Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 37
Encephalitis lethargica (von Economo’s encephalitis) JOSEPH R. BERGER1* AND JOEL A. VILENSKY2 Department of Neurology and Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
1
2
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Fort Wayne, IN, USA
INTRODUCTION The early 20th-century illness referred to as encephalitis lethargica (EL) has been known by a large number of other names, including von Economo’s encephalitis, epidemic encephalitis, lethargic encephalitis, sleeping sickness, sleepy sickness, Schlafkrankheit, Schlummerkrankheit, von Economo’s disease or, simply, Economo’s disease. Some authorities named it on the basis of the region of brain chiefly involved. For example, Kinnier Wilson referred to it as mesencephalitis and Bernard Sachs as a basilar encephalitis (Sacks, 1990). This illness spread in epidemic fashion throughout Europe, beginning in the winter of 1916–1917. Sporadic cases continued to be identified following the epidemic period, which perhaps lasted until 1930. In addition to its epidemic nature, this polioencephalitis (inflammation of the gray matter) of the brainstem exhibited a polymorphic clinical expression within and among each case and had pronounced geographic and temporal variability. Often the patients had lingering and permanent sequelae (Vilensky and Gilman, 2011).
with bizarre complaints occurring in association with intractable stupor (von Economo, 1917a, b; Casals et al., 1998). von Economo described the experience in the following manner:
HISTORY
Towards the end of 1916 the wards of the Vienna Psychiatric Clinic contained quite a number of patients with a strange variety of symptoms — cases which had apparently only one feature in common — a difficulty to fit into any known diagnostic scheme. They had been admitted under the most varied descriptions, such as, meningitis, acute disseminated sclerosis [multiple sclerosis], amentia, delirium, etc. The patients all showed a slight influenza-like prodrome condition with trifling pharyngeal symptoms, a slight rise of temperature soon followed by a variety of nervous symptoms, though generally one sign or another pointed to the midbrain as the source. I noticed particularly in a few of these patients a condition of marked lethargy combined with disturbances of eye-muscles, recalling the mythical sleeping sickness, nona, rampant in north Italy during the nineties of the last century, of which I had heard during a youth spent in the Austrian Kustenland (von Economo, 1931).
Born of Greek parentage in Braila, Romania on August 21, 1876 and raised in Trieste, Austria, Constantin Baron Economo von San Serff (Arts, 2000) was a skilled neuroanatomist whose interests included the anatomy and physiology of the midbrain, pons, and trigeminal nerve pathway (Fig. 37.1). In 1917 he started his monumental studies on EL, which established his fame worldwide, but he also worked on cytoarchitectural studies and human brain evolution (Kolle, 1959). While treating patients in the Psychiatric-Neurological Clinic of the University of Vienna, von Economo examined 7 patients
The illness had an acute and chronic phase, although they often blended into one another. The initial phase of the illness was typically a viral prodrome generally with features of an upper respiratory tract infection. While it appeared almost contemporaneously with the influenza outbreak, its clinical features appeared different than those of influenza, it predated the great influenza epidemic, and new cases were observed well after the influenza pandemic had ended, suggesting to most contemporary authors that they were two separate disorders.
*Correspondence to: Dr. Joseph R. Berger, Department of Neurology, University of Kentucky College of Medicine, Kentucky Clinic L-445, Lexington, KY 40536-0284, USA. E-mail: [email protected]
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Fig. 37.1. Constantin Baron Economo von San Serff.
During the acute phase of EL, sleep, ocular motility, fever, and movement disorders were typically observed, but virtually any neurologic sign or symptom could also be exhibited. In the chronic phase, parkinsonism was a common sequela, although not the only neurologic sequela. Through 1960, the illness was believed to be responsible for as many as 50% of parkinsonism cases. For example, in the period 1920–1938 it was estimated that about two-thirds of all cases of parkinsonism in London were postencephalitic. Similar estimates in New York from this era suggested that as many as 26% of all parkinsonism cases were postencephalitic (Krusz et al., 1987). Over the course of the succeeding 15–20 years, the illness appeared to have changed in nature with a less florid acute phase and a more commonly observed chronic phase of frequently devastating neurologic sequelae. Competing descriptions of EL at the same time as that of von Economo made him very concerned that he would receive the appropriate recognition for the primacy of his observations. Of particular concern was a description of a similar illness by the French physician, Rene´ Cruchet. Cruchet and colleagues published a paper on 40 cases seen in the French military hospital for neuropsychiatric disorders, Quarante cas d’encphalomylite subaigue, in the Bulletin de la Socit Mdicale des Hoˆpitaux de Paris in 1917 (Cruchet et al., 1917). These patients represented 3% of all hospital admissions. In his 1929 monograph, von Economo emphasized that this publication appeared 10 days after his own, giving his paper priority.
A decade later and before the appearance of von Economo’s own monograph, Cruchet published a monograph entitled, Encephalitis pidemique – les 64 premires observations. According to von Economo, only three of the 64 cases described by Cruchet qualified as EL and 40 of them occurred before the appearance of the illness in 1915 (von Economo, 1931). Some authors have elected to refer to the illness as EL of von Economo– Cruchet (Chastel, 2000). However, because von Economo recognized the uniqueness of the illness, Yahr (1978) argued that credit for the description of the disorder belongs to him and we agree. Furthermore, it must be emphasized that primacy can never be absolutely determined because EL remained a clinical diagnosis without a pathognomonic constellation of symptoms or signs or diagnostic laboratory test. Historic surveys suggested that EL likely occurred previously. An example is the 1673–1675 epidemic in London of sleeping illness, an illness referred to as “febris comatosa” by Sydenham and typically accompanied by singultus. From 1695 through 1800 there were isolated case reports of sporadic somnolent ophthalmoplegia. In 1712 an epidemic of Schlafsucht occurred in Germany that was described by Camerarius as a Schlafkrankheit with delirium that was especially vivid and powerful during the night. This illness was associated with oculomotor features, of which ptosis predominated (von Economo, 1917a, b). In 1890–1891, an illness of epidemic delirium and lethargy, with which von Economo was familiar because of his mother’s recollection of it, called “nona,” appeared in northern Italy. This illness also bore striking similarities to the epidemic described by Livius in the year 412 (Ebstein, 1921). Crookshank (1918), after a review of the world’s literature, was convinced that EL was not new. Among the similar epidemics that he identified were the English sweats (England, 1529), mal mazzuco (Italy, 1597), Kriebelkrankheit (Germany in the 1500 s and 1672–1675), Raphania (Sweden, 1754–1757), and nona. Zinsser also identified similar epidemics in 1712 in Germany and another in 1769 in France labeled “coma somnolentum” (Zinsser, 1928). Many of the EL-like epidemics, including nona, were, interestingly, also associated with influenza epidemics. In the United Kingdom and United States, nona was sometimes used as a synonym for EL (Dragotti, 1918; Anonymous, 1919; Bassoe, 1919; Smith, 1921), but victims of nona either returned to full health or died, and there were no reports of neuropsychiatric sequelae. Unfortunately, there are few long-term follow-up data for patients who were labeled with nona. The initial appearance of von Economo’s encephalitis was probably in Romania by April and May, 1915 (Urechia, 1921), although Watson (1928) contended its
ENCEPHALITIS LETHARGICA (VON ECONOMO’S ENCEPHALITIS) origin may have been in China. A fascinating story recounted by P. Yakovlev times the appearance of EL to the movement of Mongolian troops into the Balkans during the unrest preceding World War I (Johnson, 1998). Subsequently, EL was described in the winter of 1916 on the French front of Verdun and by Christmas season 1916–1917 in epidemic form in Vienna. An epidemic followed in France in March 1918. During the latter, Sainton described three diagnostic symptoms: somnolence, oculomotor paresis, and fever. By 1919, it had overrun most European countries and the United States and spread to Canada, Central America, and India (Wilson, 1940). By comparison, it was not until May 1918 that the influenza epidemic first appeared, although Oxford (2000) suggested influenza in Europe may have been present as early as 1916. Between 1919 and 1930, peaks of EL occurred in 1920 and 1924, with more than 17 000 cases reported in the latter year (Wilson, 1940). By 1928, more than 5000 titles had been published in the world medical literature on the illness (Wilson, 1940). Over time, the acute cases became less common. On the other hand, chronic neurologic sequelae attributed to EL remained devastating (Editorial, 1927). Nevertheless, since the epidemic period, cases of EL continue to be described in the neurologic literature.
