The Lancet Neurology

Neurological Associations of COVID-19--Manuscript Draft--

Manuscript Number: THELANCETNEUROLOGY-D-20-00494

Article Type: Rapid Review

Keywords: COVID-19, coronavirus, SARS-CoV-2, neurology, encephalitis, encephalopathy,myelitis, myelopathy, Guillain-Barré Syndrome, cerebrovascular disease, stroke,vasculitis, nervous system, virus

Corresponding Author: Tom SolomonUniversity of LiverpoolLiverpool, UNITED KINGDOM

First Author: Mark A Ellul, MRCP

Order of Authors: Mark A Ellul, MRCP

Laura Benjamin, PhD

Bhagteshwar Singh, MRCP

Suzannah Lant, MBChB

Benedict Daniel Michael, PhD

Rachel Kneen, FRCPCH

Sylviane Defres, MRCP

James J Sejvar, MD

Tom Solomon, FRCP

Manuscript Region of Origin: UNITED KINGDOM

Abstract: BackgroundThe COVID-19 pandemic, caused by SARS-CoV-2, is of a scale not seen since the1918 influenza pandemic. Although the predominant clinical presentation is withrespiratory disease, neurological manifestations are being recognised increasingly.Based on knowledge of other coronaviruses, especially those that caused the SARSand MERS epidemics, we might expect to see rare cases of central nervous system(CNS) and peripheral nervous system (PNS) disease caused by SARS-CoV-2.Recent developmentsA growing number of case reports and series describe a wide array of neurologicalmanifestations, but many lack detail, reflecting the challenge of studying such patients.Anosmia and ageusia are common, relatively specific for SARS-CoV-2 infection andmay occur in the absence of other clinical features. Encephalopathy is relativelycommon, being reported for 16 (7.5%) of 214 hospitalised COVID-19 patients inWuhan, China, and 40 (69%) of 58 in intensive care with COVID-19 in France.Encephalitis and Guillain-Barré syndrome have been described in case reports. SARS-CoV-2 is detected in the cerebrospinal fluid of some patients. Unexpectedly, acutecerebrovascular disease is also emerging as an important complication of severedisease, possibly due to a pro-inflammatory hypercoagulable state with elevated CRP,D-dimer, and ferritin.Where next?Careful clinical, diagnostic and epidemiological studies are needed to help define themanifestations and burden of neurological disease caused by SARS-CoV-2. Precisecase definitions must be used to distinguish non-specific complications of severedisease, such as hypoxic encephalopathy and critical care neuropathy, from thosecaused directly or indirectly by the virus; these include infectious, para- and post-infectious encephalitis, hypercoagulable states leading to stroke, and acuteneuropathies such as Guillain-Barré syndrome. Recognising SARS-CoV-2 neurologicaldisease in patients whose respiratory infection is mild or asymptomatic may provechallenging, especially if the primary COVID-19 illness occurred weeks earlier. Theproportion of infections leading to neurological disease will remain small. However

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these patients may be left with severe neurological sequelae. With so much of thepopulation infected, the overall number of neurological patients, and their associatedhealth, social and economic costs, may be large. Healthcare planners andpolicymakers must prepare for this eventuality.

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Neurological Associations of COVID-19

Authors Mark Ellul1,2, Laura Benjamin3, Bhagteshwar Singh1,4,5, Suzannah Lant1, Benedict Daniel Michael1,2, Rachel Kneen6, Sylviane Defres1,4, Jim Sejvar7, Tom Solomon1,2,4 Affiliations 1. National Institute for Health Research Health Protection Research Unit on Emerging and Zoonotic Infections, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK 2. The Walton Centre NHS Foundation Trust, Liverpool, UK 3. UCL Queen Square Institute of Neurology, London, UK 4. Tropical and Infectious Diseases Unit, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK 5. Christian Medical College, Vellore, India 6. Alder Hey Children’s NHS Foundation Trust, Liverpool, UK 7. Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA Author Statement MAE, BDM, JS and TS devised the idea for the study. All authors contributed to the literature search. MAE, BDM and TS designed and drafted the figures. MAE, BS, BDM, RK, SD, JS and TS prepared the initial manuscript draft. All authors contributed to, reviewed and approved the final draft of the paper.

Manuscript

Summary Background The COVID-19 pandemic, caused by SARS-CoV-2, is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. Based on knowledge of other coronaviruses, especially those that caused the SARS and MERS epidemics, we might expect to see rare cases of central nervous system (CNS) and peripheral nervous system (PNS) disease caused by SARS-CoV-2. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations, but many lack detail, reflecting the challenge of studying such patients. Anosmia and ageusia are common, relatively specific for SARS-CoV-2 infection and may occur in the absence of other clinical features. Encephalopathy is relatively common, being reported for 16 (7.5%) of 214 hospitalised COVID-19 patients in Wuhan, China, and 40 (69%) of 58 in intensive care with COVID-19 in France. Encephalitis and Guillain-Barré syndrome have been described in case reports. SARS-CoV-2 is detected in the cerebrospinal fluid of some patients. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication of severe disease, possibly due to a pro-inflammatory hypercoagulable state with elevated CRP, D-dimer, and ferritin. Where next? Careful clinical, diagnostic and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease, such as hypoxic encephalopathy and critical care neuropathy, from those caused directly or indirectly by the virus; these include infectious, para- and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognising SARS-CoV-2 neurological disease in patients whose respiratory infection is mild or asymptomatic may prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will remain small. However these patients may be left with severe neurological sequelae. With so much of the population infected, the overall number of neurological patients, and their associated health, social and economic costs, may be large. Healthcare planners and policymakers must prepare for this eventuality. Search Strategy and selection criteria We searched PubMed and Scopus for articles on COVID-19 and neurological disease published in English from database inception, to April 23, 2020, using the terms “COVID-19”, “Novel coronavirus”, “SARS-CoV-2”, or “coronavirus” in combination with “neurological”, “nervous system”, “encephalitis”, “encephalopathy”, “seizure”, “ataxia”, "myelopathy", “Guillain-Barré syndrome”, “myopathy”, “peripheral neuropathy”, “neuritis”, “cerebrovascular”, “stroke”, “neuromuscular”, or “brain", modified as per requirements for each database’s search tool. We reviewed references of relevant studies for additional articles that might have been missed in the initial search. Experts in the field were consulted to ensure important preprints and unpublished studies were not missed. Articles were included on the basis of relevance and originality with regards to the topics covered in this Rapid Review.

