Clinical manifestations

Presentation and course

Encephalitis lethargica is a highly polymorphic disease that tends to appear in epidemic outbreaks, with signs and symptoms fluctuating to some degree from one epidemic to another. The most common prodromal symptoms are headache, slight sore throat, chilly sensations, general weakness, and mild gastrointestinal disturbances. The most prominent signs are lethargy, sleepiness, or stupor both at the onset and through at least the early stages of the disease. This lethargy may be more apparent than real, however, as the patient is conscious of passing stimuli and, once aroused, immediately becomes alert and sensible (“false sleep” or “pseudo somnolence”). In contrast, the patient may exhibit insomnia, alone or alternating with somnolence. Sometimes, patients exhibit delirium. Paralyses or pareses, most often associated with the cranial nerves, result in oculomotor abnormalities (eg, diplopia, ptosis, accommodation paralysis, sluggish pupils, strabismus, nystagmus), facial paralyses, masticatory paralyses, dysphagia, or dysarthria, and occasionally there are paralyses of the trunk or limbs. Some patients develop parkinsonian rigidity, catatonic stupor, and catalepsy. Other patients show hyperkinetic phenomena, including myoclonias, “fascicular twitchings,” epileptiform convulsions, choreic movements, and maniacal states. Some patients experience sensory disturbances, including pain (eg, headache, facial, muscular). Isolated cases of a cerebellar type of ataxia have been reported. The CSF is generally normal or has a slightly increased cell count (05; 70).

The mortality rates for encephalitis lethargica varied greatly with time and geography. Between 1919 and 1927, in New York City and England, the annual rate varied from 29% to 75%. Although encephalitis lethargica was typically not considered to be contagious, there were some well-researched instances in which the condition did appear to spread from person to person (58).

Encephalitis lethargica could also be complicated by severe changes in behavior, particularly in children.

Von Economo said of children with encephalitic lethargica in his 1931 monograph, “We see here how organic encephalitic lesions may produce in previously normal individuals a strange alteration of personality, which cannot be otherwise described than as a kind of moral insanity or erethic imbecility.” Von Economo continued to note that these children “annoy strangers on the street, pluck their clothing, make faces at them or abuse them; they tramp, beg, lie, steal, write on the walls, squander all the money they can lay hands on in sweets, cannot be controlled at school, run away from home and spend their time at the cinema and in the streets, indulge in sexual misbehaviour of every kind and make other dangerous acts” (68). Except in the very young, there was no deterioration of intellect (10). The pejorative term “Apache” was used to characterize these children, referring to the wild behavior attributed to Apache Indians (26). Hill estimated that, whereas 70% of pediatric encephalitic lethargica survivors showed some psychological changes, approximately one third exhibited behavioral disorders (28). In the acute phase, encephalitis lethargica was characterized by intractable somnolence, which was then attributed to abnormalities of the diencephalon. This indicated that sleep mechanisms are localized in the subcortical brain (37).

Encephalitis lethargica was often complicated by lingering or permanent somatic or psychological sequelae, the most serious of which was postencephalitic parkinsonism (22). Postencephalitic parkinsonism could develop within a short time of the original episode, after a number of symptomatic changes, or even months or years (in some cases many years) after symptoms have purportedly disappeared. The hallmark features of postencephalitic parkinsonism comprise rigidity, tremor, dysarthria, flexed postures, and masked facies (70). The best differentiators of postencephalitic parkinsonism from idiopathic parkinsonism are onset below middle age, symptoms lasting more than 10 years, presence of oculogyric crises, and palilalia (29; 34).

Other features that Hoehn and Yahr considered uncommon in the idiopathic form but common in postencephalitic parkinsonism include oculomotor and other cranial nerve palsies, pyramidal tract signs, dystonic phenomena, sleep disturbances, personality changes, and autonomic dysfunction (29).

The presumptive direct relationship between encephalitis lethargica and postencephalitic parkinsonism has been questioned (58; 59). These authors noted that careful analysis of the historical data indicated that many (perhaps, the majority) of persons with postencephalitic parkinsonism did not have a prior well-defined encephalitic disease but often had had a condition (eg, influenza) that was diagnosed post hoc as encephalitis lethargica. Based on these data, it has been thought that the relationship between encephalitis lethargica and parkinsonism is more complex than perceived, ie, that encephalitis lethargica alone was not responsible for the subsequent development of parkinsonism.

Prognosis and complications

Whereas some patients appear to show a complete recovery, others show persisting somatic impairments (eg, movement disorders) or psychological impairments (eg, behavioral disorders, especially in children). Postencephalitic parkinsonism was believed to be a sequel in up to 80% of affected individuals (22).