TRANSMISSION Transmission of the illness from person to person was thought to be rare (Symonds, 1921; Hall, 1923) and perhaps accounted for no more than 5% of cases (von Economo, 1931). Nevertheless, there were relatively well-documented instances of such transmission (Zinsser, 1928). Kinnier Wilson (1940) described transmission among husband and wife, nurse and patient, soldiers in adjoining beds, and mother and infant. Additionally, there was a very well-known example of 12 cases of 22 residents with five fatalities that were observed in 2 weeks in a girls’ home in Derby, England (Symonds, 1921) and 28 within 20 days in a women’s asylum in Germany (Krause, 1922) The Derby example is very hard to dismiss because it was thoroughly investigated by Dr. A. Salusbury MacNalty who had done previous work on EL, and who had a distinguished medical career, becoming Chief Medical Officer for England in 1935. He did a complete epidemiologic investigation of the incident in which he excluded all other possible factors but contagion (MacNalty, 1919). Despite these reports, no contact transmission was documented among 1156 cases seen in Vienna (Hoff, 1924) or in 520 cases in Germany (Faßbender, 1921). The incubation time for EL was uncertain, but generally believed to be a minimum of 1 day to a maximum of
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2 months, with a typical range of 8–18 days and a mean of 10 days (Wilson, 1940). These data were determined by cases in which persons recently migrated from areas of high endemicity. No age was spared, but persons between the ages of 10 and 45 years were more commonly affected. Nearly 50% of cases occurred between the ages of 10 and 30 (Wilson, 1940). There was no overall sex predilection, although higher incidences of one sex or the other was described for various epidemics (Marlowe et al., 2011). Pregnancy bestowed an unfavorable course on the illness and transmission to both the fetus and newborn was described (von Economo, 1931; Wilson, 1940). In such cases abortion was typically the recommended course (Neal, 1942). Transient infection with influenza was proposed to result in an increased nasal mucous membrane permeability for the encephalitic virus (Eden and Yates, 1927). Contemporary studies of histocompatibility antigens in modern putative patients having suffered from von Economo’s encephalitis have failed to reveal any differences in phenotypic frequencies for human leukocyte antigen (HLA)-A, B, C, and DR antigens (Lees et al., 1982). Elizan and colleagues (1980) also found no difference in HLA typing in postencephalitic parkinsonism (PEP) patients.
ETIOLOGY The infectious disease hypothesis von Economo (1917a, b) in his initial paper reporting his Viennese experience speculated on the cause of the disease. He stated that initially he had considered a toxic process, such as sausage poisoning, because of the poor nutrition caused by the war. However, he noted the absence of gastrointestinal disturbances. Others later rejected this idea because there were typically only single cases of EL within households, some of the victims were exclusively breast-fed infants, and the disease was occurring worldwide, all of which cast doubt on an environmental etiologic agent (Matheson, 1929). von Economo also considered and dismissed poison gas and typhoid as causes. von Economo next rejected polio, because there was not a polio epidemic in Vienna at the time. And, finally, his patients had negative Wasserman tests, indicating that EL was not related to syphilis. von Economo (1917a, b) believed that the histologic findings suggested a single inflammatory process. Furthermore, he reported that in meningeal tissue from deceased patients, there were “coccus-like” formations. However, he was very reticent to accept these findings and requested that other physicians who had access to material from fatal EL cases send him brain samples so that these results could be verified.
748 J.R. BERGER AND J.A. VILENSKY In his second 1917 article on EL, von Economo Influenza A has always been of particular interest in (1917a, b) indicated that research at the Pathological light of the temporal relationship of the EL outbreak Institute had confirmed that a specific “infectious” virus and the influenza epidemic. von Economo (1917a, b) conwas the cause of EL. This claim was based on the sidered the possibility that EL was an influenzal encephapparent transmissibility of the disease via brain tissue alitis, primarily because encephalitis had been associated (unfiltered) from a deceased patient to a monkey. von with earlier influenza epidemics. von Economo believed Economo further stated that a Gram-positive Diplosthat the synchrony in the seasonality of the two conditions treptoccocus was the specific cause of the disease supported the view that they were related, and also stated because it resulted in EL symptoms when injected into that he had seen many “grippe” cases in Vienna. Furthera monkey. During the epidemic period there was a masmore, he stated that most of the EL cases had begun with sive search for the putative organism that was causing feelings of a cold, headache, general malaise, and possibly EL (Matheson, 1929). Tissues (typically brain) and fluids joint pain. In his 1929 monograph on EL, von Economo (cerebrospinal fluid (CSF), blood, and nasopharyngeal devoted an entire section to this question: Influenza, influwashings) from EL victims were injected into the brains enza encephalitis and EL. He noted that the neuropatholof a large variety of animal species (especially rabbits) in ogy of EL is different from that of influenza encephalitis attempts to develop an animal model of the disease and (patients who died from influenza may show some capilisolate the causative agent – either bacteria that could be lary hemorrhages in the brain but not the inflammatory cultured or a “filterable” virus that could pass through processes evident in EL (cf. below)). However, he also the smallest pores of available filters, although viruses indicated that, despite this difference, it would be equally were not actually identified as structures until 1935 futile to deny any epidemiologic connection between EL with the invention of the electron microscope. Among and influenza. “A connection is obvious not only from the the more prominent etiologies proposed contemporecrudescence of the encephalitis epidemics in the wake raneously with the epidemic were those of alleging the of the influenza pandemic of 1918–21 and its simultacausative agent was herpes (Levaditi and Harvier, neous subsidence in the years 1922–25, but also from 1920; Levaditi et al., 1921a, b) or streptococcus. Levaditi historical considerations” (von Economo, 1929). Similar and colleagues claimed to be able to produce keratoto von Economo, some other clinicians of the time conjunctivis and encephalitis in rabbits that they attribbelieved influenza might “predispose to infection with uted to a herpes infection in samples, particularly the virus of EL” (Wilson-Smith, 1920; Symonds, 1921; saliva, from patients with EL. Rosenow injected dead Flexner, 1923; Kramer, 1924). A putative association Streptococcus viridans that had been cultured from between influenza and EL was hardly universally mainthe oropharnynx and nasopharynx of a patients with tained. A.J. Hall, a contemporary physician, stated: EL into rabbit brains and observed features that resemWhen the first series of cases came under our bled PEP (Rosenow, 1922; Claassen and Boes, 2009). observation in the Sheffield district in March These observations led to the development of vaccines 1918, many possible explanations were considdesigned to treat EL (Louis, 2002). ered and discussed; but amongst them influenza Van Rooyen and Rhodes, in their 1948 textbook, was never thought of or suggested by any who Virus Diseases of Man, said of the EL bacterial work: saw this series of extraordinary cases. If there is Many [of the investigators] were undoubtedly a connection between epidemic encephalitis and working with contaminants which either gained influenza, it is unusually well concealed from access during the postmortem in the case of the the clinician (Hall, 1918). brain, or else were present in the nasopharynx More recently, data and articles have appeared that have quite apart from the encephalitis. Certain workers both supported and refuted the influenza etiology, but were also unaware of the existence of spontaneous the preponderance of recent studies suggests that an encephalitis of rabbits (p. 1072). active influenza brainstem encephalitis was not causal. On the viral experiments, they commented: “The experiRavenholt and Foege, in 1982, described two sets of epiments were usually very inconclusive, however, and no demiologic data supportive of the idea that influenza did recognized strain of virus emerged. The effects noted cause EL. For Seattle, Washington, from 1918 to 1926, were probably in the main nonspecific, or else due to an they reported that peaks in influenza deaths occurred unrecognized bacterial contaminant or to spontaneous consistently about 1 year prior to peaks in EL deaths. encephalitis” (p. 1073). And, they also said of the work Based on this correlation they postulated a common etiproposing EL to be a herpes viral infection, “In general, ology. However, although the monthly mortality for however, herpetic encephalitis, as it is presently observed, influenza during 1918–1919 reached 400, the maximum appears not to resemble EL very closely” (p. 1073). number of deaths per month for EL was 8 – so accepting
ENCEPHALITIS LETHARGICA (VON ECONOMO’S ENCEPHALITIS) similar etiology would seem to be unjustified. Reid and colleagues (2001) were also highly critical of these data, stating that the pattern reported for Seattle was not observed globally and that all the Ravenholt and Foege data show are that both diseases peaked in late winter. Ravenholt and Foege’s (1982) second set of data is from Samoa. In Western Samoa, after the importation of the influenza virus there from passengers on a ship on November 7, 1918, approximately 20% of the population died from influenza and there were many reports of EL, which had not been found previously to have been present there. In contrast, American Samoa (just 70 km away), which maintained a strict quarantine, did not have any cases of influenza or EL. However, the validity of the data is very hard to assess. For example, Ravenholt and Foege viewed deaths between 1919 and 1922 due to fa-aniniva (interpreted as fatal diseases of the head) as being due to EL, but clearly this is a post hoc diagnosis. Furthermore, it may simply suggest that the causative agents of each of these illnesses were concurrently prevented from entering American Samoa. Importantly, no other study has replicated these findings. Modern experimental studies pertaining to the influenza hypothesis were thoroughly reviewed by McCall and colleagues (2008). These studies (Table 37.1) can be divided by type: (1) serology – examined antibodies against influenza present in the serum of PEP patients; Table 37.1 Experimental studies of the influenza hypothesis for encephalitis lethargica (EL) Study
Conclusions
Gamboa et al. (1974)
Influenza antigens detected in hypothalamus and midbrain in 6 PEP but no PD patients No difference between 23 PEP and 421 PD controls for antibodies to influenza strain PR/8/34 No difference between 20 PEP and 55 PD and controls in antibodies to strains PR/8/24 and Sw/1976 Negative immunostains for several flu strains in 1 acute EL and 1 PEP brain No influenza RNA in 7 PEP patients
Marttila et al. (1977a) Marttila et al. (1977b) Elizan et al. (1989) Isocson et al. (1995) McCall et al. (2001) Lo et al. (2003)
mRNA of b2-microglobulin but not influenza in brains of EL and PEP patients mRNA of b-actin but not influenza in 8 EL brains
Modified from McCall et al. (2008). PEP, postencephalitic parkinsonism; PD, Parkinson’s disease.
