The Emerging Spectrum of COVID-19 Neurology: Clinical, Radiological and Laboratory Findings

Brain Page 2 of 63
The emerging spectrum of COVID-19 neurology: clinical,

radiological and laboratory findings
Ross W. Paterson,1,2,3,4,* Rachel L. Brown,1,5,* Laura Benjamin,6,7 Ross Nortley,1,8 Sarah
Wiethoff,1 Tehmina Bharucha,9 Dipa L. Jayaseelan,1,10 Guru Kumar,2 Rhian E.
Downloaded from https://academic.oup.com/brain/article-abstract/doi/10.1093/brain/awaa240/5868408 by guest on 08 July 2020

Raftopoulos,11 Laura Zambreanu,1,10 Vinojini Vivekanandam,9 Anthony Khoo,9 Ruth
Geraldes,8 Krishna Chinthapalli,8 Elena Boyd,8 Hatice Tuzlali,8 Gary Price,9 Gerry Christofi,9
Jasper Morrow,1 Patricia McNamara,9 Benjamin McLoughlin,9 Soon Tjin Lim,9 Puja R.
Mehta,9 Viva Levee,9 Stephen Keddie,1 Wisdom Yong,12 S. Anand Trip,1,12 Alexander J.M.
Foulkes,1,10 Gary Hotton,9 Thomas D. Miller,13 Alex D. Everitt,14 Christopher Carswell,14
Nicholas W.S. Davies,14 Michael Yoong,15 David Attwell,16 Jemeen Sreedharan,11 Eli
Silber,11 Jonathan M. Schott,1 Arvind Chandratheva,6 Richard J. Perry,6 Robert Simister,6
Anna Checkley,9 Nicky Longley,9 Simon F. Farmer,9 Francesco Carletti,9 Catherine
Houlihan,9 Maria Thom,1 Michael P. Lunn,1 Jennifer Spillane,9,17 Robin Howard,9,17 Angela
Vincent,1,18 David J. Werring,6 Chandrashekar Hoskote,9 Hans Rolf Jäger,1 Hadi Manji1,9,*
and Michael S. Zandi1,9,* for the UCL Queen Square National Hospital for Neurology and
Neurosurgery COVID-19 Study Group
*These authors contributed equally to this work.
C The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness.
Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-
disciplinary meeting was established at the National Hospital, Queen Square, in early March

2020 in order to discuss and begin to understand neurological presentations in patients with
suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data
were collected from cases where the diagnosis of COVID-19 was confirmed through RNA
PCR, or where the diagnosis was probable/possible according to World Health Organization
criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and
six possible. Five major categories emerged: (i) encephalopathies (n = 10) with
delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or
partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12)
including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis
(n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis
(n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also
received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial
recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-
thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral
neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial
plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with
miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is
associated with a wide spectrum of neurological syndromes affecting the whole neuraxis,
including the cerebral vasculature and, in some cases, responding to immunotherapies. The
high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic
change, is striking. This complication was not related to the severity of the respiratory
COVID-19 disease. Early recognition, investigation and management of COVID-19-related
neurological disease is challenging. Further clinical, neuroradiological, biomarker and
neuropathological studies are essential to determine the underlying pathobiological
mechanisms, which will guide treatment. Longitudinal follow-up studies will be necessary to
ascertain the long-term neurological and neuropsychological consequences of this pandemic.
ScholarOne, 375 Greenbrier Drive, Charlottesville, VA, 22901 Support (434) 964 4100
Brain Page 4 of 63
Author affiliations:
1 University College London, Queen Square Institute of Neurology, London, UK
2 Darent Valley Hospital, Dartford, Kent, UK
3 UK Dementia Research Institute, London, UK
4 UK Dementia Research Institute

5 UCL Institute of Immunity and Transplantation, London, UK
6 UCL Institute of Neurology, Stroke Research Centre, Russell Square House, London, UK
7 University of Liverpool, Brain Infections Group, Liverpool, Merseyside, UK
8 Wexham Park Hospital, Berkshire, UK
9 National Hospital for Neurology and Neurosurgery, University College London Hospitals
NHS Foundation Trust, Queen Square, London, UK
10 Watford General Hospital, Watford, Hertfordshire, UK
11 King’s College Hospital, Denmark Hill, London, UK
12 Northwick Park Hospital, Harrow, London, UK
13 Lister Hospital, Stevenage, Hertfordshire, UK
14 Imperial College London, London, UK
15 Barts and The London NHS Trust, London, UK
16 UCL, Department of Physiology, London, UK
17 Guy’s and Saint Thomas' Hospitals NHS Trust, London, UK
18 University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe

Hospital, Oxford, UK
Correspondence to: Dr Michael S. Zandi PhD FRCP
University College London Queen Square Institute of Neurology
London WC1N 3BG
UK
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E-mail: m.zandi@ucl.ac.uk
Running title: The emerging spectrum of COVID-19 neurology
Keywords: COVID-19; SARS-CoV-2; encephalitis; ADEM
Abbreviations: ADEM = acute demyelinating encephalomyelitis; COVID-19 = coronavirus

disease 19; GBS = Guillain-Barré syndrome; IVIG = intravenous immunoglobulin; SARS-
CoV-2 = severe acute respiratory syndrome coronavirus 2
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Introduction
Since December 2019, almost 10 million cases and 500 000 deaths due to the novel
coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been
reported worldwide (WHO situation report). Although the respiratory system complications
of coronavirus disease 19 (COVID-19) have been the most frequent and life threatening,

there are increasing reports of central and peripheral nervous system (PNS) involvement.
These neurological complications have included encephalopathy (Helms et al., 2020),
meningo-encephalitis (Moriguchi et al., 2020), ischaemic stroke (Beyrouti et al., 2020), acute
necrotizing encephalopathy (Poyiadji et al., 2020), and Guillain-Barré Syndrome (GBS)
(Toscano et al., 2020). Radiological series have shown infarcts, microhaemorrhages, features
of posterior reversible encephalopathy syndrome, or nerve root enhancement (Franceschi et
al., 2020; Mahammedi et al., 2020). Zanin and colleagues (2020) have described a case of
CNS demyelination post-COVID-19. Detailed neurological assessment and investigation is
challenging in those who are critically ill, limiting the opportunity to delineate the underlying
pathophysiology and hence, treatment options. The postulated mechanisms of the various
neurological syndromes include, either individually or in combination, direct viral neuronal
injury (Zubair et al., 2020), a secondary hyperinflammation syndrome (Mehta et al., 2020),
para- and post-infectious inflammatory or immune-mediated disorders, or the effects of a
severe systemic disorder with the neurological consequences of sepsis, hyperpyrexia,
hypoxia, hypercoagulability and critical illness.
Here we describe the detailed emerging spectrum of neurological disorders encountered in 43

