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.
Pandemics are large-scale outbreaks of infectious disease that can cause an excess in morbidity and mortality globally, or at least over a wide geographic area, and lead to socio-economic disruption. Increase in global travel, urbanisation, climate change, environmental degradation, displacement and consumption of wild animals are factors thought to have increased the likelihood of pandemics during the past century [
As the world deals with the Sars-CoV2 pandemic, reports of neurologic manifestations have increased. Understanding neurological complications of previous pandemics, and the pathophysiological mechanisms that underlie them, are fundamental to place the current situation in perspective, and help address the enduring consequences once current waves of acute infection subside. This narrative review assesses the neurological manifestations of past and current pandemics, to aid our understanding of the current pandemic and prepare for future outbreaks.
Pathogens can lead to nervous system impairment through multiple mechanisms. There may be direct infection and replication leading to the clinical syndromes of encephalitis, myelitis and meningitis [ Mechanisms of pathogen-induced neurological injury Mechanisms Description Neurologic manifestations Blood brain barrier (BBB) (haematological entry) Penetration of endothelial barriers via (BBB disruption associated with acute host inflammatory responses may facilitate invasion): Transcellular penetration (using pinocytosis or receptor-mediated entry) Paracellular entry (by disrupting tight junctions) Via entry of infected leukocytes from the peripheral circulation into the CNS (Trojan horse mechanism) [ Encephalitis Meningoencephalitis Meningitis Anterior myelitis Encephalopathy Peripheral nerves (trans-synaptic spread) Pathogens: Move along peripheral nerves via retrograde (from axon terminal to cell body) or anterograde (from cell body to axon terminal) transport Invade the PNS by binding to receptors on axons of sensory, autonomic and motor neurons, including the olfactory and vagal nerves [ Sepsis-associated Diffuse disturbance of brain function as a consequence of the systemic inflammatory response of sepsis [ Presents as impaired attention and arousal [ Release of inflammatory mediators affecting both the BBB and the cerebral microcirculation [ Encephalopathy Acute haemorrhagic leukoencephalitis (AHL) Secondary to metabolic dysfunction Can be isolated or in the context of sepsis and organ failure: Severe hypoxia Shock-induced hypoperfusion Metabolic disturbances Electrolyte imbalances (hyponatremia or hypernatremia, hypocalcaemia or hypercalcemia) Seizures Encephalopathy Diffuse ischaemia Secondary to coagulopathy and vasculitis Hyperinflammation in SIRS and sepsis leads to coagulopathy and a prothrombotic state Both direct pathogen invasion and the proinflammatory state of sepsis lead to endothelial damage [ Infections may cause vasculitis, either due to pathogen invasion, exaggerated immune response, or immune dysregulation triggered by bacterial toxins or antigens [ Stroke Cerebral venous thrombosis Intracranial haemorrhage Peripheral neuropathy Autoimmune Triggered especially by viruses, which serve as antigenic stimulus and lead to lesions of the PNS and CNS Associated with molecular mimicry between the pathogen and molecules on the axolemmal surface, glial membranes at the node of Ranvier [ Guillain-Barré syndromes Acute disseminated encephalomyelitis (ADEM) Transverse myelitis Acute motor axonal neuropathy (AMAN) Acute inflammatory demyelinating polyneuropathy (AIDP) Persistence and latency of viral infections After direct invasion of the nervous system Persistent viral infections: continuous viral replication Latent viral infections: dormant state with minimal or no production of viral material [ Neurocognitive disorders (HIV) Subacute sclerosing panencephalitis (measles) Mechanisms of injury to the nervous system
Pathogens are divided according to the main mode of transmission (vector-borne, water/food-borne and direct or indirect with infected individuals). Its features, including notable pandemics, non-neurological and neurological manifestations may be found in Fig. Pandemics and selected epidemics in which neurological manifestations were reported Disease (pathogen) Event/distribution Mode of transmission Incubation period Non-neurological features Neurologic manifestations Mechanism of neurological injury Treatment Bubonic plague (Yersinia pestis) 541: Justinian plague—Eurasia 1347: Bubonic plague—Eurasia 1855: Third world plague—China, India, Hong Kong Current: Seasonal epidemics in Africa (mainly Madagascar) Bite of infected rodents’ fleas Direct contact with infected bodily fluids, fomites, and inhalation of infected respiratory droplets 1–7 days Initial symptoms are fever, malaise, myalgia. Lymphadenitis develops near the location of flea bite (bubo), characterizing the bubonic form, (most common). Other forms are the septicaemic and pulmonary plague Meningitis (may present late in the course of disease even in patients under antibiotics) Direct invasion Antibiotic therapy with chloramphenicol if plague meningitis. For other forms, gentamicin OR doxycycline OR ciprofloxacin can be used West Nile (West Nile virus) Late 1990s: Romania, Russia, Israel 1999–2003: Americas Bite by virus-carrying 3–14 days Most infected are asymptomatic. Between 20 and 40% will develop a flu-like illness with fever, headache, malaise, myalgia, skin rash and gastrointestinal symptoms Meningitis Encephalitis Anterior myelitis Direct invasion Supportive care. No controlled trial has successfully tested the efficacy of specific drugs Japanese Encephalitis (Japanese encephalitis virus)* Endemic in 24 countries of tropical South East Asia and West Pacific Large epidemics every 2–15 years in temperate areas of Asia Bite by virus-carrying 5–15 days Vast majority of infections are either asymptomatic or very mild. If present, symptoms include self-limiting fever and eventual coryza and/or diarrhoea Encephalitis Anterior myelitis GBS Transverse myelitis ADEM Associated with NMDA encephalitis Direct invasion Post-infectious—autoimmune Supportive care during the acute phase. Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Zika (Zika virus) 2007: Yap island (western Pacific Ocean) 2013: French Polynesia 2014–2016: Americas 2016: Singapore, Vietnam, Thailand, Guinea-Bissau, Angola 2018: India Bite of virus-carrying 3–14 days Infected adults are either asymptomatic (50–80%) or have mild flu-like symptoms: fever, rash, arthralgia, conjunctivitis and myalgia). Maternal-foetal transmission occurs in 20–30% of cases, among which 4–7% will lead to foetal loss Congenital Zika syndrome: microcephaly, subcortical calcifications, corpus callosum, cortex malformations, retinal alterations Meningoencephalitis Transverse myelitis GBS Direct invasion Post-infectious—autoimmune Supportive care during the acute phase. Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Chikungunya fever (Chikungunya virus) 1960s: Asia 2005–2007: Kenya, Indian Ocean islands, India, South East Asia 2007: Italy 2014: France 2014–current: Americas 2017–current: Pakistan Bites of virus-carrying mosquitoes, predominantly 3–7 days Fever, polyarthralgia (usually bilateral and symmetric), headache, myalgia, conjunctivitis, arthritis, nausea, vomiting and maculopapular rash, for 7–10 days. Some patients persist with arthralgia for months to years after the acute disease Acute encephalitis Meningoencephalitis GBS (including Miller Fisher and Bickerstaff’s syndromes) Transverse myelitis Myeloradiculitis ADEM Optic neuropathy Direct invasion Post-infectious—autoimmune Supportive care during the acute phase. Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Malaria ( Endemic with local outbreaks in 91 tropical and subtropical countries of Africa, Central and South America and Asia (nearly half of the world population). Eliminated from Europe in 1975 Epidemic potential expected to increase with increasing temperatures associated with climate changes Mosquito bite of infective female 9–14 days Fever, headache, sweats, chills, malaise, myalgia, gastrointestinal symptoms The classical (but seldom observed) malaria attack lasts 6–10 h, consisting of a cold stage (shivering), a hot stage (fever, headaches, vomiting) and a sweating stage (sweats and fatigue) Encephalopathy Seizures Para-infectious- secondary to sequestration of erythrocytes into cerebral blood vessels, release of cytokines, BBB permeability and metabolic dysfunction Supportive care during the acute phase including correction of metabolic dysfunction Yellow fever (yellow fever virus)* Endemic in 47 countries of Africa, South and Central Americas nineteenth century: USA, Europe (Atlantic ports), the Caribbean, Central America 2016–current: expansion to non-endemic areas in Africa and South America Mosquito bites from 3–6 days Fever, myalgia, chills, backache, headache, lack of appetite, nausea and vomiting for 3–4 days. Some are asymptomatic. Between 15 and 25% of infected enter a 2nd toxic phase with fever, vomiting, epigastric pain, renal failure, haemorrhagic diathesis, transaminase and direct bilirubin rise with deep jaundice Febrile seizures in the acute phase (young children) Encephalitis Encephalopathy Yellow fever vaccine associated neurotropic disease: Meningitis, encephalitis, myelitis, GBS and ADEM Direct invasion Post-infectious—autoimmune (associated with the yellow fever 17D vaccine) Para-infectious—secondary to metabolic dysfunction Supportive care during the acute phase, including correction of metabolic dysfunction Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Dengue (dengue virus)* Evolved from sporadic cases in 1970s to endemic in over 100 countries worldwide with explosive outbreaks in new areas Bite of virus-carrying mosquitoes, predominantly 4–10 days 40–80% are asymptomatic. Self-limiting symptoms last 5–7 days and include high fever, headache (specially retroorbital), myalgia, arthralgia and, rash. Around 5% will have the severe form of disease, manifest during the defervescence period (after the 1st week) in which there is plasma leakage due to increased vascular permeability, with or without bleeding and can lead to shock and severe organ involvement Encephalopathy Encephalitis Aseptic meningitis ADEM Transverse myelitis GBS Mononeuropathies of cranial nerves Optic neuropathy Muscle dysfunction Intracranial haemorrhages Direct invasion Para-infectious—secondary to metabolic dysfunction ? Para-infectious—secondary to coagulopathy and vasculitis Post-infectious—autoimmune Supportive care during the acute phase and for para infectious manifestations. Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Poliomyelitis (Poliovirus) End of nineteenth century—1955: Large cyclical outbreaks during summer on Northern Europe and United States 2008: Nigeria and West Africa Oral-faecal route by ingestion of contaminated water or food. The virus multiplies in the oropharyngeal and intestinal mucosa from where it spreads for target organs, including the CNS 7–10 days Most infections are either asymptomatic or accompanied by mild flu-like symptoms like fever fatigue, headache and vomiting Anterior myelitis Meningitis Encephalitis Post-polio syndrome Direct invasion Supportive care. Rehabilitation in the chronic phase Enterovirus-71 (Enterovirus-71)* Cyclical epidemics in the Asia–Pacific region every 2–3 years 1970s: Japan, Bulgaria and Hungary 1980s: Hong Kong, Australia 1997–1998: Malaysia, Japan, Taiwan 2008—China Oral-faecal route by ingestion of contaminated water or food. The virus multiplies in the oropharyngeal and intestinal mucosa from where it spreads for target organs, including the CNS 3–10 days In children, it can cause hand-feet-mouth disease: childhood exanthema with fever, papulovesicular rash on the palms and soles and oral ulcers, manifesting also as upper respiratory tract infection and gastroenteritis. Adults are frequently asymptomatic Encephalitis, mainly brainstem Aseptic meningitis Encephalomyelitis Cerebellar ataxia Anterior myelitis Transverse myelitis GBS Myoclonus-opsoclonus Direct invasion Post-infectious—autoimmune Supportive care during the acute phase. Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Variant Creutzfeldt-Jakob disease (bovine spongiform encephalopathy [BSE] prion) 1985: Bovine spongiform encephalopathy (BSE) described 1995: Beginning in the UK and spread to 13 countries Ingestion of contaminated food (especially bovine meat), and rarely via blood transfusion or organ transplantation 15–20 years Symptoms are eminently associated with the CNS infection Psychiatric manifestations: depression, delusions, hallucinations Sensory disturbances, especially pain Dementia Ataxia Movement disorders: myoclonus, chorea, tremor Direct invasion Symptomatic management of neuropsychiatric disturbances. Palliative care during the inexorable last stages of the disease Cholera 1817–1824: 1st Cholera pandemic—Asia, Middle East, Caspian Sea basin 1829–1837: 2nd Cholera pandemic—Europe, Egypt, North America 1846–1860: 3rd Cholera pandemic—Europe, North America, Asia, Middle East 1863–1875: 4th Cholera pandemic—Asia, Europe, Africa, North America 1881–1896: 5th Cholera pandemic—Europe, Japan, Persia, Egypt 1899–1923: 6th Cholera pandemic—Russia, Ottoman Empire, Philippines, USA 1961–1975: 7th Cholera pandemic—Indonesia, Bangladesh, Soviet Union, North Africa, Italy 1991–94: South America, DRC (then Zaire) 2010—Haiti, Dominican Republic 2011–2018—Nigeria, DRC, Ghana, Sierra Leone, Ghana, Tanzania, Somalia, Algeria, Zimbabwe 2017–current: Yemen Oral-faecal route by ingestion of contaminated food or water 12 h–5 days Most infected are asymptomatic but still display faecal shedding of the bacteria. Symptoms can range from mild to severe and include watery diarrhoea and vomiting. Stools can resemble rice water, with flakes of mucus, with a fishy odour. There is no fever. Dehydration can rapidly ensue, potentially leading to hypovolemic shock Seizures, secondary to electrolytic disturbances Peripheral neuropathy—reported during an outbreak in 2013 Para-infectious—secondary to metabolic dysfunction Aggressive rehydration and electrolyte disturbances correction (both oral and intravenous), antibiotic therapy with Doxycycline (1st line for adults) or azithromycin (1st line for children and pregnant women) for the moderately and severely ill patients, zinc supplementation (among children) Flu (influenza virus) 1889: Russian Flu—started in Siberia and Kazakhstan (H3N8), spread to Europe and Asia 1918–1920: Spanish Flu (H1N1)—first observed in Europe and USA before going global 1957: Asian Flu (H2N2)—start in Hong Kong, spread to China, USA and Europe 1968: Hong Kong flu (H3N2)—global 2009: Swine flu (H1N1 pdm09)—global Direct contact with respiratory droplets from infected people or fomites 1–4 days Common symptoms include fever, chills, cough, sore throat, runny nose, myalgia, headache, fatigue, gastrointestinal symptoms (more frequent in children). Complications include pneumonia, myocarditis and sepsis. Pregnant women, those aged < 5 or > 65 and who have underlying health conditions are at increased risk of complications Aseptic meningitis Encephalitis Encephalopathy Stroke Acute necrotising encephalitis Kleine-Levin syndrome GBS Transverse myelitis Encephalopathic condition of Reye’s syndrome Encephalitis lethargica Post-encephalitic Parkinsonism ? Direct invasion Para-infectious—septic-related Para-infectious—secondary to metabolic dysfunction Para-infectious—secondary to coagulopathy Post-infectious—autoimmune Supportive care. Both oseltamivir and high dose corticosteroids can be used in the acute phase. Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Coronaviruses (Sars-CoV, MERS-CoV, Sars-Cov2) 2002–03: Sars-CoV—global (30 countries), start in China 2012: MERS-CoV 22 countries, start in the middle East 2019: Sars-Cov2—global Direct contact with infected people’s respiratory droplets or fomites 2–14 days Some are asymptomatic. For these coronaviruses most will develop mild upper respiratory tract symptoms such as cough, sore throat, coryza, fever, chills, fatigue, myalgia, headache nausea. A parcel will evolve with severe pneumonia and respiratory failure Encephalopathy Meningoencephalitis Acute necrotising encephalitis Optic neuritis Stroke Myopathy GBS (including Miller Fisher and Bickerstaff’s syndromes) Mononeuropathies of cranial nerves ADEM Direct invasion Para-infectious—septic-related Para-infectious—secondary to metabolic dysfunction Para-infectious—secondary to coagulopathy and vasculitis Post-infectious—autoimmune Supportive care during the acute phase. Post infectious autoimmune conditions receive the standard immunomodulatory treatment for the condition Ebola (Ebola virus) 1976: Sudan, DRC (then Zaire) 1995–1997: Gabon, DRC (then Zaire) 2001–2003: Uganda, Gabon, Republic of Congo 2007–2009: DRC, Uganda 2013–2016: Guinea, Liberia, Sierra Leone, Nigeria, Mali, Senegal, Italy, USA, Spain, United Kingdom 2018–current: DRC, Uganda Contact with virus-carrying bats (main reservoir) or with infected wild animals (intermediary hosts). It easily spreads via direct contact with bodily fluids or fomites (caring for the sick and handling deceased patients is particularly high risk) Also transmitted via sexual contact (up to 12 months after the acute infection) 2–21 days Early symptoms include high fever, malaise and body aches for 3 days, evolving to gastrointestinal symptoms which include nausea, large-volume diarrhoea and vomiting for 7—10 days. At this stage, some patients will go into shock and can present with haemorrhagic manifestations (conjunctival, gastrointestinal and mucosal bleeding) Meningoencephalitis Encephalopathy Post Ebola syndrome: memory loss, headaches, muscles aches among survivors Direct invasion Para-infectious—septic-related Para-infectious—secondary to metabolic dysfunction Supportive care with early rehydration, correction of electrolyte disturbances and treating secondary infections Measles (measles virus)* Until 1963: massive global outbreaks every 2–3 years, until vaccine is developed, decreasing number of cases worldwide 2019–current: outbreaks in all regions of the world (increase in number of cases and resurgence in areas of Europe and USA in the last 10 years) Direct contact with respiratory droplets and aerolised particles from infected people and fomites. Aerolised particles can remain in the air for up to 2 h 7–14 days Starts with high fever and one or more of the three symptoms: coryza, cough and conjunctivitis. Koplik spots (small white spots) appear in the mouth 2–3 days after start of symptoms. Maculopapular rash appears 3–4 days after the onset of symptoms Acute Encephalitis (primary measles encephalitis) Acute post-measles encephalitis Measles inclusion-body encephalitis (MIBE) Subacute sclerosing panencephalitis (SSPE) ADEM Direct invasion Post-infectious—persistent or latent infection Post-infectious- autoimmune Supportive care in the cute phase. Acute post measles encephalitis can be treated with corticosteroids, intravenous IgG is a possible 2nd line treatment. MIBE treatment is supportive and ribavirin is reported as beneficial. SSPE patients receive palliative care an symptoms control AIDS (human immunodeficiency virus-HIV) 1981–current: global Exchange of body fluids from infected people, including blood, breast milk, semen and vaginal secretions. The virus is also transmitted vertically during pregnancy and delivery 2–6 weeks for the 1st acute infection symptoms 2–15 years until the development of AIDS The acute infection presents as a flu-like illness with fever, sore throat, body rash, fatigue, myalgia and lymphadenopathy for 1–2 weeks. After years of chronic infection symptoms related to the immune system damage appear and are related to the opportunistic infections that ensue. They include weight loss, chronic diarrhoea, fever, skin lesions, and any other symptom related to organ damage associated with the opportunistic infections Aseptic meningitis Subacute encephalitis Neurocognitive disorders Peripheral neuropathy GBS Vacuolar myelopathy Stroke Amyotrophic lateral sclerosis-like Myopathy Predisposes secondary infections due to reactivated viruses: Progressive multifocal leukoencephalopathy (PML) (JC virus), primary CNS lymphoma (Epstein-Barr virus), neurocryptococcosis (Cryptococcus neoformans), neurotoxoplasmosis (Toxoplasma gondii) Direct invasion Para-infectious—secondary to coagulopathy and vasculitis Post-infectious—autoimmune Post-infectious—persistent or latent infection (including secondary reactivation of other latent viruses) Early initiation of ART against HIV is effective against both direct effects of the virus and complications secondary to opportunistic infections. It has also shown to slow progression of cognitive disorders associated with the disease Treatment of peripheral neuropathy involves both alleviation of pain and prevent progression by either initiating ART or suspending ART-related peripheral neuropathy Smallpox (Variola virus) Endemic in Asia since Antiquity Endemic in Europe since eleventh century with various outbreaks 165AD:Antonine Plague—Rome 735–737: Japan sixteenth-seventeenth century: Americas—decimation of native populations eighteenth century: USA Direct contact with fluids from patients’ sores, fomites and respiratory droplets from infected people 7–19 days After 2–4 days of fever, myalgia, headache, fatigue and eventual vomiting. An early rash on the tongue and mouth installs followed by generalised skin rash. It progresses to pustular rash around the 6th day, which then forms a crust and a scab. 3 weeks after the start of rash most scabs will have fallen off Post-infectious encephalomyelitis Post-vaccinal encephalomyelitis Post-infectious—autoimmune Supportive care Immunomodulatory treatment for post infectious complications of autoimmune nature (such as Guillain–Barré, Miller Fischer and Bickerstaff’s syndromes) usually involve intravenous immunoglobin or plasmapheresis. ADEM is typically treated with high dose intravenous corticosteroids, regardless of its precipitating cause *Where diseases are endemic around the world with outbreaks/epidemics, dates are limited ** Imaging and laboratory features of each pandemic disease Disease Imaging Laboratory Plague [ Only once case report in the literature, of paediatric plague with positive PCR in the CSF for CSF: moderate neutrophil pleocytosis, increased protein, low glucose. Lymphocytic pleocytosis and normal glucose have also been described in some patients Bloods: neutrophilic leucocytosis West Nile virus [ Brain CT is usually normal. If present, Brain MRI abnormalities are more likely to be seen during the 1st week and include leptomeningeal enhancement, T2/Flair hyperintense lesions in periventricular areas, deep brain structures (thalami, basal ganglia, red nucleus, cerebral peduncle, substantia nigra) and mesial temporal lobes. DWI sequences may detect lesions before T2/FLAIR Most AFP cases have normal images, but some may present with abnormalities in the anterior horn and roots CSF: pleocytosis, which can be neutrophilic or lymphocytic, normal glucose and elevated protein in encephalitis or meningitis. Similar findings in AFP but with raised protein levels Bloods: leucocytosis, elevated AST, ALT and serum lipase are commonly described Japanese encephalitis [ CT: bilateral thalamic hypodensities, which may be haemorrhagic and only visualised in the MRI. MRI changes include hyperintense lesions of thalamus, midbrain, pons, cerebellum, basal