BACKGROUND As of 23rd April 2020, the COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has caused more than 2.7 million confirmed cases worldwide, and almost 200,000 deaths. It is becoming the largest and most serious pandemic since the 1918 influenza pandemic. Whilst the most common and important presentation is with respiratory disease, there are increasing reports of neurological features such as headaches, muscle aches, anosmia, ageusia, altered consciousness and cerebrovascular accidents. The extent to which these represent non-specific complications of systemic disease, versus infection and/or inflammation of the nervous system and vasculature is yet to be determined. In this rapid review we consider which neurological manifestations that might be expected for COVID-19 given what we know about related coronaviruses and respiratory viruses more broadly; we summarize the evidence to date for COVID-19, and examine putative disease mechanisms; finally we suggest a framework for investigating patients with suspected COVID-19 neurological disease to support clinico-epidemiological, disease mechanism and treatment studies. Evidence from other coronaviruses Before SARS-CoV-2, six coronaviruses were known to infect humans. Four that cause seasonal, predominantly mild, respiratory illness, have a high incidence globally, accounting for about 15-30% of upper respiratory tract infections.1 Two have led to major epidemics; Severe Acute Respiratory Syndrome (SARS) was caused by SARS-CoV in 2002-3 and Middle East Acute Respiratory Syndrome (MERS) by MERS-CoV in 2012.2,3 Both the more innocuous coronaviruses and these epidemic strains have been associated with occasional disease of the central nervous system (CNS) and peripheral nervous system (PNS). The SARS epidemic, which originated in China, caused around 800 deaths in 29 countries.4 The clinical characteristics of respiratory disease were similar to the current picture of COVID-19, but with a higher case fatality rate of around 10%.5 Both CNS and PNS disease were reported (Table 1). Two encephalopathic patients with seizures were described, who had normal computer tomography (CT) scans, routine cerebrospinal fluid (CSF) findings, and SARS-CoV detected in the CSF by a polymerase chain reaction (PCR) test.6–8 A third patient recovering from SARS became encephalopathic in week 4, and died. A CT scan showed brain oedema, ischaemic change and necrosis. Virus was cultured from brain tissue at autopsy.8 PNS and/or muscle disease was reported in four patients with severe SARS, three of whom had multi-organ failure and were ventilated.9 The neurological disorders occurred around 3 weeks after respiratory symptom onset: two developed a predominantly motor neuropathy, one had neuropathy with evidence of myopathy, and one had myopathy alone. Neurophysiology showed an axonal, predominantly motor neuropathy. Whether these manifestations were SARS-specific or secondary to critical illness is not known.10 MERS-CoV MERS, which was first reported in Saudi Arabia, has higher mortality than SARS, at around 50%, and continues to cause outbreaks following camel to human viral transmission.11,12 CNS involvement was described in three adults in Saudia Arabia, all with pre-existing medical conditions including diabetes and hypertension. One presented to hospital with an encephalitic syndrome, and two had MERS and then deteriorated neurologically.13 All three were positive for MERS-CoV in respiratory samples; two had CSF tested, which was negative. Magnetic resonance imaging (MRI) for the first patient showed

white matter change consistent with acute disseminated encephalomyelitis (ADEM), the second had a stroke, thought secondary to vasculitis, and the third had encephalitis.13 Four of 23 MERS patients in one South Korean hospital developed neurological features, around 3 weeks after the initial respiratory symptoms.14 One had features suggestive of Bickerstaff’s brainstem encephalitis; and three had features of peripheral neuropathy. Seasonal human coronaviruses The four seasonal coronaviruses, HCoV-229E, -NL63, -OC43, and -HKU1 mostly cause mild to moderate respiratory disease in humans but have occasionally been associated with neurological syndromes. In particular, HCoV-OC43 has been implicated in childhood encephalitis, through infectious, para- and post-infectious mechanisms. An 11-month-old child with severe combined immunodeficiency developed fatal encephalitis; RNA sequencing of brain tissue revealed HCoV-OC43, confirmed by immunohistochemistry.15 An immunocompetent 15-year-old boy developed acute disseminated encephalomyelitis (ADEM) one week after upper respiratory tract illness; HcoV-OC43 PCR was positive in nasopharyngeal samples and CSF.16 In a series of 22 children (median age 36 months) from Chenzhou, China, with suspected CNS infection and coronavirus IgM antibodies in serum and/or CSF, the commonest neurological features were headache (in 10), neck stiffness (7) and seizures (5).17 Ten had a CSF pleocytosis, and eight of 16 with brain imaging had abnormalities. All 22 were said to have made a full recovery.17

Other respiratory viruses

A broader range of neurological complications has been described for other respiratory viruses, particularly seasonal and pandemic influenza viruses.1 These include acute necrotising encephalopathy associated with mutations in the RANBP2 gene, and acute infantile encephalopathy predominantly affecting the frontal lobes in children, and acute haemorrhagic leukoencephalopathy and myelopathy in adults.18,19 The estimated incidence of neurological disorders during the 2009 H1N1 influenza pandemic was 1.2 per 100,000, with children affected more than adults.20–23 The 1918 H1N1 “Spanish” influenza pandemic was associated with post-infectious encephalitis lethargica.24 Occasional CNS disease has also been described for respiratory syncytial virus, rhinoviruses and human metapneumoviruses, mostly in children.1

RECENT DEVELOPMENTS

COVID-19 and neurological disease

As the COVID-19 pandemic progresses there are increasing reports of neurological disease (Table 1). The challenges in managing patients with a highly contagious infection, and the overwhelming numbers of cases mean that many early reports lack detail, with limited CSF analysis, imaging or follow up. Many reports are in non-peer-reviewed websites such as MedRxiv. Encephalopathy The largest study to date, from Wuhan where the pandemic began, described retrospectively 214 patients with COVID-19, of whom 88 (41.1%) had severe respiratory disease, and 78 (36.4%) had

neurological features.25 In 58 (74.4%) patients with CNS symptoms, the most common features were dizziness (36 patients, 46.1%), headache (28,35.9%), and impaired consciousness (16, 20.5%). In a French case series of 58 intensive care patients with COVID-19, 40 (69%) were encephalopathic with agitation or confusion, including 39 (67%) with corticospinal tract signs.26 MRI in 13 patients showed leptomeningeal enhancement for eight and acute ischemic change for two (see below); CSF examination for 7 patients showed no pleocytosis. Fifteen (33%) of 45 who had been discharged had a dysexecutive syndrome. A 56-year-old man from Beijing with severe respiratory symptoms was described whose level of conscious deteriorated on the intensive care unit.27 CSF cell counts and biochemistry were not reported, but SARS-CoV-2 was detected in the CSF by sequencing. CT scan showed no clear evidence of brain inflammation. He improved and he was discharged one month later. Clinicians in the USA described a 74-year-old with a history of atrial fibrillation and stroke who developed COVID-19 respiratory disease and altered mental status, but no evidence of brain inflammation on CT or CSF testing. Electroencephalogram (EEG) changes were non-specific.28 CSF was not tested for SARS-CoV2. A woman in her fifties who presented in the USA with cough, fever and altered mental status had a positive nasal swab for SARS-CoV-2.29 Brain imaging showed haemorrhagic lesions consistent with acute necrotising encephalopathy (Figure 1, Left). The CSF cell count was not reported, owing to a traumatic lumbar puncture; CSF, negative for herpes simplex virus 1 and 2 and West Nile virus, was not tested for SARS-CoV2. No patients in these reports would fulfil established criteria for clinical diagnosis of encephalitis (inflammation of the brain), as opposed to encephalopathy (altered mental status which might be secondary to a range of systemic, metabolic or other disease mechanisms).30–33 However, to date there are two COVID-19 patients with evidence of CNS inflammation34,35. Encephalitis A 24-year-old man from Japan with 9 days headache, fatigue, fever and then sore throat, presented with seizures, reduced consciousness and neck stiffness.34 CSF analysis showed 12 cells/mm3, predominantly lymphocytes, with a raised opening pressure. Other routine CSF findings were not reported. He had ground glass changes on chest CT; RT-PCR for SARS-Cov-2 in nasopharyngeal swab was negative, but CSF was positive. Brain MRI showed hyperintensity in the right medial temporal lobe consistent with encephalitis (Figure 1, Right). Serum IgM antibody tests were negative for herpes simplex virus and varicella zoster virus but CSF PCR testing for these pathogens was not reported. A 60-year-old with five days of fever, irritability and confusion, followed by cough was positive for SARS-CoV-2 on nasopharyngeal swab.35 His CSF had a mild lymphocytic pleocytosis and moderately elevated protein, but was negative for SARS-CoV-2. CT and MRI were normal, but an EEG showed generalised slowing. Investigations for other infectious or autoimmune causes of encephalitis were negative. He apparently had a good response to high dose steroids, becoming alert the day after the first infusion. Cerebrovascular disease There have been several reports linking COVID-19 to acute cerebrovascular disease, with one neurology magazine describing in Italy “a dramatic increase in the number of vascular events,

