.17 The animal died 46 hours later in stupor. The brain is reported as having been typical of hemorrhagic encephalitis from which von Wiesner recovered a Gram-positive diplococcus. This he cultivated and, on injection into apes, produced somnolence and mental weakness. The reports of these investigators led other scientists to search for the cause of epidemic encephalitis. Strauss, Hirshfeld, and Loewe18 obtained nasopharyngeal mucus of fatal cases, passed it through Berkefeld candles and injected rabbits both subdurally and intracranially. They claim to have produced the disease in these animals. Similar results were obtained with a rhesus. The monkey developed lethargy, general malaise, temperature, and ptosis of the left eyelid, but recovered. Rabbits, intracranially injected, died in from four to five days with punctate hemorrhages in the brain, intense congestion, marked meningitis, and mononuclear infiltrations about the vessels. The authors claim to have repeated these experiments many times. Loewe, Hirshfeld, and Strauss19 report a filterable virus obtained from the nasopharyngeal mucus of a fatal case. The virus is reported as being capable of producing lesions in monkeys and rabbits similar to those found in the human brain. The virus has been carried through four generations in rabbits, transmitted to a monkey in the fifth generation, and then brought back to rabbits. The cerebrospinal fluid of a fatal case caused the disease in rabbits, and transfers from brain to brain through filtrates have been successful in four generations. They suggest a possible connection between the disease and influenza.
Experimental inoculations were carried out at the Army Medical School, Washington, D. C., with fresh material from one of Wegeforth's cases.20 The spinal dura was opened 28 hours after death in one case and aerobic cultures were taken from the subdural and subarachnoid spaces. These cultures were
negative. Specimens were also taken from three levels of the spinal cord, macerated, filtered, and injected into a monkey intracerebrally, into another monkey by lumbar subarachnoid injection, into a rabbit, a monkey, and a mouse intraperitoneally. None of these animals became sick and the cultures were negative. From a patient 11 days after the earliest symptom of the disease disappeared, the spinal fluid was removed and injected into a monkey by lumbar inoculation, and into a rabbit by cysterna magna inoculation. An additional rabbit was injected into the cysterna, with this fluid and in addition with horse serum to produce a sterile meningitis. All of these animals remained unaffected.
Evidence of direct communicability from man to man is lacking. An analysis of the available records from stations where the disease was reported in the Army shows no evidence of communicability.
Among the factors which may influence the occurrence of the disease, season, age, and sex are of interest. The apex of occurrence in the United States among Smith's cases was in March.9 Skversky's cases in the American Expeditionary Forces occurred during January, February, and March.21 Fairbanks22 states that March and April showed the greatest prevalence.
The age incidence is of importance from a differential diagnostic viewpoint between anterior poliomyelitis and encephalitis lethargica, the former occurring more commonly among children under the age of 7 and the latter more commonly in persons older than this. Of course, the occurrence in the Army would fall entirely in the latter class.
Characteristic lesions are confined to the central nervous system. Multiple inflammatory foci are found, particularly in the region of the basal ganglia, lateral ventricle, and about the aqueduct of Sylvius, also about the pons and medulla. Macroscopically there is usually only evidence of congestion of the meninges and cortex, with more or less edema. On sectioning the brain, and especially sections through the basal nuclei, peduncle, pons, and medulla, punctate hemorrhages are found. Microscopically miliary hemorrhages are very numerous. Neal14 describes the lesions as mainly of three kinds: (1) Infiltration, especially of the walls of the vessels (lymphocytes and plasma cells), to a less extent in other areas; (2) hemorrhages of varying size in both the white and gray matter; (3) lesions of the nerve cells-some degeneration of the ganglion cells.
Wegeforth and Ayer20 report the pathological findings of four cases as follows:
The pathology of these four cases of so-called "lethargic encephalitis" was presented with a varying degree of completeness. The brains all appeared alike. A great degree of engorgement of all vessels was conspicuous; moreover, the pia was noted as pinker than normal, and this is explained by the free blood present in the meninges. The brains were abnormally soft to touch. In every case the chief seats of the lesions were the brain stem and the basal ganglions. The important lesions may conveniently be divided into (1) perivascular exudation and (2) diffuse infiltration of parenchyma. While both types of lesions vary greatly in intensity, extent, and symmetry, they were seen especially in the gray matter about the canal, fourth ventricle, and aqueduct, though deeper tissues were also affected and white matter was not spared. The cells concerned in both types of lesion were all mononuclear; a small mononuclear cell and a large mononuclear cell, frequently phagocytic, many
of which appear to be neuroglia cells, together with the lymphocyte and plasm cells, were recognized. Polymorphonuclear leukocytes were conspicuous by their absence even in the case of short duration. Mitotic figures appeared in small numbers both in the perivascular and in the diffuse exudate. That the two processes were interrelated is apparent from the appearance of diffuse exudate chiefly in the immediate neighborhood of affected vessels. That the diffuse infiltrating exudate was not necessarily related to a destructive process is borne out by the normal or only slightly changed appearance of nerve cells in its midst; however, when the exudate was excessive, marked nerve cell changes, including neurophagia, resulted. Bacteria were sought for with care and none was seen.
