The Neurological Sequelae of Pandemics and Epidemics

Journal of Neurology https://doi.org/10.1007/s00415-020-10261-3

REVIEW

The neurological sequelae of pandemics and epidemics

Fernanda Valerio1 · Daniel P. Whitehouse1 · David K. Menon1,2 · Virginia F. J. Newcombe1,2

Received: 30 June 2020 / Revised: 3 October 2020 / Accepted: 7 October 2020 © The Author(s) 2020

Abstract Neurological manifestations in pandemics frequently cause short and long-term consequences which are frequently overlooked. Despite advances in the treatment of infectious diseases, nervous system involvement remains a challenge, with limited treatments often available. The under-recognition of neurological manifestations may lead to an increase in the burden of acute disease as well as secondary complications with long-term consequences. Nervous system infection or dysfunction during pandemics is common and its enduring consequences, especially among vulnerable populations, are frequently forgotten. An improved understanding the possible mechanisms of neurological damage during epidemics, and increased recognition of the possible manifestations is fundamental to bring insights when dealing with future outbreaks. To reverse this gap in knowledge, we reviewed all the pandemics, large and important epidemics of human history in which neurological manifestations are evident, and described the possible physiological processes that leads to the adverse sequelae caused or triggered by those pathogens.

Keywords CNS infections · Peripheral neuropathies · Pandemics/history · Meningitis · Encephalitis

Introduction involvement of infectious disease can lead to prolonged hospital stay and signifcantly increase rehabilitation time Pandemics are large-scale outbreaks of infectious disease and long-term care needs after discharge [135], posing a that can cause an excess in morbidity and mortality globally, far-reaching socioeconomic burden. or at least over a wide geographic area, and lead to socio- As the world deals with the Sars-CoV2 pandemic, reports economic disruption. Increase in global travel, urbanisation, of neurologic manifestations have increased. Understand- climate change, environmental degradation, displacement ing neurological complications of previous pandemics, and and consumption of wild animals are factors thought to have the pathophysiological mechanisms that underlie them, are increased the likelihood of pandemics during the past cen- fundamental to place the current situation in perspective, and tury [79]. The majority of pathogens responsible for out- help address the enduring consequences once current waves breaks can cause neurologic illness, which are frequently of acute infection subside. This narrative review assesses the overlooked, under-reported and under-diagnosed. Even in neurological manifestations of past and current pandemics, tertiary centres of developed countries, up to 30% of patients to aid our understanding of the current pandemic and pre- with a CNS infection never receive an etiological diagno- pare for future outbreaks. sis [135], and in low resource settings lacking diagnostic tools, neurological manifestations are often poorly charac- terised. Aside from the associated mortality, neurological Mechanisms of pathogen‑mediated neurological disease

* Fernanda Valerio Pathogens can lead to nervous system impairment through [email protected] multiple mechanisms. There may be direct infection and rep- 1 University Division of Anaesthesia, Addenbrooke’s lication leading to the clinical syndromes of encephalitis, Hospital, University of Cambridge, Box 93, Hills Road, myelitis and meningitis [65]. Para-infectious complications Cambridge CB2 0QQ, UK such as sepsis and metabolic dysfunction related and coag- 2 Wolfson Brain Imaging Centre, University of Cambridge, ulopathy can lead to encephalopathy and vascular events. Cambridge, UK

Vol.:(0123456789)1 3 Journal of Neurology

The infection can also trigger an indirect immune-mediated infected individuals developed the neuroinvasive disease, attack both in the central and peripheral nervous system but the incidence is higher among those > 65 years, which [32], as seen in Guillain–Barré syndromes (GBS) or acute also have higher mortality. The neurologic syndromes can disseminated encephalomyelitis (ADEM). Finally, some overlap and be divided in meningitis, meningoencephalitis, viruses can persist mutated or latent in the central nervous and acute faccid paralysis secondary to anterior myelitis and system (CNS) or peripheral ganglia, leading to potential late typically occurs in the acute phase of the disease. Extrapy- reactivation and clinical disease. Further details are provided ramidal signs are seen in some encephalitic cases during the in Table 1; Fig. 1. acute illness, and may be transient or last months after the resolution of the disease. Seizures and encephalopathy have also been reported [123]. Pathogens responsible for pandemics and important epidemics Japanese encephalitis throughout history Large epidemics of Japanese encephalitis Virus (JEV) occur Pathogens are divided according to the main mode of every 2–15 years in South-East Asia and Western Pacifc, transmission (vector-borne, water/food-borne and direct making it the world’s most commonly diagnosed epidemic or indirect with infected individuals). Its features, includ- encephalitis (~ 70,000 cases/year). Among the arthropod- ing notable pandemics, non-neurological and neurological borne viruses, JEV leads to the greatest loss of disability- manifestations may be found in Fig. 2 and Table 2. We have adjusted life years, due to the frequent neurological seque- summarised imaging and laboratory fndings in Table 3. A lae of the condition. While the majority of infections are more complete description of the neurological manifesta- asymptomatic or mild, 0.1–1% cause encephalitis, mainly tions follows. in children. It manifests in the acute phase of the disease. Symptoms include impaired consciousness, headache, vom- Vector‑borne iting, and seizures. Pyramidal and extrapyramidal signs, involvement of cranial nerves, eye movement abnormalities Bubonic plague and anterior myelitis are described. Similar neurological features are seen in adults. Other immunological manifestations The frst Plague pandemic, known as the Plague of Justin- include GBS, ADEM, transverse myelitis and N-methyl- ian, occurred during the sixth century and is believed to d-aspartate (NMDA) receptor encephalitis, weeks after the have hastened the end of the Roman Empire. The second onset of the viral illness. Approximately one-ffth of patients commenced with a wave known as the “Black Death” and is with JEV-encephalitis die and 44% of those with neurologi- estimated to have resulted in the deaths of over 100 million cal involvement have incomplete recovery [140]. people; the highest of any pandemic in history. Currently, most human cases are located in Africa, and annual epidem- Zika ics are reported in Madagascar [156]. Meningitis is reported in up to 7% of all patients, typically after the 1st week in The Zika virus was described in Uganda in 1947 and has those who received incomplete or delayed treatment for the caused outbreaks in Asia and the Pacifc. In 2014–2016 it bubonic form. Younger patients have higher incidence of caused an epidemic of microcephaly among newborns in Yersinia meningitis (around 11% of children) [8, 14, 82]. It the northeast of Brazil [31]. The congenital Zika syndrome presents as a bacterial meningitis, with neutrophilic pleocy- occurs in 5–14% of pregnancies of infected mothers, and tosis in the CSF. The gold standard for diagnosis is the cul- includes severe microcephaly, skull collapse, subcortical ture of Y. pestis in blood, sputum, bubo aspirate or CSF, but calcifcations, corpus callosum anomalies, decreased white the bacteria can also be detected using point of care testing matter, ventriculomegaly, cerebral cortex thinning, abnor- with immunochromatographic assays or quantitative PCR in mal gyral patterns, vermis hypoplasia, chorioretinal atrophy, portable thermocyclers [35, 158]. focal pigmented mottling of the retina, optic nerve atrophy and congenital contractures [90, 94]. Zika virus-associated West Nile virus (WNV) GBS (both axonal and demyelinating) has been described 5–15 days after the acute disease [94]. This virus was frst identifed in the West Nile province of Uganda in 1937 [122]. In 1999 an outbreak occurred in Chikungunya fever New York which spread to the rest of the Americas, leading to the largest epidemics of meningitis or encephalitis Chikungunya virus was isolated during an outbreak in 1952 ever reported in the western hemisphere [69]. Under 1% of in Tanzania, and signifcant epidemics have been described

1 3 Journal of Neurology

Table 1 Mechanisms of pathogen-induced neurological injury Mechanisms Description Neurologic manifestations

Direct invasion Blood brain barrier (BBB) (haematological Penetration of endothelial barriers via (BBB Encephalitis entry) disruption associated with acute host infam- Meningoencephalitis matory responses may facilitate invasion): Meningitis Transcellular penetration (using pinocytosis or Anterior myelitis receptor-mediated entry) Encephalopathy Paracellular entry (by disrupting tight junc- tions) Via entry of infected leukocytes from the peripheral circulation into the CNS (Trojan horse mechanism) [28, 65] Peripheral nerves (trans-synaptic spread) Pathogens: Move along peripheral nerves via retrograde (from axon terminal to cell body) or antero- grade (from cell body to axon terminal) transport Invade the PNS by binding to receptors on axons of sensory, autonomic and motor neu- rons, including the olfactory and vagal nerves [68, 77, 84, 116, 142] Para-infectious Sepsis-associated Difuse disturbance of brain function as a Encephalopathy consequence of the systemic infammatory Acute haemorrhagic leukoencephalitis (AHL) response of sepsis [45, 148] Presents as impaired attention and arousal [165] Release of infammatory mediators afecting both the BBB and the cerebral microcircula- tion [120] (“cytokine storm”) Secondary to metabolic dysfunction Can be isolated or in the context of sepsis and Seizures organ failure: Encephalopathy Severe hypoxia Difuse ischaemia Shock-induced hypoperfusion Metabolic disturbances Electrolyte imbalances (hyponatremia or hypernatremia, hypocalcaemia or hypercal- cemia) Secondary to coagulopathy and vasculitis Hyperinfammation in SIRS and sepsis leads to Stroke coagulopathy and a prothrombotic state Cerebral venous thrombosis Both direct pathogen invasion and the proin- Intracranial haemorrhage fammatory state of sepsis lead to endothe- Peripheral neuropathy lial damage [144], which then shifts to a procoagulant state and has increased vascular permeability [57, 126] Infections may cause vasculitis, either due to pathogen invasion, exaggerated immune response, or immune dysregulation triggered by bacterial toxins or antigens [136] Post-infectious Autoimmune Triggered especially by viruses, which serve as Guillain-Barré syndromes antigenic stimulus and lead to lesions of the Acute disseminated encephalomyelitis PNS and CNS (ADEM) Associated with molecular mimicry between Transverse myelitis the pathogen and molecules on the axolem- Acute motor axonal neuropathy (AMAN) mal surface, glial membranes at the node Acute infammatory demyelinating polyneu- of Ranvier [150] or myelin proteins of the ropathy (AIDP) host, which leads to T-cell activation and an autoimmune response [106]

1 3 Journal of Neurology

Table 1 (continued) Mechanisms Description Neurologic manifestations Persistence and latency of viral infections After direct invasion of the nervous system Neurocognitive disorders (HIV) Persistent viral infections: continuous viral Subacute sclerosing panencephalitis (measles) replication Latent viral infections: dormant state with minimal or no production of viral material [84].Can be reactivated upon host immunosuppression, and the activation of both innate and adaptive immune system can disrupt CNS homeostasis [65]

BBB blood–brain-barrier, PNS peripheral nervous system, CNS central nervous system, AHL acute haemorrhagic leukoencephalitis, ADEM acute disseminated encephalomyelitis, HIV human immunodefciency virus

Fig. 1 Mechanisms of injury to the nervous system worldwide. The most recent started in 2013, afecting the viral invasion and manifest early during the infection [19]. Southern USA, Mexico, Central and South America, with Myelitis can occur either in the acute phase or later in the over 2 million infections reported [146]. Young children and course of the disease. Tardive post-infectious complications, older adults are at a higher risk of complications, which thought to be autoimmune in nature, include ADEM, optic may afect approximately one percent of infected individu- neuropathy, GBS, brainstem encephalitis and Bickerstaf’s als. Encephalopathy and encephalitis are caused by direct encephalitis-Miller-Fisher overlap [19].

1 3 Journal of Neurology

Water or food‑borne paralysis secondary to anterior myelitis, early in the course of the infection. After a period of stable neurological func- Enteroviruses tion (≥ 15 years), 30–40% of polio survivors develop progressive and persistent new muscle weakness and increased Enteroviruses cause over 90% of viral meningitis in children fatigue, characterising the post-polio syndrome. The patho- under 10 years and is most frequently by echoviruses and genesis is not completely understood but thought to be Coxsackie-B [77]. Two enteroviruses that caused epidem- related to a disturbance of the denervation/re-innervation ics and remarkable neurological manifestations are detailed equilibrium with further denervation. In 2016, it was esti- below. mated that there are 15–20 million polio survivors worldwide [76]. Poliovirus Enterovirus‑71(EV71) Poliomyelitis was sporadically reported until the end of the nineteenth century, when large summer epidemics in This virus was isolated in 1969 and is a common cause of North America and Europe began occurring annually [96]. hand, foot, and mouth disease in children. Cyclical large The development and implementation of vaccination pro- epidemics occur in the Asian-Pacifc region every 2–3 years grammes since 1955 decreased its incidence dramatically, and it circulates at a low level in the rest of the world, with though outbreaks still occur in Africa and Asia, and it is small outbreaks in Europe, North America and Africa [130]. endemic in Nigeria, Afghanistan and Pakistan. Around 1 in Children may develop CNS manifestations after 3–5 days of 150 infections will lead to paralytic poliomyelitis [96]. When prodrome [100]. During an outbreak in Malaysia, 10–30% of the virus reaches the CNS, there is a meningitic phase fol- hospitalised children had neurological manifestations, which lowed by spinal poliomyelitis and onset of an acute faccid included aseptic meningitis, encephalitis and acute faccid

Fig. 2 Timeline of important pandemics including key neurological complications. These are noted for the frst pandemic caused by an infection