ischemic strokes, and thrombosis”.36 There were cerebrovascular manifestations for 13 (5.9%) of 221 COVID-19 patients in the Wuhan retrospective case series: 11 (5%) developed ischaemic stroke, one (0.5%) had intracerebral haemorrhage, and one cerebral venous sinus thrombosis.37 Compared with the other COVID-19 patients, those with acute cerebrovascular disease were older, and more likely to have cardiovascular risk factors. Stroke occurred at median 9 days after respiratory illness onset. Median C-reactive protein was 51.1mg/L and D-dimer 6.9mg/L in patients with acute cerebrovascular disease; substantially higher than for other COVID-19 patients,37 and for a comparative cohort of stroke patients without COVID-19.38 The findings suggest a pro-inflammatory, coagulopathic state in the setting of critical illness. Coagulopathy with anti-phospholipid antibodies has also been described in one COVID-19 patient who had a stroke and peripheral ischaemia.39 In some patients, COVID-19 infection was not apparent until a couple of days after the presentation with stroke.25 In the French series small asymptomatic ischaemic strokes were found for three of 13 COVID-19 patients who underwent MRI.26 Peripheral nervous system and muscle disease Nineteen (8.9%) of the 214 patients in the Wuhan series were reported to have PNS disease. Few details were given, but 12 (5.6%) had ageusia and 11 (5.1%) anosmia; visual impairment and nerve pain were also described. In a European study, olfactory dysfunction was reported for 357 (85.6%) of 417 COVID-19 patients, including 284 (79.6%) with anosmia; 342 (88.8%) reported gustatory disorders.40 Anosmia has been suggested as a useful diagnostic marker.41 A study of 259 patients, including 68 positive for SARS-CoV-2 found hyposmia and hypogeusia were both strongly associated with COVID-19.42 In Jinzhou, China, a 61-year-old who presented with demyelinating Guillain-Barré syndrome (GBS) developed a dry cough 7 days after admission; a pharyngeal swab was positive for SARS-CoV-2.43 Lymphocytopenia and thrombocytopenia, characteristic for SARS-CoV-2 infections, were present on hospital admission suggesting the infection was not nosocomial. Five Italian patients developed GBS five to ten days after mild to moderate COVID-19 respiratory disease.44 Four had SARS-CoV-2 PCR positive nasopharyngeal swabs, the fifth had positive serology. All were PCR negative for SARS-CoV-2 in CSF, and three had albuminocytologic dissociation. All five had flaccid tetraplegia or tetraparesis, with no autonomic dysfunction. Electrophysiology was consistent with an axonal variant of GBS in three patients and demyelination in two. All were treated with intravenous immunoglobulin, and one also had plasma exchange. At four weeks two were still ventilated on intensive care, two were having physiotherapy and one had been discharged. Muscle injury association with raised creatine kinase affected 23 (10.7%) of the 214 patients in the Wuhan series.25 Rhabdomyolysis due to COVID-19 has also been reported.45,46

Disease mechanisms

Infection and inflammation of the nervous system As for other neurotropic viruses, there are critical questions for SARS-CoV-2 around routes of entry into the nervous system, and the relative contribution of virus infection versus host response in the subsequent damage (Figure 2). Viral entry to the brain via the olfactory bulb, the only part of the CNS not protected by dura, is one plausible route for SARS-CoV-2, especially given the anosmia in COVID-19. Herpes simplex virus, the most common sporadic viral cause of encephalitis, is thought to enter via the olfactory or trigeminal nerves.47 In mouse models, following intranasal injection HCoV-OC43 invades the CNS by the

olfactory route,48 and becomes widely distributed in the cerebrum and cerebellum.49 Alternative entry routes include carriage across the blood brain barrier, following viraemia, or via infected leukocytes.1 The angiotensin converting enzyme 2 (ACE-2) receptor, which SARS-CoV-2 binds to for entry into cells,50 is found in the respiratory epithelium, and in brain vascular endothelium and smooth muscle.51 SARS-CoV-2 replicates in neuronal cells in vitro.52 Damage within the CNS or PNS may be caused directly by virus or by the body’s innate and adaptive immune responses to infection. Data so far do not suggest that SARS-CoV-2 or related coronaviruses are highly neurovirulent, unlike herpes simplex virus, some enteroviruses and some arthropod-borne viruses, which can cause rampant destruction of neurons after entering the nervous system.47 Autopsy material from a patient who developed encephalopathy weeks after presenting with SARS showed oedema, neuronal necrosis and broad gliocyte hyperplasia, suggesting chronic progressive viral cerebritis.8 Immunohistochemical staining demonstrated SARS-CoV in the brain was associated with elevated expression of monokine induced by interferon-g (Mig) and infiltration of CD68+ monocytes/macrophages plus CD3+ T lymphocytes; in the blood interferon-g–inducible protein (IP)10 and Mig were elevated.8 These findings were consistent with viral CNS entry triggering infiltration of immune cells and cytokine/chemokine release, which was unable to control viral replication, and ultimately contributed to tissue damage. The late onset of neurological symptoms after MERS-CoV infection for a patient with Bickerstaff’s encephalitis, and three with peripheral nerve disease14 suggests a post-infectious, immune mediated process, although anti-ganglioside antibodies were negative. For encephalopathies associated with H1N1 influenza the rapid onset and lack of brain inflammation on CSF examination or imaging is felt consistent with a possible para-infectious innate “cytokine storm” rather than direct viral damage.18 There has been even less work on disease mechanisms for coronavirus PNS disease than CNS disease. However, by comparison with other viruses, we might expect to see immune-mediated disease, e.g. GBS, and direct anterior horn cell viral damage causing acute flaccid myelitis.53 Cerebrovascular disease Early indicators suggest cerebrovascular disease in COVID-19 may be due to a coagulopathy. SARS-CoV-2 can cause damage to endothelial cells, which express ACE-2 receptor, activating inflammatory and thrombotic pathways.54 Endothelial cell infection and/or monocyte activation, upregulation of tissue factors, and the release of microparticles activating the thrombotic pathway causing thrombotic microangiopathy may occur for SARS-CoV-2, as for other viruses.55,56 The latter is postulated to represent part of the secondary haemophagocytic lymphohistiocytosis spectrum described in severe COVID-19.57 Thrombocytopenia with elevated D-dimer and CRP in severe COVID-19 and stroke are consistent with a virus associated microangiopathic process.37 Endothelial dysfunction could potentially lead to micro- and macro-vascular, arterial and potentially venous complications in the brain, as described systemically.58 Acute ischaemic stroke may also occur through the early inflammatory process following acute infection destabilising a carotid plaque or triggering atrial fibrillation.59 Such COVID-19 patients might present with stroke rather than severe respiratory disease. A vasculitis process similar to that for varicella zoster virus, where viral replication in the cerebral arterial wall triggers local inflammation,60 is also plausible: endothelial infection by SARS-CoV-2 with inflammation and apoptosis of endothelial cells has been shown in kidney, heart, bowel and lung at autopsy,54 but cerebral vessels have not yet been investigated.

