Herbis, non verbis, fiunt medicamenta vitae: The Italian botanist Arturo Nannizzi (1887-1961) and his contribution to the treatment of parkinsonism following encephalitis lethargica.

We describe the Italian contribution to the description and treatment of parkinsonism following encephalitis lethargica (EL): postencephalitic parkinsonism (PEP). Special attention is devoted to the description of postencephalitic symptoms by Giuseppe Panegrossi (1871-1953) and to the treatment based on Atropa belladonna introduced in Italy and extensively supported by Arturo Nannizzi (1887-1961), who was charged by the queen of Italy with conducting research into this plant and advocating its cultivation for healing purposes. This article gives us the unique opportunity to revisit the figure of this distinguished botanist, providing a summary of his biography, interests, and achievements.

Back to the future: encephalitis lethargica as an autoimmune disorder?

More than 100 years after its emergence, the exact pathophysiological mechanisms underlying encephalitis lethargica (EL) are still elusive and awaiting convincing and complete elucidation. This article summarizes arguments proposed over time to support or refute the hypothesis of EL as an autoimmune neuropsychiatric disorder triggered by an infectious process. It also provides a critical evaluation of modern cases labeled as EL and a comprehensive differential diagnosis of autoimmune neurological conditions that could mimic EL. The evidence supporting the autoimmune nature of historical EL is sparse and not entirely convincing. It is possible that autoimmune mechanisms were involved in the pathogenesis of this disease as an idiosyncratic response to a yet unidentified infectious agent in genetically predisposed individuals. Although there has been an increase in the incidence of presumed autoimmune encephalomyelitis since the peak of EL pandemics, most evidence does not support an underlying autoimmune mechanism. There are significant differences between historical and recent EL cases in terms of clinical symptomatology, epidemiology, and neuropathological features, suggesting that they are different entities with only superficial similarity. The term "encephalitis lethargica," still frequently used in the medical literature, should not be used for cases occurring at present in the sporadic form. Historical EL should be kept apart from recent EL, as they differ in important aspects.

Neuropsychiatric features of Parkinson's disease in the era prior to the use of dopaminergic therapies.

BACKGROUND: Psychosis in Parkinson's disease includes hallucinations and delusions. Other non-psychotic neuropsychiatric features include depression, anxiety and apathy. There is currently controversy over whether psychosis in Parkinson's is an intrinsic part of the disorder or the result of dopaminergic medications. This study aimed to examine a historical cohort of individuals with Parkinson's prior to the use of dopaminergic therapy to assess the prevalence of psychotic and other neuropsychiatric features. METHODS: The case notes of patients with Parkinson's disease admitted to the National Hospital for Neurology and Neurosurgery, London between 1924 and 1946 were examined. Demographic and clinical variables were extracted along with any neuropsychiatric features. Cases meeting criteria for encephalitis lethargica were excluded. RESULTS: 115 cases of individuals with Parkinson's disease were identified. 58 (41.7%) were female. Mean age was 54.0 (SD 9.6) years and mean time since Parkinson's diagnosis was 5.3 (SD 5.7) years. No individuals met criteria for encephalitis lethargica. No cases of hallucinations or delusions were reported. There was one case of an illusion in a patient who was using anticholinergic medication. Other neuropsychiatric features reported were sleep disorder (present in 10, 8.7%), depression (8, 7.0%), memory impairment (5, 4.3%), impulsivity (4, 3.5%), bradyphrenia (4, 3.5%), impaired attention (3, 2.6%), anxiety (1, 0.9%), fatigue (1, 0.9%) and apathy (1, 0.9%). CONCLUSIONS: Prior to the use of dopaminergic therapies, patients with Parkinson's disease admitted to hospital rarely, if ever, reported psychotic symptoms, although other neuropsychiatric symptoms were more prevalent. The main limitation is that a lack of systematic enquiry about psychotic symptoms may have resulted in underreporting.

Encephalitis lethargica. What is still wrong?