COVID-19 patients referred to the National Hospital, Queen Square COVID-19
multidisciplinary team meeting (COVID-MDT), run in partnership with infectious disease
and virology colleagues at University College London Hospital (UCLH).
Materials and methods

We reviewed retrospectively the clinical, radiological, laboratory and neuropathological
findings from patients referred to the COVID-MDT neurology/encephalitis and
neurovascular multi-disciplinary team meetings. The cases summarized were discussed
between 9 April and 15 May 2020. Neurological syndromes developing after definite,
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probable or possible COVID-19, which were likely to be associated with COVID-19 on

clinical grounds, were included. Cases for which a more likely alternative pathology was
found were excluded.
The probability of COVID-19-related neurological disease was determined using WHO

criteria [‘Global surveillance for human infection with coronavirus disease (COVID-19)’]: (i)
definite (SARS-CoV-2 RNA PCR positive from nasopharyngeal swab, CSF or pathological

specimen); (ii) probable (clinical and laboratory features highly suggestive of COVID-19—
lymphopenia, raised D-dimer, suggestive chest radiology in the absence of PCR evidence)
(Guan et al., 2020); and (iii) possible, in whom temporal or laboratory features indicate an
association but another cause was also found (Ellul et al., 2020). Where possible, laboratory
results shown are those nearest to onset of neurological symptoms.
The classification of the severity of COVID-19 infection was adapted from Wu and
McGoogan (2020). Mild disease included patients with non-pneumonia or mild pneumonia,
severe disease included patients with dyspnoea and hypoxia requiring supplementary oxygen,
and critical disease included patients with respiratory failure requiring assisted ventilation,
septic shock, and/or multi-organ dysfunction. Where possible, laboratory results shown are
those nearest to onset of neurological symptoms. Consensus clinical criteria were used to
classify individuals with specific neurological syndromes including encephalitis (Solomon et
al., 2012; Graus et al., 2016), acute demyelinating encephalomyelitis (ADEM) (Pohl et al.,
2016), and GBS (Willison et al., 2016). We obtained assent and/or written consent from
patients or from their relatives. This study is approved and registered as a service evaluation
of our MDT (ref 06-202021-SE) at University College London Hospitals NHS Trust.
Some patient details have been submitted for publication as case reports by their treating
physicians: Patients 7 and 11 (Khoo et al., in press), Patient 12 (Zambreanu et al., in press),
Patient 15 (Dixon et al., 2020), and Patients 36, 37, 39, 41 and 42 (Beyrouti et al., 2020).
Data availability
The data that support the findings of this study are available from the corresponding author,
upon reasonable request. The data are not publicly available due to ethical restrictions e.g.
their containing information that could compromise the privacy of the patients reported.
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Results
The patients included 24 males and 19 females with ages ranging from 16–85 years. Twenty-
three of our patients (53%) were non-white. On the basis of a positive nasal-pharyngeal throat
SARS-CoV-2 PCR test, 29 were defined as definite COVID-19, eight were probable and six
were possible for this association. The severity of the COVID-19 symptoms varied from mild

to critical. The patients presented with a wide range of CNS and PNS features including
neuroinflammatory diseases and stroke from 6 days before and up to 27 days following the
onset of the COVID-19 symptoms. The patients are divided into five categories based on the
clinical, neuroradiological, neurophysiological and laboratory features, as summarized in
Table 1. We provide a brief summary of the neurological phenotypes in Tables 2–4. Full
details of the clinical, viral, immunological, radiological and neurophysiological
investigations, management and treatment responses are detailed in the Supplementary
material.
CNS syndromes
Encephalopathies
The 10 patients described (Patients 1–10, six female, four male; four White, five Black and
one Asian) had a parainfectious or septic encephalopathy with delirium. These patients (e.g.
Vignette A) were mostly >50 years old and presented with confusion and disorientation, with
psychosis in one, and seizures in another. Neuroimaging was within normal limits, and CSF
studies were normal when performed. Treatments were largely supportive with 7 of 10
making a complete recovery, and 2 of 10, a partial recovery at the time of discharge (Table 2
and Supplementary material).
Vignette A: acute parainfectious encephalopathy with psychosis
A 55-year-old female (Patient 7), with no previous psychiatric history, was admitted with a
14-day history of fever, cough, muscle aches, breathlessness, as well as anosmia and
hypogeusia. She required minimal oxygen treatment (oxygen saturation 94% on room air)
and was well on discharge 3 days later. The following day, her husband reported that she was
confused and behaving oddly. She was disorientated and displayed ritualistic behaviour such
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as putting her coat on and off repeatedly. She reported visual hallucinations, seeing lions and
monkeys in her house. She developed ongoing auditory hallucinations, persecutory delusions,
a Capgras delusion and complex systematized delusional misperceptions. She displayed
intermittently aggressive behaviour with hospital staff and her family. Her psychotic
symptoms persisted after disorientation improved. Brain MRI, EEG and lumbar puncture
were normal. Her clinical course fluctuated over 3 weeks with a trend towards improvement,

albeit after the introduction of haloperidol, followed by risperidone.
Neuroinflammatory syndromes
Twelve patients (Patients 11–22, 27–66 years old; eight female, four male; four White, three
Black, three Asian; two other/mixed) presented with inflammatory CNS syndromes. Two had
an encephalitis; one (Patient 11, Vignette B) had features of an autoimmune encephalitis with
opsoclonus, stimulus sensitive myoclonus and convergence spasm. Although brain imaging,
EEG and CSF were normal, the clinical picture was highly suggestive of an autoimmune
brainstem encephalitis. The second encephalitis patient (Patient 12) presented with confusion
and a single seizure, with MRI abnormalities suggestive of autoimmune or ‘limbic’
encephalitis in the thalami, medial temporal regions and pons (Fig. 1A–D, Table 2 and
Supplementary material).
Nine patients were categorized within the spectrum of ADEM (e.g. Vignette C). Four patients
had haemorrhagic change on imaging, including microbleeds; and one had necrosis. Two
patients had myelitis in addition to brain imaging changes, and one further had myelitis with
normal brain imaging. Patient 17 (Vignette D) with acute haemorrhagic leucoencephalitis
(based on clinical and imaging features) failed to respond to corticosteroids and required
decompressive craniectomy for incipient brain herniation; a brain biopsy at the time of
surgery showed evidence of perivenular inflammation supporting aggressive hyper-acute
ADEM. She made significant recovery after the decompression followed by intravenous
immunoglobulin (IVIG), but requires ongoing rehabilitation. Patient 15 developed a severe
necrotizing encephalitis that resulted in death. Patient 16 was unusual in presenting with a
GBS and subsequently developed an ADEM-like illness (Fig. 2H–O, Vignette E).
Despite the striking imaging findings of these patients (Figs 1, 2 and 4), the CSF parameters
were abnormal in only half. In none of the cases tested were specific antibodies (e.g. to
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NMDAR, MOG, AQP4, LGI1 or GAD) identified in the serum or CSF. Treatments were
with corticosteroids in nine, and IVIG in three. A full clinical response was seen in 1 of 12,
partial recovery at the time of writing in 10 of 12, and one patient died.
Vignette B: post-infectious probable brainstem and cortical autoimmune