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(2) reverse transcriptase polymerase chain reaction (RT-PCR) – tests for influenza viral RNA in preserved EL and PEP patient brain tissue samples; and (3) antigen (immunohistochemistry) – utilizing anti-influenza antibodies to search for influenza proteins still present in brain tissue samples. Despite the strong apparent weight of the findings against the influenza hypothesis (all but one of the seven reviewed studies dating from 1977 to 2003 reported negative results), these investigators noted the studies are all limited by the extreme rarity of acute EL material and by the difficulty of retrospective confirmatory diagnosis of acute EL. Furthermore, they also described a possible flaw in the RT-PCR studies associated with primer mismatch due to influenza viral mutation between 1918 and the later sequences, against which primers were designed. The authors also questioned whether any viral segments originally presented in the EL tissue samples might have undergone autolysis because of the lack of refrigeration in morgues at the time. Lastly, McCall and colleagues (2008) noted that it is impossible to prove a negative and that influenza causation would provide a convenient explanation for EL’s disappearance, because the 1918-like influenza strains ceased human circulation some time before 1933, when the first human influenza strain was reconstructed from archival material by Taubenberger (2006). Empiric studies provide little support of an influenza etiology, but technical limitations and the shortage of appropriate material for testing limit the degree of confidence. Therefore, unless another cause of classical EL is positively identified, its return in the context of another influenza pandemic remains formally possible. In a rodent model, studies by Takahashi and colleagues (1995) demonstrated that a neurovirulent form of influenza localizes selectively in the ventral substantia nigra and hippocampus.
The autoimmune hypothesis In 2004, Dale and colleagues described 20 patients with an EL-like phenotype, all of whom had had a preceding pharyngitis. In contradistinction to the studies cited above in which archival material or actual patients with PEP were studied, these patients had sporadic disease in the modern age. The authors investigated the possibility that EL could be a postinfectious autoimmune central nervous system (CNS) disorder with an etiology similar to that of Sydenham’s chorea. Sixty-five percent of the cases had elevated antistreptolysin-O titers and 95% had autoantibodies reactive against basal ganglia antibodies in their CSF; such antibodies were only present in 2–4% of a control group. The authors thus hypothesized that EL may be secondary to autoimmunity against deep gray nuclei and may be a pediatric autoimmune
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neuropsychiatric disorder associated with streptococcal infection (PANDAS) disease. In 2009, Lopez-Alberola et al. described seven new cases of putative EL, four of whom also had elevated antibasal ganglia antibodies in their CSF, but only one of whom had a positive streptococcal serology. However, fluorodeoxyglucose positron emission tomography (FDG-PET) studies identified abnormal patterns of cerebral metabolism in 4/7 patients, with the most frequent pattern being an increased glucose metabolism in the basal ganglia. Vincent’s editorial accompanying the publication of the Dale paper highlighted some problems pertaining to the hypothesis that EL is a PANDAS disease (Vincent, 2004). She began by suggesting that the acute “fulminating” form of EL that was evident during the epidemic period is no longer manifested in the sporadic cases that still occur. She noted that 60% of Dale et al.’s patients did not have magnetic resonance imaging to document basal ganglia disease, and 35% did not have antistreptolysin-O elevation. Furthermore, the putative antibasal ganglia antibodies detected were not proven to cross-react with streptococcal antigens, and they varied in specificity among patients, suggesting that they might be secondary to an immune condition rather than causative. In addition, PANDAS, by definition, must have a pediatric onset, but 3 of Dale’s original patients were above age 35 and EL during the epidemic period was never considered a pediatric disease. Interestingly, in a 2009 report, Dale and colleagues seemed to rescind the PANDA theory on EL and suggested instead that at least the hyperkinetic form of EL was due to the development of autoantibodies to the extracellular domain of NR1/NR2 subunits of the N-methyl-D-aspartate receptor (NMDAR-Ab). Sera from 10 (50%) of 20 pediatric patients with putative EL were found to be NMDAR-Ab-positive with dyskinesias, parkinsonism, and somnolence. The authors noted some recent studies that have identified EL-like features in young females with ovarian teratomas who also were serum- and CSF-positive for NMDAR-Ab. They concluded that the dyskinetic (hyperkinetic) form of EL may be an NMDAR-Ab encephalitis that can affect very young children (Dale et al., 2009). As with the PANDA hypothesis, this one is also open to question. For example, does the Dale study (Dale et al., 2009) imply that the different forms of EL had different etiologies? Did adults who had the hyperkinetic form of EL also have NMDAR-Ab encephalitis? Despite the apparent inconsistencies, it is important to emphasize that these ideas for the etiology of EL were presented as hypotheses, which represent the first new frameworks within which to view this syndrome almost since the epidemic period. Thus, in that sense, they make a very significant contribution to the EL literature.
CLINICAL ILLNESS Acute encephalitis lethargica (EL) In 1921, H. F. Smith, working for the US Public Health Service, defined epidemic encephalitis as: an epidemic syndrome characterized in most instances by a gradual onset with headache, vertigo, disturbances of vision, ocular palsies, changes in speech, dysphagia, marked asthenia, fever (usually of a low grade), obstinate constipation, incontinence of urine, a peculiar mask-like expression of the face, and a state of lethargy which gradually develops in the majority of the recognized cases into a coma that is more or less profound (p. 207) (Fig. 37.2). If EL was repeatedly described as fitting the above description, then many of the diagnostic ambiguities associated with the disease would not have occurred. Among the approximately 9000 publications on EL from the entire epidemic period, however, many described the symptomatology but few were in agreement as to the most reliable signs and symptoms associated with the disease (Peng, 1993). The signs/symptoms that were linked with acute EL in these many articles include virtually every neurologic sign and symptom described in neurology textbooks. This variability in diagnostic criteria was explained during the period by suggesting that in different geographic/temporal epidemics, different signs/symptoms predominated and that there were great day-today (hour-to-hour) shifts in the symptomatology, and by suggesting that the variability was associated with different areas of CNS injury by the same agent. Nevertheless, it is difficult for a contemporary clinician to appreciate why,
Fig. 37.2. Enacephalitis lethargica symptomatology. (Reproduced from Smith, 1921.)