Clinical vignette

One of the most well-known cases of encephalitis lethargica was that of Patricia Maguire, who was also known as Oak Park’s (Illinois) “sleeping beauty.” In January 1932, 27-year-old Patricia began feeling increasingly drowsy each day. After falling asleep on a train, she returned home and slumbered fitfully for 9 days and then, on February 24, became comatose. After about a year and a half, she began to show signs of consciousness with open eyes, alert expressions, and the ability to respond to simple commands, although her eyes did not respond to light, and she could not speak. Unfortunately, these positive signs did not last, and she again became comatose. Maguire died of pneumonia in 1937. Her brain was removed after death and revealed an atrophied frontal lobe, which was believed to confirm a diagnosis of encephalitis lethargica.

Although no good images of Patricia Maguire are available, there are many still and moving images of patients with encephalitis lethargica (64). German neuropsychiatrists Karl Kleist and Ernst Herz made a detailed film (13 minutes) of one young patient, and a segment of that film is available here.

Biological basis

Etiology and pathogenesis

At the time of the epidemic, various bacterial or viral causes were proposed for the condition, but no definitive findings were reached. There has been extensive debate about a possible role of the “Spanish” H1N1 influenza A pandemic virus in the development of encephalitis lethargica (52). Modern efforts to demonstrate influenza RNA segments in the brains of encephalitis lethargica victims, however, have not been successful (39; 35). Nevertheless, these results are far from conclusive, so there remains a possibility that a recurrence of bird-based influenza will result in a recurrence of encephalitis lethargica (40; 38), which advocates that influenza did cause encephalitis lethargica. Foley exhaustively examined the historical record pertaining to the relationship between encephalitis lethargica and influenza and concluded that, whereas any individual feature of encephalitis lethargica could be found in influenza, the combination of symptoms was unique, suggesting that encephalitis lethargica was not likely caused by influenza (24; 25; 19).

Although a viral etiology has always been suspected in postencephalitic parkinsonism, no definitive infectious agent has been isolated. Several case reports suggested that infection with atypical enterovirus can result in postencephalitic parkinsonism and a picture similar to encephalitis lethargica (01; 53). Evidence for encephalitis lethargica's autoimmune nature is also limited, suggesting it may have been a unique response to an unknown pathogen in genetically susceptible individuals. Contemporary autoimmune encephalomyelitis cases, though increasing, differ significantly from historical encephalitis lethargica in symptoms, epidemiology, and pathology (12).

In three cases, parkinsonism has been described following SARS-COV-19 infection. In these cases, a viral invasion of the brainstem, in these cases, has been speculated (14; 23; 42). However, the possibility of SARS-CoV-2 causing an encephalitis lethargica-like state remains speculative (04; 27). Morassi and colleagues described two isolated cases of SARS-CoV-2-related encephalitis with prominent parkinsonism (43). FDG-PET/CT findings in these patients were consistent with postencephalitic parkinsonism. FDG-PET/CT demonstrated the presence of cortical hypometabolism along with hypermetabolism in the regions of the brainstem, mesial temporal lobes, and basal ganglia.

Dale and colleagues attempted to determine the cause of encephalitis lethargica by identifying 20 new cases of encephalitis lethargica in England between 1999 and 2002; 11 of the patients had preceding pharyngitis (16). They then investigated the possibility that the patients’ phenotype could be a postinfectious autoimmune CNS disorder, similar in that respect to Sydenham chorea. Western immunoblotting showed that 19 of the patients had autoantibodies reactive against human basal ganglia antigens. The authors concluded that an encephalitis lethargica-like syndrome is still prevalent and that encephalitis lethargica may be secondary to autoimmunity against deep gray matter neurons resulting from a prior group A Streptococcus infection (ie, a PANDAS disease) (16). The conclusions of Dale and colleagues were then questioned in a 2004 editorial in Brain, which noted that only a minority of the cases had two of the more diagnostic signs of encephalitis lethargica: ophthalmoplegia and oculogyric crises (66). Additional criticism can be found in a study by Singer and colleagues, who took serum from patients in three groups (patients with PANDAS, patients with Tourette syndrome, and age-matched controls). ELISA and Western blots against crude soluble extracts of postmortem brain regions and Western blots against putative antigens were performed. Antibodies were found for all groups, but there were no differences in antibody frequencies between patient groups and controls (48). According to Vernino, these results cast doubt on the role of neurologic antibodies in these pediatric neuropsychiatric movement disorders but do not exclude an immune-mediated (or even antibody-mediated) etiology for these diseases (and presumably for encephalitis lethargica) (57).

In a report, Dale and colleagues seemed to rescind the PANDA theory and suggested instead that at least the dyskinetic form of encephalitis lethargica may be due to the development of autoantibodies to the extracellular domain of NR1/NR2 subunits of the N-methyl-D-aspartate receptor (NMDAR-Ab) (17). Sera from 10 of 20 pediatric patients with putative encephalitis lethargica was found to be NMDAR-Ab positive with dyskinesias, insomnia, and seizures. The authors referred to studies that have identified encephalitis lethargica-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 encephalitis lethargica is an NMDAR-Ab encephalitis that can affect very young children.