encephalitis
A 65-year-old female (Patient 11), with a 2-year history of cognitive decline and presumed
sporadic early onset Alzheimer’s disease, presented with right hand and then widespread
involuntary movements, 6 days after fever, cough and myalgia. She had difficulty speaking
and became disorientated and confused, complaining of well-formed visual hallucinations of
people inside her house and objects flying around the room. She complained of deteriorating
vision, with difficulty reading, and intermittent double vision. On admission she had
widespread stimulus sensitive myoclonus involving the tongue and all four limbs with
marked hyperekplexia. There was episodic opsoclonus and prominent convergence spasm on
visual fixation. She had a non-fluent aphasia with oral apraxia, difficulty repeating sentences
and was only able to follow single stage commands. MRI brain, EEG and CSF examination
were normal. SARS-CoV-2 PCR was positive on nasopharyngeal swab. Levetiracetam and
clonazepam were used to treat her myoclonus, and 2 weeks after onset of neurological
symptoms, she received a course of steroids for a clinical diagnosis of presumed post-
infectious autoimmune encephalitis affecting cortex and brainstem. Cognition and visual
symptoms improved although there were on-going symptoms at the time of writing.
Vignette C: ADEM with haemorrhage in a critically ill patient
A 52-year-old male (Patient 13) presented with a 10-day history of cough, fever, dyspnoea
and myalgia. On admission he was hypoxic and non-invasive ventilation was commenced. He
had bilateral chest X-ray changes consistent with COVID-19 and SARS-CoV-2 RNA PCR
was positive. Oxygen requirements increased and mechanical intubation was required. On
Day 17 of intensive care admission he was slow to wean from sedation. His conscious level
was impaired (responding to pain only) despite a prolonged withdrawal from sedation. He
was hyper-reflexic with lower limb clonus. Brain MRI showed bilateral white matter changes
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with haemorrhage (Fig. 1E–H). There was slow and still on-going neurological improvement
over 4 weeks with supportive treatment alone, which continues at the time of writing.
Vignette D: acute haemorrhagic leukoencephalopathy form of ADEM

requiring decompressive craniectomy

A 47-year-old female (Patient 17), previously well and who worked in a high-risk occupation
for COVID-19, presented with right-sided headache and left hand numbness. This was
preceded by 7 days of cough, fever and shortness of breath. On the day of presentation, she
had persistent severe headache and progressive onset of left-sided numbness followed by left-
sided weakness including the face. A few hours later, she was drowsy, with severe left upper
limb weakness, mild left leg weakness and hemisensory loss. CT head imaging demonstrated
marked right hemisphere vasogenic oedema with midline shift. She required 4 l of oxygen
and had lower zone chest X-ray and CT chest changes compatible with probable COVID-19
as well as lymphopenia, and elevated D-dimer. Head MRI demonstrated severe right
hemispheric vasogenic oedema with a leading edge on contrast imaging, and smaller areas of
T2 hyperintense changes in the left hemisphere, in keeping with a diagnosis of an acute
haemorrhagic leukoencephalopathy form of ADEM. She was treated with high dose
intravenous methylprednisolone (1 g daily for 5 days). After 48 h of treatment her conscious
level fell, she developed a fixed dilated right pupil and underwent emergency right hemi-
craniectomy. She subsequently received oral prednisolone 60 mg daily and 5 days of IVIG.
She was extubated 4 days postoperatively and continues to improve clinically, and is able to
weight bear with support. Pathological findings from brain biopsy taken at surgery supported
a diagnosis of hyperacute ADEM (Fig. 2E–G). The brain tissue was negative in PCR for
SARS-CoV-2.
Vignette E: sequential para-infectious involvement of central and

peripheral nervous system
A 52-year-old male (Patient 16) presented with a 3-day history of headache, back pain,
vomiting and progressive limb weakness. There was bilateral facial and neck weakness,
symmetrical upper and lower limb flaccid (proximal > distal) weakness, generalized
areflexia, extensor plantar responses and preserved sensation. MRI of the neuroaxis was
normal except for gadolinium enhancement of the cervical and lumbar roots (Fig. 2H and L).
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CSF was acellular, with a raised protein. Nerve conduction studies supported a diagnosis of
GBS and he was treated with IVIG. On Day 3 of admission, he deteriorated with increasing
weakness, dysphagia, ophthalmoplegia, and lymphopenia. Due to type-2 respiratory failure,
he required ventilation. The patient became febrile (38.9°C), with increasing oxygen
requirements, and antibiotics were commenced. Chest CT showed bilateral pulmonary
infiltrates. SARS-CoV-2 RNA PCR was positive on throat swab, but negative in CSF. On

