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Histopathology of most cases in the acute phase showed reddish-grey discolouration of the brainstem grey matter with lymphocytic infiltrates surrounding vessels and diffuse inflammation with haemorrhage 1 In the chronic phase, persistent inflammation was evident with generalised brain atrophy and degeneration of the substantia nigra 1 The aetiology remains unproven, and it is not clear whether all the cases in the literature truly represent a single disease 5 The prevailing contemporary hypothesis was that proposed by von Economo himself—that the disease was owing to an infectious agent, although he observed that cases appeared to predate the emergence of the 1918 influenza pandemic 2 5 von Economo’s view that the disease was the result of direct viral infection of the central nervous system (CNS) has now been largely superseded by the proposition that the disease reflected a para/post-infectious inflammatory process 5 Although evidence for this is lacking, it fits neatly with the modern view of other neurological syndromes such as Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM) and N-methyl-D-aspartate receptor (NMDA-R) antibody encephalitis, the latter of which may be triggered by herpes simplex virus in some 6 7 Indeed, NMDA-R antibodies were present in serum (and cerebrospinal fluid (CSF) when available for study) in around 50% of 20 children with dyskinetic ‘encephalitis lethargica’ (collected over many years),8 and antibodies to the dopamine receptor in a proportion of the remaining more akinetic cases Many of the clinical features overlap, although encephalitis lethargica is more heterogeneous in both its acute symptoms and its natural history 2 A para/postinfectious pathogenesis, rather than direct viral infection, is in keeping with the observations that single members of families were often affected, which puzzled epidemiologists at the time;and that an infectious agent was not readily detected in CSF or brain tissue 2 It is possible that encephalitis lethargica represented a final common pathway of brain inflammation potentially triggered by several different infectious agents, although were this the case the reasons for the disease’s decline remain obscure A young patient had been admitted in April 1918 with self-inflicted laceration across the neck, preceded by headache and sleeplessness for 2 weeks 10 Six months after the initial presentation, they developed neck and back pain with reduced mobility, 2 months later developing expressive aphasia with retained comprehension, and death occurred less than a month later 10 The postmortem results describe a widespread meningoencephalomyelitis with vascular proliferation, perivascular inflammation, thrombosis, haemorrhage and destruction of nervous tissue 10 A subsequent case series collated by Sir Thomas Horder, also published in 1920, comprises 25 cases described by several neurologists from Bristol, and is notable for detailed and varied descriptions of cases of encephalitis lethargica in patients of all ages 11 Their dilemmas trying to unify these disparate clinical presentations are clearly evident The 2009 H1N1 pandemic was associated with complications of the nervous system in up to 4% of those diagnosed with H1N1 influenza infection and most commonly included altered mental status, seizures, narcolepsy and encephalopathy, particularly in children 16–18 Several seemingly pathognomic encephalopathy syndromes have emerged, including acute necrotising encephalopathy with bilateral thalamic involvement 16–18 The virus is rarely identified by molecular tests of the CSF in these patients, and it has been suggested that the mechanism for the complications may be a parainfectious cytokine storm 18 Coronaviruses The severe CoV, severe acute respiratory syndrome (SARS) and MERS, have been associated with limited reports of both central and peripheral nervous system disease, including ADEM 19 Sporadic, seasonal CoV have also occasionally been implicated in neurological disease 20 COVID-19, caused by SARS-CoV-2, represents the most devastating respiratory pandemic since the influenza pandemics of 1918 (‘Spanish flu’;H1N1), 1957 (‘Asian flu’;H2N2) and 1968 (‘Hong Kong flu’;H3N2) 21 Reports of neurological syndromes associated with SARS-CoV2 are frequent, initially reported where the virus began in Wuhan,22 and continued in case reports and series from across the world 21 23 24 A UK-wide surveillance study identified 153 cases with CNS disorders reflecting cerebrovascular events, altered mental status including 7 patients with encephalitis, and a surprising number of psychiatric syndromes, such as psychosis and catatonia 21 It is currently unclear how many cases are causally related to SARS-CoV-2 and in what proportion this is a coincidental infection 23 It is becoming apparent that dysfunction of the clotting cascade, together with possible endotheliopathy, is in some cases associated with cerebrovascular disease in COVID-19 21 23 24 The number of patients with encephalopathy is also striking, and in a few cases the virus has been detected in CSF 21 25 Many cases of GBS and its variants are also emerging 26 Conclusion The historical papers of von Economo, Horder and others are refreshing in their straightforward and detailed accounts of the symptoms
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