1 3 Journal of Neurology - chloramphenicol if chloramphenicol plague meningitis. - gen other forms, For tamicin OR doxycy - cline OR ciprofoxa cin can be used controlled trialcontrolled has the tested successfully efcacy of specifc drugs the acute phase. Post the acute phase. Post - autoim infectious mune conditions the standard receive immunomodulatory the for treatment condition the acute phase. Post the acute phase. Post - autoim infectious mune conditions the standard receive immunomodulatory the for treatment condition Treatment Antibiotic therapy with therapy Antibiotic Supportive care. No No care. Supportive Supportive care during care Supportive Supportive care during care Supportive autoimmune autoimmune - of neuro Mechanism logical injury Direct invasion Direct Direct invasion Direct Direct invasion Direct Post-infectious— Direct invasion Direct Post-infectious— - present late in thepresent course of disease in patients even under antibiotics) NMDA encephalitis NMDA - micro syndrome: subcortical cephaly, calcifcations, cor pus callosum, cortex malformations, alterations retinal - manifesta Neurologic tions Meningitis (may Meningitis (may Meningitis Encephalitis Anterior myelitis Encephalitis Anterior myelitis GBS myelitis Transverse ADEM Associated with Congenital Zika Congenital Meningoencephalitis myelitis Transverse GBS - - - malaise, myal fever, gia. Lymphadenitis near the develops location of fea bite (bubo), character izing the bubonic com - (most form, mon). Other forms theare septicaemic and pulmonary plague asymptomatic. asymptomatic. 20 and Between a 40% will develop illness with fu-like headache, fever, malaise, myalgia, - and gastro skin rash symptoms intestinal infections are either are infections asymptomatic mild. If or very symptoms present, include self-limiting and eventual fever coryza and/or diar rhoea either- asympto matic (50–80%) or mild fu-like have fever, symptoms: arthralgia,rash, conjunctivitis and Maternal- myalgia). transmission foetal occurs in 20–30% of cases, among which 4–7% will lead to loss foetal Non-neurological Non-neurological features Initial symptoms are are Initial symptoms Most infected are are infected Most Vast majority of Vast Infected adults are adults are Infected Incubation period 1–7 days 3–14 days 5–15 days 3–14 days rodents’ feas rodents’ bodily infected fuids, fomites, and inhalation of respiratory infected droplets mosquitoes. mosquitoes. Culex reservoirs are Birds in nature mosquitoes. mosquitoes. Culex in The virus exists cycle an enzootic and birds between with mosquitoes pigs as amplifying and humans as hosts dead-end hosts mosquitoes, mosquitoes, Aedes relations sexual - and blood transfu sion. Vertically duringtransmitted pregnancy Mode of transmission Bite of infected Bite of infected contactDirect with Bite by virus-carryingBite by Bite by virus-carryingBite by Bite of virus-carrying - plague—Eurasia plague—Eurasia plague—China, India, Hong Kong epidemics in Africa - Madagas (mainly car) Russia, Israel Russia, countries of tropical South Asia and East Pacifc West in 2–15 years every of areas temperate Asia (western Pacifc Pacifc (western Ocean) nesia Thailand, Vietnam, Guinea-Bissau, Angola Event/distribution 541: Justinian 541: Justinian 1347: Bubonic world 1855: Third Current: Seasonal Late 1990s: Romania, Late 1990s: Romania, 1999–2003: Americas Endemic in 24 epidemics Large 2007: Yap island 2007: Yap Poly 2013: French 2014–2016: Americas 2016: Singapore, 2018: India Pandemics and selected epidemics in which neurological manifestations were reported were manifestations neurological and selected epidemics in which Pandemics (Yersinia pestis) (Yersinia virus) (Japanese encephali - tis virus)* 2 Table Disease (pathogen) Bubonic plague West Nile (West Nile Nile (West West Japanese Encephalitis Zika (Zika virus)

1 3 Journal of Neurology - the acute phase. Post the acute phase. Post - autoim infectious mune conditions the standard receive immunomodulatory the for treatment condition ing the acute phase including correction - of metabolic dysfunc tion Treatment Supportive care during care Supportive Supportive care dur care Supportive autoimmune - ondary sequestra to tion of erythrocytes blood cerebral into of release vessels, BBB cytokines, permeability and - metabolic dysfunc tion - of neuro Mechanism logical injury Direct invasion Direct Post-infectious— Para-infectious- sec - Para-infectious- Miller Fisher and Miller Fisher syn - Bickerstaf’s dromes) - manifesta Neurologic tions Acute encephalitis Acute Meningoencephalitis GBS (including myelitis Transverse Myeloradiculitis ADEM neuropathy Optic Encephalopathy Seizures (usually bilateral bilateral (usually and symmetric), - myal headache, gia, conjunctivitis, arthritis, nausea, and vomiting maculopapular rash, Some 7–10 days. for patients persist with arthralgia for months years to after the acute disease sweats, chills, chills, sweats, malaise, myalgia, gastrointestinal symptoms seldom observed) malaria lasts attack - 6–10 h, consist ing of a cold stage a hot (shivering), head - (fever, stage vomiting) aches, stage and a sweating and fatigue) (sweats Non-neurological Non-neurological features Fever, polyarthralgia polyarthralgia Fever, Fever, headache, headache, Fever, The classical (but Incubation period 3–7 days 9–14 days - - rying mosquitoes, predominantly and aegypti Aedes toler colder-climate albop - ant Aedes ictus. Other forms include: blood borne transmission, transmission vertical during 2nd trimes - intrapartum ter, when transmission mother is viraemic during delivery infective female female infective Anopheles. Also, though blood organ transfusion, shared transplant, use of needles, and during vertically pregnancy Mode of transmission Bites of virus-car Mosquito bite of Mosquito Indian Ocean islands, India, South Asia East cas stan outbreaks in 91 and sub - tropical countriestropical of Africa, and Central South America and half of Asia (nearly popula - the world tion). Eliminated in Europe from 1975 increase to expected with increasing associ - temperatures ated with climate changes Event/distribution 1960s: Asia 2005–2007: Kenya, 2007: Italy 2014: France 2014–current: Ameri - 2017–current:- Paki Endemic with local Epidemic potential (continued) (Chikungunya virus) (Chikungunya )** falciparum 2 Table Disease (pathogen) Chikungunya fever fever Chikungunya Malaria ( Plasmodium

1 3 Journal of Neurology - ing the acute phase, including correction - of metabolic dysfunc tion mune conditions the standard receive immunomodulatory the for treatment condition the acute phase and infectious para for Post manifestations. - autoim infectious mune conditions the standard receive immunomodulatory the for treatment condition Treatment - autoim infectious Post Supportive care dur care Supportive Supportive care during care Supportive autoimmune autoimmune (associated with the 17D fever yellow vaccine) ondary metabolic to dysfunction ondary metabolic to dysfunction secondary to and coagulopathy vasculitis autoimmune - of neuro Mechanism logical injury Direct invasion Direct Post-infectious— - Para-infectious—sec Direct invasion Direct - Para-infectious—sec ? Para-infectious— Post-infectious— - acute phase (young acute phase (young children) - associated neuro disease: Men - tropic ingitis, encephalitis, GBS and myelitis, ADEM cranial nerves cranial rhages - manifesta Neurologic tions Febrile in the seizures Encephalitis Encephalopathy vaccine fever Yellow Encephalopathy Encephalitis meningitis Aseptic ADEM myelitis Transverse GBS Mononeuropathies of neuropathy Optic Muscle dysfunction haemor Intracranial - backache, headache, headache, backache, of appetite, lack nausea and vomiting Some 3–4 days. for asymptomatic. are 15 and Between 25% of infected enter a 2nd toxic phase with fever, epigastric vomiting, failure, pain, renal haemorrhagic diath- esis, transaminase bilirubinand direct rise with deep jaundice tomatic. Self- tomatic. limiting symptoms and 5–7 days last include high fever, (specially headache - myal retroorbital), gia, arthralgia and, 5% Around rash. the severe will have of disease, form during manifest the defervescence period (after the in which week) 1st there is plasma leak increased due to age permeabil vascular - with or without ity, bleeding and can shock lead to organ and severe involvement Non-neurological Non-neurological features Fever, myalgia, chills, chills, myalgia, Fever, - asymp 40–80% are Incubation period 3–6 days 4–10 days - and Aedes from Haemogogus spe - are cies. Monkeys and are also infected in jungle reservoirs areas ery. Breast milk Breast ery. and bloodborne are transmission also possible mosquitoes, mosquitoes, predominantly and aegypti Aedes colder-climate Aedes tolerant albopictus . Perinatal occurs transmission when the mother is near deliv infected Mode of transmission Mosquito bites Mosquito Bite of virus-carrying countries of Africa, South and Central Americas Europe USA, ports),(Atlantic the Caribbean, Central America non-endemic sion to in Africaareas and South America sporadic cases in sporadic endemic in 1970s to 100 countries over with worldwide outbreaks explosive areas in new Event/distribution Endemic in 47 century:nineteenth 2016–current:- expan Evolved from from Evolved (continued) fever virus)* fever virus)* 2 Table Disease (pathogen) Yellow fever (yellow (yellow fever Yellow Dengue (dengue

1 3 Journal of Neurology - Rehabilitation in theRehabilitation phase chronic the acute phase. Post the acute phase. Post - autoim infectious mune conditions the standard receive immunomodulatory the for treatment condition ment of neuropsy chiatric disturbances. during care Palliative last the inexorable of the disease stages Treatment Supportive care. care. Supportive Supportive care during care Supportive - manage Symptomatic autoimmune - of neuro Mechanism logical injury Direct invasion Direct Direct invasion Direct Post-infectious— Direct invasion Direct brainstem clonus tions: depression, tions: depression, delusions, halluci - nations pain especially chorea, myoclonus, tremor - manifesta Neurologic tions Anterior myelitis Meningitis Encephalitis syndrome Post-polio Encephalitis, mainly Encephalitis, mainly meningitis Aseptic Encephalomyelitis ataxiaCerebellar Anterior myelitis myelitis Transverse GBS - Myoclonus-opso - manifesta Psychiatric Sensory disturbances, Dementia Ataxia disorders: Movement either asymptomatic or accompanied mild fu-like by fever like symptoms headache fatigue, and vomiting cause hand-feet- mouth disease: - exan childhood thema with fever, papulovesicular on therash palms and soles oral - ulcers, manifest ing also as upper respiratory tract - and gastro infection enteritis. are Adults - asymp frequently tomatic eminently associ - eminently ated with the CNS infection Non-neurological Non-neurological features Most infections are are infections Most In children, it can In children, Symptoms are are Symptoms Incubation period 7–10 days 3–10 days 15–20 years ingestion of contam - ingestion or food. inated water The virus multiplies in the oropharyn- and intestinal geal where mucosa from target for it spreads including organs, the CNS ingestion of contam - ingestion or food. inated water The virus multiplies in the oropharyn- and intestinal geal where mucosa from target for it spreads including organs, the CNS nated food (espe - nated food meat), bovine cially via blood and rarely or organ transfusion transplantation Mode of transmission Oral-faecal route by by route Oral-faecal Oral-faecal route by by route Oral-faecal Ingestion of contami - Ingestion century—1955: out - cyclical Large breaks during sum - mer on Northern and United Europe States Africa West in the Asia–Pacifc in the Asia–Pacifc every region 2–3 years garia and Hungary Australia Japan, Taiwan form encephalopa - form (BSE) describedthy the UK and spread 13 countriesto Event/distribution End of nineteenth End of nineteenth 2008: Nigeria and Cyclical epidemics Cyclical 1970s: Japan, Bul - 1980s: Hong Kong, 1997–1998: Malaysia, 2008—China 1985: Bovine spongi - 1985: Bovine 1995: Beginning in (continued) virus) (Enterovirus-71)* Jakob disease Jakob spongiform (bovine encephalopathy [BSE] prion) 2 Table Disease (pathogen) - (Polio Poliomyelitis Enterovirus-71 Enterovirus-71 Variant Creutzfeldt- Variant

1 3 Journal of Neurology - and electrolyte dis - and electrolyte turbances correction - and intrave (both oral ther nous), antibiotic withapy Doxycycline adults) line for (1st (1st or azithromycin and children line for for women) pregnant and the moderately ill patients, severely zinc supplementation (among children) Treatment Aggressive rehydration rehydration Aggressive ondary metabolic to dysfunction - of neuro Mechanism logical injury - Para-infectious—sec ary to electrolytic ary electrolytic to disturbances ropathy—reported during an outbreak in 2013 - manifesta Neurologic tions Seizures, second - Seizures, Peripheral neu - asymptomatic but asymptomatic faecal display still shedding of the bac - teria. can Symptoms mild to from range and include severe diarrhoeawatery Stools and vomiting. ricecan resemble of with fakes water, mucus, with a fshy is no There odour. Dehydration fever. ensue, can rapidly leading potentially hypovolemic to shock Non-neurological Non-neurological features Most infected are are infected Most Incubation period 12 h–5 days by ingestion of ingestion by contaminated food or water Mode of transmission Oral-faecal route route Oral-faecal era pandemic— era Asia, Middle East, Caspian Sea basin pan - Cholera demic—Europe, NorthEgypt, America pandemic— era NorthEurope, America, Asia, Middle East pandemic— era Asia, Europe, Africa, North America pandemic— era Japan, Europe, Egypt Persia, pandemic— era Ottoman Russia, Philippines, Empire, USA pan - Cholera demic—Indonesia, Soviet Bangladesh, North Union, Africa, Italy America, DRC (then Zaire) can Republic Ghana, Sierra DRC, Leone, Ghana, Somalia, Tanzania, Algeria, Zimbabwe Event/distribution 1817–1824: 1st Chol - 1817–1824: 1st 1829–1837: 2nd Chol - 1846–1860: 3rd 1863–1875: 4th Chol - 1881–1896: 5th Chol - 1899–1923: 6th Chol - 1961–1975: 7th 1991–94: South 2010—Haiti, Domini - 2011–2018—Nigeria, 2017–current: Yemen (continued) cholerae) 2 Table Disease (pathogen) (Vibrio (Vibrio Cholera