ENCEPHALITIS LETHARGICA (VON ECONOMO’S ENCEPHALITIS) 751 with this variability, the clinicians of the period ascribed a and juvenile (Vilensky and Gilman, 2011). von Economo unifying designation to the syndrome. Most likely, there classified the chronic forms as either parkinsonian appeared to be an emphasis on sleep and ocular muscle or other. disorders, and also that the described symptoms and signs The somnolent-ophthalmoplegic form typically exhibited together, did not fit any other established neurodeveloped soon after prodromal symptoms. Patients logic condition. Crafts (1927) stated it as follows: were described as dazed and confused, with their somnolence and deliria being unrelated to temperature elevaAnd while no other disease, perhaps, presents so tions. They exhibited features of mild meningeal many difficulties in diagnosis as does this protean irritation characterized by stiff neck, Brudzinski´s and complex, the fact must always be borne in mind, Kernig’s sign, pain on eyeball compression, diplopia, that while it usually offers a very close resemand ptosis. Other features include frequent yawning, blance to one or another condition, careful and trismus, and singultus, and, occasionally, cranial nerve painstaking study and comparison will reveal palsies with weak phonation and dysphagia, vertigo, either some incongruity, some essential symptom and limb weakness. Pupillary abnormalities were lacking or a superabundance of elements, thus observed, including the frequent absent of accommodaoffering a definite aid or conclusive basis for tion. Less commonly, supranuclear palsies occurred (von differential diagnosis (p. 60). Economo, 1931). In his description of this form of the illThus, indistinct clinical observations were used to make ness, von Economo recorded that “It is frequently seen a diagnosis of EL because at the time there simply were that a patient cannot properly lift his arm or leg, or that no definitive laboratory tests to confirm a diagnosis. his grasp is weak, and the muscles markedly hypotonic The earliest clinical features of the illness were very . . . This lack of tonus is frequently shown by the inability non-descript and included extreme malaise, low-grade of patients to rise up or sit down; they therefore assume fever, mild pharyngitis, ptosis, diplopia, shivering, heada huddled position and tend to gravitate to one side.” ache, vertigo, and vomiting. However, neurologic manKinnier Wilson described a patient thusly, “A lady found ifestations could also present very quickly. Kinnier her shopping hindered by an overwhelming desire for Wilson described one case in which rapidly evolving neusleep; she would rush home to throw herself on a couch rologic disease developed thusly: in the hall (not even waiting to go up to her bedroom) and sink at once into deep slumber continuing for hours. The first case I ever saw was that of a girl who, Within 4 years, Parkinsonism occurred” (Wilson, walking home from a concert, suddenly felt an 1940). He described a 12-year-old girl who had recently acute pain in the head and at the same moment had a violent illness in the following fashion, “Once, her left arm flopped and left leg gave way; at tea, she was in the act of putting a piece of toast in within half an hour she was asleep, showing her mouth when her eyes closed and the hand was kept contracted pupils, divergent squint, and left hemiimmobile, the bread touching her lip for several plegia; sinking deeper into lethargy, temperatures minutes” (Wilson, 1940). Although lethargy was an to 105.8 and death supervening in 12 days important sign, the patients also could be easily awak(Wilson, 1940). ened and were often aware of all that had transpired The illness assumed several relatively distinct forms in around them. referred to as pseudosomnolence or false its acute and chronic phases. sleep (Vilensky and Gilman, 2011). To facilitate diagnosis within EL’s vast array of Whereas the mortality of the somnolentsymptoms, some clinicians from the period divided the ophthalmoplegic form of the illness was higher than disease into temporal stages (typically acute and chronic) other forms, exceeding 50%, a greater number of surand symptom-based types (forms). von Economo (1929) vivors experienced few or no sequelae than followed classified the acute manifestations into three categories, other forms. von Economo related this form of the the somnolent-ophthalmoplegic form, the hyperkinetic disorder to lesions of the posterior wall of the third venform, and the amyostatic-akinetic form. As the epidemic tricle near the oculomotor nucleus. In contrast, the period progressed and EL became associated with virtuinsomnia seen in the other forms was linked to a ally every possible neurologic sign and symptom, many lesion in the lateral wall of the third ventricle near the other types were identified, such as: psychiatric, aborcorpus striatum that was suggested to exert an inhibitive, cerebellar, hemiplegic, cortical, spinal, polyneuritic, tory function on the cerebrum and thalamus (Von cataleptic, meningeal, anterior poliomyelitic, hyperalgeEconomo, 1930). sic, general, infantile, progressive, aberrant/autonomic, The hyperkinetic form was characterized by an initial monosymptomatic, tabetic, insomnia, paralytic, myeltic, hypomaniacal excitement followed by general prostrapallido-pyramidal., mixed striatal, myoclonic, thalamic, tion, pallor and rapid failure of strength, violent neuralgic
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pains in face and limbs, visual and tactile hallucinations, and sleep reversal or inversion. During the manic phase vocalizations included singing, shouting, and whistling. Examination revealed pupillary abnormalities, including unreactive and Argyll Robertson pupils, chorea that may be either unilateral or bilateral, peculiar torsions and myorrhythmias, trismus and similar involvement of orbital muscles, and myoclonic twitches that were shortlived and either non-rhythmic or rhythmic (Riddoch, 1927). Str€ umpel (1920) described the myoclonus in one of his patients as: “extremely painful, mainly localized in the abdomen . . . even after the myoclonus stopped the patients complained about some weird deep pain and about hurtful paresthesias in their extremities and body.” Sudden death might supervene (von Economo, 1931). Among the first-hand descriptions of patients afflicted with this disorder is the following by Kinnier Wilson in his 1940 textbook: The patient tosses about in bed, pushes the blankets back, pulls them up again, sits up, throws himself back again in a wild sort of haste, jumps out of bed, strikes out aimlessly, talks incoherently, clucks his tongue, and whistles, this unrest lasting for days and nights without stop. The least common of the three forms proposed by von Economo for acute illness was the amyostatic-akinetic form. This form was characterized by peculiar rigidity and a lack of movements in the absence of real weakness. It was said that “movement is arrested soon after its inception due to lack of impulse.” There were typically no corticospinal tract findings. The slowness and paucity of movement are striking and patients do not alter their body position spontaneously. When addressed, their eyes might turn to the examiner but not their heads. Flexibitas cerea might develop. The emotions were hardly noticeable, although the patients were mentally intact with normal comprehension. The examination revealed muscle rigidity, normal tendon reflexes, often a peculiar bent posture when standing, and vasomotor disturbances, e.g., edema, skin exfoliation, sleep disturbances, including somnolence, insomnia, and sleep inversion. This condition might last months and could have either a slow or rapid recovery. Str€ umpel (1920) described one of his patients: “absolutely still in bed, eyes are wide open . . . their mind stays absolutely clear . . . complete lack of initiation of movements or speech . . . muscle rigidity, arms in interosseus position . . . patients sometimes keep arms lifted for a very long time.” In children, the psychiatric effects were often as severe as the physical consequences. Approximately one-third of affected children underwent a rapid transformation from normal behavior to delinquency, often
leading to institutionalization. Many neurologic and psychologic theories were proposed to explain these severe behavioral changes, and the therapeutic approaches employed ranged from training in dedicated schools to frontal leukotomy (Vilensky et al., 2007). During the acute illness blood leukocytosis could range up to 25 000–30 000 cells/mm3, but the leukocytosis was generally quite mild, 10–12 000 cells/mm3 (Howell, 1925). CSF analysis typically revealed a moderate increase in opening pressure, although von Economo (1917a, b) also noted that, despite persistent somnolence or other deficits, opening pressure returned to normal after couple of weeks. The CSF (Howell, 1925) was almost always clear and colorless with a moderate pleocytosis
Chapter 37
Encephalitis lethargica (von Economo’s encephalitis) JOSEPH R. BERGER1* AND JOEL A. VILENSKY2 Department of Neurology and Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
1
2
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Fort Wayne, IN, USA
INTRODUCTION The early 20th-century illness referred to as encephalitis lethargica (EL) has been known by a large number of other names, including von Economo’s encephalitis, epidemic encephalitis, lethargic encephalitis, sleeping sickness, sleepy sickness, Schlafkrankheit, Schlummerkrankheit, von Economo’s disease or, simply, Economo’s disease. Some authorities named it on the basis of the region of brain chiefly involved. For example, Kinnier Wilson referred to it as mesencephalitis and Bernard Sachs as a basilar encephalitis (Sacks, 1990). This illness spread in epidemic fashion throughout Europe, beginning in the winter of 1916–1917. Sporadic cases continued to be identified following the epidemic period, which perhaps lasted until 1930. In addition to its epidemic nature, this polioencephalitis (inflammation of the gray matter) of the brainstem exhibited a polymorphic clinical expression within and among each case and had pronounced geographic and temporal variability. Often the patients had lingering and permanent sequelae (Vilensky and Gilman, 2011).