Lesions that may be considered subsidiary in our cases were hemorrhage and meningitis. Hemorrhages were few in number and very small, so insignificant, in fact, that they utterly failed of detection in the gross examination. However, a certain amount of free blood and fibrin, mixed with the perivascular exudate, was frequently seen. Blood vessel changes were of two types. There was almost constantly evidence of proliferation of the intima in vessels in areas of exudation, those in unaffected territory usually showing no abnormality. The second type of lesion noted was infiltration of the vessel walls (especially intraadventitial), with mononuclear cells, chiefly lymphocytes and plasma cells. This condition was observed by itself in the meninges and associated with perivascular exudate in the substance of the brain. It is likely that more of the exudate was intramurally situated than appearance indicates; this would explain the very moderate cellular infiltration of the meninges and associated low cell count in the spinal fluid. The cord and organs in the cases examined appeared essentially normal. It is unfortunate that no notes on the root ganglions are available. Lesions in the cerebral cortex were in all either nonexistent or negligible.
For purposes of description, the symptoms may be divided arbitrarily into three stages, namely, the prodromal stage, stage of active manifestations, and state of convalescence. The prodromal stage is manifested by a more or less sudden onset, with dull headache, drowsiness, variable febrile manifestations, sometimes diarrhea, nausea, and vomiting, with or without cranial nerve symptoms. The duration is ordinarily short, commonly two to five days. It merges into the stage of active manifestations when the triad syndrome, lethargy, cranial nerve palsies, and the more marked febrile state are present. Disturbance of vision and diplopia, ophthalmoplegia or paralysis of the oculomotor nerve, ptosis, rigidity of the neck muscles, vertigo, dysphagia, aphonia, and the more marked lethargic state characterize this stage. Twitching of the body or face and an ataxic gait, resembling Parkinson's disease, are often described. Sensory changes are but seldom described in the literature. The duration of this stage is variable, lasting from one to several weeks. It is true of this stage that confusion with anterior poliomyelitis, on the one hand, and brain tumor, on the other, exists.
The stage of convalescence is marked by improvement in the lethargic state, normal temperature, diminution or disappearance of the cranial nerves palsies, tremor, and ataxia.
Wegeforth and Ayer20 remarked that it was unusual to find signs of organic nerve disease in the first week. In the second week, sometimes later, widespread neurological disorders became evident, with cerebral symptoms. Drowsiness occurred in almost every case, sometimes developing into coma, and at times alternating with irritability or anxiety. However, orientation and cerebration were usually uneffected until just before death. The long projection nerve fibers showed profound disturbance in seven of their cases, as indicated
by ataxia, spasticity, Babinski's reflexes, and clonus. Diplopia was present in seven cases, although oculomotor palsy was seldom actually seen. The second most frequent local disorder was weakness of the facial muscles, usually unilateral, and seen in five cases. Pupillary disturbances and irregularity, inequality, and abnormal reaction were common. Weakness of the jaw muscles was observed three times, while profound disturbance of respiration was twice noted. They make special emphasis of the clinical manifestations-insidiousness of onset, recurrent and incomplete paralysis, and implication of cerebral nerves confined to motor functions. Skversky21 reported two of his cases as showing a fairly well-marked Parkinsonian picture. In 9 out of 10 of his cases there was a definite febrile period either preceding, or concomitant with, the attack of encephalitis lethargica, that included coryza, mumps, bronchopneumonia, and in one case possibly paratyphoid B. Before admission, the following symptoms were complained of: Headache in 5 cases; diplopia, 2; dysphagia, 1; temperature, 4; mental dullness, 6; and an unsteady gait in 1. After admission, 4 cases showed involvement of the third and seventh cranial nerves. Nystagmus was present in 3, masked face, 5; tremor, 5; insomnia, 2; slow speech, 3; and the pill-rolling movement in 1 case. Spaeth,23 reporting on ocular symptoms of encephalitis, observed in 5 cases, showed reduced pupillary reaction to light in 3 and to accommodation in 4; diplopia was complained of in 3 cases; dilatation was present in 3 and irregularity in 1.
Hershberg24 reported involvement of the third, sixth, seventh, and ninth nerves in his patient at Base Hospital No. 69, A. E. F. There was deviation of the uvula to the right. The Kernig and Babinski reflexes were absent. Nystagmus was present and the eye grounds were negative.