Day 5, he became unresponsive and a repeat brain MRI showed a pattern of T2 symmetrical
widespread white matter hyperintensities, which progressed further on Day 12 (Fig. 2I–K and
M–O). Intravenous methylprednisolone (IVMP, 1 g/day) was given for 5 days, with
neurological improvement following treatment on Day 3: eyes opened spontaneously, he
could obey commands, mouth words, and move both hands. Two weeks after completion of
IVMP the patient was alert, breathing without assistance, talking and able to flex both arms.
Stroke
Eight patients (Patients 23–30; aged 27–64, six male, two female, five White, two Asian, one
Black) had ischaemic stroke in the context of hypercoagulability and a significantly raised D-
dimer (>7000 mg/l) in each of the six cases measured. Thrombus was observed in large intra-
and extra-cranial vessels in four patients. Four patients had pulmonary thromboembolism
(e.g. Patient 27, Vignette F) (Table 4).
Vignette F: ischaemic stroke with concurrent pulmonary embolism
A 58-year-old male (Patient 27), previously independent in a high-risk occupation for

developing COVID-19, presented with acute onset aphasia and dense right-sided weakness.
This was preceded by a 2-day history of lethargy and cough. He was found to be drowsy and
unresponsive. Brian CT confirmed a proximal middle cerebral artery thrombus and territorial
infarct (Fig. 3A–D) with local mass effect. He was transferred to a specialist hospital due to
risk of vasogenic oedema leading to malignant middle cerebral artery syndrome. Due to the
degree of established infarction neither intravenous thrombolysis nor mechanical
thrombectomy were appropriate. CT angiogram also showed a saddle pulmonary embolism,
which was managed conservatively with split dose low molecular weight heparin. His
condition was critical in the hyperacute period with fluctuating level of consciousness and
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tachycardia, but stabilized. His D-dimer was in excess of 80 000 µg/l on admission but
reduced to 2800 µg/l after 7 days of anticoagulation. Lupus anticoagulant was positive. The
patient was discharged to a rehabilitation unit on Day 8.
Peripheral nervous system

Seven patients (Patients 31–38) with GBS were seen (aged 20–63, all male, five White, one
Black, one other), with onset of neurological symptoms from 1 day before to 21 days after
typical COVID-19 symptoms. One patient developed a brachial plexopathy onset 2 weeks
after COVID-19 symptoms. Of this group, half had definite COVID-19, three requiring
intensive care. All GBS patients were treated with IVIG; the patient with brachial plexopathy
received corticosteroids. All but two of this group have started to make partial recovery at the
time of writing.
Miscellaneous
The remaining five patients (Patients 39–43) were difficult to categorize. They comprised
myelopathy with normal imaging; one patient with bilateral abducens nerve palsy due to
intracranial hypertension (pseudo-tumour cerebri) who presented with abdominal pain,
diarrhoea and rash and had possible cardiac involvement with COVID-19; a complex
paediatric case with a congenital developmental disorder and stable epilepsy who developed
non-convulsive status epilepticus; and a patient with a bacterial brain abscess with
Streptococcus intermedius. One patient, a 27-year-old male with acute myeloid leukaemia,
COVID-19 lung disease and seizures with some encephalopathy, demonstrated a significant
burden of microhaemorrhages (Patient 41; Fig. 3E–H). He had been treated with Gilteritinib
as part of his acute myeloid leukaemia therapy.
Summary of key features

Despite the wide range of initial presentations, with a better appreciation of the five main
categories outlined above, the key clinical features and investigations could be proposed as
summarized in Table 1. None of the eight patients tested for SARS-CoV-2 PCR in CSF were
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positive, and none of the autoantibodies seen in autoimmune forms of encephalitis (NMDAR,
LGI1) or encephalomyelitis (AQP4, MOG) were detected in serum or CSF samples. Raised
D-dimers were, predictably, highly raised in those patients with stroke but were also above
normal levels, and occasionally markedly elevated in each of the other groups. Those with
encephalopathies improved without specific treatments. The patients with inflammatory CNS
diseases were treated with corticosteroids (n =10) and corticosteroids in combination with

IVIG (n = 3) and have had variable outcomes to date, but the follow-up period is still short.
One patient with ADEM made some improvement spontaneously without specific treatment.
Six of seven patients with GBS had partial response to treatment at the time of writing.
Discussion
The widespread effects of COVID-19 include neurological disorders but there have been, to
date, no detailed clinical reports of their nature (Guan et al., 2020; Helms et al., 2020; Mao et
al., 2020; Varatharaj et al., 2020). Our London and regional cohort describes a range of
neurological syndromes including encephalopathies, para- and post-infectious CNS
syndromes including encephalitis, ADEM with haemorrhage and necrotic change, transverse
myelitis, ischaemic stroke and GBS.
The neurological complications of SARS-CoV2 have similarities to those described in the

other coronavirus epidemics, specifically severe acute respiratory syndrome (SARS) in 2003,
and Middle East acute respiratory syndrome (MERS) in 2012. The cases described in those
reports included encephalopathy, encephalitis and both ischaemic and haemorrhagic stroke
attributed to hypercoagulability, sepsis and vasculitis, and GBS (Umapathi et al., 2004; Tsai
et al., 2005; Kim et al., 2017). However, overall numbers of infected individuals were much
smaller, 8000 with SARS and 2500 with MERS, and neurological presentations were few in
comparison with those being recognized in the current pandemic.
In a series from Wuhan, 78 of 214 COVID-19 patients, recruited over 4 weeks, developed
neurological manifestations. These patients tended to be more severely affected, older and
with more comorbidities and, for some, the neurological symptom was the first presentation
of COVID-19 (Mao et al., 2020). However, apart from stroke in six patients (2.8%), the
neurological features could be due to viral infection (loss of smell and taste) or to the
consequences of severe systemic illness in an intensive care setting, such as sepsis and
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hypoxia. More specific details came from 64 consecutive patients reported by the Strasbourg
group (Helms et al., 2020) with agitation in 40/58 (69%), confusion in 26/40 (65%) and
corticospinal tract signs in 39/59 (67%). MRI abnormalities were seen in 22 patients with
meningeal enhancement, ischaemic stroke and perfusion changes. CSF examination was
negative for SARS-CoV-2 in all seven cases tested. There are isolated case reports in the
literature of myoclonus (Rábano-Suárez et al., 2020) and demyelination (Varatharaj et al.,

