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.

Acute hypokinetic-rigid syndrome following SARS-CoV-2 infection.

OBJECTIVE: To report a case of a patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who acutely developed a hypokinetic-rigid syndrome. METHODS: Patient data were obtained from medical records from the Hospital Universitario 12 de Octubre in Madrid, Spain. [123I]-ioflupane dopamine transporter (DaT) SPECT images were acquired 4 hours after a single dose of 185 MBq of 123I-FP-CIT. Quantitative analysis was performed with DaTQUANT software providing the specific binding ratio and z score values of the striatum. RESULTS: We report a previously healthy 58-year-old man who developed hyposmia, generalized myoclonus, fluctuating and transient changes in level of consciousness, opsoclonus, and an asymmetric hypokinetic-rigid syndrome with ocular abnormalities after a severe SARS-CoV-2 infection. DaT-SPECT confirmed a bilateral decrease in presynaptic dopamine uptake asymmetrically involving both putamina. Significant improvement in the parkinsonian symptoms was observed without any specific treatment. CONCLUSION: This case study provides clinical and functional neuroimaging evidence to support that SARS-CoV-2 can gain access to the CNS, affecting midbrain structures and leading to neurologic signs and symptoms.

[Encephalitis lethargica. The epidemic at the dawn of neurology]. / Encefalitis letargica. La epidemia en los albores de la neurologia.

Lethargic encephalitis is a neurological illness that shows a wide range of symptoms and signs, including neurological and psychiatric spectrum. It presented in an epidemic way, following influaenza relapses. The last relapse started at the beginning of 20th century and it was deeply described by Constantin von Economo. The illness described first in Europe and North America, was described in many others countries including Chile. There were beautiful descriptions by Chilean physicians like Lea-Plaza, Tello, Iturra and Cienfuegos. Their works showed the complexity of the illness like European physicians did too. The etiology is still unknown; however growing evidence about autoinmune aetiology is gaining force with the use of actual medical technology. In this work, we show encephalitis lethargica, focusing in clinical picture, the beauty of medical descriptions that physicians did at this date.

TITLE: Encefalitis letargica. La epidemia en los albores de la neurologia.La encefalitis letargica es un cuadro neurologico con una variada gama de manifestaciones clinicas en el ambito neurologico y tambien en el psiquiatrico. El cuadro se ha presentado de manera epidemica en brotes que han seguido a los de la gripe. El ultimo brote acaecido a comienzos del siglo XX lo describio en profundidad Constantin von Economo. La epidemia notificada inicialmente en Europa y luego en Norteamerica se presento tambien en otras latitudes, incluyendo Chile. Asi, las descripciones de Lea-Plaza, Tello, Iturra, Cienfuegos y otros medicos chilenos dieron cuenta del cuadro en Chile con toda la complejidad que tambien tuvo en Europa. El origen sigue siendo un misterio, aunque la evidencia creciente de que fuera autoinmune gana fuerza con los hallazgos de la tecnologia medica actual. En este trabajo presentamos el cuadro, privilegiando la riqueza clinica y la belleza de las descripciones realizada por los medicos de la epoca en que esta enfermedad se presento.

Gabrielle Lévy and the Roussy-Lévy syndrome.

In 1934, Gabrielle Lévy died at the age of 48. She became well known for an article she published on a hereditary polyneuropathy in cooperation with Gustav Roussy, resulting in the eponym Roussy-Lévy syndrome. Not much is known about this extraordinary neurologist/neuropathologist. Her family declared that she died from the disease she was studying. She was a pupil of Pierre Marie, with whom she worked at the Salpêtrière in Paris and wrote on war neurology. In cooperation with Marie, she published a number of articles on postencephalitic syndromes, which also became the subject of her 1922 thesis. Three years later, she became associate physician at the Paul-Brousse Hospital in Paris, where the study of brain tumors became one of the subjects of her scientific work. Remarkably, Lévy was first author in a few of her many articles, although Roussy confirmed that she often initiated the study and even wrote the main part. In this article her career is considered in the context of the struggle of women physicians to improve their position during the early-twentieth century. She probably died from a brain tumor or a postencephalitic syndrome.

Medical and molecular perspectives into a forgotten epidemic: encephalitis lethargica, viruses, and high-throughput sequencing.

The emergence of encephalitis lethargica (EL), an acute-onset polioencephalitis of unknown etiology as an epidemic in the years 1917-1925 is still unexplainable today. Questioned by the first descriptor of EL himself, Constantin von Economo, there has been much debate shrouding a possible role of the "Spanish" H1N1 influenza A pandemic virus in the development of EL. Previous molecular studies employing conventional PCR for the detection of influenza A virus RNA in archived human brain samples from patients who died of acute EL were negative. However, the clinical and laboratory characteristics of EL and its epidemiology are consistent with an infectious disease, and recently a possible enterovirus cause was investigated. With the rapid development of high-throughput sequencing, new information about a possible viral etiology can be obtained if sufficient specimens for analysis were still available today. Here, we discuss the implications of these technologies for the investigation of a possible infectious cause of EL from archived material, as well as a prospectus for future work for acquiring viral nucleic acids from these sources.

Evidence for an enterovirus as the cause of encephalitis lethargica.