1 3 Journal of Neurology oseltamivir and high dose corticosteroids can be used in the acute phase. Post - autoim infectious mune conditions the standard receive immunomodulatory the for treatment condition the acute phase. Post the acute phase. Post - autoim infectious mune conditions the standard receive immunomodulatory the for treatment condition Treatment Supportive care. Both care. Supportive Supportive care during care Supportive septic-related ondary metabolic to dysfunction ondary coagu - to lopathy autoimmune septic-related ondary metabolic to dysfunction ondary coagulop - to and vasculitis athy autoimmune - of neuro Mechanism logical injury ? Direct invasion ? Direct Para-infectious— - Para-infectious—sec - Para-infectious—sec Post-infectious— Direct invasion Direct Para-infectious— - Para-infectious—sec - Para-infectious—sec Post-infectious— - gica Parkinsonism encephalitis drome condition of Reye’s syndrome encephalitis and Miller Fisher syn - Bickerstaf’s dromes) nerves cranial - manifesta Neurologic tions Post-encephalitic Post-encephalitic Aseptic meningitis Aseptic Encephalitis Encephalopathy Stroke necrotising Acute syn - Kleine-Levin GBS myelitis Transverse Encephalopathic Encephalitis lethar Encephalopathy Meningoencephalitis necrotising Acute neuritisOptic Stroke Myopathy GBS (including Mononeuropathies of ADEM include fever, include fever, cough, sore chills, throat, runny nose, headache, myalgia, - gastroin fatigue, symptoms testinal in frequent (more Com - children). plications include - pneumonia, myo and sepsis. carditis women, Pregnant those < 5 aged or > 65 and who underlying have health conditions risk at increased are of complications matic. For thesematic. For most coronaviruses mild will develop upper respiratory symptoms tract as cough, such throat, sore coryza, fatigue, chills, fever, headache myalgia, nausea. A parcel with will evolve pneumonia severe and respiratory failure Non-neurological Non-neurological features Common symptoms Common symptoms - asympto Some are Incubation period 1–4 days 2–14 days respiratory droplets respiratory droplets people infected from or fomites infected people’s people’s infected respiratory droplets or fomites Mode of transmission Direct contactDirect with Direct contactDirect with started in Siberia and Kazakhstan to (H3N8), spread and Asia Europe Flu (H1N1)—frst in Europe observed before and USA going global (H2N2)—start in spread Hong Kong, and China, USA to Europe (H3N2)—global (H1N1 pdm09)— global CoV—global (30 CoV—global countries), start in China countries, start in the middle East global Event/distribution 1889: Russian Flu— 1889: Russian 1918–1920: Spanish 1957: Asian Flu fu 1968: Hong Kong 2009: Swine fu 2002–03: Sars- 2012: MERS-CoV 22 2019: Sars-Cov2— (continued) CoV, MERS-CoV, MERS-CoV, CoV, Sars-Cov2) 2 Table Disease (pathogen) Flu (infuenza virus) Coronaviruses (Sars- Coronaviruses

1 3 Journal of Neurology early rehydration, rehydration, early correction- of electro and disturbances lyte secondarytreating infections the cute phase. measles post Acute encephalitis can be withtreated corticos - intravenous teroids, IgG is a possible 2nd MIBE line treatment. is supporttreatment - and ribavirin is ive reported as benefcial. SSPE patients receive an care palliative control symptoms Treatment Supportive care with care Supportive Supportive care in care Supportive - septic-related ondary metabolic to dysfunction sistent or latent sistent infection immune - of neuro Mechanism logical injury Direct invasion Direct Para-infectious— - Para-infectious—sec - auto Post-infectious- Direct invasion Direct Post-infectious—per - memory loss, muscles headaches, among sur aches vivors (primary measles encephalitis) encephalitis body encephalitis (MIBE) panencephalitis (SSPE) - manifesta Neurologic tions Meningoencephalitis Encephalopathy Ebola syndrome: Post Acute Encephalitis Acute post-measles Acute Measles inclusion- Subacute sclerosing ADEM include high fever, include high fever, malaise and body 3 days, for aches - gastro to evolving symptoms intestinal include nau - which sea, large-volume - diarrhoea and vom 7—10 days. iting for some this stage, At patients will go and can shock into withpresent haem - - orrhagic manifesta tions (conjunctival, and gastrointestinal mucosal bleeding) and one or more of and one or more the three symptoms: coryza, cough and conjunctivi - spots tis. Koplik (small white spots) appear in the mouth after 2–3 days start of symptoms. Maculopapular rash appears 3–4 days after of the onset symptoms Non-neurological Non-neurological features Early symptoms symptoms Early Starts with high fever Starts with high fever Incubation period 2–21 days 7–14 days - carrying bats or (main reservoir) wild with infected animals (intermedi - ary It easily hosts). via direct spreads contact with bodily fuids or fomites the (caring for and handling sick deceased patients is particularly high risk) Also via transmitted contact (up to sexual 12 months after the acute infection) respiratory droplets respiratory droplets par and aerolised infected ticles from people and fomites. particlesAerolised in thecan remain air 2 h up to for Mode of transmission Contact with virus- Direct contactDirect with - (then Zaire) (then Zaire) DRC of Gabon, Republic Congo Uganda Liberia, Sierra Leone, Nigeria, Italy, Mali, Senegal, Spain, United USA, Kingdom Uganda global outbreaksglobal 2–3 years, every is until vaccine - decreas developed, ing number of cases worldwide outbreaks in all of theregions world in number (increase of cases and resur of in areas gence in and USA Europe the 10 years) last Event/distribution 1976: Sudan, DRC 1976: Sudan, DRC 1995–1997: Gabon, 2001–2003: Uganda, 2007–2009: DRC, 2013–2016: Guinea, 2018–current: DRC, Until 1963: massive 1963: massive Until 2019–current: (continued) virus)* 2 Table Disease (pathogen) Ebola (Ebola virus) Measles (measles

1 3 Journal of Neurology ART against HIV is against ART both against efective efects of thedirect virus- and compli cations secondary opportunisticto It has also infections. - pro slow to shown gression of cognitive associated disorders with the disease involves neuropathy of both alleviation pain and prevent either progression by or sus - initiating ART pending ART-related peripheral neuropathy Treatment Early initiation of Early of peripheral Treatment Supportive care Supportive - sistent or latent sistent (including infection - secondary reactiva tion of other latent viruses) ondary coagulop - to and vasculitis athy autoimmune autoimmune - of neuro Mechanism logical injury Direct invasion Direct - Para-infectious—sec Post-infectious— Post-infectious—per Post-infectious— disorders sclerosis-like due to ary infections viruses:reactivated - multifo Progressive - cal leukoencepha (PML) (JC lopathy virus), primary CNS lymphoma (Epstein-Barr virus), neurocrypto - coccosis (Crypto - coccus neoformans), - neurotoxoplasmo sis (Toxoplasma gondii) encephalomyelitis alomyelitis - manifesta Neurologic tions Aseptic meningitis Aseptic Subacute encephalitis Neurocognitive Peripheral neuropathy GBS myelopathy Vacuolar Stroke lateral Amyotrophic Myopathy second - Predisposes Post-infectious Post-infectious enceph - Post-vaccinal tion presents as tion presents illness a fu-like sore with fever, throat, body rash, and myalgia fatigue, lymphadenopathy After 1–2 weeks. for of chronic years - symp infection the to related toms immune system appear damage to related and are the opportunistic that infections include ensue. They loss, chronic weight diarrhoea, fever, skin lesions, and other symptom any organ to related associated damage with the opportunistic infections fever, myalgia, myalgia, fever, fatigue headache, and eventual An vomiting. on the rash early and mouthtongue installs followed skin generalised by It progresses to rash. around rash pustular which the 6th day, a crustthen forms and a scab. 3 weeks after the start of scabs will most rash of fallen have Non-neurological Non-neurological features - The acute infec After 2–4 days of After 2–4 days 1st acute infection acute infection 1st symptoms of development AIDS Incubation period 2–6 weeks for the for 2–6 weeks until the 2–15 years 7–19 days fuids from infected infected fuids from people, including milk, blood, breast semen and vaginal The virussecretions. is also transmitted during vertically and pregnancy delivery fuids from patients’ patients’ fuids from and fomites sores, respiratory droplets people infected from Mode of transmission Exchange of body Exchange Direct contactDirect with Antiquity since eleventh century with various outbreaks Plague—Rome century: Ameri - cas—decimation of populations native USA Event/distribution 1981–current: global Endemic in Asia since Asia in Endemic Endemic in Europe 165AD:Antonine 735–737: Japan sixteenth-seventeenth eighteenth century: (continued) immunodefciency virus-HIV) virus) 2 Table Disease (pathogen) AIDS (human Smallpox (Variola (Variola Smallpox

1 3 Journal of Neurology

- paralysis secondary to anterior myelitis, GBS and transverse myelitis [59]. The most common CNS manifestation is brainstem encephalitis, severely afecting the medulla and frequently evolving to cardiac dysfunction and neurogenic pulmonary oedema. Seizures may occur in children under two years. Myoclonic jerks are frequent in encephalitic cases. Up to one-ffth of children with severe neurological manifestations have sequelae, and only a quarter of those with brainstem encephalitis and cardiorespiratory failure have a full neurological recovery [20].

Variant Creutzfeldt‑Jakob (vCJD)

Bovine spongiform encephalopathy (BSE) was first described in 1985 and peaked in 1992/1993. The frst cases of vCJD in humans were described in 1995 in the UK [149], and were found to be caused by the BSE prion [26]. vCJD afects a younger age group when compared to sporadic CJD with a median onset age of 26 years in the UK and 36 years in France [15]. The incubation period may be as long as 15–20 years [27]. In the earliest phase of vCJD psychiatric features are prominent with depression, short-lived delusions and hallucinations being most common [15]. Over 60% of patients may have persistent painful sensory features which are frequently lateralised. The majority of patients present with cerebellar features 4 to 6 months after disease onset. Myoclonus is a late feature, occurring more 6 months after onset, and chorea, tremor and dystonia are also common at this stage. Oculomotor problems and complaints of diplopia may be present in half of patients [15]. All patients develop cognitive impairment (with initial symptoms being disori- entation and poor memory) and eventually dementia. Pro- blood brain barrier BBB blood brain therapy, antiretroviral gression to death occurs on average 14 months after disease onset.

Direct or indirect contact with infected individuals

Infuenza

Infuenza viruses can be divided in seasonal and pandemic.

severe severe Sars GBS Guillain–Barré of America, States ADEM acute disseminated encephalomyelitis, system, syndromes, nervous CNS central United The seasonal infuenza A viruses (H3N2 and H1N1) cause yearly epidemics, while pandemics of infuenza are the consequence of cross-species transmission, followed by adap- tion to humans [77]. The CNS is the most common site of extra-respiratory complication of infuenza infections [77]. Febrile seizures and encephalopathy are the most frequent

has rarely been reportedbeen Asia in adults in Encephalopathy of cause a as rarely has neurological manifestations, afecting predominantly children [137]. Other acute neurologic presentations include meningitis, encephalitis (including acute necrotising encephalopathy and acute haemorrhagic leukoencephalopathy), (continued) and an increased frequency of ischaemic stroke, all during USA of Congo, USA Republic Democratic the acute disease [11, 137]. Infuenza may also be associ- acute respiratory respiratory MERS Middle East ART syndrome, syndrome, with outbreaks/epidemics, limited dates are the endemic around diseases are world *Where vivax ** Plasmodium 2 Table immu intravenous involve usually syndromes) as Guillain–Barré, and Bickerstaf’s (such nature of autoimmune complications Miller Fischer infectious post Immunomodulatory for treatment precipitatingits of cause corticosteroids, regardless with treated intravenous dose high typically is ADEM plasmapheresis. or noglobin DRC ated with Reye’s syndrome, an acute encephalopathy with