Encephalitis lethargica developed in epidemic from 1919 to 1926 in Europe and throughout the world. From the clinical point of view, the disturbances of consciousness and alertness and the possible outcomes of a postencephalitic Parkinsonism has attracted much attention. For a long time, it was thought that such a disease may still occur sporadically. In this review, the authors examined historical and current pictures of epidemics that may be related to Encephalitis lethargica. The previous Nona and Russian Influenza exhibited frequent neurological symptoms. The Spanish flu, formerly related to Encephalitis lethargica, would appear an epidemic that had its development in a partially overlapping period. The current pandemic linked to COVID-19 sometimes has aspects that can resemble Encephalitis lethargica. Based on historical analysis and the more recent immunological data, it could be suggested that Encephalitis lethargica was an autoimmune encephalitis that arose in a secondary form to the action of a viral agent. It cannot be ruled out that this agent was a coronavirus. From the nosological point of view, the term Encephalitis lethargica should be abolished in designating autoimmune encephalitis pictures that run sporadically.

[Encephalitis Lethargica: Awakenings].

Postencephalitic parkinsonism is a characteristic chronic sequelae of encephalitis lethargica, a pandemic disorder which swept the whole world in 1917-1928. Based on his clinical experiences at the Mount Carmel hospital, Oliver Sacks published Awakenings in 1973, and an American drama film Awakenings was premiered in 1990. Success and setbacks of the levodopa trial in postencephalitic parkinsonism patients were chronologically described, and the mother's delight on her son's "return" was impressive; this scene can be shared by us neurologists, even if it was transient. Above all, the exemplary performances of the two distinguished actors, Robin Williams and Robert De Niro (especially the latter), enlivened the most excellent moments of the movie.

Paroxysmal Panting: On Respiratory Crisis and Other Respiratory Curiosities in the Aftermath of Encephalitis Lethargica.

Pandemics in the early 20th century (and now with SARS-CoV-2) have been dominated by respiratory viruses damaging the lungs. Less is known about abnormal respiratory patterns from brain inflammation. One of the first descriptions of respiratory rhythm abnormalities was seen with an acute attack of epidemic encephalitis (encephalitis lethargica), and reports appeared soon after the original description in 1921. We reviewed these ill-remembered disorders of respiration rate, respiratory patterns, and respiratory tics. Most commonly, dysregulations occurred during the phase when ocular signs appeared. The early symptoms were an unrelenting tachypnea (panting) without air hunger and an inspiratory hold (fixés en inspiration forcée). Initially regarded as hysterical in nature, the later bizarre disorders of respiration were considered equally serious with attacks of gasping, panting, puffing, inspiratory breath holding, coughs, giggles, sighing, grunting, and moaning. These respiratory disorders were seen exclusively as part of a parkinsonian syndrome. Most remarkably, these attacks could be provoked by oxygen administration. These respiratory abnormalities with encephalitis lethargica are not well remembered. One purpose of recalling these episodes is to call attention to central causes of respiratory illness even in pandemics with respiratory viruses.

Arnold Netter Netter (1855-1936) and infectious pathology of the nervous system.

Arnold Netter (1855-1936) was a paediatrician who clinically applied the progress that his Pasteurian contemporaries had made possible through their bacteriological discoveries. From a neurological point of view, he brought looking for Kernig's sign into mainstream use to confirm the clinical diagnosis of meningitis and made diagnostic lumbar puncture systematic. He was one of the first to cure meningococcal and pneumococcal meningitis, long before the era of antibiotics, using subtractive lumbar puncture and intraspinal serotherapy. Netter's attentive vigilance enabled him to recognise, from its onset, the first poliomyelitis epidemic of the 20th century which took place in the summer of 1909. He described the clinical and epidemiological characteristics, identifying the viral rather than microbial origin. Netter detected the first cases of encephalitis lethargica in Paris in 1918. The disease had been described by Constantin von Economo (1876-1931) in Vienna the previous year. Netter spent fifteen years studying this new disease, which caused a pandemic a century ago. He filled in the clinical picture and used his understanding of cerebrospinal fluid and pathological anatomy to enhance knowledge and improve treatment of this neurological pathology.

A history of oculogyric crises during the encephalitis lethargica pandemic.