ganglia and cerebral cortex CSF: usually lymphocytic pleocytosis (though it can be acellular), normal protein and glucose levels Blood: neutrophilia and hyponatremia are frequent Zika virus [ Brain MRI abnormalities of symptomatic congenital Zika syndrome affects both white and grey matter and include: severe microcephaly, ventriculomegaly, skull collapse, florid grey-matter interface calcifications, corpus callosum anomalies, cerebral cortex thinning, abnormal gyral patterns, pontine atrophy, cerebellum hypoplasia, chorioretinal atrophy, microphthalmia, cataracts and optic nerve atrophy. Neuroimaging of encephalitic adult cases in non-specific and can be normal. Most commonly reported findings are asymmetric subcortical T2/Flair hyperintense lesions (also seen in DWI) CSF: moderate pleocytosis and mildly raised protein, with mostly normal glucose in meningoencephalitis. In GBS, usually normal WBC and increased protein levels Blood: leukopenia, thrombocytopenia, increase transaminases levels Chikungunya fever [ Brain CT and MRI can be normal even in encephalitic cases. Both imaging modalities can show unspecific oedema and haemorrhage in different areas of the cerebrum during the acute phase. ADEM cases present with typical confluent areas of T2/FLAIR hyperintensity consistent with demyelination. Myelopathic patients have spinal cord T2/Flair hyperintense lesions in the affected segment CSF: pleocytosis (although it can be very modest or normal) and raised protein in meningoencephalitis and myeloradiculitis Blood: lymphopenia (almost always present), thrombocytopenia, elevated AST and ALT and hypocalcaemia Malaria [ Brain imaging findings do not correlate with parasitaemia, and can be normal. CT may display vasogenic oedema specially involving the posterior brain, ischaemic hypodensities in thalamus and cerebellar white matter. Brain MRI shows non-specific T2WI hyperintensities in the thalamus, periventricular white matter, corpus callosum, occipital sub-cortex and basal ganglia CSF: very mild pleocytosis, low glucose and increased protein levels Blood: Anaemia, hyperbilirubinemia (due to haemolysis), thrombocytopenia, haemoglobinuria and elevated transaminases are usually present in a range of severities. Young children and pregnant women may have hypoglycaemia and metabolic acidosis Yellow fever [ There’s a paucity of MRI studies in yellow fever-related encephalitis. Case reports have described lesions associated with the rare complication of yellow fever 17D vaccination with unspecific T2WI hyperintense lesions in cerebral peduncles, medulla, spinal cord and cerebral white matter There’s scarce information about CSF in yellow fever in the literature Bloods: leukopenia (with relative neutropenia), thrombocytopenia, elevated aminotransferases and bilirubin levels, increased prothrombin time (PT), albuminuria Dengue fever [ Brain CT may reveal intraparenchymal foci of haemorrhages. Brain MRI of meningoencephalitis frequently shows hyperintensity on T2WI and DWI in both thalami, basal ganglia, cortical grey matter and subcortical white matter. Petechial haemorrhages and diffuse brain oedema are common CSF: frequently normal in most encephalitic cases. Modest lymphocytic pleocytosis with normal or raised protein levels may be present in dengue myelitis, encephalitis or meningitis Blood: leukopenia, thrombocytopenia and rising haematocrit Poliomyelitis [ MRI show T2W hyperintense ventral motor tracts both in the spinal cord and in the motor cortex CSF: pleocytosis (neutrophilic in the 1st days which then progresses to lymphocytic), mildly elevated protein levels and normal glucose in the acute phase Enterovirus-71 [ In encephalitic patients, brainstem is the most affected site. Brain MRI shows T2W hyperintense in the midbrain, dentate nuclei, dorsal aspect of the pons (pontine tegmentum), basal ganglia and medulla. Usually there’s no supratentorial involvement CSF: mild lymphocytic pleocytosis (though it may be normal), and usually normal protein and glucose levels in acute encephalitic patients Bloods: leucocytosis, mainly neutrophilic, especially in those with central involvement Variant Creutzfeldt-Jakob disease [ Brain MRI of most cases of vCJD show the characteristic “pulvinar sign”—an area of high signal in T2W in the posterior thalamus rather than any other area. Other areas which may be involved include dorsomedial thalamic nuclei and the periaqueductal grey matter. Hyperintensities in T2Wand DWI in the caudate, putamen and cortical areas, characteristically involved in sCJD, may also affected vCJD patients CSF: usually normal, sometimes with modest total protein elevation. CSF 14-3-3 is positive only in half of vCJD patients Influenzae [ Encephalitic patients may present with normal imaging. Specific encephalitic syndromes have been described in those patients, divided in splenial sign (T2 and DWI high signal in the splenium of corpus callosum); ANE-pattern (acute necrotising encephalitis- hyper signal in T2WI in thalami, midbrain, pons, cerebellum, centrum semiovale); PRES pattern (hyperintense signal in T2WI in centrum semiovale, more prominent posteriorly); malignant brain oedema (diffuse brain oedema). Post infectious cerebellitis displays T2WI hyperintense images in the cerebellum, with brainstem compression and hydrocephalus. Encephalitis lethargica patients presented with loss of neurons in the midbrain, subthalamus and hypothalamus. Post viral parkinsonism subjects had depigmentation of the substantia nigra and locus coeruleus CSF: normal or with pleocytosis, proteins frequently elevated, normal glucose, in encephalitic cases Bloods: variable, may be closer to normal. Frequent lymphocytopenia, thrombocytopenia, elevated AST, CRP Coronavirus [ While there’s scarce information about brain images of patients infected with Sars-Cov1 and MERS-CoV, recent studies have reported variated lesions in patients with neurologic manifestations