Epidemiology

Although neurological complications are rare in SARS, MERS and COVID-19, the size of the current pandemic means that even a very small incidence could build up to a large number of cases. Table 2 shows that for SARS and MERS, per 100,000 cases, the minimum incidence for CNS complications ranges from 37 to 224 and for PNS complications from 49 to 180; the extrapolated incidence for neurological complications of COVID-19, based on these related viruses, is also shown for some countries. Given the 2.6 million cases of COVID-19 globally as of 23rd April 2020, this projects to a total of 984-5955 patients with CNS, and 1303-4785 with PNS complications. These numbers will rise as the pandemic continues. Although the numbers are small compared with respiratory disease, neurological complications, particularly encephalitis and stroke can cause lifelong disability with associated long-term care needs, and ultimately the disease burden may be considerable. Policymakers should take account of this now.

WHERE NEXT?

Investigating for neurological disease

As SARS-CoV-2 continues to spread, and patients with neurological symptoms are seen increasingly, it is essential that the desire to publish quickly is balanced with the need for careful clinical, diagnostic and epidemiological studies. Clinicians must adopt a methodical approach to investigating patients with possible COVID-19 neurological disease, and consider systematically the evidence for viral infection, and the presenting clinical diagnosis, using case definitions that distinguish confirmed, probable and possible (Table 3 and Supplementary data). Given that SARS-CoV-2 causes a large number of asymptomatic or mildly symptomatic infections it is crucial to remember that patients with neurological disease from other causes may be infected coincidentally with the virus; this is especially important as SARS-CoV-2 infections may occur in hospital through nosocomial transmission. A full work-up is needed to rule out other established causes of brain infections before attributing disease to COVID-19.30,33 Such a work-up has been lacking completely for many published reports to date. It is also important to distinguish between evidence of nasopharyngeal or systemic SARS-CoV-2 infection, and evidence of neurological infection (Table 3). For patients with altered consciousness or agitation, consider possible causes of encephalopathy, including hypoxia, drugs, toxins, and metabolic derangement; only diagnose encephalitis if there is clinical evidence of brain inflammation such as a CSF pleocytosis, imaging changes, or histology (Supplementary Table 2).30 Even if virus is detected in the CSF encephalitis should not be diagnosed unless there is evidence of brain inflammation. For patients with possible peripheral nerve disease, aim to perform CSF examination including albuminocytologic ratio, nerve conduction studies and electromyography during recovery, even if they cannot be done in the hyperacute phase of the illness. In patients with neuropathy or cerebrovascular disease, where the damage is likely caused by host response to viral infection, establishing causality is even more challenging, especially if patients present after virus has cleared from the nasopharynx. Clinical case definitions for COVID-19, based on the history and typical findings for chest imaging and blood investigations (Table 3) will be useful whilst we await reliable antibody tests.

Again, exclusion of other causes is important. Consider cerebral angiography, intracranial vessel wall imaging and, if necessary, brain biopsy, looking for vasculitis among those that are encephalopathic or have a stroke syndrome. For other stroke syndromes, the link with SARS-CoV-2 may ultimately need to be proven by careful case-control studies. In investigating patients with limb weakness and sensory change it is critical to distinguish between disease of the peripheral nerves such as GBS, and inflammation of the spinal cord, which can present with flaccid paralysis if the anterior horn cells are involved.53 CSF examination, neurophysiological studies and spinal imaging are essential. For patients on intensive care, determining whether neuropathy, myopathy, encephalopathy or cerebrovascular disease are non-specific manifestations of critical illness or are specific to the virus itself may be especially challenging; there are no reliable markers for critical illness, though it tends to occur after several weeks.10 Up to 70% of patients with sepsis may develop encephalopathy or polyneuropathy.61 In the Wuhan series, neurological complications were more common in those with severe disease, which may suggest some of the neurological manifestations were related to critical illness.62,63 In conclusion, given knowledge of other coronaviruses and respiratory viruses we should not be surprised to see a wide range of CNS and PNS manifestations of COVID-19. Currently the focus is on neurological complications of patients with obvious COVID-19 respiratory disease; however, we are likely to see neurological disease in patients with few or no typical features of COVID-19, based on knowledge of other epidemic viral infections.31 Hypercoagulable states and cerebrovascular disease, which have been seen rarely for some acute viral infections are growing to be an important neurological complication of COVID-19. Overall, the proportion of patients with neurological disease is likely to remain small compared with respiratory disease. However, the continuing pandemic, and expectation that 50-80% of the world’s population may be infected before herd immunity develops, suggest that the overall number of patients with neurological disease, and the associated health, social and economic costs, may be large. Long-term neurological sequelae may become more apparent as patients recover from their acute respiratory disease. Healthcare planners and policymakers need to be aware of the growing burden. Careful clinical, diagnostic and epidemiological studies are needed to help define the neurological disease manifestations and burden. This will involve collaboration of a range of clinical and research expertise, and harmonised approaches across regions, using standardised case record forms such as on https://braininfectionsglobal.tghn.org/covid-neuro-network/ . Case-control studies to help establish causality and risk factors will be challenging, especially given the difficulties of safely assessing appropriate controls, the current lack of reliable antibody testing, and the likely very high incidence of the virus among controls as the spread continues.

Declaration of Interests: TS was an adviser to the GlaxoSmithKline Ebola Vaccine programme and chaired a Siemens Diagnostics clinical advisory board. All other authors report no competing interests. Acknowledgements: The research was funded by the NIHR Global Health Research Group on Brain Infections (No. 17/63/110) and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford (Grant No. NIHR200907). TS is based at the University of Liverpool. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. MAE, SL and TS are supported by the European Union's Horizon 2020 research and innovation program ZikaPLAN (Preparedness Latin America Network; grant agreement No. 734584). MAE is also supported by the Association of British Neurologists though a Clinical Research Training Fellowship. BDM has received funding from the Medical Research Council, Wellcome Trust and Academy of Medical Sciences. We are grateful also for the support of the Centre of Excellence in Infectious disease Research (CEIDR), Liverpool.

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FIGURES Figure 1: Brain Imaging

Left. Acute Necrotising Encephalopathy associated with SARS-CoV2 infection29 Magnetic resonance images demonstrate T2 Fluid-attenuated inversion recovery (FLAIR) hyperintensity within the bilateral medial temporal lobes and thalami (A, B, E, F) with evidence of haemorrhage indicated by hypointense signal intensity on susceptibility-weighted images (C, G) and rim enhancement on postcontrast images (D, H). Right. Encephalitis associated with SARS-CoV234 A: Diffusion weighted images (DWI) showed hyperintensity along the wall of inferior horn of right lateral ventricle. B,C: FLAIR images showed hyperintense signal changes in the right mesial temporal lobe and hippocampus with slight hippocampal atrophy. These findings indicated right lateral ventriculitis and encephalitis mainly on right mesial lobe and hippocampus.

Figure 2: Potential mechanisms of SARS-CoV-2 neurological disease based on knowledge of other viruses.

BBB= blood-brain barrier (A) Virus may enter the nervous system across the blood brain barrier, possibly by infected leukocytes, or through retrograde transport along olfactory or other cranial or peripheral neurons.64 Viruses can enter neurons to cause cytopathology. (B) Innate immune responses to viral infection and resultant inflammation may cause tissue damage, as is thought to occur in acute encephalopathy syndromes in influenza infection.18

(C) Pathological adaptive immune responses include damage caused by cytotoxic T cells65 and antibody mediated response against host tissue, either in the central or

peripheral nervous system.66,67 The latter may be caused by molecular mimicry between the pathogen and host epitopes, or tissue damage may result in failure of

tolerance to self-antigens.