1 3 Journal of Neurology - glucose and elevated protein in encephalitis or meningitis. Similar fnd - protein and elevated glucose levels ings in AFP but with protein raised described monly protein in meningoencephalitis and myeloradiculitis protein and hypocalcaemia and ALT AST elevated Lymphocytic pleocytosis and normal glucose have also been described and normal pleocytosis have glucose Lymphocytic in some patients normal glucose in meningoencephalitis. In GBS, usually normalnormal WBC in meningoencephalitis. In GBS, usually glucose levels protein and increased mal protein and glucose levels and glucose mal protein penia, haemoglobinuria and elevated transaminases are usually present present usually are transaminases penia, haemoglobinuria and elevated have may women and pregnant children Young of severities. in a range and metabolic acidosis hypoglycaemia elevated aminotransferases and bilirubin levels, increased prothrombin prothrombin increased and bilirubin levels, aminotransferases elevated time (PT), albuminuria CSF: pleocytosis, which can be neutrophilic or lymphocytic, normal or lymphocytic, can be neutrophilic which CSF: pleocytosis, and serum com - lipase are ALT AST, elevated Bloods: leucocytosis, CSF: pleocytosis (although it can be very modest or normal) (althoughCSF: pleocytosis modest it can be very and raised thrombocytopenia, present), always (almost Blood: lymphopenia CSF: moderate neutrophil pleocytosis, increased protein, low glucose. glucose. low protein, increased pleocytosis, neutrophil CSF: moderate leucocytosis Bloods: neutrophilic CSF: moderate pleocytosis and mildly raised protein, with mostly with mostly protein, raised and mildly pleocytosis CSF: moderate levels transaminases increase thrombocytopenia, Blood: leukopenia, Laboratory Blood: neutrophilia and hyponatremia are frequent are and hyponatremia Blood: neutrophilia CSF: usually lymphocytic pleocytosis (though pleocytosis it can be acellular), nor lymphocytic CSF: usually CSF: very mild pleocytosis, low glucose and increased protein levels protein and increased glucose low mild pleocytosis, CSF: very thrombocyto - Blood: Anaemia, hyperbilirubinemia haemolysis), (due to There’s scarce information about CSF in yellow fever in the literature fever about CSF in yellow information scarce There’s thrombocytopenia, neutropenia), (with relative Bloods: leukopenia - be seen during and include leptomenin to theweek 1st likely more lesions in periventricular enhancement, T2/Flair hyperintense geal structures deep brain areas, nucleus, red (thalami, basal ganglia, peduncle, substantia nigra)cerebral lobes. DWI and mesial temporal T2/FLAIR lesions before detect may sequences abnormalities in the anterior horn and roots imaging modalities can show unspecifc oedema and haemorrhage in imaging modalities can show of the areas diferent cerebrum during the acute phase. ADEM cases withpresent hyperintensity of T2/FLAIR typical confuent areas spinal cord patients have Myelopathic with consistent demyelination. lesions in theT2/Flair hyperintense afected segment (but negative culture), with culture), normal (but negative pestis Y. PCR in the CSF for tive MRI - microceph matter and include: severe afects both white and grey skull interface collapse, forid grey-matter ventriculomegaly, aly, calcifcations, corpus cortex thinning, callosum anomalies, cerebral - cho hypoplasia, cerebellum abnormal patterns, gyral pontine atrophy, microphthalmia, cataracts atrophy. nerve and optic rioretinal atrophy, of encephalitic adult cases in non-specifc and can be Neuroimaging reportednormal. asymmetric fndings are commonly subcortical Most lesions (also seen in DWI) T2/Flair hyperintense and only visualised in the MRI. MRI changes include hyperintense include hyperintense visualised in the MRI. MRI changes and only and lesions of thalamus, basal ganglia pons, cerebellum, midbrain, cortex cerebral normal. CT may display vasogenic oedema specially involving the involving oedema specially vasogenic display normal. CT may in thalamus and cerebellar hypodensities posterior ischaemic brain, in non-specifc T2WI hyperintensities MRI shows Brain white matter. the corpus thalamus, periventricular callosum, occipital white matter, sub-cortex and basal ganglia litis. Case reports have described lesions associated with the litis. Case reportsrare have with unspecifc T2WI 17D vaccination fever of yellow complication and peduncles, medulla, spinal cord lesions in cerebral hyperintense white matter cerebral Brain CT is usually normal. MRI abnormalities Brain If present, CT is usually Brain are with present normal but some may images, AFP cases have Most Brain CT and MRI can be normal even in encephalitic cases. Both in encephalitic cases. Both CT and MRI can be normalBrain even Imaging once case report Only in the of paediatric literature, plague with posi - Brain MRI abnormalitiesBrain Zika syndrome congenital of symptomatic CT: bilateral thalamic hypodensities, which may be haemorrhagic may which thalamic bilateral hypodensities, CT: Brain imaging fndings do not correlate imaging fndings do not Brain with parasitaemia, and can be There’s a paucity of MRI studies in yellow fever-related encepha - fever-related in yellow a paucity of MRI studies There’s Imaging and laboratory features of each pandemic disease of each Imaging and laboratory features West Nile virus [ 29 , 123 131 147 ] West Chikungunya fever [ 19 , 41 42 86 146 ] fever Chikungunya Plague [ 8 , 34 35 82 109 158 ] 3 Table Disease Zika virus [ 7 , 90 93 94 105 ] Japanese encephalitis [ 131 , 140 145 ] Malaria [ 78 , 107 111 153 ] Yellow fever [ 85 , 89 ] fever Yellow

1 3 Journal of Neurology lymphocytic), mildly elevated protein levels and normal in the glucose levels protein elevated mildly lymphocytic), acute phase pleocytosis with normal or raised protein levels may be present in be present may withpleocytosis normal levels protein or raised encephalitis or meningitis dengue myelitis, ally normal protein and glucose levels in acute encephalitic patients normal levels and glucose protein ally involvement central CSF 14-3-3 is positive only in half of vCJD patients only CSF 14-3-3 is positive glucose, in encephalitic cases glucose, CRP AST, thrombocytopenia, elevated CSF: pleocytosis (neutrophilic in the 1st days which then progresses to which in thedays (neutrophilic CSF: pleocytosis 1st CSF: frequently normal in most encephalitic cases. Modest lymphocytic normal lymphocytic encephalitic cases. Modest in most CSF: frequently and rising thrombocytopenia haematocritBlood: leukopenia, Laboratory CSF: mild lymphocytic pleocytosis (though it may be normal), (though and usu - pleocytosis it may CSF: mild lymphocytic in those with especially neutrophilic, mainly Bloods: leucocytosis, CSF: usually normal, sometimes with modest total protein elevation. elevation. normal, with total protein modest sometimes CSF: usually CSF: normal or with pleocytosis, proteins frequently elevated, normal elevated, CSF: normal frequently or with proteins pleocytosis, normal. be closer to lymphocytopenia, Frequent may Bloods: variable, cord and in the motor cortex and in thecord motor MRI of meningoencephalitis frequently shows hyperintensity on hyperintensity shows MRI of meningoencephalitis frequently cortical in both thalami, matter basal ganglia, grey T2WI and DWI haemorrhages and difuse Petechial and subcortical white matter. common oedema are brain shows T2W hyperintense in the T2W hyperintense dentate midbrain, nuclei, dorsal shows and medulla. aspect of the pons (pontine tegmentum), basal ganglia no supratentorial involvement there’s Usually sign”—an area of high signal in T2W thesign”—an area posterior thalamus rather include be involved may Other other area. which areas than any dorsomedial thalamic nuclei and the periaqueductal matter. grey in the caudate, putamen and corti DWI - Hyperintensities in T2Wand also afected vCJD in sCJD, may involved characteristically cal areas, patients encephalitic syndromes have been described in those patients, divided have encephalitic syndromes high signal in the splenium of corpus in splenial sign (T2 and DWI signal callosum); ANE-pattern encephalitis- hyper (acute necrotising in T2WI thalami, centrum pons, cerebellum, midbrain, semiovale); PRES pattern signal in T2WI centrum (hyperintense semiovale, oedema (difuse brain malignant brain posteriorly); prominent more T2WI hyperintense displays cerebellitis infectious oedema). Post - and hydro in the compression with cerebellum, brainstem images with patients presented loss of cephalus. Encephalitis lethargica viral Post in theneurons subthalamus midbrain, and hypothalamus. subjects had depigmentationparkinsonism of the substantia nigra and locus coeruleus MRI show T2W hyperintense ventral motor tracts both in the tracts spinal motor ventral T2W hyperintense MRI show Imaging of haemorrhages. Brain foci intraparenchymal reveal CT may Brain In encephalitic patients, brainstem is the most afected site. Brain MRI is theafected site. Brain most In encephalitic patients, brainstem Brain MRI of most cases of vCJD show the characteristic “pulvinar the “pulvinar characteristic cases of vCJD show MRI of most Brain Encephalitic patients may present with present normal imaging. Specifc Encephalitic patients may (continued) Poliomyelitis [ 38 , 58 63 81 ]] Poliomyelitis Dengue fever [ 17 , 49 129 ] Dengue fever 3 Table Disease Enterovirus-71 [ 59 , 67 100 125 130 133 ] Enterovirus-71 Variant Creutzfeldt-Jakob disease [ 15 , 88 ] Creutzfeldt-Jakob Variant Infuenzae [ 1 , 18 30 44 51 ]

1 3 Journal of Neurology - - ALT). Electrolyte disturbances disturbances Electrolyte ALT). > rhaquia and generally normal glucose and generally rhaquia LDH and increased increased CRP, albumin, raised phils, decreased interleukin-6 (AST transaminases elevated topenia, - hypoka loss: hypo/hypernatremia, with the disease-associated volume Coagulation abnormali and hypomagnesemia. - laemia, hypocalcaemia occur ties may cytic pleocytosis with high protein and mildly low glucose low and mildly withcytic pleocytosis high protein of measles antibody high titres SSPE—only protein. elevated acute infection Bloods: variable. Frequent fndings are lymphopenia, decreased eosino - decreased lymphopenia, fndings are Frequent Bloods: variable. CSF: normal or with with pleocytosis, degrees variable of proteinor CSF: few case reports, evaluated only to detect viruses’ genetic material genetic viruses’ detect to only case reports, evaluated CSF: few in the thrombocy (earlier disease) or leucocytosis, Bloods: leukopenia Laboratory - encephalitis: lympho CSF: acute encephalitis and post-measles with present and pleocytosis normal, but may MIBE—CSF is usually during thrombocytopenia and T cell cytopenia theBloods: Leukopenia, - infected with Sars-Cov1 and MERS-CoV, recent studies have have studies recent and MERS-CoV, with Sars-Cov1 infected reported lesions in patients with variated manifestations neurologic day. comes up every information and novel secondary Sars-Cov2 to reported theWithin pleiad of described lesions, thefrequently most or tubular shape) afecting mainly abnormalities SWI (withare ovoid the splenium, juxta cortical and main white matter tracts, U-fbres lesions on T2WI and DWI non-confuent white matter hyperintense cor with associated or not haemorrhagic lesions and often involving peduncles, symmetricpus callosum and middle cerebellar thalamic haemorrhage- compat and necrosis lesions with oedema, petechial cerebral the to ible withbrainstem, ANE (with extension variable Other white matter tracts) and cerebellar described lesions include spaces sign abnormalities subarachnoid in nerve of optic prominence enhancement bulb, contrast the lobe and olfactory medial temporal Some nerves. and cranial lesions, leptomeninges of intraparenchymal in the T2WI hyperintensities periventricular patients also developed and ADEM-com - of demyelination, suggestive and spinal cord, areas been described 19 patients have patible lesions in COVID Case reports have described punctate lesions in T2WI hyperintense Case reports have the corpus subcortical callosum and peri white matter, - ventri fourth lesions withcle, compatible microvascular shows multifocal hyperintense T2WI in both cerebral hemispheres, hemispheres, T2WI in both cerebral hyperintense multifocal shows of dorsal striatum and cortex oedema. MIBE presents involvement - cerebel lesions in the hyperintense brainstem, with T2WI and DWI cortical and subcorticallum, multifocal matter lesions (including grey and thalamus), enhancement withoutbasal ganglia contrast lesions in T2WI thehyperintense white matter of both parietal and the corpus callosum and basal lobes. It progressesinvolve to temporal encephalomalacia culminating with generalised ganglia, Imaging of patients images about brain information scarce While there’s Patients with presumed Ebola meningoencephalitis are rarely scanned. with rarely Ebola meningoencephalitis are presumed Patients In the acute phase and acute post-measles encephalitis brain MRI In theencephalitis brain acute phase and post-measles asymmetric with patchy course, initially SSPE has a progressive (continued) Coronavirus [ 55 , 66 70 102 162 163 165 ] Coronavirus 3 Table Disease Ebola [ 10 , 21 22 60 80 115 ] Measles [ 6 , 16 39 47 74 124 ]

1 3 Journal of Neurology MIBE acute disseminated ADEM multiple sclerosis, sclerosis, multiple MS attenuated inversion recovery recovery fuid ‐ attenuated inversion - LDH lactate dehydro protein, C reactive Guillain–BarréGBS syndromes, with high or normal and normal protein levels glucose after exposure) weeks to (days phase of HIV infection CSF: HIV aseptic meningitis: monocytic or lymphocytic pleocytosis pleocytosis meningitis: monocytic or lymphocytic CSF: HIV aseptic CSF patterns variate Specifc opportunisticlead to agents in the acute frequent are and thrombocytopenia Bloods: lymphopenia Laboratory alanine aminotransferase, CRP alanine aminotransferase, - - progressive multifocal leukoencephalopathy, leukoencephalopathy, multifocal progressive PML acute necrotising encephalitis, necrotising acute ANE ALT ALT aspartate aminotransferase, acute immunodefciency syndrome, syndrome, immunodefciency acute AIDS hyperintense lesions afecting mainly periventricular and deep white lesions afecting mainly hyperintense with associated encephalomalacia, with no mass efect or matter, lead to may vasculopathy cerebral enhancement. HIV-associated and medium arter aneurysms of large multiple nodular and fusiform concentric alternating zones of MRI shows ilesional oedema. Brain ring and isointense in T2WI withcontrast post enhance - hypo/hyper ment periventricular white matter with no mass efect and enhancement in the basal ganglia spaces mostly along perivascular ment, spread and cerebellum. brainstem hemispheres, and white matter of cerebral pseudocysts gelatinous spaces can coalesce into Dilated perivascular (“soap bubble”) with high signal in T2WI. Cryptococcomas usu - are nodular lesions in the T2WI hyperintense parenchyma cerebral ally shows disease usually with enhancement. The meningeal variable enhancement and pachymeningeal leptomeningeal subcortical in lesions, especially U-fbres subcortical demyelinating the parieto-occipital Multiple punctate areas. high T2 signal lesions it from sign”) diferentiate (“milky way area thearound involved lesions multiple sclerosis with high signal in T2 iso/hypointense T1 hypointense, are which enhancement with sub ependymal extension and homogeneous DWI of theand crossing corpus callosum ies which can cause subarachnoid or intraparenchymal haemorrhages or intraparenchymal can cause subarachnoid ies which with presents myelopathy vacuolar HIV-related or embolic infarcts. but cervical cord at the thoracic level, (mainly atrophy spinal cord symmetric bilateral be afected) with dorsal column frequent may involvement thecommon being: most dependent of its agent, and at the corticomedullaryganglia junction with 1–3 cm and per HIV-associated encephalopathy usually presents with presents symmetric T2WI usually encephalopathy HIV-associated in the non-specifc T2WI hyperintensities - CMV encephalitis shows lesions with leads to little enhance - - Neurocryptococcosis usually and asymmetric with periventricular and multifocal - PML is typically as supratentorial presents mass lesions classically - CNS lymphoma CNS opportunistic infections in AIDS patients have characteristic characteristic in AIDS patients have CNS opportunistic infections causes nodular lesions in the basal typically - Neurotoxoplasmosis Imaging I susceptibility weighted images, AST images, weighted I susceptibility human immunodefciency virus,immunodefciency human HIV posterior reversible encephalopathy syndrome, syndrome, encephalopathy disease 2019, PRES posterior reversible coronavirus acute respiratory respiratory MERS Middle East COVID19 syndrome, syndrome, severe Sars weighted images, SW images, difusion ‐ weighted (continued) DWI sporadic Creutzfeldt–Jakob disease, Creutzfeldt–Jakob sporadic disease, sCJD Creutzfeldt–Jakob vCJD variant 127 , 134 161 ] subacute sclerosing panencephalitis measles inclusion-body encephalitis, SSPE subacute sclerosing Cholera was not included in this table as its neurological manifestations are related solely to metabolic disturbances and no structural changes in the described imaging or CSF are brain and no structural metabolic disturbances to changes solely related are included in this not table manifestations as its neurological was Cholera FLAIR images, T2WI T2 weighted AFP acute faccid paralysis, fuid, imaging, CSF cerebrospinal resonance MRI magnetic tomography, CT computed images, genase, genase, HIV [ 54 , 95 110 132 ] 5 24 99 117 118 3 Table Disease central nervous system, system, nervous central CNS encephalomyelitis, encephalomyelitis,