A pandemic of what came to be known as encephalitis lethargica spread starting in the winter of 1916-1917 and continued into the 1930s. Neurological after-effects, namely permanent parkinsonian syndromes and various abnormal movements, permanently disabled the survivors of the one or two million victims, often children or young adults. Among them, a small proportion developed a symptom that was little known up to that point and that is currently exceptional: oculogyric crises; that is, a lateralised, dystonic upward movement of the eyes known as a tonic eye fit. This paper proposes a history of the recognition of this symptom, its inclusion in the neurological nosography, and the pathophysiological hypotheses postulated a century ago.

René Cruchet (1875-1959), beyond encephalitis lethargica.

René Cruchet (1875-1959) was a pediatrician from Bordeaux known for his seminal description of encephalitis lethargica during World War I, at the same time as Constantin von Economo (1876-1931) in Vienna published his own description, which, unlike Cruchet's description, provided precious anatomopathological data in addition to the clinical data. Cruchet was interested in tics and dystonia and called for treatment using behavioral psychotherapy that was, above all, repressive. Cruchet was also a physiologist and an innovator in aeronautic medicine-notably, he helped pioneer the study of "aviator's disease" during World War I. Moreover, he possessed an encyclopedic knowledge, while publishing in all medical fields, writing philosophical texts as well as travel logs.

On the English (1931) and Spanish (1932) translations of von Economo's classic monograph on encephalitis lethargica.

The "second" seminal monograph by Constantin von Economo on encephalitis lethargica appeared in print in German in 1929, following his initial report of the disease (eponymously associated with his name) before the Viennese Society of Psychiatry and Neurology and the publication of his "first" monograph on the subject in 1917. The 1929 book was translated into English and Spanish and published by Humphrey Milford in Oxford and Espasa-Calpe in Madrid in 1931 and 1932, respectively. The present article gives some details of those translations and the neuropsychiatrists who produced them. Moreover, four previously unpublished letters by von Economo are presented, relating to the English edition of Die Encephalitis lethargica. These letters are of historical interest, as they provide insights into von Economo's personality and view of the translation.

Encefalitis de Von Economo / Von Economo Encephalitis

Introducción: Constantin von Economo reportó en 1917 múltiples casos de manifestaciones neurológicas secundarias a la pandemia de la gripe española, clasificándolos en tres grandes grupos: forma somnolienta-oftalmopléjica, mutismo y la hipercinética, con secuelas similares a la enfermedad de Parkinson. Objetivo: presentar un caso de reciente aparición de patología rara en Cali, Colombia con manejo adecuado en unidad de cuidados intensivos (UCI). Presentación del caso: paciente de 9 años con disminución de la fuerza en extremidades, disartria y somnolencia, que inició deterioro neurológico progresivo requiriendo manejo en UCI. El equipo multidisciplinario diagnosticó encefalitis letárgica e iniciaron manejo con plasmaféresis e inmunosupresión con mejoría significativa. Discusión y conclusiones: como la prevalencia es escasa, el diagnóstico exige un alto índice de sospecha como la ocurrencia de un cuadro infeccioso previo al inicio de los síntomas, ya que se considera una reacción autoinmune cruzada contra antígenos de la sustancia nigra. En algunos casos hay alteraciones en los estudios imagenológicos o en citoquímico de líquido cefalorraquídeo. El manejo con pulsos de metilprednisolona y filtración de plasma con plasmaféresis brinda mejoría significativa con disminución de las secuelas a futuro.

Introduction: In 1917, Constantin von Economo reported multiple cases of neurological manifestations secondary to the Spanish flu pandemic. He classified them into three main clinical forms: somnolent-ophthalmoplegic, mutism and hyperkinetic, causing sequelae resembling Parkinson ́s disease. Objective: to present a case of a recent appearance rare disease entity, in Cali Colombia, receiving appropriate management in the Intensive Care Unit (ICU). Case presentation: 9-year-old patient presenting with limb muscle weakness, dysarthria and somnolence, evidencing progressive neurological deterioration requiring admission to the ICU for management. A diagnosis of encephalitis lethargica (EL) was made by the attending multidisciplinary team and management with plasmapheresis and immunosuppression was started, obtaining significant improvement. Discussion and conclusions: as the prevalence is low, the diagnosis requires a high level of suspicion in cases presenting with infectious conditions prior to the development of symptoms, since it is considered an autoimmune cross-reaction against substantia nigra antigens. Alterations in brain imaging or in cerebrospinal fluid cytometry may be found in some cases. Management with methylprednisolone pulse therapy and filtration plasmapheresis provides significant improvement with a decrease in future sequelae.