(D) Viral infection may cause blood vessel damage either by direct infection or immune-mediated vasculitis.68 Alternatively, the virus may activate the endothelium

triggering inflammatory and thrombotic pathways with release of microparticles leading to thrombotic microangiopathy as part of a secondary haemophagocytic

lymphohistiocytosis.56

TABLES

Table 1. Published cases and series of neurological disease associated with SARS, MERS and COVID-19 Table 2. Estimated incidence of neurological disease associated with SARS, MERS and COVID-19 Table 3. Provisional case definitions for establishing SARS-CoV-2 causality in neurological diseases, based on previously established principles

Virus First author Number of

patients Clinical features /

syndrome(s) Key neurological investigations Coronavirus diagnostic tests Therapy for neurological disease and outcome

SARS-CoV2 Mao/Li25,37 85 36 dizziness, 28 headache, 16 impaired consciousness, 13 cerebrovascular disease (11 ischaemic stroke, 1 CVST, 1 cerebral haemorrhage), 1 ataxia, 1 epilepsy, 12 hypogeusia, 11 hyposmia, 3 hypopsia, 5 nerve pain, 23 muscle injury.

CSF analysis not reported. CT brain imaging performed for patients with cerebrovascular disease, not reported for other patients. No NCS or EMG reported.

RT-PCR positive in throat swab. CSF not reported.

Survival in 8 of 13 patients with cerebrovascular disease; 7 patients remain hospitalised, functional outcome not reported. Outcome in other patients not reported (majority are still hospitalised).

Helms26 49 Neurological signs in patients on the intensive care unit: 40 agitation, 39 corticospinal tract signs, 14 dysexecutive syndrome, 3 ischaemic stroke.

13 patients had MRI. 8 of these had leptomeningeal enhancement, 11 perfusion abnormalities, 3 ischaemic stroke.

All patients were positive by RT-PCR in nasopharyngeal samples, 7 patients were tested in CSF and all were negative.

Treatment and outcome not reported.

Bernard-Valnet69 1 Meningoencephalitis EEG: nonconvulsive status epilepticus. MRI brain normal. CSF analysis: 17 cells/mm3 (97% lymphocytes), protein 0.46g/L.

RT-PCR positive in nasal swab, negative in CSF.

Markedly improved 96 hours after admission.

1 Meningoencephalitis MRI brain normal, CSF analysis: 21 cells/mm3 (89% lymphocytes), protein 0.46g/L.

RT-PCR positive in nasal swab, negative in CSF.

Neurological symptoms resolved after 24 hours.

Moriguchi34 1 Meningoencephalitis CSF cell count 12/mm3. MRI: hyperintensity along the wall of the right lateral ventricle on diffusion weighted imaging, and hyperintense signal in the right medial temporal lobe and hippocampus on T2 weighted images (Figure 1, Right).

RT-PCR negative in nasopharyngeal swab, positive in CSF.

Treated empirically for bacterial pneumonia and viral encephalitis. Still on intensive care at time of report (day 15)

Pilotto35 1 Encephalitis CT and MRI brain normal. CSF pleocytosis (18/µL), protein 0.69g/L.

RT-PCR positive in nasopharyngeal swab; negative in CSF.

Responded quickly to high dose intravenous steroids

Duong70 1 Meningoencephalitis without respiratory failure

CT brain normal. CSF analysis: 70 white cells/mm3 (100% lymphocytes), protein 1g/L. EEG showed generalised slowing.

"Positive"- details not reported. CSF RT-PCR not available.

Improvement at 5 days. Ongoing hallucinations.

Poyiadji29 1 Acute necrotising encephalopathy

MRI showed haemorrhagic rim-enhancing lesions within bilateral thalami, medial temporal lobes and subinsular regions (Figure 1, Left). CSF cell count not reported

RT-PCR positive in nasopharyngeal swab. CSF RT-PCR unable to be performed.

IVIG. Outcome not reported

Ye71 1 Encephalopathy with meningism

CSF analysis and CT brain normal RT-PCR positive in nasopharyngeal swab; negative in CSF

No specific treatment, gradual improvement.

Filatov28 1 Encephalopathy CT brain: previous left MCA infarct, no acute changes. EEG: bilateral slowing and focal slowing in the left temporal region with sharply countered waves. CSF analysis: normal.

Positive, source not specified Supportive therapy. Patient remained in ICU at time of publication.

Zhang72 1 ADEM CSF analysis: normal. EEG: no evidence of seizures. MRI brain: extensive areas of high signal in white matter and thalami.

RT-PCR positive- site not specified.

Treated with IVIG. Some improvement after 5 days.

Zhao73 1 Myelitis CSF analysis not performed, CT brain showed lacunar infarcts

RT-PCR positive in nasopharyngeal swab.

Treated with dexamethasone and IVIG. No significant improvement.

Zhao43 1 GBS - respiratory symptoms developed 7 days after onset of neurological symptoms

CSF cell count normal, protein 1.24g/L. NCS showed evidence of demyelination.

RT-PCR positive in oropharyngeal swab.

IVIG. Normal strength and reflexes on discharge.

Toscano44 5 GBS NCS: axonal pattern in 3 patients, demyelinating in 2. MRI showed enhancement of caudal nerve roots in 2 patients, enhancement of facial n. in one, no signal change in 2. CSF analysis: all patients had normal WCC, 3 patients had elevated protein.

4 patients RT-PCR positive in nasopharyngeal swab. One positive by serological test. RT-PCR in CSF negative in all patients.

At 4 weeks: 2 were still ventilated in intensive care, 2 were having physiotherapy and one was discharged.

Gutiérrez-Ortiz74 1 Miller Fisher syndrome CT brain with contrast: normal. CSF analysis: WCC normal, protein 0.8g/L. GD1b-IgG positive

RT-PCR positive in oropharyngeal swab, negative in CSF

Treated with IVIG.

1 Polyneuritis cranialis CT brain: normal. CSF analysis: WCC normal, protein 0.62g/L.

RT-PCR positive in oropharyngeal swab, negative in CSF

No specific treatment. Complete recovery in 2 weeks.

Lechien40 357 Olfactory dysfunction: 284 (80%) with anosmia; 342 (89%) with gustatory disorders

CT/MRI not performed All RT-PCR positive, specimen not specified.

Treated with nasal corticosteroids (8%), oral corticosteroids (2.5%), nasal irrigation (17%).

Morassi75 6 4 ischaemic stroke, 2 haemorrhagic stroke.

CT/MRI demonstrated probable thromboembolic ischaemic strokes in 2, ischaemic strokes in 2 and haemorrhage in 2.

All RT-PCR positive in nasopharyngeal swabs.

Ischaemic strokes treated with antiplatelets. None treated with thrombolysis or mechanical thrombectomy.