1 3 Journal of Neurology mitochondrial dysfunction and hepatic metabolic failure, reported among critically ill patients, later during the course triggered by drugs (especially aspirin) [121]. of the disease. However, it is not clear whether this is a con- Late post infectious neurological complications of infu- sequence of direct viral CNS infection, the host infamma- enza have been extensively reported and are more frequent tory response, and/or immunologic processes [139]. in adults. These include including GBS, cerebellitis, Kleine- Levin syndrome, myositis and transverse myelitis [137, MERS‑CoV 150]. A link between encephalitis lethargica (von Economo disease) and infuenza A has been suggested with an out- MERS has been an ongoing pandemic since initial reports in break of encephalitis lethargica cases noted after the 1918 2012 and has already afected > 2500 people, 35% of which Infuenza pandemic [56]. During the acute phase, patients died [155]. In Saudi Arabia, seizures were reported during presented with excessive sleepiness, disorders of ocular the acute phase, in > 8% of patients and confusion in > 25% motility, fever and movement disorders; frequently preceded [113]. ADEM, encephalitis and stroke (possibly due to vas- by fu-like symptoms. The chronic phase typically devel- culitis) have also been described [3]. Notably none of these oped 1–5 years after acute disease, but has been delayed conditions had MERS-CoV detected in CSF. A Korean study by up to 45 years. Symptoms include Parkinsonism with reported Bickerstaf’s brainstem encephalitis and polyneu- psychiatric symptoms, abnormal ocular movements, speech ropathy among patients with MERS in the frst few weeks abnormalities, spasticity and brisk refexes; a constellation of infection [64]. of symptoms memorably described by the neurologist Oli- ver Sacks in his book “Awakenings” [114]. There remains SARS‑CoV‑2 controversy whether encephalitis lethargica is caused by direct CNS invasion by the infuenza virus, or represents a In December 2019, a new coronavirus appeared in Wuhan, virus-related autoimmune phenomenon [56]. Other cases of China. A large current worldwide pandemic has resulted in post-encephalitic Parkinsonism not related to encephalitis six million recorded cases and over 1 million deaths, as of lethargica have been reported after infuenza infections [61]. end of September 2020 [62]. Neurological complications of the disease have been reported and its mechanisms are Coronaviruses still being scrutinised by the scientifc community [36]. A retrospective Chinese study with 214 hospitalised patients Since the beginning of the twenty-frst century three corona- described neurological features in just over one third of viruses (CoV) have been responsible for pandemics; severe cohort, including dizziness, headaches and impaired con- acute respiratory syndrome (SARS-CoV1) in 2003, Middle sciousness [83]. A French cohort of 58 critically ill patients East respiratory syndrome (MERS-CoV) in 2012 and SARS- reported encephalopathy and corticospinal signs. Brain MRI CoV2 (also known as COVID-19) in 2019. Most human was performed in 13 patients, 8 of whom had leptomenin- coronaviruses cause only mild respiratory symptoms and geal enhancement and 2 had acute ischaemic lesions [55]. four strains are endemic worldwide, responsible for up to There are reports of COVID patients with rhombencephalitis one third of upper respiratory tract infections in immuno- [151] and meningoencephalitis [159], some with positive competent individuals: HCoV-229E, -OC43, -NL63 and Sars-CoV2 in the CSF [92], most of which presented with -HKU1 [32]. seizures and encephalopathy. Acute haemorrhagic leukoen- Coronaviruses can invade the CNS and have been associ- cephalitis [108], demyelinating lesions [162], ADEM [102] ated with many neurological sequelae including demyelinat- and acute myelitis have also been reported [2]. Peripheral ing diseases [4], optic neuritis [33], and Parkinson disease nervous system manifestations include anosmia/ageusia in [37]. HCov-OC43 was linked to a case of ADEM [160], over 80% of infected [73], GBS (both demyelinating and fatal encephalitis in an immunodefcient child [91], and to a axonal) [138], Miller-Fisher syndrome (MFS) and isolated subset of Chinese children with encephalitis [75]. abducens palsies [48]. An increased frequency of acute cerebrovascular events among COVID patients is reported Sars‑CoV1 [101], at a similar frequency to previous studies of patients with sepsis [12]. This may be the consequence of a hyper- The 2002–2003 pandemic affected > 8000 people in 30 coagulable state [164] related either to the viral infection or countries, 10% of whom died [71]. SARS-Cov1 was found to the host response [97]. in CSF samples and brain tissue of encephalopathic patients There are increasing reports of many patients sufering with symptoms including seizures [72] and optic neuritis, from a long-term syndrome lasting more than 3 months post manifesting in the acute phase [157]. Large artery ischaemic infection which has been badged as “long COVID.” Neuro- stroke were reported in 2.4% [141]. Neuromuscular disor- logical-type symptoms including neurocognitive difculties, ders including myopathy and axonal motor neuropathy were depression and other mental health conditions, peripheral

1 3 Journal of Neurology neuropathies and muscular weakness [46]. This is distinct measles virus after failure to completely clear the primary from critical illness acquired weakness, and the neurocogni- infection, and manifests initially as behavioural changes and tive sequelae described in post intensive care syndrome [9], cognitive decline, followed by myoclonic jerks, dyskinesias as the majority of the patients reporting this syndrome have and ataxia, progressing to coma and death [16, 47]. Measles not been hospitalised. vaccination reduces SSPE incidence.

Ebola HIV/AIDS

First described in 1976, Ebola has caused several outbreaks, Since the beginning of the pandemic in the 1980s, 75 million mainly in African countries, the largest in 2014–2016. Neu- people have been infected with HIV, and 32 million have rological complications begin in the late stage when patients died [152]. While the introduction of combined antiretroviral can have encephalopathy, seizures (probably due to meta- therapies (cART) has decreased mortality and morbidity of bolic abnormalities), meningitis and meningoencephalitis acquired immunodefciency syndrome (AIDS) and oppor- [21]. The exact prevalence of neurological complications in tunistic infections (OI), the prevalence of complications the acute phase is unknown. The CNS may be a reservoir for associated with long-term HIV infections and its treatment Ebola virus; it was recovered from the CSF (at higher lev- have increased, particularly the neurologic ones [95]. Acute els than the blood) of an Ebola survivor 9 months after the HIV infection can cause headache and neck stifness second- patient’s recovery, when it then developed meningoencepha- ary to aseptic meningitis [119]. litis and radiculitis [60]. Long-term neurological sequelae The most common CNS OI are tuberculous meningoen- are not uncommon among survivors, with memory loss in cephalitis, neurotoxoplasmosis, cryptococcal meningitis, up to 40%, headaches in one third and muscle pain in 13% cytomegalovirosis and progressive multifocal leukoencepha- [128]. lopathy (PML) secondary to JC virus [95]. Others include primary CNS lymphoma (associated with Epstein-Barr Measles virus) and varicella-zoster vasculitis, with encephalopathy, cranial nerves palsies, strokes and seizures [119]. Until the introduction of attenuated measles vaccine, the Immune reconstitution infammatory syndrome (IRIS) disease killed 2–3 million people/year [154]. The mortality may occur weeks to months after recovery from an immu- associated with measles decreased steadily since widespread nodefcient state. Low CD4 before initiation of cART is vaccination programs were put in place in the beginning of the strongest predictor of IRIS. It can afect any organ and the twenty-frst century. However, since 2016, declining vac- CNS-IRIS prevalence is around 1%, occurring in response to cination rates have resulted in epidemics in all WHO regions, dying opportunistic agents (frequently linked to Cryptococ- including in previously measles-eradicated areas, like USA cus or PML) or as a fulminant encephalitis associated with and Western Europe [104]. Though pneumonia is the main CD8 + T cells infltration [95]. cause of death, severe CNS manifestations may occur. Pri- Up to 50% of HIV patients may be afected by HIV-asso- mary measles encephalitis (PME) manifests during the ciated neurocognitive disorders (HAND) which range from exanthem due to direct CNS invasion with seizures, distur- asymptomatic to dementia [52]. HAND is a subcortical cog- bances of consciousness and focal signs. Up to 15% of such nitive disorder and presents with psychomotor retardation, patients die and a quarter have permanent neurological dam- executive dysfunction, defcits of working memory, retrieval, age [16]. The most frequent CNS complication of measles judgment, attention and impulse control, manifesting as a is acute post measles encephalitis, which occurs 2–30 days long-term complication of the infection. In the cART-era the after infection and afects around 0.1% of children after a incidence of HIV-related dementia has decreased to under measles infection. Another complication is measles-induced 5% [95], HIV disease markers are no longer closely related ADEM, which begins weeks or months after rash clearance to cognitive impairment [50], and patients receiving cART [16, 47]. Prognosis is better than with PME. Measles inclu- have a better cognitive performance than patients who are sion body encephalitis (MIBE) is another complication, in cART-naïve [52]. This indicates that the pathophysiology which a progressive measles virus brain infection afecting of cognitive impairment may be related to the infamma- patients with impaired cellular immunity, manifesting within tory process which occurs in the presence of the virus in 1 year of the primary infection. It presents as altered con- the CNS. sciousness, refractory seizures and focal signs. Mortality is HIV infection can lead to a distal symmetric polyneu- 75% [16, 47]. Subacute sclerosing panencephalitis (SSPE) ropathy, which can be related both to neurotoxic antiret- manifests 4–15 years after an acute measles infection, with rovirals and to the viral infection per se, afecting small a higher incidence in children who had the disease before fbres and causing numbness and painful distal limbs symp- the age of 5 [47]. SSPE is caused by persistence of a mutant toms. Polyneuropathy afects 30–70% of HIV patients and

1 3 Journal of Neurology immunosuppression no longer predicts its severity [103]. It with decreased level of consciousness, headache, dizziness, may be related to neurotoxicity secondary to viral replica- seizures and focal signs, also in the acute phase. Post-dengue tion or to an immune reconstitution mechanism, damaging immune-mediated complications include GBS, transverse peripheral nerves and usually manifests in the chronic phase myelitis, ADEM, mononeuropathies of cranial nerves, optic of the disease [95]. GBS (mainly demyelinating) has been neuropathy, muscle dysfunction and intracranial haemor- associated with HIV very early in the infection [54]. rhages during the convalescence stage [17]. HIV is independently associated with increased risk for War, conficts and natural disasters can facilitate the stroke which may be secondary to viral efects on endothe- spread of diseases like cholera. Cholera has caused seven lial dysfunction, vasculopathy and hyperviscosity [103]. pandemics in the last two centuries. Electrolyte disturbances Protease inhibitors used as antiretrovirals may also have a and hypoglycaemia (mainly in children) secondary to severe negative efect on vascular endothelial function. diarrhoea and acute dehydration can lead to symptomatic Vacuolar myelopathy manifests in chronic AIDS [119]. seizures [23]. Concurrent outbreaks of cholera and periph- An amyotrophic lateral sclerosis-like syndrome has been eral neuropathies have been described among undernour- reported, and may resolve resolved after initiation of cART ished displaced populations, in the subacute phase of the [95, 119]. Myopathy can occur regardless of the course of disease [112]. HIV infection, and is associated with direct virus lesion, The recent decrease in coverage of MMR (measles, infammatory response, or ART (zidovudine) [95]. mumps and rubella) vaccine in some areas has also led to an increase of cases of rubella and mumps. Mumps can cause aseptic meningitis and encephalitis in the early days of the Other diseases and potential threats disease and ADEM as a late post infectious complication [6]. The major neurological manifestation of rubella is the con- Increases in global temperatures and a changing climate can genital rubella syndrome (CRS) in foetuses whose mothers lead to environmental adaptations of beneft for various dis- are infected during pregnancy. CRS includes causes enceph- ease vectors, including mosquitoes. These are the key vector alopathy, microcephaly and sensorineural hearing loss. for malaria, whose epidemic potential should increase in Encephalitis has also been reported during the exantematic susceptible tropical countries (extending to highland areas) phase [6]. that had controlled the disease or be reintroduced in tem- Smallpox was a cause of massive epidemics until its perate climates that had previously eliminated it. The most eradication in the 1980s by global immunisation programs. severe form of malaria (and cause of 500,000 deaths per Since most of people living today are not vaccinated against year) is cerebral [107], afecting mainly young children dur- it and the viable variola virus is still kept in two maximum ing the acute illness. security laboratories [87], it is feared that it could be used in Yellow fever, another mosquito-borne virus, was a major bioterrorist attacks. Neurological complications of smallpox threat to human health until the beginning of the twentieth were uncommon and have been poorly studied, but descrip- century, having caused multiple epidemics and deaths in tions are compatible with demyelinating/inflammatory cities distant from endemic areas, in North America, the encephalomyelitis, 5 to 16 days after the acute disease [13]. Caribbean and Europe [89]. The expansion of the disease to Post-vaccination encephalomyelitis has also been described, non-endemic areas means that susceptible non-vaccinated mainly in young children [13]. populations are now prone to new epidemics. The virus can rarely invade the CNS and cause encephalitis and meningitis early in the course of infection. Encephalopathy is also com- Conclusion: preparing for the future mon in the context of hepatic failure of severe forms of the disease. Though extremely rare, yellow fever vaccine-asso- Pandemics and epidemics have been present for thousands ciated neurotropic disease is reported, causing encephalitis, of years, and have played a pivotal role in history. Much of GBS and ADEM [89]. previous focus has been on the acute illnesses themselves, The mosquito-borne dengue virus has expanded from a with relatively little attention paid to the social, human and sporadic disease afecting 9 countries in the 1970s to being economic consequences of neurological sequelae. However, endemic in over 100 countries; half of the world is now it is these sequelae that often lead to signifcant amounts of at risk. Neurological complications can occur at any stage. mortality and long-term morbidity. Dengue encephalopathy is the most common and involves Under-recognition of neurological manifestations means impaired consciousness in the context of shock, liver fail- that few studies have been conducted in previous pandem- ure and electrolyte disturbances in the frst 10 days of the ics to understand, treat and prevent neurological compli- disease. Meningitis and encephalitis due to CNS invasion of cations, and so the burden of secondary complications is the virus are also possible, though rare, and patients present even greater. With the recent developments in imaging, new