secondary to Sars-Cov2 and novel information comes up every day. Within the pleiad of described lesions, the most frequently reported are SWI abnormalities (with ovoid or tubular shape) affecting mainly the splenium, juxta cortical U-fibres and main white matter tracts, non-confluent white matter hyperintense lesions on T2WI and DWI associated or not with haemorrhagic lesions and often involving corpus callosum and middle cerebellar peduncles, symmetric thalamic lesions with oedema, petechial haemorrhage and necrosis compatible with ANE (with variable extension to the brainstem, cerebral and cerebellar white matter tracts) Other described lesions include prominence of optic nerve subarachnoid spaces sign abnormalities in the medial temporal lobe and olfactory bulb, contrast enhancement of intraparenchymal lesions, leptomeninges and cranial nerves. Some patients also developed T2WI hyperintensities in the periventricular areas and spinal cord, suggestive of demyelination, and ADEM-compatible lesions in COVID 19 patients have been described CSF: normal or with pleocytosis, with variable degrees of proteinorrhaquia and generally normal glucose Bloods: variable. Frequent findings are lymphopenia, decreased eosinophils, decreased albumin, raised CRP, increased LDH and increased interleukin-6 Ebola [ Patients with presumed Ebola meningoencephalitis are rarely scanned. Case reports have described punctate T2WI hyperintense lesions in the subcortical white matter, corpus callosum and peri fourth ventricle, compatible with microvascular lesions CSF: few case reports, evaluated only to detect viruses’ genetic material Bloods: leukopenia (earlier in the disease) or leucocytosis, thrombocytopenia, elevated transaminases (AST > ALT). Electrolyte disturbances with the disease-associated volume loss: hypo/hypernatremia, hypokalaemia, hypocalcaemia and hypomagnesemia. Coagulation abnormalities may occur Measles [ In the acute phase and acute post-measles encephalitis brain MRI shows multifocal hyperintense T2WI in both cerebral hemispheres, involvement of dorsal striatum and cortex oedema. MIBE presents with T2WI and DWI hyperintense lesions in the brainstem, cerebellum, multifocal cortical and subcortical grey matter lesions (including basal ganglia and thalamus), without contrast enhancement SSPE has a progressive course, initially with patchy asymmetric hyperintense lesions in T2WI in the white matter of both parietal and temporal lobes. It progresses to involve the corpus callosum and basal ganglia, culminating with generalised encephalomalacia CSF: acute encephalitis and acute post-measles encephalitis: lymphocytic pleocytosis with high protein and mildly low glucose MIBE—CSF is usually normal, but may present with pleocytosis and elevated protein. SSPE—only high titres of measles antibody Bloods: Leukopenia, thrombocytopenia and T cell cytopenia during the acute infection HIV [ HIV-associated encephalopathy usually presents with symmetric T2WI hyperintense lesions affecting mainly periventricular and deep white matter, with associated encephalomalacia, with no mass effect or enhancement. HIV-associated cerebral vasculopathy may lead to multiple nodular and fusiform aneurysms of large and medium arteries which can cause subarachnoid or intraparenchymal haemorrhages or embolic infarcts. HIV-related vacuolar myelopathy presents with spinal cord atrophy (mainly at the thoracic level, but cervical cord may be affected) with frequent bilateral symmetric dorsal column involvement CNS opportunistic infections in AIDS patients have characteristic dependent of its agent, the most common being: - Neurotoxoplasmosis typically causes nodular lesions in the basal ganglia and at the corticomedullary junction with 1–3 cm and perilesional oedema. Brain MRI shows concentric alternating zones of hypo/hyper and isointense in T2WI with post contrast ring enhancement - CMV encephalitis shows non-specific T2WI hyperintensities in the periventricular white matter with no mass effect and no enhancement - Neurocryptococcosis usually leads to lesions with little enhancement, spread along perivascular spaces mostly in the basal ganglia and white matter of cerebral hemispheres, brainstem and cerebellum. Dilated perivascular spaces can coalesce into gelatinous pseudocysts (“soap bubble”) with high signal in T2WI. Cryptococcomas are usually T2WI hyperintense nodular lesions in the cerebral parenchyma with variable enhancement. The meningeal disease usually shows leptomeningeal and pachymeningeal enhancement - PML is typically multifocal and asymmetric with periventricular and subcortical demyelinating lesions, especially subcortical U-fibres in the parieto-occipital areas. Multiple punctate high T2 signal lesions around the involved area (“milky way sign”) differentiate it from multiple sclerosis lesions - CNS lymphoma classically presents as supratentorial mass lesions which are T1 hypointense, T2 iso/hypointense with high signal in DWI and homogeneous enhancement with sub ependymal extension and crossing of the corpus callosum CSF: HIV aseptic meningitis: monocytic or lymphocytic pleocytosis with high or normal protein and normal glucose levels Specific opportunistic agents lead to variate CSF patterns Bloods: lymphopenia and thrombocytopenia are frequent in the acute phase of HIV infection (days to weeks after exposure) Cholera was not included in this table as its neurological manifestations are related solely to metabolic disturbances and no structural changes in the brain imaging or CSF are described Timeline of important pandemics including key neurological complications. These are noted for the first pandemic caused by an infection
The first Plague pandemic, known as the Plague of Justinian, occurred during the sixth century and is believed to have hastened the end of the Roman Empire. The second commenced with a wave known as the “Black Death” and is estimated to have resulted in the deaths of over 100 million people; the highest of any pandemic in history. Currently, most human cases are located in Africa, and annual epidemics are reported in Madagascar [