with bizarre complaints occurring in association with intractable stupor (von Economo, 1917a, b; Casals et al., 1998). von Economo described the experience in the following manner:
HISTORY
Towards the end of 1916 the wards of the Vienna Psychiatric Clinic contained quite a number of patients with a strange variety of symptoms — cases which had apparently only one feature in common — a difficulty to fit into any known diagnostic scheme. They had been admitted under the most varied descriptions, such as, meningitis, acute disseminated sclerosis [multiple sclerosis], amentia, delirium, etc. The patients all showed a slight influenza-like prodrome condition with trifling pharyngeal symptoms, a slight rise of temperature soon followed by a variety of nervous symptoms, though generally one sign or another pointed to the midbrain as the source. I noticed particularly in a few of these patients a condition of marked lethargy combined with disturbances of eye-muscles, recalling the mythical sleeping sickness, nona, rampant in north Italy during the nineties of the last century, of which I had heard during a youth spent in the Austrian Kustenland (von Economo, 1931).
Born of Greek parentage in Braila, Romania on August 21, 1876 and raised in Trieste, Austria, Constantin Baron Economo von San Serff (Arts, 2000) was a skilled neuroanatomist whose interests included the anatomy and physiology of the midbrain, pons, and trigeminal nerve pathway (Fig. 37.1). In 1917 he started his monumental studies on EL, which established his fame worldwide, but he also worked on cytoarchitectural studies and human brain evolution (Kolle, 1959). While treating patients in the Psychiatric-Neurological Clinic of the University of Vienna, von Economo examined 7 patients
The illness had an acute and chronic phase, although they often blended into one another. The initial phase of the illness was typically a viral prodrome generally with features of an upper respiratory tract infection. While it appeared almost contemporaneously with the influenza outbreak, its clinical features appeared different than those of influenza, it predated the great influenza epidemic, and new cases were observed well after the influenza pandemic had ended, suggesting to most contemporary authors that they were two separate disorders.
*Correspondence to: Dr. Joseph R. Berger, Department of Neurology, University of Kentucky College of Medicine, Kentucky Clinic L-445, Lexington, KY 40536-0284, USA. E-mail: [email protected]
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Fig. 37.1. Constantin Baron Economo von San Serff.
During the acute phase of EL, sleep, ocular motility, fever, and movement disorders were typically observed, but virtually any neurologic sign or symptom could also be exhibited. In the chronic phase, parkinsonism was a common sequela, although not the only neurologic sequela. Through 1960, the illness was believed to be responsible for as many as 50% of parkinsonism cases. For example, in the period 1920–1938 it was estimated that about two-thirds of all cases of parkinsonism in London were postencephalitic. Similar estimates in New York from this era suggested that as many as 26% of all parkinsonism cases were postencephalitic (Krusz et al., 1987). Over the course of the succeeding 15–20 years, the illness appeared to have changed in nature with a less florid acute phase and a more commonly observed chronic phase of frequently devastating neurologic sequelae. Competing descriptions of EL at the same time as that of von Economo made him very concerned that he would receive the appropriate recognition for the primacy of his observations. Of particular concern was a description of a similar illness by the French physician, Rene´ Cruchet. Cruchet and colleagues published a paper on 40 cases seen in the French military hospital for neuropsychiatric disorders, Quarante cas d’encphalomylite subaigue, in the Bulletin de la Socit Mdicale des Hoˆpitaux de Paris in 1917 (Cruchet et al., 1917). These patients represented 3% of all hospital admissions. In his 1929 monograph, von Economo emphasized that this publication appeared 10 days after his own, giving his paper priority.
A decade later and before the appearance of von Economo’s own monograph, Cruchet published a monograph entitled, Encephalitis pidemique – les 64 premires observations. According to von Economo, only three of the 64 cases described by Cruchet qualified as EL and 40 of them occurred before the appearance of the illness in 1915 (von Economo, 1931). Some authors have elected to refer to the illness as EL of von Economo– Cruchet (Chastel, 2000). However, because von Economo recognized the uniqueness of the illness, Yahr (1978) argued that credit for the description of the disorder belongs to him and we agree. Furthermore, it must be emphasized that primacy can never be absolutely determined because EL remained a clinical diagnosis without a pathognomonic constellation of symptoms or signs or diagnostic laboratory test. Historic surveys suggested that EL likely occurred previously. An example is the 1673–1675 epidemic in London of sleeping illness, an illness referred to as “febris comatosa” by Sydenham and typically accompanied by singultus. From 1695 through 1800 there were isolated case reports of sporadic somnolent ophthalmoplegia. In 1712 an epidemic of Schlafsucht occurred in Germany that was described by Camerarius as a Schlafkrankheit with delirium that was especially vivid and powerful during the night. This illness was associated with oculomotor features, of which ptosis predominated (von Economo, 1917a, b). In 1890–1891, an illness of epidemic delirium and lethargy, with which von Economo was familiar because of his mother’s recollection of it, called “nona,” appeared in northern Italy. This illness also bore striking similarities to the epidemic described by Livius in the year 412 (Ebstein, 1921). Crookshank (1918), after a review of the world’s literature, was convinced that EL was not new. Among the similar epidemics that he identified were the English sweats (England, 1529), mal mazzuco (Italy, 1597), Kriebelkrankheit (Germany in the 1500 s and 1672–1675), Raphania (Sweden, 1754–1757), and nona. Zinsser also identified similar epidemics in 1712 in Germany and another in 1769 in France labeled “coma somnolentum” (Zinsser, 1928). Many of the EL-like epidemics, including nona, were, interestingly, also associated with influenza epidemics. In the United Kingdom and United States, nona was sometimes used as a synonym for EL (Dragotti, 1918; Anonymous, 1919; Bassoe, 1919; Smith, 1921), but victims of nona either returned to full health or died, and there were no reports of neuropsychiatric sequelae. Unfortunately, there are few long-term follow-up data for patients who were labeled with nona. The initial appearance of von Economo’s encephalitis was probably in Romania by April and May, 1915 (Urechia, 1921), although Watson (1928) contended its
ENCEPHALITIS LETHARGICA (VON ECONOMO’S ENCEPHALITIS) origin may have been in China. A fascinating story recounted by P. Yakovlev times the appearance of EL to the movement of Mongolian troops into the Balkans during the unrest preceding World War I (Johnson, 1998). Subsequently, EL was described in the winter of 1916 on the French front of Verdun and by Christmas season 1916–1917 in epidemic form in Vienna. An epidemic followed in France in March 1918. During the latter, Sainton described three diagnostic symptoms: somnolence, oculomotor paresis, and fever. By 1919, it had overrun most European countries and the United States and spread to Canada, Central America, and India (Wilson, 1940). By comparison, it was not until May 1918 that the influenza epidemic first appeared, although Oxford (2000) suggested influenza in Europe may have been present as early as 1916. Between 1919 and 1930, peaks of EL occurred in 1920 and 1924, with more than 17 000 cases reported in the latter year (Wilson, 1940). By 1928, more than 5000 titles had been published in the world medical literature on the illness (Wilson, 1940). Over time, the acute cases became less common. On the other hand, chronic neurologic sequelae attributed to EL remained devastating (Editorial, 1927). Nevertheless, since the epidemic period, cases of EL continue to be described in the neurologic literature.