2020; Zanin et al., 2020).
Ten of our patients had transient encephalopathies with features of delirium, and psychosis in
one. Delirium with agitation is described in case reports and in the larger studies mentioned
above, and cognitive dysexecutive syndromes have been reported at discharge (Rogers et al.,
2020). While our patients had transient syndromes, detailed neuropsychological testing and
follow-up is required to determine the extent of cognitive dysfunction in recovery, and to
examine psychiatric and psychological factors (Brown et al., 2020). The underlying
mechanisms for the encephalopathy may be multifactorial resulting from the combined or
independent effects of sepsis, hypoxia and immune hyperstimultion (‘cytokine storm’)
(Mehta et al., 2020).
Two of our cases had a probable autoimmune encephalitis, one with typical clinical features
of opsoclonus and myoclonus, and another with typical radiological images as seen in
‘limbic’ encephalitis (Graus et al., 2016). These patients did not have NMDAR, LGI1 or
related autoantibodies (Supplementary Table 1). The issue of whether SARS-CoV-2 will
trigger a significant number of cases of autoimmune encephalitis, with probable antibody-
mediated mechanisms, will become clear in time.
The cluster of cases with an ADEM-like illness warrants close surveillance. ADEM, an
immune-mediated demyelinating disorder, is a disease mainly of children (Pohl et al., 2016),
with an adult incidence in the UK of 0.23/100 000 (Granerod et al., 2010; Absoud et al.,
2015). The nine cases described were accrued over a 5-week period. In Greater London
(population 8.9 million, Office of National Statistics 2018), we would expect to see this
incidence of cases in 5 months, which indicates that COVID-19 is associated with an
increased incidence of ADEM. SARS-CoV-2 was not detected in CSF in any of the eight
patients tested and the single neuropathological sample obtained did not confirm the presence
of SARS-CoV-2 in brain tissue, and was supportive of the diagnosis of ADEM. While we
cannot exclude the possibility of direct CNS infection in some cases, without further
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neuropathological studies or development of accurate CSF viral markers and serological

testing, the imaging and clinical features are most supportive of a para- or post-infectious
disease mechanism. Long-term follow-up is now required to establish the natural history of
the cases that we have identified.
The GBS cases were not unexpected. The temporal relationship between the COVID 19
respiratory illness and the onset of symptoms would be consistent with a post-infectious

immune-mediated mechanism. Up to two-thirds of patients with GBS describe an antecedent
respiratory or gastroenterological illness. The most common pathogens include
Campylobacter jejuni, cytomegalovirus, Mycoplasma pneumonia, HIV and more recently the
Zika virus. The first report of GBS and SARS-CoV-2 from Italy describes five cases of GBS
out of a total of 1200 admissions (Toscano et al., 2020). The expected incidence of GBS is
0.6–2.7/100 000/year (Willison et al., 2016) and further epidemiological and mechanistic
study is required to determine if there is a true increase in incidence of GBS in COVID-19
patients. Our GBS cases appeared to be similar to conventional GBS patients with respect to
clinical presentation, neurophysiology showing demyelinating changes in the majority of
patients, CSF parameters and the response to treatment with IVIG.
Stroke associated with a generalized thrombotic predisposition in COVID-19 is of particular

interest. Four out of the eight patients had cardiovascular risk factors for stroke including
atrial fibrillation. Four also had pulmonary emboli. COVID-19 is associated with a pro-
thrombotic state and highly elevated D-dimer levels, and abnormal coagulation parameters
have been shown to be associated with poor outcome (Tang et al., 2020). The frequent
occurrence of cerebral microbleeds seen in some of the patients, however, was unexpected
(Fig. 3). Cerebral microbleeds are usually due to extravasation of red blood cells, and in the
context of COVID-19 could be due to endothelial dysfunction related to viral binding to the
ACE-2 receptors expressed on endothelial cells. Indeed, a recent report described direct viral
infection of the endothelial cell and diffuse endothelial inflammation in multiple organ
systems (Varga et al., 2020). The strokes we have encountered with COVID-19 have been
severe, and further epidemiological study is required to determine the association between
COVID-19 and stroke; randomized trials to determine the optimal use of antiplatelet drugs,
low molecular weight heparin and other stroke therapies are required.
Muscle pain and elevated creatinine kinase have been reported as relatively common
manifestations of SARS-CoV-2 infection (Chen et al., 2020; Guan et al., 2020; Huang et al.,
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2020) and there are case reports of rhabdomyolysis (Rivas-Garcia et al., 2020). Like other
large neurological case series (Varatharaj et al., 2020), we did not observe such cases, but
this could reflect referral bias to our MDT, which was set up to discuss the most challenging
and severe cases.
Within our cohort of 12 patients with CNS-inflammatory syndromes, a range of clinical and
radiological presentations were observed, including some suggestive of post-infective ADEM

or transverse myelitis and others with more unusual haemorrhagic changes that made
classification challenging. A recent MRI study of 37 patients with severe COVID-19 and
abnormal brain imaging found three patterns of CNS white matter changes, which could
occur in isolation or in combination (Kremer et al., 2020). Pattern 1 featured medial temporal
lobe signal abnormalities similar to that seen in viral or autoimmune encephalitis; whereas
patterns 2 and 3 featured microhaemorrhages, either in the context of multifocal white matter
hyperintense lesions or as separate features, respectively. Whether these patterns represent
the same pathology over different timelines, different immunological or other mechanisms, or
combinations, is currently unclear, but could have important implications for management
decisions, such as the use of steroids, and rehabilitation. In the Kremer et al. (2020) study,
haemorrhagic lesions correlated with clinical indicators of disease severity. Especially in the
intensive care cohort, it can be unclear when brain injury occurs, as imaging is usually only
undertaken when a patient is slow to wake after a prolonged period of ventilation.
Histopathological correlates are now emerging for some lesions. Reichard et al. (2020)
described a case similar to those described in the Kremer et al. study and reported features of
both vascular and ADEM-like pathology, with macrophages and axonal injury. Conversely,
von Weyhern et al. (2020) found lymphocytic panencephalitis and meningitis, and brainstem
perivascular and interstitial inflammatory change with neuronal loss as prominent features in
six post-mortem patients. In our one case who underwent cranial decompression, brain
histology was in keeping with ADEM. Similar to the ADEM-like cases, the GBS cases also
largely point to a post-infectious autoimmune mechanism, with most developing the
neurological disease within 3 weeks of the documented infection. The risk factors for
neurological disease remain unknown, and require further epidemiological study.
The potential mechanisms underpinning the syndromes described include either individually,
or in combination, direct viral injury, a secondary hyperinflammation syndrome related to
cytokines including IL-6 (Mehta et al., 2020), vasculopathy and/or coagulopathy, post-
Brain Page 18 of 63
17
infectious inflammation including autoantibody production to neuronal antigens, and the

effects of a severe systemic disorder with the neurological consequences of sepsis and
hypoxia. Evidence of direct viral infection has proved elusive so far with only a few cases
with SARS-CoV-2 in CSF reported, and few supportive histopathological features, though
clearly further study would be helpful (Reichard et al., 2020, Von Weyhern et al., 2020).
Elevation of pro-inflammatory cytokines was found to correlate with COVID-19 disease

