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  • Updated 03.03.2024
  • Released 12.08.2006
  • Expires For CME 03.03.2027

Encephalitis lethargica



Encephalitis lethargica was a mysterious epidemic disease of the 1920s and 1930s that was better known as the “sleepy” or “sleeping” sickness. Importantly, it was associated with the subsequent development of postencephalitic parkinsonism, a condition that was popularized in Oliver Sacks’ 1973 book, Awakenings, and the 1990 movie of the same name. Encephalitis lethargica evolved to have many manifestations other than a “lethargic type,” including types that were primarily characterized by insomnia or movement disorders. In the acute stage, encephalitis lethargica was characterized by intractable somnolence, which was then attributed to abnormalities of the diencephalon. Since then, anatomical localization of sleep has been focused on the subcortical brain. Differentiating points from idiopathic Parkinson disease include young age of onset, oculogyric crises, altered sleep-wake cycle, respiratory disturbances, and pyramidal signs. A variety of respiratory abnormalities were noted, particularly, unrelenting tachypnoea (panting) without air hunger and an inspiratory hold (fixés en inspiration forcée). These respiratory disorders, in fact, were considered hysterical in nature but later considered serious. Pathologically, there is diffuse involvement of gray matter of the brain dominantly, the diencephalon, and the mesencephalon. There has been extensive debate about the possible role of the “Spanish” H1N1 influenza A pandemic virus in the development of encephalitis lethargica, but this relationship has not yet been established. The role of the substantia nigra and intracellular inclusion bodies (Lewy bodies) in the pathogenesis of idiopathic Parkinson disease was based on observations of severe nigral pathology in encephalitis lethargica. Over a century later, the exact causes of encephalitis lethargica remain unknown, with debates on its autoimmune nature and significant differences between historical and recent cases. No definite treatment for encephalitis lethargica is available. The prognosis is variable. Many of the survivors had permanent neurologic sequelae, and some were completely akinetic.

Key points

• Encephalitis lethargica is an acute polio-encephalitis of largely unknown etiology.

• Encephalitis lethargica can only be diagnosed clinically.

• Oculogyric crises were not associated with acute cases during the epidemic period.

• Differentiating points from Parkinson disease are a young age of onset, oculogyric crises, altered sleep cycle, respiratory disturbances, and pyramidal signs.

• Putative cases have linked the hyperkinetic form of the condition with NMDAR-Ab encephalitis.

• Although no clear data link encephalitis lethargica with influenza, such a linkage is still supported by some data and some clinicians.

Historical note and terminology

On April 17, 1917, at a meeting of the Vienna Society for Psychiatry and Neurology, Dr. Constantin von Economo described a new disease, encephalitis lethargica (68). Shortly thereafter, von Economo published his first article on the disease (67). He described a series of cases in which the patients exhibited “a kind of sleeping sickness” with an unusually prolonged course. Headache and malaise were the first symptoms, followed by somnolence, often associated with delirium, from which the patient could be easily awakened. This state could rapidly lead to death or could persist for long periods, either progressing to coma or ending with recovery. These signs were generally accompanied by paralysis in some of the cranial nerves, especially those affecting the eye. Ptosis was a typical sign. Von Economo concluded that he believed the disease was an “encephalitis,” with the variability relating to variations in neural localization of the causative agent.

The disease then began appearing in increasing frequency throughout the world, with official figures showing peaks of about 10,000 cases in 1920 and 1924 (44), with a possible total mortality of 500,000 cases (47) during the entire epidemic period, which lasted until about 1940. Sporadic reports of encephalitis lethargica cases have continued to appear since then.

During the epidemic period, the signs and symptoms of the disease rapidly increased so that eventually 28 “types” were described, with signs and symptoms encompassing virtually every neurologic system (60), including some that were antithetical to von Economo’s original description (eg, an “insomnia” type). Kroker convincingly argued that curing encephalitis lethargica became the foremost aim of American neurology (especially New York City neurologists) during this period and that the secondary goal of this effort was to significantly increase the prominence and potential of American neurology (33). Thus, there may have been some political aspects to the large number of encephalitis lethargica diagnoses. This possible overdiagnosis was also noted during the epidemic period (26).

Wijdicks and Boes studied respiratory rhythm abnormalities reported in patients with epidemic encephalitis (encephalitis lethargica). The authors focused their extensive literature search on disorders of respiration rate, respiratory patterns, and respiratory tics. The respiratory abnormalities most frequently noted included unrelenting tachypnoea (panting) without air hunger and an inspiratory hold (fixés en inspiration forcée). These respiratory disorders, in fact, were previously considered hysterical in nature but later were considered serious. Wijdicks and Boes considered these respiratory disorders part of a parkinsonian syndrome and taught that these attacks could have been provoked by oxygen therapy (69).

Even after 100 years, many issues related to encephalitis lethargica remain elusive. Authors are still struggling to answer the questions: what causes it? How is this disease transmitted? Could an epidemic of encephalitis lethargica happen again? (30; 56). Encephalitis lethargica garnered attention for its impact on consciousness and a potential link to postencephalitic Parkinsonism. Although once considered sporadic, some reviews suggest it might be an autoimmune response to a viral agent, possibly a coronavirus. Historical epidemics like Russian influenza and Spanish flu showed similar neurologic symptoms. Interestingly, some COVID-19 cases present resemblances to encephalitis lethargica (21).

It is now being argued that the crucial involvement of the substantia nigra and the role of intracellular inclusion bodies (Lewy bodies) in the pathogenesis of idiopathic In fact, Parkinson disease may have originated from the finding of dominant nigral pathology in patients with encephalitis lethargica (31).

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