Zhang39 1

1

1

Stroke Stroke Stroke

CT brain: multiple cerebral infarctions in bilateral frontal, parietal, and occipital lobes, basal ganglia, brainstem and cerebellar hemispheres Antiphospholipid antibody positive CT brain: multiple cerebral infarctions in right frontal and bilateral parietal lobes CT brain: multiple cerebral infarctions in frontal lobes, right frontal, parietal, temporal and occipital lobes and bilateral cerebellar hemispheres All cases positive for anticardiolipin IgA antibodies and anti-B2-glycoprotein 1 IgA and IgG

RT-PCR positive, specimen not specified RT-PCR positive, specimen not specified RT-PCR positive, specimen not specified

IVIG, oseltamivir Antibiotics Antibiotics, ribavirin, rosuvastatin

Klok58 3 Ischaemic stroke CT brain performed in all cases, but no details given

“Proven COVID-19” - details not reported

Jin45 1 Rhabdomyolysis CK raised: 11,842 U/L*, myoglobin raised: 12,000 µg/L+

RT-PCR positive in throat swab Antibiotics and supportive therapy

Suwanwongse46

1 Rhabdomyalysis Creatinine kinase raised (13,581 U/L) RT-PCR positive in nasopharyngeal swab.

Treated with hydroxychloroquine and supportive therapy.

SARS-CoV Xu8 1 Encephalopathy CT brain: cerebral oedema, areas of ischaemia. CSF findings not reported

Antibody positive in serum. SARS-CoV detected in brain tissue by RT-PCR and immunohistochemistry.

Supportive treatment only. Death 35 days after onset.

Hung7 1 Encephalopathy with seizures CT brain: normal. CSF analysis: normal. RT-PCR positive in serum and CSF

Supportive therapy. Seizure free at discharge, no further details of outcome.

Lau6 1 Encephalopathy with seizures MRI brain: normal. CSF analysis: normal. EEG: normal.

RT-PCR positive in CSF, stool and peritoneal fluid. Serum SARS-CoV IgG titre <1:25 day 1, 1:1600 day 39.

Supportive therapy.

Tsai9 1 Motor-predominant peripheral neuropathy

NCS/EMG findings consistent with critical illness polyneuropathy. CSF analysis not performed.

RT-PCR positive in throat swab. Serum coronavirus antibody positive

Almost complete recovery at 2 months.

1 Motor-predominant peripheral neuropathy

CSF analysis: normal. NCS: axonal sensorimotor polyneuropathy

RT-PCR positive in serum. Serum coronavirus antibody positive.

No specific treatment. Nearly full return of muscle power at 7 weeks.

1 Myopathy with peripheral neuropathy

CSF analysis: normal. NCS: axonal sensorimotor polyneuropathy. EMG: early recruitment with fibrillations and positive waves. CK: 9050 U/l

Serum coronavirus antibody positive. RT-PCR negative.

No specific treatment. Modest improvement in strength, no improvement in sensory problems at day 87.

1 Myopathy EMG: normal recruitment with active spontaneous activity and abundant brief small polyphasic waves. NCS: normal. CK: 366 U/l

RT-PCR positive in throat swab. Serum coronavirus antibody positive

No specific treatment. Full power at 7 weeks.

MERS-CoV Alghatani76 2 Intracerebral haemorrhage CT brain: right frontal haemorrhage with oedema and midline shift. CSF analysis not reported.

RT-PCR positive in sputum. Death 2 months after onset.

Polyneuropathy NCS: length dependent axonal polyneuropathy. CSF analysis: normal. MRI spine: normal.

RT-PCR positive in respiratory secretions

IVIG. Slow improvement after 6 months.

Arabi13 1 Encephalopathy/ADEM MRI brain: multiple areas of signal abnormality in deep white matter, periventricular areas, midbrain, cerebellum and upper cervical cord. CSF analysis: normal

RT-PCR positive in tracheal aspirate, negative in CSF

Death 34 days after onset

1 Multiple cerebral infarcts MRI brain: acute infarction in the parasagittal region and temporal, parietal, and occipital lobes. CSF analysis not reported

RT-PCR positive in respiratory sample

Death 9 days after onset

1 Encephalopathy/ADEM MRI brain: confluent T2WI/FLAIR hyperintensity within the white matter of both cerebral hemispheres and along the corticospinal tract. CSF analysis: normal cell count, protein 0.85 g/L

RT-PCR positive in respiratory samples, negative in CSF

Discharged home, detailed outcome not reported

Kim14 1 Bickerstaff’s brainstem encephalitis overlapping with GBS (hypersomnolence, quadriparesis, ptosis, ophthalmoplegia mild ataxia, areflexia)

MRI brain: normal, CSF analysis: normal, ganglioside antibodies negative. NCS normal on day 46.

RT-PCR positive in sputum, negative in CSF

IVIG. Full recovery by day 60.

1 GBS or critical care neuropathy (distal limb weakness and hyporeflexia

NCS normal. CSF not analysed. “laboratory confirmed MERS infection”

No specific treatment. Weakness resolved after 53 days. Ongoing sensory symptoms at 7 months.

1 Peripheral sensory symptoms NCS: normal. CSF not analysed “laboratory confirmed MERS infection”

No specific treatment. Symptoms gradually improved over 6 months.

1 Peripheral sensory symptoms NCS not performed, CSF not analysed. Exposed to MERS and developed respiratory illness. No laboratory confirmation reported.

No specific treatment. Symptoms resolved over 4 months.

ADEM = acute disseminated encephalomyelitis; CK = creatinine kinase; CSF = cerebrospinal fluid; CT = computed tomography; CVST = cerebral venous sinus thrombosis; EEG = electroencephalogram; EMG = electromyography; FLAIR = fluid-attenuated inversion recovery (MRI sequence); GBS = Guillain-Barré syndrome; ICU = intensive care unit; IVIG = intravenous immunoglobulin; NCS = nerve conduction study; MRI = magnetic resonance imaging; RT-PCR = reverse transcription polymerase chain reaction; T2WI= T2-weighted image (MRI sequence); WCC = white cell count

Table 1. Published cases and case series of neurological disease associated with SARS, MERS and COVID-19

SARS MERS COVID-19, UK COVID-19, USA COVID-19, China COVID-19, World

Estimated Total Cases*

8096 2228 139243 843937 83878 2658387

Extrapolated Minimum

Case Count

Extrapolated Maximum Case Count

Extrapolated

Minimum Case Count

Extrapolated Maximum Case Count

Extrapolated

Minimum Case Count

Extrapolated Maximum Case Count

Extrapolated

Minimum Case Count

Extrapolated Maximum Case Count

CNS disease, no. of patients (incidence)

3 (37/100,000) 5 (224/100,000) 52 312 312 1890 31 188 984 5955

PNS disease, no. of patients (incidence)

4 (49/100,000) 4 (180/100,000) 68 251 414 1519 41 151 1303 4785

Total, no. of patients (incidence)

7 (86/100,000) 8 (404/100,000) 120 563 726 3410 72 339 2286 10740

*calculated based on available data up until 23/04/2020; COVID-19 cases from https://coronavirus.jhu.edu/map.html

Table 2. Estimated incidence of neurological disease associated with SARS, MERS and COVID-19

Confirmed Probable Possible

SARS-CoV-2 meningitis, encephalitis, myelitis/myelopathy**

SARS-CoV-2 detected in CSF/ brain tissue †, OR Evidence of SARS-CoV-2-specific intrathecal antibody; AND No other explanatory pathogen of cause found

SARS-CoV-2 detected in respiratory or other non-CNS sample ‡, OR Evidence of SARS-CoV-2-specific antibody in serum indicating acute infection+§; AND No other explanatory pathogen or cause found

