Kornelia Tyrakowska, Natalia Hajduk, Przemysław Talik

The elusive etiology of encephalitis lethargica: autoimmune mechanisms, viral hypotheses, and lessons from historical and contemporary evidence

2026-09-09

Background. Encephalitis lethargica (EL) remains one of the most enigmatic neurological disorders of the twentieth century. First comprehensively described in 1917 by Constantin von Economo, it is characterized by acute onset of fever, impaired consciousness, profound somnolence or coma, hallucinations, seizures, and a wide spectrum of focal neurological deficits. The marked clinical heterogeneity of the disease has historically complicated its nosological classification and differential diagnosis from other inflammatory and neurodegenerative conditions. Contemporary cases resembling EL (EL-like syndromes) more frequently present features consistent with autoimmune encephalitis.

Objectives. This article provides an integrative, clinically oriented review of historical EL and contemporary EL-like syndromes, synthesizing classical historical observations with contemporary neuropathological and immunological evidence. Particular emphasis is placed on the transition from the acute encephalitic phase to the chronic stage dominated by postencephalitic parkinsonism (PEP).

Materials and methods. A narrative review was conducted of the historical and contemporary literature on encephalitis lethargica and EL-like syndromes, focusing on its etiology, clinical features, neuropathology, and treatment.

Results. Despite a clear temporal association with the 1918–1920 influenza pandemic, the etiology of historical EL remains unresolved. Competing hypotheses include direct viral neurotropism, autoimmune mechanisms, and post-infectious immune-mediated processes. Observational evidence is consistent with a post-infectious autoimmune model, in which an aberrant immune response targets structures within the basal ganglia and related circuits. This framework aligns with pathogenic mechanisms observed in other post-infectious neuroimmunological disorders. However, the quality of available clinical evidence remains limited, and the autoimmune hypothesis should be regarded as provisional.

Conclusions. The proposed autoimmune paradigm, if confirmed, would have important implications for the diagnosis and management of contemporary EL-like syndromes. Early recognition and consideration of immunomodulatory therapy may improve outcomes and reduce long-term neurological sequelae in selected patients, although high-quality controlled trials are lacking. Symptomatic treatment remains crucial, particularly in the chronic phase. EL and EL-like syndromes should be viewed not merely as a historical curiosity but as a valuable model for understanding contemporary post-infectious and autoimmune neuropsychiatric disorders.

Keywords: PEP, encephalitis lethargica, von Economo’s disease, Constantin von Economo, postencephalitic parkinsonism, EL-like syndromes.

© Farm Pol, 2026, 82(3): 151–158