No Metagenomic Evidence of Causative Viral Pathogens in Postencephalitic Parkinsonism Following Encephalitis Lethargica

Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.

“You Are Older, although You Do Not Know That”: Time, Consciousness, and Memory in “A Kind of Alaska” by Harold Pinter (1930–2008)

<i>“A Kind of Alaska”</i> is a one-act play by the British playwright and Nobel Prize winner Harold Pinter (1930–2008), based on the book <i>Awakenings</i> by the neurologist Oliver Sacks (1933–2015). This play, first performed in 1982, is centered around the character of Deborah, a middle-aged woman, struck by <i>encephalitis lethargica</i> (“sleeping sickness”) at the age of 16, who wakes up after 29 years of apparent sleep following the injection of an unnamed drug. This article analyzes how Pinter’s drama investigated the mysterious and fascinating relationship between time, memory, and consciousness. The term “awakenings,” chosen by Sacks himself, clearly refers to the restoration of voluntary motor function in patients with postencephalitic parkinsonism who responded to levodopa. However, it also suggests that these patients had an impairment of awareness. Actually, beyond the acute phase, subjects with postencephalitic parkinsonism were not sleeping but severely akinetic and therefore probably aware of the passage of time. Oliver Sacks probably did not entirely recognize the intrinsic contradiction between prolonged sleep (with consequent impairment of awareness and subjective “time gap”) of the acute lethargic phase and the severe akinesia with preserved awareness of the time-passing characteristic of postencephalitic parkinsonism. This confusion was further compounded by Harold Pinter in his play.

Spotlight on Oculogyric Crisis: A Review

Background: Oculogyric crisis (OGC) is a form of acute dystonia characterized by sustained dystonic, conjugate, and upward deviation of the eyes. It was initially reported in patients with postencephalitic parkinsonism. But later, other factors such as medications, movement disorders, metabolic disorders, and focal brain lesions were also found to be associated with OGC. Methods: The literature regarding OGC was searched via PubMed, Google Scholar, and through citations in relevant articles till December 2019, with keywords including OGC, oculogyric eye movements, tonic eye movement, neuroleptics and OGC, antipsychotics and OGC, and all combinations of these. Only original articles (abstract or full text) that were published in the English language were reviewed. Results: Hypodopaminergic state is implicated in the pathogenesis of OGC. Common risk factors are younger age, male sex, severe illness, high neuroleptic dose, parenteral administration of neuroleptics, high potency of neuroleptic drugs, abrupt discontinuation of anticholinergic medication, and family history of dystonia. Conclusion: OGC is an acute dystonic reaction leading to tonic upward deviation of eyes. It is associated with various neurometabolic, neurodegenerative, and movement disorders and medications such as antipsychotics, antiemetics, antidepressants, antiepileptics, and antimalarials. OGC can adversely impact the compliance and prognosis of the primary illness. Hence, it needs to be managed at earlier stages with appropriate medication, primarily anticholinergics.

The centennial lesson of encephalitis lethargica

We commemorate the centenary of Constantin von Economo's description of encephalitis lethargica, a mysterious disease that had a significant effect on 20th-century neuroscience. In the acute phase, encephalitis lethargica was marked by intractable somnolence, which von Economo attributed to lesions in the diencephalon, thereby paving the way for future efforts to localize the regulation of sleep in the subcortical brain. At the same time, neuropathologic findings in postencephalitic parkinsonism affirmed the role of the substantia nigra in the pathophysiology of parkinsonism. The occurrence of psychiatric symptoms in patients with encephalitis lethargica—such as mood disorders, obsessive-compulsive behavior, and bradyphrenia—drew attention to the organic basis of mental illness.

Russell Meyers (1905–1999): pioneer of functional and ultrasonic neurosurgery

Advances in functional neurosurgery, including neuromodulation and more recently ultrasonic ablation of basal ganglia structures, have improved the quality of life for patients with debilitating movement disorders. What is little known, however, is that both of these neurosurgical advances, which remain on the cutting edge, have their origin in the pioneering work of Russell Meyers, whose contributions are documented in this paper. Meyers' published work and professional correspondence are reviewed, in addition to documents held by the Department of Neurosurgery at the University of Iowa. Meyers was born in Brooklyn, New York, and received his neurosurgical training at hospitals in New York City under Jefferson Browder. In 1939, a chance encounter with a young woman with damaged bilateral ventral striata convinced Meyers that the caudate could be resected to treat Parkinsonism without disrupting consciousness. Shortly thereafter, he performed the first caudate resection for postencephalitic Parkinsonism. In 1946, Meyers became the first chairman of neurosurgery at the State University of Iowa (now the University of Iowa), which led to the recruitment of 8 faculty members and the training of 18 residents during his tenure (1946–1963). Through collaboration with the Fry brothers at the University of Illinois, Meyers performed the first stereotactic ultrasonic ablations of deep brain structures to treat tremor, choreoathetosis, dystonia, intractable pain, and hypothalamic hamartoma. Meyers left academic neurosurgery in 1963 for reasons that are unclear, but he continued clinical neurosurgery work for several more years. Despite his early departure from academic medicine, Meyers' contributions to functional neurosurgery provided a lasting legacy that has improved the lives of many patients with movement disorders.