Patient meets suspected case definition of COVID-19 according to national or WHO guidance (as below), based on clinical symptoms and epidemiological risk factors. In the context of known community SARS-CoV-2 transmission, supportive features* include: Clinical: new onset of least one of: cough, fever, muscle aches, loss of smell, loss of taste; Laboratory: lymphopenia, raised d-dimer; Radiological: evidence of unilateral or bilateral abnormalities consistent with infection or inflammation (e.g. ground glass changes)

Strong association Probable association Possible association

Acute disseminated encephalomyelitis** (ADEM) associated with SARS-CoV-2 infection

Neurological disease onset <= 6 weeks after acute infection, AND SARS-CoV-2 RNA detected in any sample, OR

Neurological disease onset <= 6 weeks after acute infection, AND SARS-CoV-2 RNA detected in any sample; OR

Antibody evidence of acute SARS-CoV-2 infection; AND

Antibody evidence of acute SARS-CoV-2 infection; AND

No evidence of other commonly associated causes Evidence of other commonly associated causes

Guillain-Barré syndrome** and other acute neuropathies associated with SARS-CoV-2 infection

Neurological disease onset <= 6 weeks after acute infection, AND SARS-CoV-2 RNA detected in any sample;

OR

Neurological disease onset <= 6 weeks after acute infection, AND SARS-CoV-2 RNA detected in any sample;

OR

Antibody evidence of acute SARS-CoV-2 infection;

AND

Antibody evidence of acute SARS-CoV-2 infection;

AND

No evidence of other commonly associated causes ¶ Evidence of other commonly associated causes ¶

Stroke or CNS vasculitis** associated with SARS-CoV-2 infection

CNS Vasculitis: SARS-CoV-2 detected in CSF/brain tissue†; OR Evidence of SARS-CoV-2-specific intrathecal antibody; AND The presence of histopathological features of angiitis within the brain AND

All other stroke types: SARS-CoV-2 detected in CSF or other sample‡; OR Evidence of SARS-CoV-2-specific antibody in serum indicating acute infection; AND No other known traditional cardiovascular risk factors¥

CNS Vasculitis: SARS-CoV-2 detected in CSF/brain tissue†; OR Evidence of SARS-CoV-2-specific intrathecal antibody; AND Laboratory and imaging support for brain inflammation (MR scan evidence compatible with CNS vasculitis with characteristic angiographic changes; elevated levels of cerebrospinal fluid protein and/or cells, and/or the presence of oligoclonal bands)

No other explanatory pathogen or cause found

AND No other explanatory pathogen or cause found

All other stroke types: SARS-CoV-2 detected in CSF or other sample; OR Evidence of SARS-CoV-2-specific antibody indicating acute infection; AND • Other traditional cardiovascular risk factors¥

Confirmed Probable Suspected

WHO COVID-19 case definitions77

A person with laboratory confirmation78 of SARS-CoV-2 infection, irrespective of clinical signs and symptoms. Confirmatory tests include a nucleic acid amplication test (e.g. RT-PCR) or validated antibody test, • In an area WITH established circulation of

virus: one positive RT-PCR test or identification of virus on sequencing. One or more negative tests do not rule out infection if clinical suspicion.

• In an area WITHOUT established circulation

of virus: one positive RT-PCR test for two different viral genome targets, OR one positive result with partial or whole genome sequencing

A suspect case, for whom testing for the COVID-19 virus is inconclusive OR A suspect case, for whom testing could not be performed for any reason

A patient with acute respiratory illness (fever and at least one sign/symptom of respiratory distress) AND history of travel to or residence in a location reporting community transmission of COVID-19 disease during the 14 days prior to onset OR A patient with acute respiratory illness (fever and at least one sign/symptom of respiratory distress) AND having been in contact with a confirmed or probable case in the last 14 days prior to symptom onset OR A patient with severe acute respiratory illness (fever and at least one sign/symptom of respiratory distress AND requiring hospitalisation) AND in the absence of an alternative explanation that fully explains the clinical presentation

*These case definitions are suggestions based on published information to date; they are likely to need refining as more data emerge.

**See Supplementary Material for case definitions of meningitis, encephalitis, myelitis/myelopathy, acute disseminated encephalitis, Guillain-Barré Syndrome, and stroke, TIA and central nervous system vasculitis.

† detection in CSF or brain tissue by PCR, culture, or immunohistochemistry, as appropriate; ‡ detection in non-CNS sample by PCR or culture. § Serological evidence of acute infection can be defined as i) detection of IgM, or ii) IgG seroconversion or iii) >=4-fold rise in antibody titres in paired acute and convalescent serum samples. ¶ These include: infection with one of Campylobacter jejuni, Mycoplasma pneumoniae, Cytomegalovirus (CMV), Epstein–Barr virus (EBV), hepatitis E virus, Zika virus, or HIV; or vaccination in the last 6 weeks. Associated causes may differ depending on geographical location. ¥ traditional cardiovascular risk factors include; hypertension, current smoker, diabetes, hypercholesterolemia, and atrial fibrillation.

Table 3. Provisional case definitions for neurological diseases associated with SARS-CoV-2 infection, based on previously established principles31,32,79

Neurological Associations of COVID-19 - Supplementary Material Mark Ellul, Laura Benjamin, Bhagteshwar Singh, Suzannah Lant, Benedict Daniel Michael, Rachel Kneen, Sylviane Defres, Jim Sejvar, Tom Solomon

Case definitions for neurological syndromes

i. Meningitis ii. Encephalitis

iii. Myelitis/myelopathy iv. Acute disseminated encephalomyelitis (ADEM) v. Guillain-Barré Syndrome (GBS)

vi. Cerebrovascular disease (stroke, transient ischaemic attack, central nervous system vasculitis)

Supplementary Material

i. Meningitis1

Level 1 Meningitis

Level 2 Possible meningitis

Level 3 Meningism

Level 4 Suspected meningitis

Suspected meningitis with no other diagnoses apparent, but does not fulfil level 3 criteria

[ ] Absence of an alternative diagnosis for symptoms AND [ ] Neck stiffness OR [ ] Kernig’s sign positive OR [ ] Brudzinsky’s sign positive

[ ] Fever (≥ 38ºC)

[ ] CSF total white cell count > 5 cells/mm3

OR

[ ] Meningeal enhancement seen on contrast enhanced CT or MRI

[ ] Level 1 Meningitis

[ ] Level 2 Possible meningitis

[ ] Level 3 Meningism

[ ] Level 4 Suspected meningitis

ii. Encephalitis2,3

Level 1 Encephalitis

Level 2 Possible encephalitis

Level 3 Encephalopathy

Level 4 Suspected encephalopathy

[ ] Suspected encephalopathy (an alteration in consciousness, cognition, personality or behaviour) with no other diagnosis apparent, but does not fulfill level 3 criteria

[ ] Acute or sub-acute (<4 weeks) alteration in consciousness, cognition, personality or behaviour persisting for more than 24 hours AND [ ] Absence of an alternative diagnosis for symptoms

[ ] New onset seizure OR [ ] New focal neurological signs OR [ ] Fever (≥ 38ºC) OR [ ] Movement disorder (includes: Parkinsonism, oromotor dysfunction etc.) OR [ ] EEG consistent with encephalopathy +/- epileptiform features

[ ] CSF total white cell count > 5 cells/mm3

OR

[ ] Neuroimaging compatible with encephalitis OR [ ] Confirmation of brain inflammation on brain biopsy

[ ] Level 1 Encephalitis

[ ] Level 2 Possible encephalitis

[ ] Level 3 Encephalopathy

[ ] Level 4 Suspected encephalopathy

iii. Myelitis 4

*if the patient wakes up with symptoms, symptoms must continue to worsen from the point of waking