It was the lethargic condition in persons suffering from this disease that suggested the diagnosis "sleeping sickness." Bassoe12 stated that there is not so much real sleep as is indicated by the sleepy expression. In fact, some patients suffer from insomnia and the lethargy bears almost the same relation to sleep that laughter of the pseudobular paralysis patient does to the normal laugh. Vaughan25 held that the stupor is partly apparent and partly real.
Blood findings were reported upon as being negative. A mild leukocytosis was occasionally present, but often nothing of diagnostic value. In like manner, the spinal fluid showed no characteristic change.
COURSE AND PROGNOSIS
The course and ultimate results are extremely variable. Some cases run a rapid, mild course, ending in from two to three weeks with apparently complete recovery. Other cases run a stormy course, terminating in death in a few days, while some show a slow convalescence extending into months and leaving the individual permanently incapacitated. Skversky,21 discussing the slow convalescence, stated that it often requires months and then leaves the individual with an unsteady gait, general weakness, a masked face, etc. Hershfield15 reported the duration of the active stage from 6 to 60 days, with an average of 32 days. It is difficult to prophesy as to the residual disturbances. A spastic gait, paralyses of the limbs, speech difficulties, and mental and emotional instability have been reported. Fairbanks22 reported that opthalmophlegia and facial
paralysis may clear up on one side before attacking the other, and that either form of paralysis may clear up and then recur. This author further reported that the mergence from lethargy and the restoration of general health is extremely slow. Duration of the clinical phenomena is so variable and convalescence so prolonged that it is difficult to give even an average duration of the affection. Eliminating the abortive cases, it is safe to state that six weeks is the minimum duration. In the majority of cases many weeks, even months, may pass before full restoration to health-if it occurs-is achieved. Impairment of intellect may remain. Among other sequelæ, tremor and disturbance of coordination are conspicuous. The tremor may be of the paralysis agitans type, or it may be of a finer degree and either general or confined to the extremities. Ataxia is commonly of the cerebellar type, but is also frequently present for fine movement of the fingers. Disturbances in swallowing, or in speech, may be more or less noticeable for a long time, yet are rarely persistent. According to Fairbanks,22 the lack of emotional expression in the face often extends over a long period.
As previously stated, a study of the cases in the Army during the World War can be only fragmentary. An analysis of 20 clinical records shows 2 deaths in the United States among 8 cases, and 2 deaths among 12 cases in the American Expeditionary Forces. These 20 cases are the only ones that permit of detailed analysis. The records show that 7 were returned to duty, 7 discharged from the service on account of disability, 4 died, and 2 were unaccounted for. Among the cases returned to duty, the duration of hospitalization varied from 18 to 115 days, an average of 53.3 days. Among those discharged on surgeon's certificate of disability, the period of hospitalization varied from 32 to 329 days, an average of 180 days.
Diagnosis usually can be made by the more or less sudden onset with lethargy, cranial nerve palsy, practically normal blood and spinal fluid findings, with febrile manifestations, and the absence of sensory, trophic, and meningeal irritation symptoms. This disease has been confused with others, notably botulism poliomyelitis, tubercular meningitis, myelitis, brain tumor, and brain abscess.
The strong clinical, epidemiological, and pathological evidence that encephalitis lethargica is a distinct disease from classic poliomyelitis is supported by animal experimentation.
The symptoms of tuberculous meningitis may simulate those of encephalitis lethargica. Fairbanks22 remarked that it may be impossible to differentiate the two and may require post-mortem findings to overcome the doubt. An onset with meningeal symptoms and pinched facial expression so characteristic of tuberculous meningitis is strongly suggestive. The results of lumbar puncture showing increased pressure, pleocytosis of mononuclear cells, and formation of the pellicle on standing, taken along with the finding of tubercle bacilli on microscopic examination (or after animal inoculation), would confirm the diagnosis.
Myelitis is differentiated by the presence of sensory, trophic, and sphincter changes, possibly optic neuritis, and absence of the cranial nerve palsies; furthermore, lethargy is not usually seen in myelitis. Although fatal cases run a
short course and often die of respiratory failure, this failure is due to paralysis of the muscles of respiration. Respiratory paralysis is a common cause of death in encephalitis lethargica. When it occurs, it is due to involvement of the respiratory center.
In brain tumor, the onset is usually more gradual, there is absence of elevated temperature and usually presence of optic nerve changes from pressure, as well as localizing symptoms. These latter, however, may be absent if the growth is located, for example, in the frontal lobe. As previously stated, one case discharged from the service on account of disability was diagnosed encephalitis lethargica, later changed to psychoneurosis, and then to brain tumor.
PREVENTIVE MEASURES AND TREATMENT
In the absence of any evidence of direct communicability, and in the absence of recognized etiology, nothing is known of the prophylaxis in this disease. So far as the records would indicate, there were no steps taken during the war to prevent its spread. As previously mentioned, there was no discoverable connection between the occurrence of one case and another that would point to direct or indirect transmission.