1 3 Journal of Neurology information about the presentation of CNS diseases is avail- Cambridge Biomedical Research Centre grant and a Senior Investiga- able and can assist in the proper diagnosis of neurologic tor Award. VFJN was supported by an Academy of Medical Sciences/ The Health Foundation Fellowship. manifestations of infectious diseases. However, even in developed countries, diagnostic tests are limited and treat- Author contributions FV and VFJN conceived the idea. FV performed ments are often inadequate or non-existent, with signifcant the literature review and initial draft. All authors contributed substan- long-term economic and healthcare consequences. There- tially to the writing of the manuscript. fore, it is reasonable to expect that in low and middle-income Funding countries with poorer access to diagnostic tests and treat- DW was supported by an Academic Clinical Fellowship. DKM was supported by the NIHR through the NIHR Cambridge Bio- ments, the neurological involvement by these diseases will medical Research Centre grant and a Senior Investigator Award. VFJN have a greater economic impact. Potentially limiting future was supported by an Academy of Medical Sciences/The Health Foun- human capital by leaving long-term motor and cognitive dation Fellowship. No funding source had any role in the writing of impairments. this manuscript and decision to submit for publication. This urgent need to pay more attention to the short- and Compliance with ethical standards longer term sequelae of pandemics has been brought into sharp focus with COVID-19 where there have been numer- Conflicts of interest On behalf of all authors, the corresponding author ous reports of short-term sequelae and a growing apprecia- states that there is no confict of interest. tion of longer term problems. There is a growing recognition of the need to work globally with international collabora- Open Access This article is licensed under a Creative Commons Attri- tions being formed to better understand the neurological bution 4.0 International License, which permits use, sharing, adapta- consequences of COVID-19 [53]. These include (but are tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, not exclusive to) the CoroNerve Study Group [143], Euro- provide a link to the Creative Commons licence, and indicate if changes pean Academy of Neurology’s EAN Neuro-COVID Registry were made. The images or other third party material in this article are Consortium (ENERGY) [98], and the Global Consortium included in the article’s Creative Commons licence, unless indicated Study of Neurological Dysfunction in COVID-19 (GCS- otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not NeuroCOVID) [40]. permitted by statutory regulation or exceeds the permitted use, you will However, it is also important to learn from previous pan- need to obtain permission directly from the copyright holder. To view a demics to understand what to expect and plan responses to copy of this licence, visit http://creativeco mmons .org/licen ses/by/4.0/ . improve the outcomes. This knowledge of what has occurred the past is useful to highlight symptoms and signs to be vigilant for ensuring such sequelae are not missed. For References example, encephalitis lethargica and post-encephalitic parkinsonism have been seen after viral infections, most notably 1. Akins PT, Belko J, Uyeki TM, Axelrod Y, Lee KK, Silverthorn J (2010) H1N1 encephalitis with malignant edema and review the 1918–19 infuenza pandemic [43]. Indeed, a case of par- of neurologic complications from infuenza. Neurocrit Care kinsonism in a patient post COVID-19 has been described, 13:396–406 including a reduction of 18F-fuorodopa uptake bilaterally 2. AlKetbi R, AlNuaimi D, AlMulla M, AlTalai N, Samir M, in the putamina [25], In the months to years following this Kumar N (2020) Acute myelitis as a neurological complication of Covid-19: a case report and MRI fndings. Radiol Case Rep pandemic it would be important to continue to look for such 15(9):1591–1595 patients. 3. Arabi YM, Harthi A, Hussein J, Bouchama A, Johani S, Hajeer As new infections continue to emerge, new pandemics AH, Saeed BT, Wahbi A, Saedy A, AlDabbagh T, Okaili R, will certainly happen. Despite advances in the treatment of Sadat M, Balkhy H (2015) Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus infectious diseases in the last century, those afecting the (MERS-CoV). Infection 43:495–501 nervous system are still challenging. An improved under- 4. Arbour N, Day R, Newcombe J, Talbot PJ (2000) Neuroinvasion standing of the pathophysiology of neurologic damage and by human respiratory coronaviruses. J Virol 74:8913–8921 recognising its possible manifestations is fundamental to 5. Bag AK, Curé JK, Chapman PR, Roberson GH, Shah R (2010) JC virus infection of the brain. Am J Neuroradiol 31:1564–1576 develop new treatments and management strategies. 6. Bale JF Jr (2014) Measles, mumps, rubella, and human parvo- Neurological involvement in pandemics and epidem- virus B19 infections and neurologic disease. Handb Clin Neurol ics is common and can cause devastating consequences 121:1345–1353 amongst afected populations. There is an urgent need for 7. Baud D, Gubler DJ, Schaub B, Lanteri MC, Musso D (2017) An update on Zika virus infection. Lancet 390:2099–2109 better address this issue in pandemics, including the current 8. Becker TM, Poland JD, Quan TJ, White ME, Mann JM, Barnes SARS-CoV-2 outbreak. AM (1987) Plague meningitis–a retrospective analysis of cases reported in the United States, 1970–1979. West J Med Acknowledgements DW was supported by an Academic Clinical 147:554–557 Fellowship. DKM was supported by the NIHR through the NIHR

1 3 Journal of Neurology

9. Biehl M, Sese D (2020) Post-intensive care syndrome and 31. de Araújo TVB, Rodrigues LC, de Alencar Ximenes RA, de COVID-19 — Implications post pandemic. Clevel Clin J Med. Barros M-F, Montarroyos UR, de Melo APL, Valongueiro S, https://doi.org/10.3949/ccjm.87a.ccc055 de Albuquerque M, Souza WV, Braga C, Filho SPB, Cordeiro 10. Billioux BJ, Smith B, Nath A (2016) Neurological complications MT, Vazquez E, Cruz DCS, D, Henriques CMP, Bezerra LCA, of Ebola virus infection. Neurotherapeutics 13:461–470 da Silva Castanha PM, Dhalia R, Marques-Júnior ETA, Mar- 11. Boehme AK, Luna J, Kulick ER, Kamel H, Elkind MSV (2018) telli CMT, (2016) Association between Zika virus infection and Infuenza-like illness as a trigger for ischemic stroke. Ann Clin microcephaly in Brazil, January to May, 2016: preliminary report Transl Neurol 5:456–463 of a case-control study. Lancet Infect Dis 16:1356–1363 12. Boehme AK, Ranawat P, Luna J, Kamel H, Elkind MS (2017) 32. Desforges M, Le Coupanec A, Dubeau P, Bourgouin A, Lajoie Risk of acute stroke after hospitalization for sepsis: a case-cross- L, Dubé M, Talbot PJ (2020) Human coronaviruses and other over study. Stroke 48:574–580 respiratory viruses: underestimated opportunistic pathogens of 13. Booss J, Davis LE (2003) Smallpox and smallpox vaccination: the central nervous system? Viruses 12:14 neurological implications. Neurology 60:1241–1245 33. Dessau RB, Lisby G, Frederiksen JL (1999) Coronaviruses in 14. Boulanger LL, Ettestad P, Fogarty JD, Dennis DT, Romig D, spinal fuid of patients with acute monosymptomatic optic neu- Mertz G (2004) Gentamicin and tetracyclines for the treatment ritis. Acta Neurol Scand 100:88–91 of human plague: review of 75 cases in New Mexico, 1985–1999. 34. Drummond WK, Nelson CA, Fowler J, Epson EE, Mead PS, Clin Infect Dis 38:663–669 Lawaczeck EW (2014) Plague in a pediatric patient: case report 15. Brandel JP, Knight R (2018) Variant Creutzfeldt-Jakob disease. and use of polymerase chain reaction as a diagnostic aid. J Pedi- Handb Clin Neurol 153:191–205 atric Infect Dis Soc 3:e38–e41 16. Buchanan R, Bonthius DJ (2012) Measles virus and associ- 35. Dunning J, Morgan D, Walsh A (2017) Plague: interim guid- ated central nervous system sequelae. Semin Pediatr Neurol ance for clinicians in England managing suspected cases. Pub- 19:107–114 lic Health England (PHE). Retrieved from https://assets.publi 17. Carod-Artal FJ, Wichmann O, Farrar J, Gascón J (2013) Neuro- shing.service.gov.uk/government/uploads/system/uploads/attac logical complications of dengue virus infection. Lancet Neurol hment_data/fle/74327 5/Plagu e_clini cal_guida nce.pdf . Accessed 12:906–919 3 Sept 2020 18. Casals J, Elizan TS, Yahr MD (1998) Postencephalitic parkin- 36. Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton sonism—a review. J Neural Transm (Vienna) 105:645–676 A, Kneen R, Defres S, Sejvar J, Solomon T (2020) Neurological 19. Cerny T, Schwarz M, Schwarz U, Lemant J, Gérardin P, Keller E associations of COVID-19. Lancet Neurol 19:767–783 (2017) The range of neurological complications in Chikungunya 37. Fazzini E, Fleming J, Fahn S (1992) Cerebrospinal fuid anti- fever. Neurocrit Care 27:447–457 bodies to coronavirus in patients with Parkinson’s disease. Mov 20. Chang LY, Huang LM, Gau SS, Wu YY, Hsia SH, Fan TY, Lin Disord 7:153–158 KL, Huang YC, Lu CY, Lin TY (2007) Neurodevelopment and 38. Ferraz-Filho JR, dos Santos TU, de Oliveira EP, Souza AS (2010) cognition in children after enterovirus 71 infection. N Engl J Med MRI fndings in an infant with vaccine-associated paralytic poli- 356:1226–1234 omyelitis. Pediatr Radiol 40(Suppl 1):S138-140 21. Chertow DS, Kleine C, Edwards JK, Scaini R, Giuliani R, Spre- 39. Fisher DL, Defres S, Solomon T (2015) Measles-induced cher A (2014) Ebola virus disease in West Africa—clinical mani- encephalitis. QJM 108:177–182 festations and management. N Engl J Med 371:2054–2057 40. Frontera J, Mainali S, Fink EL, Robertson CL, Schober M, Ziai 22. Chertow DS, Nath A, Sufredini AF, Danner RL, Reich DS, W, Menon D, Kochanek PM, Suarez JI, Helbok R, McNett M, Bishop RJ, Childs RW, Arai AE, Palmore TN, Lane HC, Fauci Chou SH (2020) Global consortium study of neurological dys- AS, Davey RT (2016) Severe meningoencephalitis in a case of function in COVID-19 (GCS-NeuroCOVID): study design and Ebola virus disease: a case report. Ann Intern Med 165:301–304 rationale. Neurocrit Care 33:25–34 23. Clemens JD, Nair GB, Ahmed T, Qadri F, Holmgren J (2017) 41. Ganesan VK, Duan B, Reid SP (2017) Chikungunya virus: patho- Cholera. The Lancet 390:1539–1549 physiology, mechanism, and modeling. Viruses 9:368 24. Cliford DB, Ances BM (2013) HIV-associated neurocognitive 42. Gérardin P, Couderc T, Bintner M, Tournebize P, Renouil M, disorder. Lancet Infect Dis 13:976–986 Lémant J, Boisson V, Borgherini G, Staikowsky F, Schramm F, 25. Cohen ME, Eichel R, Steiner-Birmanns B, Janah A, Ioshpa M, Lecuit M,Michault A, Encephalchik Study Group (2016) Chi- Bar-Shalom R, Paul JJ, Gaber H, Skrahina V, Bornstein NM, kungunya virus-associated encephalitis: a cohort study on La Yahalom G (2020) A case of probable Parkinson’s disease after Réunion Island, 2005–2009. Neurology 86(1):94–102. https:// SARS-CoV-2 infection. Lancet Neurol 19:804–805 doi.org/10.1212/WNL.0000000000002234 26. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF (1996) Molec- 43. Giordano A, Schwarz G, Cacciaguerra L, Esposito F, Filippi M ular analysis of prion strain variation and the aetiology of ‘new (2020) COVID-19: can we learn from encephalitis lethargica? variant’ CJD. Nature 383:685–690 Lancet Neurol 19:570 27. Cousens SN, Vynnycky E, Zeidler M, Will RG, Smith PG (1997) 44. Goenka A, Michael BD, Ledger E, Hart IJ, Absoud M, Chow Predicting the CJD epidemic in humans. Nature 385:197–198 G, Lilleker J, Lunn M, McKee D, Peake D, Pysden K, Roberts 28. Dando SJ, Mackay-Sim A, Norton R, Currie BJ, St. John JA, M, Carrol ED, Lim M, Avula S, Solomon T, Kneen R (2014) Ekberg JAK, Batzlof M, Ulett GC, Beacham IR (2014) Patho- Neurological manifestations of infuenza infection in children gens penetrating the central nervous system: infection pathways and adults: results of a National British Surveillance Study. Clin and the cellular and molecular mechanisms of invasion. Clin Infect Dis 58:775–784 Microbiol Rev 27:691–726 45. Gofton TE, Young GB (2012) Sepsis-associated encephalopathy. 29. Davis LE, DeBiasi R, Goade DE, Haaland KY, Harrington Nat Rev Neurol 8:557–566 JA, Harnar JB, Pergam SA, King MK, DeMasters BK, Tyler 46. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L KL (2006) West Nile virus neuroinvasive disease. Ann Neurol (2020) Management of post-acute covid-19 in primary care. BMJ 60:286–300 370:m3026 30. Davis LE, Koster F, Cawthon A (2014) Neurologic aspects of 47. Grifn DE (2014) Measles virus and the nervous system. Handb infuenza viruses. Handb Clin Neurol 123:619–645 Clin Neurol 123:577–590