Level 1 Myelitis

Level 2 Possible myelitis

Level 3 Myelopathy

Level 4 Suspected myelopathy

[ ] Weakness or sensory disturbance of upper and/or lower limbs, developing to its worst severity between 4h and 21d following onset of symptoms *

[ ] Absence of an alternative diagnosis for symptoms WITH [ ] Brisk reflexes or extensor plantar response OR [ ] Bladder or bowel dysfunction OR [ ] Clearly defined sensory level

[ ] Absence of extra-axial compressive aetiology by neuroimaging (MRI or CT myelography) AND [ ] Absence of flow voids on the surface of the spinal cord suggestive of arteriovenous malformation on neuroimaging (MRI)

[ ] CSF total white cell count >5 cells/mm3

OR [ ] MRI changes consistent with myelitis (gadolinium enhancement or T2 hyperintensity) OR [ ] Elevated IgG index

[ ] Level 1 Myelitis

[ ] Level 2 Possible myelitis

[ ] Level 3 Myelopathy

[ ] Level 4 Suspected myelopathy

iv. Acute disseminated encephalomyelitis (ADEM)5,6

Level 1 ADEM

Level 2 Probable ADEM

Level 3 Suspected ADEM

[ ] Suspected ADEM with no other diagnosis apparent, but does not fit level 2 criteria

[ ] unifocal or multifocal clinical CNS event OR [ ] alteration in consciousness or behavioural change (encephalopathy) unexplained by fever/systemic illness/postictal symptoms AND [ ] abnormal brain MRI with typical diffuse, poorly demarcated lesions >1cm

[ ] no new clinical or MRI findings 3 months or more after symptom onset OR [ ] signs/symptoms/MRI findings consistent with multiphasic ADEM*

[ ] Level 1 ADEM

[ ] Level 2 Probable ADEM

[ ] Level 3 Suspected ADEM

*Multiphasic ADEM – two episodes of Level 2 ADEM separated by three months but not followed by any further events. The second ADEM event can involve either new or re-emergence of prior neurological symptoms/signs/MRI findings. Beyond a second event, the diagnosis is no longer consistent with multiphasic ADEM

v. Guillain-Barré syndrome (GBS)7

Level 1 Level 2 Level 3 Level 4

[ ] Suspected GBS with no other diagnosis apparent, but does not fulfil level 3 criteria

[ ] Bilateral and flaccid weakness of the limbs AND [ ] Absence of an alternative diagnosis for weakness AND [ ] Decreased or absent deep tendon reflexes in affected limbs AND [ ] Monophasic illness pattern with weakness nadir between 12 hours and 28 days, followed by clinical plateau

[ ]CSF total white cell count < 50 cells/mm3

OR [ ]If CSF results unavailable, electrophysiological findings consistent with GBS

[ ]CSF protein level above laboratory normal value AND CSF total white cell count < 50 cells/mm3

AND

[ ] Electrophysiological findings consistent with GBS

[ ] Level 1 [ ] Level 2 [ ] Level 3 [ ] Level 4

vi. Cerebrovascular disease8,9,10

Stroke and Transient ischaemic attack (TIA): Definitions Central Nervous System (CNS) infarction Brain, spinal cord, or retinal cell death attributable to ischemia, based on:

[ ] clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on symptoms persisting ≥24 hours or until death, and other etiologies excluded (CNS infarction includes hemorrhagic infarctions, types I and II, see ‘Intracerebral hemorrhage’)

OR

[ ] pathological, imaging, or other objective evidence of cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular distribution

Silent CNS infarction [ ] Imaging or neuropathological evidence of CNS infarction, without a history of acute neurological dysfunction attributable to the lesion.

Ischemic stroke [ ] An episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction.

Intracerebral hemorrhage [ ] A focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma. (Intracerebral hemorrhage includes parenchymal hemorrhages after CNS infarction, type I - petechiae of blood along the margins of the infarction, and type II - confluent petechiae within the infarction but without a space-occupying effect.)

Silent cerebral hemorrhage [ ] A focal collection of chronic blood products within the brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathological examination that is not caused by trauma and without a history of acute neurological dysfunction attributable to the lesion.

Stroke caused by intracerebral hemorrhage

[ ] Rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma.

Subarachnoid hemorrhage [ ] Bleeding into the subarachnoid space (the space between the arachnoid membrane and the pia mater of the brain or spinal cord)

Stroke caused by subarachnoid hemorrhage

[ ] Rapidly developing signs of neurological dysfunction and/or headache because of bleeding into the subarachnoid space (the space between the arachnoid membrane and the pia mater of the brain or spinal cord), which is not caused by trauma.

Stroke caused by cerebral venous thrombosis

[ ] Infarction or hemorrhage in the brain, spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs caused by reversible edema without infarction or hemorrhage do not qualify as stroke.

Stroke, not otherwise specified [ ] An episode of acute neurological dysfunction presumed to be caused by ischemia or hemorrhage, persisting ≥24 hours or until death, but without sufficient evidence to be classified as one of the above.

Transient ischemic attack (TIA) [ ] A transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction

Table 6. Cerebrovascular disease case definitions

Central Nervous System Vasculitis: Definite

Possible

Central Nervous System (CNS) vasculitis

Clinical presentation compatible with CNS vasculitis with exclusion of alternative possible diagnoses and of primary systemic vasculitic syndrome AND Positive CNS histology (biopsy or autopsy) showing CNS angiitis (granulomatous, lymphocytic or necrotising), including evidence of vessel wall damage.

Clinical presentation compatible with CNS vasculitis with exclusion of alternative possible diagnoses and of primary systemic vasculitic syndrome AND Laboratory and imaging support for CNS inflammation (elevated levels of CSF protein and/or cells, and/or the presence of oligoclonal bands and/or MR scan evidence compatible with CNS vasculitis), with angiographic* exclusion of other specific entities, but without histological proof of vasculitis.

*Certain disorders, perhaps most particularly moyamoya disease, may require formal contrast angiography for definitive diagnosis.

Table 7. Central nervous system (CNS) vasculitis defintion

Case definitions for neurological syndromes - References

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2. Venkatesan A, Tunkel AR, Bloch KC, et al. Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium. Clin Infect Dis 2013; 57: 1114–28.

3. Granerod J, Ambrose HE, Davies NWS, et al. Causes of encephalitis and differences in their clinical presentations in England: A multicentre, population-based prospective study. Lancet Infect Dis 2010. 10(12): 835-44.

4. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59: 499–505. 5. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central

nervous system demyelinating disorders: Revisions to the 2007 definitions. Mult. Scler. J. 2013. 19(10):1261-7 6. Sejvar JJ, Kohl KS, Bilynsky R, et al. Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): Case definitions and guidelines for collection, analysis,

and presentation of immunization safety data. Vaccine 2007. 25(31):5771-92 7. Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain-Barré syndrome and Fisher syndrome: Case definitions and guidelines for collection, analysis, and presentation of

immunization safety data. Vaccine 2011. 29(3):599-612. 8. Sacco RL, Kasner SE, Broderick JP, et al. An Updated Definition of Stroke for the 21st Century. Stroke 2013; 44: 2064–89. 9. Easton JD, Saver JL, Albers GW, et al. Definition and Evaluation of Transient Ischemic Attack. Stroke 2009; 40: 2276–93. 10. Rice CM, Scolding NJ, The diagnosis of primary central nervous system vasculitis. Practical Neurology 2020;20:109-114.