BACKGROUND: The epidemic of encephalitis lethargica (EL), called classical EL, was rampant throughout the world during 1917-1926, affecting half a million persons. The acute phase was lethal for many victims. Post-encephalitic parkinsonism (PEP) affected patients for decades. Our purpose was to investigate the cause of classical EL by studying the few available brain specimens. Cases of PEP and modern EL were also studied. Transmission electron microscopy (TEM) and immunohistochemistry were employed to examine brain from four classical EL cases, two modern EL cases and one PEP case. METHODS: Standard methods for TEM, immunohistochemistry and RTPCR were applied. RESULTS: 27 nm virus-like particles (VLP) were observed in the cytoplasm and nuclei of midbrain neurons in all classical EL cases studied. Large (50 nm) VLP and 27 nm intranuclear VLP were observed in the modern EL cases and the PEP case. Influenza virus particles were not found. VLP were not observed in the control cases. TEM of cell cultures inoculated with coxsackievirus B4 and poliovirus revealed both small and large intranuclear virus particles and small cytoplasmic particles, similar to the VLP in EL neurons. In the EL brains, nascent VLP were embedded in putative virus factories and on endoplasmic reticulum (ER). The VLP in the cases of classical EL survived, whereas ribosomes underwent autolysis due to the lack of refrigeration and slow formaldehyde fixation of whole brain. The VLP were larger than ribosomes from well preserved brain. Immunohistochemistry of classical EL cases using anti-poliovirus and anti-coxsackievirus B polyclonal antibodies showed significant staining of cytoplasm and nuclei of neurons as well as microglia and neuropil. Purkinje cells were strongly stained.A 97-bp RNA fragment of a unique virus was isolated from brain tissue from acute EL case #91558. Sequence analysis revealed up to 95% identity to multiple human Enteroviruses. Additional cases had Enterovirus positive reactions by real time PCR. CONCLUSIONS: The data presented here support the hypothesis that the VLP observed in EL tissue is an Enterovirus.

Viral parkinsonism.

Parkinson's disease is a debilitating neurological disorder that affects 1-2% of the adult population over 55 years of age. For the vast majority of cases, the etiology of this disorder is unknown, although it is generally accepted that there is a genetic susceptibility to any number of environmental agents. One such agent may be viruses. It has been shown that numerous viruses can enter the nervous system, i.e. they are neurotropic, and induce a number of encephalopathies. One of the secondary consequences of these encephalopathies can be parkinsonism, that is both transient as well as permanent. One of the most highlighted and controversial cases of viral parkinsonism is that which followed the 1918 influenza outbreak and the subsequent induction of von Economo's encephalopathy. In this review, we discuss the neurological sequelae of infection by influenza virus as well as that of other viruses known to induce parkinsonism including Coxsackie, Japanese encephalitis B, St. Louis, West Nile and HIV viruses.

Encephalitis lethargica and influenza. I. The role of the influenza virus in the influenza pandemic of 1918/1919.

An investigation of the characteristics of influenza epidemics in the nineteenth and early twentieth centuries was undertaken, principally in order to analyze the role of the 1918/1919 influenza pandemic in the etiology of encephalitis lethargica. Expectations regarding a future influenza pandemic derive principally from experiences in the 1918 epidemic. It is proposed that this pandemic was atypical with respect to many of its features, and that these have not been appropriately regarded in mapping expectations and responses of a future pandemic. Both a longer historical viewpoint (incorporating knowledge from all major nineteenth and twentieth century epidemics) and closer examination of individual epidemics at the town level is essential for producing an accurate picture of the challenge.

From juvenile parkinsonism to encephalitis lethargica, a new phenotype of post-streptococcal disorders: case report.

We report the case of a 16-year-old boy presented with a mild akinetic-rigid parkinsonism shortly after a post-streptococcal infection. After stopping corticoids, he had a rapid neurological deterioration to a fatal encephalitis lethargica-like syndrome. Serum analysis demonstrated consistently elevated anti-streptolysin-O. This case illustrates a new severe phenotype in the spectrum of the post-streptococcal disorders. This etiology should be considered in the differential diagnosis of a movement disorder with a rapid detrimental evolution.

Lack of detection of influenza genes in archived formalin-fixed, paraffin wax-embedded brain samples of encephalitis lethargica patients from 1916 to 1920.

A method was developed for detection of influenza genes in formalin-fixed brains of mice that had been experimentally infected with influenza A/NWS/33 (H1N1) virus. Using this technique, messenger ribonucleic acid (mRNA) of the beta-actin gene was detected in eight clinical brain samples from the 1916-1920 outbreak of encephalitis lethargica, showing preservation of particular mRNAs. However, we did not detect influenza nucleotide sequences of M, NP, and NS genes from these same samples. We conclude either that influenza was not the causative agent of encephalitis lethargica or, possibly, that the virus had a hit-and-run mechanism and was no longer present in the brain at the time of death of the patients.

Experimenting on the past: the enigma of von Economo's encephalitis lethargica.

Encephalitis lethargica (EL) was a complex and mysterious disease that appeared around the same time as the great influenza pandemic of 1918. The contemporaneous relationship of the 2 diseases led to speculation that they were causally related. Contemporary and subsequent observers conjectured that the influenza virus, directly responsible for the deaths of more than 20 million people, might also have been the cause of EL. A review of the extensive literature by observers of the EL epidemic suggests that most contemporary clinicians, epidemiologists, and pathologists rejected the theory that the 1918 influenza virus was directly responsible for EL. Disappearance of the acute form of EL during the 1920s has precluded direct study of this entity. However, modern molecular biology techniques have made it possible to examine archival tissue samples from victims of the 1918 pandemic in order to detect and study the genetic structure of the killer virus. Similarly, tissue samples from EL victims can now be examined for evidence of infection by the 1918 influenza virus.