1 3 Journal of Neurology

48. Gutiérrez-Ortiz C, Méndez A, Rodrigo-Rey S, San Pedro-Murillo treatment of middle east respiratory syndrome. J Clin Neurol E, Bermejo-Guerrero L, Gordo-Mañas R, de Aragón-Gómez F, 13:227–233 Benito-León J (2020) Miller fsher syndrome and polyneuritis 65. Klein RS, Garber C, Howard N (2017) Infectious immunity in cranialis in COVID-19. Neurology. https://doi.org/10.1212/ the central nervous system and brain function. Nat Immunol WNL.0000000000009619 18:132–141 49. Guzman MG, Harris E (2015) Dengue. Lancet 385:453–465 66. Klironomos S, Tzortzakakis A, Kits A, Öhberg C, Kollia E, Aho- 50. Haddow LJ, Laverick R, Daskalopoulou M, McDonnell J, Lampe romazdae A, Almqvist H, Aspelin Å, Martin H, Ouellette R, FC, Gilson R, Speakman A, Antinori A, Balestra P, Bruun T, Al-Saadi J, Hasselberg M, Haghgou M, Pedersen M, Petersson Gerstoft J, Nielsen L, Vassilenko A, Collins S, Rodger AJ (2018) S, Finnsson J, Lundberg J, Falk Delgado A, Granberg T (2020) Multicenter European prevalence study of neurocognitive impair- Nervous system involvement in COVID-19: results from a ret- ment and associated factors in HIV positive patients. AIDS rospective consecutive neuroimaging cohort. Radiology. https:// Behav 22:1573–1583 doi.org/10.1148/radiol.2020202791 51. Hayase Y, Tobita K (1997) Probable post-infuenza cerebellitis. 67. Komatsu H, Shimizu Y, Takeuchi Y, Ishiko H, Takada H (1999) Intern Med 36:747–749 Outbreak of severe neurologic involvement associated with 52. Heaton RK, Cliford DB, Franklin DR Jr, Woods SP, Ake C, Enterovirus 71 infection. Pediatr Neurol 20:17–23 Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, 68. Koyuncu OO, Hogue IB, Enquist LW (2013) Virus infections in Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra the nervous system. Cell Host Microbe 13:379–393 CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, 69. Kramer LD, Li J, Shi PY (2007) West Nile virus. Lancet Neurol McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, 6:171–181 Jernigan TL, Wong J, Grant I (2010) HIV-associated neurocogni- 70. Kremer S, Lersy F, de Sèze J, Ferré JC, Maamar A, Carsin-Nicol tive disorders persist in the era of potent antiretroviral therapy: B, Collange O, Bonneville F, Adam G, Martin-Blondel G, Rafq CHARTER study. Neurology 75:2087–2096 M, Geeraerts T, Delamarre L, Grand S, Krainik A, Caillard S, 53. Helbok R, Chou SH-Y, Beghi E, Mainali S, Frontera J, Robertson Marc Constans J, Metanbou S, Heintz A, Helms J, Schenck M, C, Fink E, Schober M, Moro E, McNett M, Bassetti CL (2020) Lefèbvre N, Boutet C, Fabre X, Forestier G, de Beaurepaire I, NeuroCOVID: it’s time to join forces globally. Lancet Neurol Bornet G, Lacalm A, Oesterlé H, Bolognini F, Messie J, Hmey- 19:805–806 dia G, Benzakoun J, Oppenheim C, Bapst B, Megdiche I, Henri- 54. Hellmuth J, Fletcher JL, Valcour V, Kroon E, Ananworanich J, Feugeas MC, Khalil A, Gaudemer A, Jager L, Nesser P, Talla Intasan J, Lerdlum S, Narvid J, Pothisri M, Allen I, Krebs SJ, Mba Y, Hemmert C, Feuerstein P, Sebag N, Carré S, Alleg M, Slike B, Prueksakaew P, Jagodzinski LL, Puttamaswin S, Phan- Lecocq C, Schmitt E, Anxionnat R, Zhu F, Comby PO, Ricolf uphak N, Spudich S (2016) Neurologic signs and symptoms fre- F, Thouant P, Desal H, Boulouis G, Berge J, Kazémi A, Pyat- quently manifest in acute HIV infection. Neurology 87:148–154 igorskaya N, Lecler A, Saleme S, Edjlali-Goujon M, Kerleroux 55. Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kum- B, Zorn PE, Mathieu M, Baloglu S, Ardellier FD, Willaume T, merlen C, Collange O, Boulay C, Faf-Kremer S, Ohana M, Brisset JC, Boulay C, Mutschler V, Hansmann Y, Mertes PM, Anheim M, Meziani F (2020) Neurologic features in severe Schneider F, Faf-Kremer S, Ohana M, Meziani F, David JS, SARS-CoV-2 Infection. N Engl J Med 382(23):2268–2270. https Meyer N, Anheim M, Cotton F (2020) Brain MRI fndings in ://doi.org/10.1056/NEJMc2008597 severe COVID-19: a retrospective observational study. Radiol- 56. Hofman LA, Vilensky JA (2017) Encephalitis lethargica: 100 ogy. https://doi.org/10.1148/radiol.2020202222 years after the epidemic. Brain 140:2246–2251 71. Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery 57. Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Vincent JL (2016) Sepsis and septic shock. Nat Rev Dis Primers Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, 2:16045 Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc 58. Howard RS (2005) Poliomyelitis and the postpolio syndrome. JW, Bellini WJ, Anderson LJ (2003) A novel coronavirus asso- BMJ 330:1314–1318 ciated with severe acute respiratory syndrome. N Engl J Med 59. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF 348:1953–1966 (1999) Neurologic complications in children with enterovirus 72. Lau KK, Yu WC, Chu CM, Lau ST, Sheng B, Yuen KY (2004) 71 infection. N Engl J Med 341:936–942 Possible central nervous system infection by SARS coronavirus. 60. Jacobs M, Rodger A, Bell DJ, Bhagani S, Cropley I, Filipe A, Emerg Infect Dis 10:342–344 Giford RJ, Hopkins S, Hughes J, Jabeen F, Johannessen I, Kara- 73. Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le Bon georgopoulos D, Lackenby A, Lester R, Liu RSN, MacConnachie SD, Rodriguez A, Dequanter D, Blecic S, El Afa F, Distinguin A, Mahungu T, Martin D, Marshall N, Mepham S, Orton R, L, Chekkoury-Idrissi Y, Hans S, Delgado IL, Calvo-Henriquez Palmarini M, Patel M, Perry C, Peters SE, Porter D, Ritchie C, Lavigne P, Falanga C, Barillari MR, Cammaroto G, Khalife D, Ritchie ND, Seaton RA, Sreenu VB, Templeton K, Warren M, Leich P, Souchay C, Rossi C, Journe F, Hsieh J, Edjlali M, S, Wilkie GS, Zambon M, Gopal R, Thomson EC (2016) Late Carlier R, Ris L, Lovato A, De Filippis C, Coppee F, Fakhry N, Ebola virus relapse causing meningoencephalitis: a case report. Ayad T, Saussez S (2020) Olfactory and gustatory dysfunctions Lancet 388:498–503 as a clinical presentation of mild-to-moderate forms of the coro- 61. Jang H, Boltz DA, Webster RG, Smeyne RJ (2009) Viral parkin- navirus disease (COVID-19): a multicenter European study. Eur sonism. Biochim Biophys Acta 1792:714–721 Arch Otorhinolaryngol 277:2251–2261 62. Coronavirus Resource Center - John Hopkins University and 74. Lee KY, Cho WH, Kim SH, Kim HD, Kim IO (2003) Acute Medicine (2020) COVID-19 dashboard by the center for systems encephalitis associated with measles: MRI features. Neuroradiol- science and engineering (CSSE) at Johns Hopkins University. ogy 45:100–106 Retrieved from https://coronavirus.jhu.edu/map.html. Accessed 75. Li Y, Li H, Fan R, Wen B, Zhang J, Cao X, Wang C, Song Z, Li 2 Oct 2020 S, Li X, Lv X, Qu X, Huang R, Liu W (2016) Coronavirus infec- 63. Kidd D, Williams AJ, Howard RS (1996) Poliomyelitis. Postgrad tions in the central nervous system and respiratory tract show dis- Med J 72:641–647 tinct features in hospitalized children. Intervirology 59:163–169 64. Kim JE, Heo JH, Kim HO, Song SH, Park SS, Park TH, Ahn JY, Kim MK, Choi JP (2017) Neurological complications during

1 3 Journal of Neurology

76. Lo JK, Robinson LR (2018) Post-polio syndrome and the late 95. Nath A (2015) Neurologic complications of human immu- efects of poliomyelitis: Part 2. treatment, management, and nodeficiency virus infection. Continuum (Minneap Minn) prognosis. Muscle Nerve 58:760–769 21:1557–1576 77. Ludlow M, Kortekaas J, Herden C, Hofmann B, Tappe D, Trebst 96. Nathanson N, Kew OM (2010) From emergence to eradication: C, Grifn DE, Brindle HE, Solomon T, Brown AS, van Riel D, the epidemiology of poliomyelitis deconstructed. Am J Epide- Wolthers KC, Pajkrt D, Wohlsein P, Martina BEE, Baumgärtner miol 172:1213–1229 W, Verjans GM, Osterhaus ADME (2016) Neurotropic virus 97. Needham EJ, Chou SHY, Coles AJ, Menon DK (2020) Neu- infections as the cause of immediate and delayed neuropathol- rological implications of COVID-19 infections. Neurocrit Care ogy. Acta Neuropathol 131:159–184 32:667–671 78. Luzolo AL, Ngoyi DM (2019) Cerebral malaria. Brain Res Bull 98. European Academy of Neurology (EAN) (2020) EANcore 145:53–58 COVID-19. Retrieved from https://www.ean.org/ean/eancore- 79. Madhav N, Oppenheim B, Gallivan M, Mulembakani P, Rubin covid-19. Accessed 2 Oct 2020 E, Wolfe N (2017) Pandemics: Risks, Impacts, and Mitigation. 99. Ofah CE, Naseer A (2016) Spectrum of imaging appearances In: Jamison DT, Gelband H, Horton S, Jha P, Laxminarayan R, of intracranial cryptococcal infection in HIV/AIDS patients in Mock CN, Nugent R (eds) Disease control priorities: improving the anti-retroviral therapy era. Clin Radiol 71:9–17 health and reducing poverty. The International Bank for Recon- 100. Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T struction and Development/The World Bank© 2018 International (2010) Clinical features, diagnosis, and management of entero- Bank for Reconstruction and Development/The World Bank., virus 71. Lancet Neurol 9:1097–1105 Washington (DC) 101. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, 80. Malvy D, McElroy AK, de Clerck H, Günther S, van Griensven De Leacy RA, Shigematsu T, Ladner TR, Yaeger KA, Skliut M, J (2019) Ebola virus disease. Lancet 393:936–948 Weinberger J, Dangayach NS, Bederson JB, Tuhrim S, Fif JT 81. Malzberg MS, Rogg JM, Tate CA, Zayas V, Easton JD (1993) (2020) Large-vessel stroke as a presenting feature of Covid-19 Poliomyelitis: hyperintensity of the anterior horn cells on MR in the young. N Engl J Med 382:e60 images of the spinal cord. AJR Am J Roentgenol 161:863–865 102. Parsons T, Banks S, Bae C, Gelber J, Alahmadi H, Tichauer M 82. Mann JM, Shandler L, Cushing AH (1982) Pediatric plague. (2020) COVID-19-associated acute disseminated encephalomy- Pediatrics 69:762–767 elitis (ADEM). J Neurol 1–4 83. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong 103. Patel PB, Spudich SS (2018) Global health neurology: HIV/ C, Zhou Y, Wang D, Miao X, Li Y, Hu B (2020) Neurologic AIDS. Semin Neurol 38:238–246 manifestations of hospitalized patients with coronavirus disease 104. Paules CI, Marston HD, Fauci AS (2019) Measles in 2019— 2019 in Wuhan, China. JAMA Neurol 77:683 going backward. N Engl J Med 380:2185–2187 84. McGavern DB, Kang SS (2011) Illuminating viral infections in 105. Petersen LR, Jamieson DJ, Powers AM, Honein MA (2016) Zika the nervous system. Nat Rev Immunol 11:318–329 virus. N Engl J Med 374:1552–1563 85. McMahon AW, Eidex RB, Marfn AA, Russell M, Sejvar JJ, 106. Pohl D, Alper G, Van Haren K, Kornberg AJ, Lucchinetti CF, Markof L, Hayes EB, Chen RT, Ball R, Braun MM, Cetron M Tenembaum S, Belman AL (2016) Acute disseminated encepha- (2007) Neurologic disease associated with 17D–204 yellow fever lomyelitis. Updat Infamm CNS Syndr 87:S38–S45 vaccination: a report of 15 cases. Vaccine 25:1727–1734 107. Postels DG, Birbeck GL (2013) Cerebral malaria. Handb Clin 86. Mehta R, Gerardin P, de Brito CAA, Soares CN, Ferreira MLB, Neurol 114:91–102 Solomon T (2018) The neurological complications of chikungu- 108. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Grifth B nya virus: a systematic review. Rev Med Virol 28:e1978 (2020) COVID-19–associated Acute hemorrhagic necrotizing 87. Meyer H, Ehmann R, Smith GL (2020) Smallpox in the post- encephalopathy: CT and MRI features. Radiology 201187 eradication era. Viruses 12:138 109. Prentice MB, Rahalison L (2007) Plague. Lancet 369:1196–1207 88. Molloy S, O’Laoide R, Brett F, Farrell M (2000) The “Pulvinar” 110. Ragin AB, Wu Y, Gao Y, Keating S, Du H, Sammet C, Kettering sign in variant Creutzfeldt-Jakob disease. AJR Am J Roentgenol CS, Epstein LG (2015) Brain alterations within the frst 100 days 175:555–556 of HIV infection. Ann Clin Transl Neurol 2:12–21 89. Monath TP, Vasconcelos PF (2015) Yellow fever. J Clin Virol 111. Rasheed A, Saeed S, Khan SA (2009) Clinical and laboratory 64:160–173 fndings in acute malaria caused by various plasmodium species. 90. Moore CA, Staples JE, Dobyns WB, Pessoa A, Ventura CV, J Pak Med Assoc 59:220–223 Fonseca EBd, Ribeiro EM, Ventura LO, Neto NN, Arena JF, 112. Rosewell A, Clark G, Mabong P, Ropa B, Posanai E, Man NW, Rasmussen SA (2017) Characterizing the pattern of anomalies Dutta SR, Wickramasinghe W, Qi L, Ng JC, Mola G, Zwi AB, in congenital Zika syndrome for pediatric clinicians. JAMA Pedi- MacIntyre CR (2013) Concurrent outbreaks of cholera and atrics 171:288–295 peripheral neuropathy associated with high mortality among 91. Morfopoulou S, Brown JR, Davies EG, Anderson G, Virasami persons internally displaced by a volcanic eruption. PLoS ONE A, Qasim W, Chong WK, Hubank M, Plagnol V, Desforges M, 8:e72566 Jacques TS, Talbot PJ, Breuer J (2016) Human coronavirus OC43 113. Saad M, Omrani AS, Baig K, Bahloul A, Elzein F, Matin MA, associated with fatal encephalitis. N Engl J Med 375:497–498 Selim MA, Al Mutairi M, Al Nakhli D, Al Aidaroos AY (2014) 92. Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino Clinical aspects and outcomes of 70 patients with Middle East J, Ueno M, Sakata H, Kondo K, Myose N, Nakao A, Takeda respiratory syndrome coronavirus infection: a single-center expe- M, Haro H, Inoue O, Suzuki-Inoue K, Kubokawa K, Ogihara rience in Saudi Arabia. Int J Infect Dis 29:301–306 S, Sasaki T, Kinouchi H, Kojin H, Ito M, Onishi H, Shimizu T, 114. Sacks OW (1991) Awakenings. Pan Macmillan Sasaki Y, Enomoto N, Ishihara H, Furuya S, Yamamoto T, Shi- 115. Sagui E, Janvier F, Baize S, Foissaud V, Koulibaly F, Savini H, mada S (2020) A frst Case of Meningitis/Encephalitis associated Maugey N, Aletti M, Granier H, Carmoi T (2015) Severe Ebola with SARS-Coronavirus-2. Int J Infect Dis 94:55–58 virus infection with encephalopathy: evidence for direct virus 93. Musso D, Gubler DJ (2016) Zika virus. Clin Microbiol Rev involvement. Clin Infect Dis 61:1627–1628 29:487–524 116. Salinas S, Schiavo G, Kremer EJ (2010) A hitchhiker’s guide to 94. Musso D, Ko AI, Baud D (2019) Zika virus infection—after the the nervous system: the complex journey of viruses and toxins. pandemic. N Engl J Med 381:1444–1457 Nat Rev Microbiol 8:645–655