This virus was first identified in the West Nile province of Uganda in 1937 [
Large epidemics of Japanese encephalitis Virus (JEV) occur every 2–15 years in South-East Asia and Western Pacific, making it the world’s most commonly diagnosed epidemic encephalitis (~ 70,000 cases/year). Among the arthropod-borne viruses, JEV leads to the greatest loss of disability-adjusted life years, due to the frequent neurological sequelae of the condition. While the majority of infections are asymptomatic or mild, 0.1–1% cause encephalitis, mainly in children. It manifests in the acute phase of the disease. Symptoms include impaired consciousness, headache, vomiting, and seizures. Pyramidal and extrapyramidal signs, involvement of cranial nerves, eye movement abnormalities and anterior myelitis are described. Similar neurological features are seen in adults. Other immunological manifestations include GBS, ADEM, transverse myelitis and
The Zika virus was described in Uganda in 1947 and has caused outbreaks in Asia and the Pacific. In 2014–2016 it caused an epidemic of microcephaly among newborns in the northeast of Brazil [
Chikungunya virus was isolated during an outbreak in 1952 in Tanzania, and significant epidemics have been described worldwide. The most recent started in 2013, affecting the Southern USA, Mexico, Central and South America, with over 2 million infections reported [
Enteroviruses cause over 90% of viral meningitis in children under 10 years and is most frequently by echoviruses and Coxsackie-B [
Poliomyelitis was sporadically reported until the end of the nineteenth century, when large summer epidemics in North America and Europe began occurring annually [
This virus was isolated in 1969 and is a common cause of hand, foot, and mouth disease in children. Cyclical large epidemics occur in the Asian-Pacific region every 2–3 years and it circulates at a low level in the rest of the world, with small outbreaks in Europe, North America and Africa [
Bovine spongiform encephalopathy (BSE) was first described in 1985 and peaked in 1992/1993. The first cases of vCJD in humans were described in 1995 in the UK [
Influenza viruses can be divided in seasonal and pandemic. The seasonal influenza A viruses (H3N2 and H1N1) cause yearly epidemics, while pandemics of influenza are the consequence of cross-species transmission, followed by adaption to humans [
Late post infectious neurological complications of influenza have been extensively reported and are more frequent in adults. These include including GBS, cerebellitis, Kleine-Levin syndrome, myositis and transverse myelitis [
Since the beginning of the twenty-first century three coronaviruses (CoV) have been responsible for pandemics; severe acute respiratory syndrome (SARS-CoV1) in 2003, Middle East respiratory syndrome (MERS-CoV) in 2012 and SARS-CoV2 (also known as COVID-19) in 2019. Most human coronaviruses cause only mild respiratory symptoms and four strains are endemic worldwide, responsible for up to one third of upper respiratory tract infections in immunocompetent individuals: HCoV-229E, -OC43, -NL63 and -HKU1 [
Coronaviruses can invade the CNS and have been associated with many neurological sequelae including demyelinating diseases [
The 2002–2003 pandemic affected > 8000 people in 30 countries, 10% of whom died [
MERS has been an ongoing pandemic since initial reports in 2012 and has already affected > 2500 people, 35% of which died [
In December 2019, a new coronavirus appeared in Wuhan, China. A large current worldwide pandemic has resulted in six million recorded cases and over 1 million deaths, as of end of September 2020 [
There are increasing reports of many patients suffering from a long-term syndrome lasting more than 3 months post infection which has been badged as “long COVID.” Neurological-type symptoms including neurocognitive difficulties, depression and other mental health conditions, peripheral neuropathies and muscular weakness [
First described in 1976, Ebola has caused several outbreaks, mainly in African countries, the largest in 2014–2016. Neurological complications begin in the late stage when patients can have encephalopathy, seizures (probably due to metabolic abnormalities), meningitis and meningoencephalitis [
Until the introduction of attenuated measles vaccine, the disease killed 2–3 million people/year [
Since the beginning of the pandemic in the 1980s, 75 million people have been infected with HIV, and 32 million have died [
The most common CNS OI are tuberculous meningoencephalitis, neurotoxoplasmosis, cryptococcal meningitis, cytomegalovirosis and progressive multifocal leukoencephalopathy (PML) secondary to JC virus [
Immune reconstitution inflammatory syndrome (IRIS) may occur weeks to months after recovery from an immunodeficient state. Low CD4 before initiation of cART is the strongest predictor of IRIS. It can affect any organ and CNS-IRIS prevalence is around 1%, occurring in response to dying opportunistic agents (frequently linked to Cryptococcus or PML) or as a fulminant encephalitis associated with CD8 + T cells infiltration [
Up to 50% of HIV patients may be affected by HIV-associated neurocognitive disorders (HAND) which range from asymptomatic to dementia [
HIV infection can lead to a distal symmetric polyneuropathy, which can be related both to neurotoxic antiretrovirals and to the viral infection per se, affecting small fibres and causing numbness and painful distal limbs symptoms. Polyneuropathy affects 30–70% of HIV patients and immunosuppression no longer predicts its severity [
HIV is independently associated with increased risk for stroke which may be secondary to viral effects on endothelial dysfunction, vasculopathy and hyperviscosity [