severity (Herold et al., 2020; Huang et al., 2020), and some patients responded to IL-1 or IL-
6 blockade (Cavalli et al., 2020; Price et al., 2020); in support of this possible mechanism,
transient splenial lesions have been reported in a number of cases, including in children with
multisystem inflammatory syndrome (MIS-C), in which elevated cytokines are thought to
play a role (Starkey et al., 2017; Abdel-Mannan et al., 2020; Hayashi et al., 2020; Riollano-
Cruz et al., 2020). Interestingly, some of the clinical features seen in our youngest patient
(Patient 39, aged 16 with pseudotumour cerebri with cranial nerve palsies) overlapped with
those seen in MIS-C, including gastrointestinal symptoms, rash and cardiac involvement
(Supplementary Table 1). Exact mechanisms in each case will be largely speculative until
clear clinical, radiological and histological correlates have been drawn; given the breadth of
clinical presentations, it is likely that a number or spectrum of these mechanisms are
involved.
Collectively, these cases presented a considerable challenge to diagnose with MRI,

neurophysiology including EEG, being difficult to obtain in an intensive care setting in
addition to the demands of safe nursing and infection control. In many cases, MRI proved
essential for making the diagnosis or confident exclusion of abnormalities, especially in
patients in the intensive care unit who were ‘slow to wake’. In addition, controversy remains
regarding the optimal treatment options including the use of high dose corticosteroids in
viraemic, and often lymphopenic patients, and the potential risks of using IVIG for ADEM
and GBS, in patients with pro-thrombotic risk factors such as elevated D-dimer levels.
This is a selective and retrospective study, with the limitations associated with this study
design, including bias towards severe disease. Nevertheless, the study has allowed a detailed
description of the neurological complications seen during and after COVID-19 infection.
Further detailed clinical, laboratory, biomarker and neuropathological studies will help
elucidate the underlying pathobiological mechanisms of COVID-19 neurological
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complications. Longitudinal follow-up studies of patients will be necessary to ascertain the

long-term consequences of this pandemic.
Acknowledgements

We acknowledge the patients and their families and friends, and the referring clinicians.
Funding
R.W.P is supported by an Alzheimer's Association Clinician Scientist Fellowship and by the
UK Dementia Research Institute. R.L.B is supported by a Medical Research Council Clinical
Research Training Fellowship. R.W.P, R.N, M.P.L and M.S.Z are supported by the NIHR
UCL/UCLH Biomedical Research Centre.
Competing interests
C.C. has sat on an advisory panel for Roche. A.V. and the University of Oxford hold patients
and receive royalties for antibody tests. M.S.Z has received lecturing fees for Eisai and UCB
pharma. No other authors declare competing interest.
Supplementary material
Supplementary material is available at Brain online.
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Figure legends
Figure 1 Imaging from Patients 12, 13 and 15 (COVID-19 autoimmune and
haemorrhagic encephalitis). Axial MRI from three individuals with para-/post-infectious
central syndromes. (A–D) Patient 12: axial fluid-attenuated inversion recovery (FLAIR)
images show bilateral hyperintensity in the mesial temporal lobes (A and B), hypothalamus

(C) temporal lobes and thalamus (D). (E–H) Patient 13: axial T2-weighted (E), diffusion
weighted imaging (DWI) (F), susceptibility weighted imaging (SWI) (G) and post-contrast
T1-weighted (H) images show multifocal clusters of lesions involving the deep white matter
of both cerebral hemispheres, intralesional cyst-like areas of varied sizes, and some
peripheral rims of restricted diffusion (F), some haemorrhagic changes (G), and T1
hypointense ‘black holes’ without contrast enhancement (H). (I–P) Patient 15: axial images
at the level of the insula and basal ganglia (I–L) and at the level of the temporal lobes and
upper pons (M–P). T2-weighted images (I and M), SWI images (J and N), DWI images (K
and O) and contrast-enhanced images (L and P). There are extensive confluent areas of T2
hyperintensity (I and M), with haemorrhagic change on SWI imaging (J and N), restricted
diffusion on DWI images (K and O) and peripheral contrast-enhancement (arrows in L and
P) in the insular region, basal ganglia and left occipital lobe (I–L) as well as in the medial
temporal lobes and upper pons (M–P).
Figure 2 Axial MRI (A–D) and histopathology (E–G) from Patient 17, diagnosed with
ADEM, and imaging (H–O) from Patient 16, with combined CNS and PNS disease. (A–
G) Patient 17: axial T2-weighted (A), SWI (B), post-gadolinium (C and D) images show
extensive confluent ‘tumefactive’ lesions involving the white matter of the right cerebral
hemisphere, corpus callosum and corona radiata with mass effect, subfalcine herniation (A),
clusters of prominent medullary veins (B, short arrows) and peripheral rim enhancement (D,
arrows). (E) The white matter shows scattered small vessels with surrounding infiltrates of
neutrophils and occasional foamy macrophages extending into the parenchyma (arrow). The
endothelium is focally vacuolated but there is no evidence of vasculitis or fibrinoid vessel
wall necrosis in any region. There were a few perivascular T cells in the white matter but the
cortex appears normal (not shown). (F) CD68 stain confirms foci of foamy macrophages in
the white matter, mainly surrounding small vessels. There was no significant microgliosis in
the cortex (not shown). (G) Myelin basic protein stain (SMI94) shows areas with focal
Brain Page 26 of 63
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myelin debris in macrophages around vessels in the white matter (arrows) in keeping with
early myelin breakdown. There is no evidence of axonal damage on neurofilament stain (not
shown). Scale bars: E = 45µm; F and G = 70 µm. (H–O) Patient 16: axial post-gadolinium
fat-suppressed T1-weighted images (H) demonstrating pathologically enhancing extradural
lumbosacral nerve roots (arrows). Note physiological enhancement of nerve root ganglia
(short arrows). Coronal short tau inversion recovery (STIR) image (L) shows hyperintense