TRANSMISSION Transmission of the illness from person to person was thought to be rare (Symonds, 1921; Hall, 1923) and perhaps accounted for no more than 5% of cases (von Economo, 1931). Nevertheless, there were relatively well-documented instances of such transmission (Zinsser, 1928). Kinnier Wilson (1940) described transmission among husband and wife, nurse and patient, soldiers in adjoining beds, and mother and infant. Additionally, there was a very well-known example of 12 cases of 22 residents with five fatalities that were observed in 2 weeks in a girls’ home in Derby, England (Symonds, 1921) and 28 within 20 days in a women’s asylum in Germany (Krause, 1922) The Derby example is very hard to dismiss because it was thoroughly investigated by Dr. A. Salusbury MacNalty who had done previous work on EL, and who had a distinguished medical career, becoming Chief Medical Officer for England in 1935. He did a complete epidemiologic investigation of the incident in which he excluded all other possible factors but contagion (MacNalty, 1919). Despite these reports, no contact transmission was documented among 1156 cases seen in Vienna (Hoff, 1924) or in 520 cases in Germany (Faßbender, 1921). The incubation time for EL was uncertain, but generally believed to be a minimum of 1 day to a maximum of
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2 months, with a typical range of 8–18 days and a mean of 10 days (Wilson, 1940). These data were determined by cases in which persons recently migrated from areas of high endemicity. No age was spared, but persons between the ages of 10 and 45 years were more commonly affected. Nearly 50% of cases occurred between the ages of 10 and 30 (Wilson, 1940). There was no overall sex predilection, although higher incidences of one sex or the other was described for various epidemics (Marlowe et al., 2011). Pregnancy bestowed an unfavorable course on the illness and transmission to both the fetus and newborn was described (von Economo, 1931; Wilson, 1940). In such cases abortion was typically the recommended course (Neal, 1942). Transient infection with influenza was proposed to result in an increased nasal mucous membrane permeability for the encephalitic virus (Eden and Yates, 1927). Contemporary studies of histocompatibility antigens in modern putative patients having suffered from von Economo’s encephalitis have failed to reveal any differences in phenotypic frequencies for human leukocyte antigen (HLA)-A, B, C, and DR antigens (Lees et al., 1982). Elizan and colleagues (1980) also found no difference in HLA typing in postencephalitic parkinsonism (PEP) patients.
ETIOLOGY The infectious disease hypothesis von Economo (1917a, b) in his initial paper reporting his Viennese experience speculated on the cause of the disease. He stated that initially he had considered a toxic process, such as sausage poisoning, because of the poor nutrition caused by the war. However, he noted the absence of gastrointestinal disturbances. Others later rejected this idea because there were typically only single cases of EL within households, some of the victims were exclusively breast-fed infants, and the disease was occurring worldwide, all of which cast doubt on an environmental etiologic agent (Matheson, 1929). von Economo also considered and dismissed poison gas and typhoid as causes. von Economo next rejected polio, because there was not a polio epidemic in Vienna at the time. And, finally, his patients had negative Wasserman tests, indicating that EL was not related to syphilis. von Economo (1917a, b) believed that the histologic findings suggested a single inflammatory process. Furthermore, he reported that in meningeal tissue from deceased patients, there were “coccus-like” formations. However, he was very reticent to accept these findings and requested that other physicians who had access to material from fatal EL cases send him brain samples so that these results could be verified.
748 J.R. BERGER AND J.A. VILENSKY In his second 1917 article on EL, von Economo Influenza A has always been of particular interest in (1917a, b) indicated that research at the Pathological light of the temporal relationship of the EL outbreak Institute had confirmed that a specific “infectious” virus and the influenza epidemic. von Economo (1917a, b) conwas the cause of EL. This claim was based on the sidered the possibility that EL was an influenzal encephapparent transmissibility of the disease via brain tissue alitis, primarily because encephalitis had been associated (unfiltered) from a deceased patient to a monkey. von with earlier influenza epidemics. von Economo believed Economo further stated that a Gram-positive Diplosthat the synchrony in the seasonality of the two conditions treptoccocus was the specific cause of the disease supported the view that they were related, and also stated because it resulted in EL symptoms when injected into that he had seen many “grippe” cases in Vienna. Furthera monkey. During the epidemic period there was a masmore, he stated that most of the EL cases had begun with sive search for the putative organism that was causing feelings of a cold, headache, general malaise, and possibly EL (Matheson, 1929). Tissues (typically brain) and fluids joint pain. In his 1929 monograph on EL, von Economo (cerebrospinal fluid (CSF), blood, and nasopharyngeal devoted an entire section to this question: Influenza, influwashings) from EL victims were injected into the brains enza encephalitis and EL. He noted that the neuropatholof a large variety of animal species (especially rabbits) in ogy of EL is different from that of influenza encephalitis attempts to develop an animal model of the disease and (patients who died from influenza may show some capilisolate the causative agent – either bacteria that could be lary hemorrhages in the brain but not the inflammatory cultured or a “filterable” virus that could pass through processes evident in EL (cf. below)). However, he also the smallest pores of available filters, although viruses indicated that, despite this difference, it would be equally were not actually identified as structures until 1935 futile to deny any epidemiologic connection between EL with the invention of the electron microscope. Among and influenza. “A connection is obvious not only from the the more prominent etiologies proposed contemporecrudescence of the encephalitis epidemics in the wake raneously with the epidemic were those of alleging the of the influenza pandemic of 1918–21 and its simultacausative agent was herpes (Levaditi and Harvier, neous subsidence in the years 1922–25, but also from 1920; Levaditi et al., 1921a, b) or streptococcus. Levaditi historical considerations” (von Economo, 1929). Similar and colleagues claimed to be able to produce keratoto von Economo, some other clinicians of the time conjunctivis and encephalitis in rabbits that they attribbelieved influenza might “predispose to infection with uted to a herpes infection in samples, particularly the virus of EL” (Wilson-Smith, 1920; Symonds, 1921; saliva, from patients with EL. Rosenow injected dead Flexner, 1923; Kramer, 1924). A putative association Streptococcus viridans that had been cultured from between influenza and EL was hardly universally mainthe oropharnynx and nasopharynx of a patients with tained. A.J. Hall, a contemporary physician, stated: EL into rabbit brains and observed features that resemWhen the first series of cases came under our bled PEP (Rosenow, 1922; Claassen and Boes, 2009). observation in the Sheffield district in March These observations led to the development of vaccines 1918, many possible explanations were considdesigned to treat EL (Louis, 2002). ered and discussed; but amongst them influenza Van Rooyen and Rhodes, in their 1948 textbook, was never thought of or suggested by any who Virus Diseases of Man, said of the EL bacterial work: saw this series of extraordinary cases. If there is Many [of the investigators] were undoubtedly a connection between epidemic encephalitis and working with contaminants which either gained influenza, it is unusually well concealed from access during the postmortem in the case of the the clinician (Hall, 1918). brain, or else were present in the nasopharynx More recently, data and articles have appeared that have quite apart from the encephalitis. Certain workers both supported and refuted the influenza etiology, but were also unaware of the existence of spontaneous the preponderance of recent studies suggests that an encephalitis of rabbits (p. 1072). active influenza brainstem encephalitis was not causal. On the viral experiments, they commented: “The experiRavenholt and Foege, in 1982, described two sets of epiments were usually very inconclusive, however, and no demiologic data supportive of the idea that influenza did recognized strain of virus emerged. The effects noted cause EL. For Seattle, Washington, from 1918 to 1926, were probably in the main nonspecific, or else due to an they reported that peaks in influenza deaths occurred unrecognized bacterial contaminant or to spontaneous consistently about 1 year prior to peaks in EL deaths. encephalitis” (p. 1073). And, they also said of the work Based on this correlation they postulated a common etiproposing EL to be a herpes viral infection, “In general, ology. However, although the monthly mortality for however, herpetic encephalitis, as it is presently observed, influenza during 1918–1919 reached 400, the maximum appears not to resemble EL very closely” (p. 1073). number of deaths per month for EL was 8 – so accepting
ENCEPHALITIS LETHARGICA (VON ECONOMO’S ENCEPHALITIS) similar etiology would seem to be unjustified. Reid and colleagues (2001) were also highly critical of these data, stating that the pattern reported for Seattle was not observed globally and that all the Ravenholt and Foege data show are that both diseases peaked in late winter. Ravenholt and Foege’s (1982) second set of data is from Samoa. In Western Samoa, after the importation of the influenza virus there from passengers on a ship on November 7, 1918, approximately 20% of the population died from influenza and there were many reports of EL, which had not been found previously to have been present there. In contrast, American Samoa (just 70 km away), which maintained a strict quarantine, did not have any cases of influenza or EL. However, the validity of the data is very hard to assess. For example, Ravenholt and Foege viewed deaths between 1919 and 1922 due to fa-aniniva (interpreted as fatal diseases of the head) as being due to EL, but clearly this is a post hoc diagnosis. Furthermore, it may simply suggest that the causative agents of each of these illnesses were concurrently prevented from entering American Samoa. Importantly, no other study has replicated these findings. Modern experimental studies pertaining to the influenza hypothesis were thoroughly reviewed by McCall and colleagues (2008). These studies (Table 37.1) can be divided by type: (1) serology – examined antibodies against influenza present in the serum of PEP patients; Table 37.1 Experimental studies of the influenza hypothesis for encephalitis lethargica (EL) Study
Conclusions
Gamboa et al. (1974)
Influenza antigens detected in hypothalamus and midbrain in 6 PEP but no PD patients No difference between 23 PEP and 421 PD controls for antibodies to influenza strain PR/8/34 No difference between 20 PEP and 55 PD and controls in antibodies to strains PR/8/24 and Sw/1976 Negative immunostains for several flu strains in 1 acute EL and 1 PEP brain No influenza RNA in 7 PEP patients
Marttila et al. (1977a) Marttila et al. (1977b) Elizan et al. (1989) Isocson et al. (1995) McCall et al. (2001) Lo et al. (2003)
mRNA of b2-microglobulin but not influenza in brains of EL and PEP patients mRNA of b-actin but not influenza in 8 EL brains
Modified from McCall et al. (2008). PEP, postencephalitic parkinsonism; PD, Parkinson’s disease.