Vacuolar myelopathy manifests in chronic AIDS [
Increases in global temperatures and a changing climate can lead to environmental adaptations of benefit for various disease vectors, including mosquitoes. These are the key vector for malaria, whose epidemic potential should increase in susceptible tropical countries (extending to highland areas) that had controlled the disease or be reintroduced in temperate climates that had previously eliminated it. The most severe form of malaria (and cause of 500,000 deaths per year) is cerebral [
Yellow fever, another mosquito-borne virus, was a major threat to human health until the beginning of the twentieth century, having caused multiple epidemics and deaths in cities distant from endemic areas, in North America, the Caribbean and Europe [
The mosquito-borne dengue virus has expanded from a sporadic disease affecting 9 countries in the 1970s to being endemic in over 100 countries; half of the world is now at risk. Neurological complications can occur at any stage. Dengue encephalopathy is the most common and involves impaired consciousness in the context of shock, liver failure and electrolyte disturbances in the first 10 days of the disease. Meningitis and encephalitis due to CNS invasion of the virus are also possible, though rare, and patients present with decreased level of consciousness, headache, dizziness, seizures and focal signs, also in the acute phase. Post-dengue immune-mediated complications include GBS, transverse myelitis, ADEM, mononeuropathies of cranial nerves, optic neuropathy, muscle dysfunction and intracranial haemorrhages during the convalescence stage [
War, conflicts and natural disasters can facilitate the spread of diseases like cholera. Cholera has caused seven pandemics in the last two centuries. Electrolyte disturbances and hypoglycaemia (mainly in children) secondary to severe diarrhoea and acute dehydration can lead to symptomatic seizures [
The recent decrease in coverage of MMR (measles, 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 disease and ADEM as a late post infectious complication [
Smallpox was a cause of massive epidemics until its eradication in the 1980s by global immunisation programs. Since most of people living today are not vaccinated against it and the viable variola virus is still kept in two maximum security laboratories [
Pandemics and epidemics have been present for thousands of years, and have played a pivotal role in history. Much of previous focus has been on the acute illnesses themselves, with relatively little attention paid to the social, human and economic consequences of neurological sequelae. However, it is these sequelae that often lead to significant amounts of mortality and long-term morbidity.
Under-recognition of neurological manifestations means that few studies have been conducted in previous pandemics to understand, treat and prevent neurological complications, and so the burden of secondary complications is even greater. With the recent developments in imaging, new information about the presentation of CNS diseases is available and can assist in the proper diagnosis of neurologic manifestations of infectious diseases. However, even in developed countries, diagnostic tests are limited and treatments are often inadequate or non-existent, with significant long-term economic and healthcare consequences. Therefore, it is reasonable to expect that in low and middle-income countries with poorer access to diagnostic tests and treatments, the neurological involvement by these diseases will have a greater economic impact. Potentially limiting future human capital by leaving long-term motor and cognitive impairments.
This urgent need to pay more attention to the short- and longer term sequelae of pandemics has been brought into sharp focus with COVID-19 where there have been numerous reports of short-term sequelae and a growing appreciation of longer term problems. There is a growing recognition of the need to work globally with international collaborations being formed to better understand the neurological consequences of COVID-19 [
However, it is also important to learn from previous pandemics to understand what to expect and plan responses to 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 example, encephalitis lethargica and post-encephalitic parkinsonism have been seen after viral infections, most notably the 1918–19 influenza pandemic [
As new infections continue to emerge, new pandemics will certainly happen. Despite advances in the treatment of infectious diseases in the last century, those affecting the nervous system are still challenging. An improved understanding of the pathophysiology of neurologic damage and recognising its possible manifestations is fundamental to develop new treatments and management strategies.
Neurological involvement in pandemics and epidemics is common and can cause devastating consequences amongst affected populations. There is an urgent need for better address this issue in pandemics, including the current SARS-CoV-2 outbreak.
DW was supported by an Academic Clinical Fellowship. DKM was supported by the NIHR through the NIHR Cambridge Biomedical Research Centre grant and a Senior Investigator Award. VFJN was supported by an Academy of Medical Sciences/The Health Foundation Fellowship.
FV and VFJN conceived the idea. FV performed the literature review and initial draft. All authors contributed substantially to the writing of the manuscript.
DW was supported by an Academic Clinical Fellowship. DKM was supported by the NIHR through the NIHR Cambridge Biomedical Research Centre grant and a Senior Investigator Award. VFJN was supported by an Academy of Medical Sciences/The Health Foundation Fellowship. No funding source had any role in the writing of this manuscript and decision to submit for publication.
On behalf of all authors, the corresponding author states that there is no conflict of interest.