Treatment was symptomatic. Most authors agree that spinal puncture is advisable. Some seem to think that a release of spinal fluid is beneficial and should be repeated. At any rate, it serves a valuable purpose in diagnosis. No specific or prophylactic treatment is known or was developed during the war period.
(1) Economo, C. v.; Die Encephalitis lethargica. Jahrbücher für Phsychiatrie, Leipzig und Wien, 1917-18, xxxviii, 253.
(2) Siemerling, E.: Ueber eine Enzephalitisepidemie. Berliner klinische Wochenschrift, Berlin, 1919, lvi, part 1, No. 22, 505.
(3) Netter, A.: L'encéphalite Léthargique épidémique. Paris Médical, 1918, xxix, No. 31, 81.
(4) Harris, Wilfred: Acute infective ophthalmoplegia, or botulism. Lancet, London, April 20, 1918, i, 568.
(5) Hall, Arthur J.: Note on an epidemic of toxic opthalmoplegia. Lancet, London, April 20, 1918, i, 568.
(6) Report of an Enquiry into an Obscure Disease. Encephalitis Lethargica. Reports to the Local Government Board on Public Health and Medical Subjects. His Majesty's Stationery Office, London, 1918, n. s. No. 121.
(7) Morguio, L.: Lethargic encephalitis. Revista Medica del Urguay, Montevideo, 1918, xxi, 463.
(8) Arden-Deltiel: Un cas d'encéphalite léthargique observé à Alger. Bull. et mem. Soc. med. hôp. de Paris, 1918, 3, s., xlii, 577.
(9) Smith, H. F.: Epidemic encephalitis (Encephalitis lethargica, Nona). Reports of studies conducted in the United States. U. S. Public Health Reports, Washington, 1921, xxxvi, No. 6, 207.
(10) Letter from the Assistant Surgeon General, U. S. Public Health Service, to Maj. H. C. Michie, M. C., dated March 5, 1924. Subject: Encephalitis lethargica. On file, Historical Division, S. G. O.
(11) Pothier, O. L.: Lethargic encephalitis; Preliminary report, Camp Lee, Va. The Journal of the American Medical Association, Chicago, 1919, lxxii, No. 10, 715.
(12) Bassoe, Peter: Epidemic Encephalitis (Nona). The Journal of the American Medical Association, Chicago. 1919, lxxii, No. 14, 971.
(13) Breinl, A.: Clinical, Pathological and Experimental Observations on the "Mysterious Disease." A Clinically Aberrant Form of Acute Poliomyelitis. The Medical Journal of Australia, Sydney, 1918, i, No. 11, 209.
(14) Neal, J. B.: Lethargic Encephalitis. International Clinics, Philadelphia and London, 1919, ii, 29th Series, 184.
(15) Hershfield, A. S.: Epidemic Encephalitis in Chicago. An Analysis. Illinois Medical Journal, Chicago, 1919, July, xxxvi, No. 1, 27.
(16) Hiss, P. H., jr.; Zinsser, Hans; and Russell, F. F.: A Text Book of Bacteriology. D. Appleton and Co., New York, 1922, 919.
(17) Von Wiesner, R. R.: Die Aetiologie der Encephalitis Lethargica. Wiener klinische Wochenschrift, Wien, 1917, xxx, No. 30, 933.
(18) Strauss, I.; Hirshfeld, S.; and Loewe, L.: Studies in Epidemic Encephalitis. New York Medical Journal, New York, 1919, cix, No. 18, 772.
(19) Loewe, L.; Hirshfeld, S.; and Strauss, I.: Studies in Epidemic Encephalitis. The Journal of Infectious Diseases, Chicago, 1919, xxv, 378.
(20) Wegeforth, P., and Ayer, J. B.: Encephalitis Lethargica. The Journal of the American Medical Association, Chicago, 1919, lxxiii, No. 1, 5.
(21) Skversky, A.: Lethargic Encephalitis in the A. E. F.: A Clinical study. The American Journal of Medical Sciences, Philadelphia, 1919, n. s., clviii, No. 6, 849.
(22) Fairbanks, A. W.: Encephalitis Lethargica. The Boston Medical and Surgical Journal, Boston, 1919, clxxxi, No. 20, 578.
(23) Spaeth, E. B.: Ocular Symptoms of Encephalitis Lethargica. On file, Historical Division, S. G. O.
(24) Hershberg, H.: Report of a Case of Lethargic Encephalitis, Base Hospital No. 69, A. E. F., New York Medical Journal, 1919, cx, No. 22, 899.
(25) Vaughan, Victor C.: Encephalitis Lethargica. The Journal of Laboratory and Clinical Medicine, St. Louis, 1918-19, iv, No. 7, 381.