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(2) reverse transcriptase polymerase chain reaction (RT-PCR) – tests for influenza viral RNA in preserved EL and PEP patient brain tissue samples; and (3) antigen (immunohistochemistry) – utilizing anti-influenza antibodies to search for influenza proteins still present in brain tissue samples. Despite the strong apparent weight of the findings against the influenza hypothesis (all but one of the seven reviewed studies dating from 1977 to 2003 reported negative results), these investigators noted the studies are all limited by the extreme rarity of acute EL material and by the difficulty of retrospective confirmatory diagnosis of acute EL. Furthermore, they also described a possible flaw in the RT-PCR studies associated with primer mismatch due to influenza viral mutation between 1918 and the later sequences, against which primers were designed. The authors also questioned whether any viral segments originally presented in the EL tissue samples might have undergone autolysis because of the lack of refrigeration in morgues at the time. Lastly, McCall and colleagues (2008) noted that it is impossible to prove a negative and that influenza causation would provide a convenient explanation for EL’s disappearance, because the 1918-like influenza strains ceased human circulation some time before 1933, when the first human influenza strain was reconstructed from archival material by Taubenberger (2006). Empiric studies provide little support of an influenza etiology, but technical limitations and the shortage of appropriate material for testing limit the degree of confidence. Therefore, unless another cause of classical EL is positively identified, its return in the context of another influenza pandemic remains formally possible. In a rodent model, studies by Takahashi and colleagues (1995) demonstrated that a neurovirulent form of influenza localizes selectively in the ventral substantia nigra and hippocampus.
The autoimmune hypothesis In 2004, Dale and colleagues described 20 patients with an EL-like phenotype, all of whom had had a preceding pharyngitis. In contradistinction to the studies cited above in which archival material or actual patients with PEP were studied, these patients had sporadic disease in the modern age. The authors investigated the possibility that EL could be a postinfectious autoimmune central nervous system (CNS) disorder with an etiology similar to that of Sydenham’s chorea. Sixty-five percent of the cases had elevated antistreptolysin-O titers and 95% had autoantibodies reactive against basal ganglia antibodies in their CSF; such antibodies were only present in 2–4% of a control group. The authors thus hypothesized that EL may be secondary to autoimmunity against deep gray nuclei and may be a pediatric autoimmune
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neuropsychiatric disorder associated with streptococcal infection (PANDAS) disease. In 2009, Lopez-Alberola et al. described seven new cases of putative EL, four of whom also had elevated antibasal ganglia antibodies in their CSF, but only one of whom had a positive streptococcal serology. However, fluorodeoxyglucose positron emission tomography (FDG-PET) studies identified abnormal patterns of cerebral metabolism in 4/7 patients, with the most frequent pattern being an increased glucose metabolism in the basal ganglia. Vincent’s editorial accompanying the publication of the Dale paper highlighted some problems pertaining to the hypothesis that EL is a PANDAS disease (Vincent, 2004). She began by suggesting that the acute “fulminating” form of EL that was evident during the epidemic period is no longer manifested in the sporadic cases that still occur. She noted that 60% of Dale et al.’s patients did not have magnetic resonance imaging to document basal ganglia disease, and 35% did not have antistreptolysin-O elevation. Furthermore, the putative antibasal ganglia antibodies detected were not proven to cross-react with streptococcal antigens, and they varied in specificity among patients, suggesting that they might be secondary to an immune condition rather than causative. In addition, PANDAS, by definition, must have a pediatric onset, but 3 of Dale’s original patients were above age 35 and EL during the epidemic period was never considered a pediatric disease. Interestingly, in a 2009 report, Dale and colleagues seemed to rescind the PANDA theory on EL and suggested instead that at least the hyperkinetic form of EL was due to the development of autoantibodies to the extracellular domain of NR1/NR2 subunits of the N-methyl-D-aspartate receptor (NMDAR-Ab). Sera from 10 (50%) of 20 pediatric patients with putative EL were found to be NMDAR-Ab-positive with dyskinesias, parkinsonism, and somnolence. The authors noted some recent studies that have identified EL-like features in young females with ovarian teratomas who also were serum- and CSF-positive for NMDAR-Ab. They concluded that the dyskinetic (hyperkinetic) form of EL may be an NMDAR-Ab encephalitis that can affect very young children (Dale et al., 2009). As with the PANDA hypothesis, this one is also open to question. For example, does the Dale study (Dale et al., 2009) imply that the different forms of EL had different etiologies? Did adults who had the hyperkinetic form of EL also have NMDAR-Ab encephalitis? Despite the apparent inconsistencies, it is important to emphasize that these ideas for the etiology of EL were presented as hypotheses, which represent the first new frameworks within which to view this syndrome almost since the epidemic period. Thus, in that sense, they make a very significant contribution to the EL literature.
CLINICAL ILLNESS Acute encephalitis lethargica (EL) In 1921, H. F. Smith, working for the US Public Health Service, defined epidemic encephalitis as: an epidemic syndrome characterized in most instances by a gradual onset with headache, vertigo, disturbances of vision, ocular palsies, changes in speech, dysphagia, marked asthenia, fever (usually of a low grade), obstinate constipation, incontinence of urine, a peculiar mask-like expression of the face, and a state of lethargy which gradually develops in the majority of the recognized cases into a coma that is more or less profound (p. 207) (Fig. 37.2). If EL was repeatedly described as fitting the above description, then many of the diagnostic ambiguities associated with the disease would not have occurred. Among the approximately 9000 publications on EL from the entire epidemic period, however, many described the symptomatology but few were in agreement as to the most reliable signs and symptoms associated with the disease (Peng, 1993). The signs/symptoms that were linked with acute EL in these many articles include virtually every neurologic sign and symptom described in neurology textbooks. This variability in diagnostic criteria was explained during the period by suggesting that in different geographic/temporal epidemics, different signs/symptoms predominated and that there were great day-today (hour-to-hour) shifts in the symptomatology, and by suggesting that the variability was associated with different areas of CNS injury by the same agent. Nevertheless, it is difficult for a contemporary clinician to appreciate why,
Fig. 37.2. Enacephalitis lethargica symptomatology. (Reproduced from Smith, 1921.)