1 3 Journal of Neurology

117. Santosh CG, Bell JE, Best JJ (1995) Spinal tract pathology in Cavallini A, Micieli G (2020) Guillain-Barré syndrome associ- AIDS: postmortem MRI correlation with neuropathology. Neu- ated with SARS-CoV-2. N Engl J Med 382:2574–2576 roradiology 37:134–138 139. Tsai L-K, Hsieh S-T, Chao C-C, Chen Y-C, Lin Y-H, Chang 118. Sartoretti-Schefer S, Blättler T, Wichmann W (1997) Spinal MRI S-C, Chang Y-C (2004) Neuromuscular disorders in severe acute in vacuolar myelopathy, and correlation with histopathological respiratory syndrome. Arch Neurol 61:1669–1673 fndings. Neuroradiology 39:865–869 140. Turtle L, Solomon T (2018) Japanese encephalitis—the prospects 119. Saylor D (2018) Neurologic complications of human immu- for new treatments. Nat Rev Neurol 14:298–313 nodeficiency virus infection. Continuum (Minneap Minn) 141. Umapathi T, Kor AC, Venketasubramanian N, Lim CC, Pang BC, 24:1397–1421 Yeo TT, Lee CC, Lim PL, Ponnudurai K, Chuah KL, Tan PH, 120. Schmutzhard E, Pfausler B (2017) Neurologic complications of Tai DY, Ang SP (2004) Large artery ischaemic stroke in severe sepsis. Handb Clin Neurol 141:675–683 acute respiratory syndrome (SARS). J Neurol 251:1227–1231 121. Schrör K (2007) Aspirin and Reye syndrome: a review of the 142. van Riel D, Verdijk R, Kuiken T (2015) The olfactory nerve: a evidence. Paediatr Drugs 9:195–204 shortcut for infuenza and other viral diseases into the central 122. Sejvar J (2014) Neuroepidemiology and the epidemiology nervous system. J Pathol 235:277–287 of viral infections of the nervous system. Handb Clin Neurol 143. Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA, 123:67–87 Tenorio EL, Sultan M, Easton A, Breen G, Zandi M, Coles JP, 123. Sejvar JJ, Haddad MB, Tierney BC, Campbell GL, Marfn AA, Manji H, Al-Shahi Salman R, Menon DK, Nicholson TR, Ben- Van Gerpen JA, Fleischauer A, Leis AA, Stokic DS, Petersen jamin LA, Carson A, Smith C, Turner MR, Solomon T, Kneen LR (2003) Neurologic manifestations and outcome of West Nile R, Pett SL, Galea I, Thomas RH, Michael BD (2020) Neuro- virus infection. JAMA 290:511–515 logical and neuropsychiatric complications of COVID-19 in 124. Sener RN (2004) Subacute sclerosing panencephalitis fndings 153 patients: a UK-wide surveillance study. Lancet Psychiatry at MR imaging, difusion MR imaging, and proton MR spectros- 7:875–882 copy. AJNR Am J Neuroradiol 25:892–894 144. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, 125. Shen WC, Chiu HH, Chow KC, Tsai CH (1999) MR imaging Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, fndings of enteroviral encephaloymelitis: an outbreak in Taiwan. Moch H (2020) Endothelial cell infection and endotheliitis in AJNR Am J Neuroradiol 20:1889–1895 COVID-19. Lancet 395:1417–1418 126. Simmons J, Pittet JF (2015) The coagulopathy of acute sepsis. 145. Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solo- Curr Opin Anaesthesiol 28:227–236 mon T (2019) Acute encephalitis in immunocompetent adults. 127. Smith AB, Smirniotopoulos JG, Rushing EJ (2008) Central nerv- Lancet 393:702–716 ous system infections associated with human immunodefciency 146. Weaver SC, Lecuit M (2015) Chikungunya virus and the virus infection: radiologic-pathologic correlation. RadioGraphics global spread of a mosquito-borne disease. N Engl J Med 28:2033–2058 372:1231–1239 128. Sneller MC, Reilly C, Badio M, Bishop RJ, Eghrari AO, Moses 147. Weiss D, Carr D, Kellachan J, Tan C, Phillips M, Bresnitz E, SJ, Johnson KL, Gayedyu-Dennis D, Hensley LE, Higgs ES, Layton M (2001) Clinical fndings of West Nile virus infection Nath A, Tuznik K, Varughese J, Jensen KS, Dighero-Kemp B, in hospitalized patients, New York and New Jersey, 2000. Emerg Neaton JD, Lane HC, Fallah MP (2019) A longitudinal study of Infect Dis 7:654–658 Ebola sequelae in Liberia. N Engl J Med 380:924–934 148. Widmann CN, Heneka MT (2014) Long-term cerebral conse- 129. Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LT, Raeng- quences of sepsis. Lancet Neurol 13:630–636 sakulrach B, Loan HT, Day NP, Farrar J, Myint KS, Warrell MJ, 149. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alp- James WS, Nisalak A, White NJ (2000) Neurological manifesta- erovitch A, Poser S, Pocchiari M, Hofman A, Smith PG (1996) tions of dengue infection. Lancet 355:1053–1059 A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 130. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, 347:921–925 Ooi MH (2010) Virology, epidemiology, pathogenesis, and con- 150. Willison HJ, Jacobs BC, van Doorn PA (2016) Guillain-Barré trol of enterovirus 71. Lancet Infect Dis 10:778–790 syndrome. Lancet 388:717–727 131. Solomon T, Vaughn DW (2002) Pathogenesis and clinical fea- 151. Wong PF, Craik S, Newman P, Makan A, Srinivasan K, Crawford tures of Japanese encephalitis and West Nile virus infections. E, Dev D, Moudgil H, Ahmad N (2020) Lessons of the month Curr Top Microbiol Immunol 267:171–194 1: a case of rhombencephalitis as a rare complication of acute 132. Swanson PA 2nd, McGavern DB (2015) Viral diseases of the COVID-19 infection. Clin Med (Lond) 20:293–294 central nervous system. Curr Opin Virol 11:44–54 152. World Health Organisation (WHO) (2019) Global health obser- 133. Tabarki B, Thabet F, Al Shaf S, Al Adwani N, Chehab M, Al vatory (GHO) data - HIV/AIDS. Retrieved from https://www. Shahwan S (2013) Acute necrotizing encephalopathy associated who.int/gho/hiv/en/. Accessed 7 May 2020 with enterovirus infection. Brain Dev 35:454–457 153. World Health Organisation (WHO) (2020) Malaria - fact sheet. 134. Tan CS, Koralnik IJ (2010) Progressive multifocal leukoencepha- Retrieved from https://www.who.int/news-room/fact-sheet s/detai lopathy and other disorders caused by JC virus: clinical features l/malaria. Accessed 15 May 2020 and pathogenesis. Lancet Neurol 9:425–437 154. World Health Organisation (WHO) (2019) Measles - fact sheet. 135. Tan K, Patel S, Gandhi N, Chow F, Rumbaugh J, Nath A (2008) Retrieved from https://www.who.int/news-room/fact-sheet s/detai Burden of neuroinfectious diseases on the neurology service in l/measles. Accessed 4 May 2020 a tertiary care center. Neurology 71:1160–1166 155. World Health Organisation (WHO) (2019) Middle East respira- 136. Teng GG, Chatham WW (2015) Vasculitis related to viral tory syndrome coronavirus (MERS-CoV). Retrieved from https:// and other microbial agents. Best Pract Res Clin Rheumatol www.who.int/emergencie s/mers-cov/en/ . Accessed 10 May 2020 29:226–243 156. World Health Organisation (WHO) (2017) Plague. Retrieved 137. Toovey S (2008) Infuenza-associated central nervous system from https://www.who.int/news-room/fact-sheets/detail/plague. dysfunction: a literature review. Travel Med Infect Dis 6:114–124 Accessed 5 May 2020 138. Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, 157. Xu J, Zhong S, Liu J, Li L, Li Y, Wu X, Li Z, Deng P, Zhang Cuzzoni MG, Franciotta D, Baldanti F, Daturi R, Postorino P, J, Zhong N, Ding Y, Jiang Y (2005) Detection of severe acute

1 3 Journal of Neurology

respiratory syndrome coronavirus in the brain: potential 163. Zhang G, Zhang J, Wang B, Zhu X, Wang Q, Qiu S (2020) role of the chemokine mig in pathogenesis. Clin Infect Dis Analysis of clinical characteristics and laboratory fndings of 95 41:1089–1096 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a 158. Yang R (2018) Plague: recognition, treatment, and prevention. J retrospective analysis. Respir Res 21:74 Clin Microbiol 56:e01519-e11517 164. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, 159. Ye M, Ren Y, Lv T (2020) Encephalitis as a clinical manifesta- Ding X, Zhao H, Zhang H, Wang C, Zhao J, Sun X, Tian R, tion of COVID-19. Brain Behav Immun. 88:945–946. https://doi. Wu W, Wu D, Ma J, Chen Y, Zhang D, Xie J, Yan X, Zhou X, org/10.1016/j.bbi.2020.04.017 Liu Z, Wang J, Du B, Qin Y, Gao P, Qin X, Xu Y, Zhang W, Li 160. Yeh EA, Collins A, Cohen ME, Dufner PK, Faden H (2004) T, Zhang F, Zhao Y, Li Y, Zhang S (2020) Coagulopathy and Detection of coronavirus in the central nervous system of a antiphospholipid antibodies in patients with Covid-19. N Engl J child with acute disseminated encephalomyelitis. Pediatrics Med 382(17):e38. https://doi.org/10.1056/NEJMc2007575 113:e73-76 165. Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, 161. Zacharia TT, Law M, Naidich TP, Leeds NE (2008) Central nerv- Spudich S (2020) Neuropathogenesis and neurologic manifes- ous system lymphoma characterization by difusion-weighted tations of the coronaviruses inthe age of corona virus disease imaging and MR spectroscopy. J Neuroimaging 18:411–417 2019: a review. JAMA Neurol 77(8):1018–1027. https://doi. 162. Zanin L, Saraceno G, Panciani PP, Renisi G, Signorini L, org/10.1001/jamaneurol.2020.2065 Migliorati K, Fontanella MM (2020) SARS-CoV-2 can induce brain and spine demyelinating lesions. Acta Neurochir (Wien). 162(7):1491–1494. https://doi.org/10.1007/s0070 1-020-04374 -x

1 3