signal abnormality of the upper trunk of the right brachial plexus (arrow). Initial axial T2 (I
and J) and T2-weighted images (K) show multifocal confluent T2 hyperintense lesions
involving internal and external capsules, splenium of corpus callosum (I), and the
juxtacortical and deep white matter (J), associated with microhaemorrhages (K, arrows).
Follow-up T2-weighted images (M and N) show marked progression of the confluent T2
hyperintense lesions, which involve a large proportion of the juxtacortical and deep white
matter, corpus callosum and internal and external capsules. The follow-up SWI image (O)
demonstrates not only the previously seen microhaemorrhages (arrows) but also prominent
medullary veins (short arrows).
Figure 3 Imaging from Patient 27, with cerebral infarction and pulmonary
thromboembolism (A–D), and Patient 41, with microhaemorrhages (E–H). (A–D) Patient
27: CT pulmonary angiogram (A) demonstrated large emboli in the right and left pulmonary
arteries (arrows). DWI (B), T2-weighted FSE (C) and SWI (D) images show restricted
diffusion (B) and T2 hyperintensity (C) in the left basal ganglia and cortical territory of left
middle cerebral artery. The SWI image (D) shows haemorrhagic transformation in the basal
ganglia (short arrow) and a long intravascular thrombus in a Sylvain branch of the left
middle cerebral artery (long arrow). (E–H) Patient 41: chest CT (E) shows severe COVID-19
pneumonitis. SWI images (F–H) demonstrate numerous cerebral microbleeds in the
temporal, frontal and parietal lobes, predominantly located at the grey/white matter junction.
Figure 4 Patients 19 and 20 (ADEM including spinal cord). Patient 19: axial T2 (A and C)
and DWI (B and D) images show multifocal lesions involving corpus callosum and corona
radiata. Axial T2-weighted images of brain MRI and sagittal T2-weighted of the spinal cord
acquired on admission (E–H) and after 26 days (I–L). Axial T2-weighted images show
multifocal hyperintense lesions in the brainstem (E and I), basal ganglia and supratentorial
Page 27 of 63 Brain
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white matter (F and J). The pontomedullary hyperintensities have become more confluent (I)
since admission (E). After 26 days, the signal abnormalities in the basal ganglia and the
supratentorial white matter (J) are grossly similar to the baseline MRI scan (F). Sagittal and
axial T2-weighted images show diffuse high T2-weighted signal intrinsic to the spinal cord at
baseline (G and H). After 26 days, the cord oedema has reduced, and the spinal cord lesions
appear less confluent and more discrete (K and L).
Brain Page 28 of 63

Table 1 Summary of clinical features of 43 patients with neurological complications of COVID-19
Cases Age, median Days of COVID-19 Main clinical Results of note % Naso- CSF or brain Treatment Clinical outcome
[range]; %male infection before features pharyhgeal SARS-CoV-2
neurological SARS-CoV-2 PCR+
presentation, PCR+ (x/number
median [range] tested)
Encephalopathy 57.5 [39–72]; 40 4.5 [−4 to +21] Delirium; psychosis Acellular CSF (6/6); 80 (8/10) (0/0) Supportive (9/10); Complete recovery
(delirium/psychosis) non-specific MRI steroids 1/10 (7/10); partial (2/10)
(n = 10)a changes (3/10)
Inflammatory CNS 53 [27–66]; 33 9 [−6 to +27] Reduced Abnormal CSF (6/11) 67 (8/12) (0/7) Corticosteroids Recovery: complete
syndromes (para- consciousness (7/12); Abnormal MRI (11/12) (10/12); IVIG (3/12) (1/12); partial (10/12);
/post- infectious) (n = UMN signs (10/12) none (death 1/12)
12)a
Stroke (n = 8)a 62.5 [27–85]; 75 8[−2 to +22] Large vessel 4/8 PE 75 (6/8) NA Low molecular Incomplete recovery
ischaemic stroke 6/6 High D–dimer weight heparin (7/8); death (1/8)
(7/8); apixaban (1/8)
Peripheral syndromes (n = 8)
GBS (n = 7) 57 [20–63]; 100 13 [−1–21] Cranial and 43 (3/7) NT IVIG (7/7) Incomplete recovery
peripheral (5/7 GBSDS 2)
neuropathy
Plexopathy 60; 100 14 Painless weakness 100 (1/1) NT IV steroids (1/1) Incomplete recovery
(n = 1) (1/1)
Miscellaneous and 20 [16–40]; 40 10 [6–26] Raised ICP; seizures; Abnormal CSF (2/4) 60 (3/5) (0/1) Varied (AED; Recovery complete
uncharacterized (n = myelitis Abnormal MRI brain steroids (1/5); tLP) (1/5); partial (3/5); nil
5) (4/5) (1/5)
AED = antiepileptic drug; GBSDS = Guillain Barré disability score; ICP = intracranial pressure; tLP = therapeutic lumbar puncture; NT = not tested; PE = pulmonary thromboembolism; UMN = upper motor
neuron.
aFeatures of eight individual patients for encephalopathy (delirium/psychosis), inflammatory CNS syndromes (para/post-infectious) and stroke described in Tables 2–4. All patient details are available in the
Supplementary material.
Page 29 of 63 Brain

Table 2 Eight patients with spontaneously improving encephalopathies (Patients 1–8)
Patient 1 2 3 4 5 6 7 8
Age, M/F, ethnicity, 65, F, White, 72, M, White, 59, F, Black, 58, M, Black, 52, F, White, 39, F, Asian, 55, F, White, 68, M, Black,
COVID-19 definite/mild definite/critical definite/mild definite/mild probable/mild definite/critical definite/severe definite/mild
diagnosis/severity
Final neurological Hypoactive Hypoactive Delirium Delirium Delirium Delirium Delirium and Hyperactive
diagnosis delirium delirium psychosis delirium
Initial neurological Fluctuating Confusion; Fluctuating Confusion; Fluctuating Delirium; Confusion; Cognitive
symptoms confusion; reversal malaise; loss of confusion nonsensical speech; consciousness; hallucinations agitation; impairment; gait
of sleep-wake cycle appetite repetitive behaviour; delirium about experiences persecutory disturbance; two
disorientation; in countries not delusions; visual falls
delusional thoughts; previously visited; hallucinations;
headache reversed combative
sleep/wake cycle behaviour;
headaches
Key neurological Disorientated to Cognitive Fluctuating Bilateral intention Cognitive Cognitive No focal signs Disorientation;
signs time and place; impairment; attention and tremor; heel-shin impairment; impairment intermittent
impaired insight; increased limb cognition; ataxia reduced verbal agitation; unable to
bradyphrenia; tone; brisk bradyphrenia; fluency follow commands;
polyminimyoclonus; reflexes dyspraxia. speaking a few
old left words only;
homonymous bilateral extensor
hemianopia plantars
D-dimer (µg/l; 0– 1190 1730 NR 970 NR 2430 1200 NR
550)
Neurological Supportive; Supportive; Supportive; Supportive; Supportive; Melatonin; on- Haloperidol, 1g IVMP 3 days;
treatments; recovery complete complete/rehab complete complete complete going cognitive risperidone; ongoing
impairment improving improvement
Imaging, further investigations and Patients 9 and 10 are provided in the Supplementary material. F = female; IVMP = intravenous methylprednisolone; M = male; NR = no result.
Brain Page 30 of 63