ENCEPHALITIS LETHARGICA (VON ECONOMO’S ENCEPHALITIS) 751 with this variability, the clinicians of the period ascribed a and juvenile (Vilensky and Gilman, 2011). von Economo unifying designation to the syndrome. Most likely, there classified the chronic forms as either parkinsonian appeared to be an emphasis on sleep and ocular muscle or other. disorders, and also that the described symptoms and signs The somnolent-ophthalmoplegic form typically exhibited together, did not fit any other established neurodeveloped soon after prodromal symptoms. Patients logic condition. Crafts (1927) stated it as follows: were described as dazed and confused, with their somnolence and deliria being unrelated to temperature elevaAnd while no other disease, perhaps, presents so tions. They exhibited features of mild meningeal many difficulties in diagnosis as does this protean irritation characterized by stiff neck, Brudzinski´s and complex, the fact must always be borne in mind, Kernig’s sign, pain on eyeball compression, diplopia, that while it usually offers a very close resemand ptosis. Other features include frequent yawning, blance to one or another condition, careful and trismus, and singultus, and, occasionally, cranial nerve painstaking study and comparison will reveal palsies with weak phonation and dysphagia, vertigo, either some incongruity, some essential symptom and limb weakness. Pupillary abnormalities were lacking or a superabundance of elements, thus observed, including the frequent absent of accommodaoffering a definite aid or conclusive basis for tion. Less commonly, supranuclear palsies occurred (von differential diagnosis (p. 60). Economo, 1931). In his description of this form of the illThus, indistinct clinical observations were used to make ness, von Economo recorded that “It is frequently seen a diagnosis of EL because at the time there simply were that a patient cannot properly lift his arm or leg, or that no definitive laboratory tests to confirm a diagnosis. his grasp is weak, and the muscles markedly hypotonic The earliest clinical features of the illness were very . . . This lack of tonus is frequently shown by the inability non-descript and included extreme malaise, low-grade of patients to rise up or sit down; they therefore assume fever, mild pharyngitis, ptosis, diplopia, shivering, heada huddled position and tend to gravitate to one side.” ache, vertigo, and vomiting. However, neurologic manKinnier Wilson described a patient thusly, “A lady found ifestations could also present very quickly. Kinnier her shopping hindered by an overwhelming desire for Wilson described one case in which rapidly evolving neusleep; she would rush home to throw herself on a couch rologic disease developed thusly: in the hall (not even waiting to go up to her bedroom) and sink at once into deep slumber continuing for hours. The first case I ever saw was that of a girl who, Within 4 years, Parkinsonism occurred” (Wilson, walking home from a concert, suddenly felt an 1940). He described a 12-year-old girl who had recently acute pain in the head and at the same moment had a violent illness in the following fashion, “Once, her left arm flopped and left leg gave way; at tea, she was in the act of putting a piece of toast in within half an hour she was asleep, showing her mouth when her eyes closed and the hand was kept contracted pupils, divergent squint, and left hemiimmobile, the bread touching her lip for several plegia; sinking deeper into lethargy, temperatures minutes” (Wilson, 1940). Although lethargy was an to 105.8 and death supervening in 12 days important sign, the patients also could be easily awak(Wilson, 1940). ened and were often aware of all that had transpired The illness assumed several relatively distinct forms in around them. referred to as pseudosomnolence or false its acute and chronic phases. sleep (Vilensky and Gilman, 2011). To facilitate diagnosis within EL’s vast array of Whereas the mortality of the somnolentsymptoms, some clinicians from the period divided the ophthalmoplegic form of the illness was higher than disease into temporal stages (typically acute and chronic) other forms, exceeding 50%, a greater number of surand symptom-based types (forms). von Economo (1929) vivors experienced few or no sequelae than followed classified the acute manifestations into three categories, other forms. von Economo related this form of the the somnolent-ophthalmoplegic form, the hyperkinetic disorder to lesions of the posterior wall of the third venform, and the amyostatic-akinetic form. As the epidemic tricle near the oculomotor nucleus. In contrast, the period progressed and EL became associated with virtuinsomnia seen in the other forms was linked to a ally every possible neurologic sign and symptom, many lesion in the lateral wall of the third ventricle near the other types were identified, such as: psychiatric, aborcorpus striatum that was suggested to exert an inhibitive, cerebellar, hemiplegic, cortical, spinal, polyneuritic, tory function on the cerebrum and thalamus (Von cataleptic, meningeal, anterior poliomyelitic, hyperalgeEconomo, 1930). sic, general, infantile, progressive, aberrant/autonomic, The hyperkinetic form was characterized by an initial monosymptomatic, tabetic, insomnia, paralytic, myeltic, hypomaniacal excitement followed by general prostrapallido-pyramidal., mixed striatal, myoclonic, thalamic, tion, pallor and rapid failure of strength, violent neuralgic
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pains in face and limbs, visual and tactile hallucinations, and sleep reversal or inversion. During the manic phase vocalizations included singing, shouting, and whistling. Examination revealed pupillary abnormalities, including unreactive and Argyll Robertson pupils, chorea that may be either unilateral or bilateral, peculiar torsions and myorrhythmias, trismus and similar involvement of orbital muscles, and myoclonic twitches that were shortlived and either non-rhythmic or rhythmic (Riddoch, 1927). Str€ umpel (1920) described the myoclonus in one of his patients as: “extremely painful, mainly localized in the abdomen . . . even after the myoclonus stopped the patients complained about some weird deep pain and about hurtful paresthesias in their extremities and body.” Sudden death might supervene (von Economo, 1931). Among the first-hand descriptions of patients afflicted with this disorder is the following by Kinnier Wilson in his 1940 textbook: The patient tosses about in bed, pushes the blankets back, pulls them up again, sits up, throws himself back again in a wild sort of haste, jumps out of bed, strikes out aimlessly, talks incoherently, clucks his tongue, and whistles, this unrest lasting for days and nights without stop. The least common of the three forms proposed by von Economo for acute illness was the amyostatic-akinetic form. This form was characterized by peculiar rigidity and a lack of movements in the absence of real weakness. It was said that “movement is arrested soon after its inception due to lack of impulse.” There were typically no corticospinal tract findings. The slowness and paucity of movement are striking and patients do not alter their body position spontaneously. When addressed, their eyes might turn to the examiner but not their heads. Flexibitas cerea might develop. The emotions were hardly noticeable, although the patients were mentally intact with normal comprehension. The examination revealed muscle rigidity, normal tendon reflexes, often a peculiar bent posture when standing, and vasomotor disturbances, e.g., edema, skin exfoliation, sleep disturbances, including somnolence, insomnia, and sleep inversion. This condition might last months and could have either a slow or rapid recovery. Str€ umpel (1920) described one of his patients: “absolutely still in bed, eyes are wide open . . . their mind stays absolutely clear . . . complete lack of initiation of movements or speech . . . muscle rigidity, arms in interosseus position . . . patients sometimes keep arms lifted for a very long time.” In children, the psychiatric effects were often as severe as the physical consequences. Approximately one-third of affected children underwent a rapid transformation from normal behavior to delinquency, often
leading to institutionalization. Many neurologic and psychologic theories were proposed to explain these severe behavioral changes, and the therapeutic approaches employed ranged from training in dedicated schools to frontal leukotomy (Vilensky et al., 2007). During the acute illness blood leukocytosis could range up to 25 000–30 000 cells/mm3, but the leukocytosis was generally quite mild, 10–12 000 cells/mm3 (Howell, 1925). CSF analysis typically revealed a moderate increase in opening pressure, although von Economo (1917a, b) also noted that, despite persistent somnolence or other deficits, opening pressure returned to normal after couple of weeks. The CSF (Howell, 1925) was almost always clear and colorless with a moderate pleocytosis