It is unclear whether the findings of Dale and colleagues (17) mean that the different forms of encephalitis lethargica had different etiologies (eg, the dyskinetic form had a different cause than the lethargic form), a hypothesis supported in a book about encephalitis lethargica (59). Since the 2009 report by Dale and colleagues, other case studies have appeared supporting a relationship between the dyskinetic (hyperkinetic) form of encephalitis lethargica and NMDAR-Ab encephalitis (45; 51).

This summary of the pathology of encephalitis lethargica is based primarily on the 1921 review of encephalitis lethargica by CP Symonds, a prominent British neurologist (50). The described pathology is only for encephalitis lethargica; the pathology associated with postencephalitic parkinsonism is not described here; for that, see (54; 32).

The gross fresh brain of an encephalitis lethargica victim shows little abnormality beyond congestion of the meningeal and intracerebral capillaries. This congestion causes the brain to be reddish in color in cross-section, and the cut vessels are widely open and oozing bright blood.

Microscopic examination of the preserved brain indicates that the most important features are vascular congestion, signs of toxic degeneration of neurons and neuronophagia, proliferation of vessel wall cells, infiltration of the perivascular (Virchow-Robin) spaces with small round cells, and glial proliferation. Degenerative loss of neurons in nuclei is variable; when present, the degenerating cells exhibit swelling and eccentricity of the nucleus, chromatolysis, and neuronophagia.

Symonds stressed that the brain of a patient who dies rapidly from encephalitis lethargica might show little pathology, perhaps only vascular congestion. Symonds accounted for this observation by noting that cellular function may be lost before any visible structural alterations. He also reported that the distribution of lesions varies greatly from patient to patient, although more lesions appear within the midbrain and basal ganglia than elsewhere. Others, however, indicated that cortical damage was frequent and basal ganglia damage rather infrequent (06). Our own analysis of 112 acute cases from the epidemic period suggests that about 80% showed cortical damage, whereas only about 40% showed basal ganglia damage (03).

Epidemiology

Encephalitis lethargica was a widespread pandemic disease during the 1920s and into the 1930s. It may have lasted until the 1950s in the Soviet Union (65). Sporadic case reports continue to appear (16; 20; 41; 49; 11; 18; 46; 02; 55), although there is no assurance that these modern cases are, in fact, identical to the 1920s era cases.

Prevention

No information is available regarding the prevention of encephalitis lethargica. If encephalitis lethargica results from bird influenza, immunization against bird influenza could be preventative for encephalitis lethargica.

Differential diagnosis

Confusing conditions

Encephalitis lethargica was diagnosed based on the exclusion of other known neurologic diseases (see Table 1). Crafts wrote, “And while no other disease, perhaps, presents so many difficulties in diagnosis as does this protean complex…that while it usually offers very close resemblance to one or another condition, careful and painstaking study and comparison will reveal either some incongruity; some essential symptom lacking or a superabundance of elements, thus, offering a definite aid or conclusive basis for differential diagnosis” (15). Unfortunately, because encephalitis lethargica lacked any definitive sign, it is possible and perhaps likely that it was substantially overdiagnosed (26). This absence would also account for the abundance of “types” that came to be associated with the disease (60).

Oculogyric crises are also often cited in case reports of the disease, but this sign was not associated with the acute condition during the epidemic period; these crises are, however, associated with its presumptive sequel, postencephalitic parkinsonism (61).

Table 1. Diagnostic Criteria of Encephalitis Lethargica

Diagnostic workup

There are no diagnostic tests for encephalitis lethargica, so it remains a clinical diagnosis.

In two cases, MRI of the brain revealed signal abnormalities in the substantia nigra, thalamus, and hippocampus. Extensive subcortical white matter abnormalities in the frontal lobes have also been described in a case (71; 13).

Management

During the epidemic period, many different treatments for encephalitis lethargica were used, and in New York, a large-scale effort supervised by the Matheson Commission was devoted to developing a vaccine to treat the disease (36). None of the treatments or vaccines proved to be efficacious. In 1997, two cases of the disease were described as responding rapidly and dramatically to intravenous methylprednisone (09). Other treatments include antibiotics, intravenous immunoglobulin therapy, and electroconvulsive therapy (18; 46; 02; 71; 13). In an isolated case report, a patient with postencephalitic parkinsonism, a disorder very close to encephalitis lethargica, responded well to a levodopa and carbidopa combination (08).

Special considerations

Pregnancy

There have been cases of the disease apparently passing from mother to newborn infant.