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

"A Kind of Alaska" is a one-act play by the British playwright and Nobel Prize winner Harold Pinter (1930-2008), based on the book Awakenings 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 encephalitis lethargica ("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.

The first psychiatric pandemic: Encephalitis lethargica, 1917-27.

Finding a link between COVID-19 and subsequent psychiatric symptoms has resulted in renewed interest in the psychiatric sequelae of pandemics. The first such instance was apparently the encephalitis lethargica pandemic which arose around the time of the First World War, moving in the shadow of a repiratory virus pandemic. The epidemic of encephalitis lethargica (EL), or Von Economo's Disease, in the years 1917-27 was the first pandemic involving the central nervous system. It moved in some places in parallel with the Great Flu Pandemic but does not seem to have been caused by it. Unlike the coronavirus, pandemic EL affected children heavily, leading often to bizarre changes in character and personality. It often left sequelae lasting for decades in the form of postencephalitic Parkinsonism (PEP). Unlike the coronavirus, it had a high mortality of around 20 percent. Although encephalitis lethargica involved a number of systems, psychiatric morbidity was most prominent and entailed severe depression, mania, catatonia and psychosis. It ended without therapeutic or public-health measures; today, sporadic cases of EL continue to be reported. The hypothesis is that we can derive from the EL psychiatric pandemic certain lessons that might be useful in studying tardive COVID symptoms today.

Encephalitis lethargica in Peru.

Encephalitis lethargica first appeared during World War 1, but reported cases gradually faded over the 1920s, and in the years following, cases were only sporadically reported. The clinical presentation was heterogeneous and typically included both acute and chronic phases. The acute phase was characterized by excessive sleepiness, disorders of ocular motility, fever, and movement disorders. On the other hand, the chronic phase was characterized by Parkinsonism, oculomotor abnormalities, involuntary movements, speech and respiratory abnormalities, and psychiatric manifestations. In Peru, Espejo-Tamayo reported 47 cases of the disease between 1919 and 1924, with an average mortality of 13%. He described three waves of the epidemic in Peru: that of 1919, with a predominance of the lethargic-paralytic syndrome; that of 1920-1921, characterized by the algic-myoclonic syndrome; and the wave that began in 1922, when the disease acquired purely striatum syndromes, as well as those associated with the lethargic-paralytic and myoclonic syndromes and mental manifestations. We summarize six cases of encephalitis lethargica reported in Peru from 1920 through 1940.

Encephalitis lethargica epidemic milestones in early sleep neurobiology researches.

Around 100 years ago, the outbreak of peculiar encephalitis promoted knowledge advancement regarding sleep and psychomotricity control. This epidemic is believed to have disappeared ten years after it started, and it remained from 1916 to 1927. Since then, only a few sporadic cases have been reported, but previously, they happened in occasional and epidemics forms. Two pioneers in describing the cases were Jean-René Cruchet and his collaborators, and Constantin Von Economo. The firsts described diffuse symptomatology, "sub-acute encephalomyelitis." However, the reports by the Austrian aristocrat had a localized aspect which was admitted by him as a new disease, "Encephalitis lethargica" (EL). In his suppositions, based on clinical and anatomopathological material analysis, von Economo found distinct centers for sleep, in the rostral hypothalamus, and wakefulness, posterior hypothalamus. He plays an essential role in new achievements about EL and sleep neurobiology comprehension. These basic structural sleep-arousal regulatory neural systems had a lasting impact on contemporary sleep research, unfolded initially mainly by Frédéric Bremer, Giuseppe Moruzzi, and Horace Winchell Magoun, based on a passive theory of sleep induction. The lasts arrived at the conception of "diffuse" and "unspecific" ascending reticular activating system (ARAS) of the brain stem. This notion was unfolding until the idea of various interconnected "waking centers" and "sleep centers" levels, and also, active sleep induction.