Table 3 Eight patients with neuroinflammatory diseases (Patients 11–18)
Patient 11 12 13 14 15 16 17 18
Age, M/F, ethnicity, 65, F, Black, 66, F, White, 52, M, Asian, 60, M, Asian, 59, F, Asian, 52, M, White, 47, F, other, 54, F, mixed,
COVID-19 definite/severe definite/mild definite/critical definite/critical definite/mild definite/critical probable/severe probable/mild
diagnosis/ severity
Final neurological Possible post- Encephalitis ADEM (with ADEM (with ADEM (with necrosis ADEM (with ADEM (with ADEM
diagnosis infectious haemorrhage) haemorrhage) and haemorrhage) haemorrhage) and acute haemorrhage)
encephalitis demyelinating
(presumed polyradiculoneuropathy
autoimmune)
Imaging: neuraxis MRI brain normal MRI brain: T2 MRI brain: MRI brain: MRI brain (Day 6): MRI brain: multifocal Severe right Multiple large lesions
(summary) hyperintense multiple multifocal and extensive, confluent confluent lesions in hemispheric with peripheral rim
signal changes clusters of confluent areas of and largely symmetrical internal and external vasogenic oedema restriction in
in upper pons, lesions in the signal change in the areas throughout capsules, splenium and with a leading periventricular white
limbic lobes, deep cerebral cerebral brainstem, limbic and deep white matter of edge on contrast matter of both cerebral
medial thalami white matter. hemispheric white insular lobes, superficial cerebral hemispheres. imaging. Smaller hemispheres
and subcortical Cyst-like areas matter with subcortical white Over 5 days, lesions areas of T2
cerebral white of varied sizes, extensive matter and deep grey increased in size and hyperintense
matter some with microhaemorrhages matter. Clusters of showed multiple changes in the left
haemorrhagic in the subcortical microhaemorrhages, microhaemorrhages and hemisphere.
foci and regions restricted diffusion and extensive prominent Marked mass-
peripheral rims peripheral rim medullary veins. effect with 10 mm
of restricted enhancement Components of brachial leftwards midline
diffusion and lumbosacral plexus shift, and mild
showed increased signal subfalcine
and enhancement herniation
D-dimer if raised; 1800 µg/l (0– 1599 ng/ml (0– 80 000 µg/l (0– 3330 mg/l (250– 2033 mg/l (250–750); NR; CSF protein raised, 1160 µg/l (0–550); NR 19 (90% lymph);
CSF studies; all 550); CSF 230); CSF 550); OCB 750); CSF OCB CSF OP raised, viral PCR viral PCR negative CSF NR 0.33; OCB negative,
neuronal matched OCB, protein raised, negative, viral negative, viral PCR negative including CSF culture scanty
antibodies viral PCR OCB, viral PCR PCR and negative including SARS-CoV-2 Staphylococcus capitis
performed were negative including SARS- antibodies SARS-CoV-2 (likely contamination)
negative CoV-2 negative negative
Treatments for 1g IVMP 3 days, 1g IVMP 3 days Supportive; 1g IVMP 3 days; Intubation, ventilation; Intubation and Intubation, 1g IVMP 3 days, then
neurological oral prednisolone then oral incomplete but incomplete levetiracetam, aciclovir ventilation, 1g IVMP 5 hemicraniectomy, oral prednisolone;
diagnosis; recovery taper, prednisolone ongoing ongoing and ceftriaxone, days, IVIG; incomplete 1g IVMP 5 days, incomplete ongoing
levetiracetam, taper, IVIG; dexamethasone; no ongoing recovery oral prednisolone, recovery
incomplete response, died
Page 31 of 63 Brain

clonazepam; IVIG; incomplete
incomplete ongoing recovery
Diagnosis, imaging and further investigations for Patients 19–22 are provided in the Supplementary material. F = female; IVMP = intravenous methylprednisolone; M = male; NR = no result; OCB = oligoclonal
band; OP = .
Brain Page 32 of 63

Table 4 Eight patients with stroke (Patient 23–30)
Patient 23 24 25 26 27 28 29 30
Age, M/F, ethnicity, COVID- 61, M, White, 64, M, White, 64, M, White 53, F, Asian, 58, M, Black, 85, M, White, 73, M, Asian, 27, F, White,
19 diagnosis, severity, time definite/mild, 2 days definite/severe,15 definite/severe, NK definite/severe, 22 probable/mild, 2 definite/mild, 10 definite/mild, 8 probable/mild,
from COVID onset days days days days days 0 days
Stroke type, Ischaemic right Ischaemic, vertebral- Ischaemic bilateral Ischaemic, Ischaemic, Ischaemic, left Ischaemic basilar Ischaemic left
observed/implicated middle cerebral basilar artery ACA-MCA and MCA- vertebral-basilar proximal left posterior artery occlusion, internal
mechanism; venous artery occlusion; occlusion; yes, PE PCA cortical and artery occlusion; middle cerebral cerebral artery no cerebral artery
thromboembolism yes, PE deep borderzone no artery occlusion; occlusion; no occlusion; yes
infarct; no yes PE PE
Fibrinogen (g/l; 1.5–4.0), D- 4.63, 27190, 10.7 9.5, 80000, 11.6 8.82, 29000, 12.6 2.91, 7750, 34.4 3.15, 75320, 12,2 5.3, 16100, 11.3 NR, NR, 14.9 NR, NR, 11.5
dimer (µg/l; 0–550),
Prothrombin time (s; 10–12)
Brain imaging (summary) MRI: acute infarct in MRI: (1st event): acute MRI: subacute Non-contrast CT: MRI: extensive Non-contrast CT: MRI: acute CT: right
the right corpus left vertebral artery infarcts within the showed acute evolving left showed infarction in the middle
striatum. Multiple thrombus and acute deep internal border right parietal MCA infarct with hyperdensity right thalamus, cerebral artery
supra- and infra- left posterior-inferior zones of the cerebral cortical and left evidence of consistent with left pons, right and right
tentorial cortical cerebellar artery hemispheres cerebellar infarct petechial thrombus in the occipital lobe and anterior
and subcortical territory infarction bilaterally, and with mass effect haemorrhage left posterior right cerebellar cerebral artery
microhaemorrhages with within the left frontal and and associated cerebral artery hemisphere territory
microhaemorrhages. white matter. hydrocephalus, mass-effect as and acute infarction
2nd event - 7 days Background despite described. infarction in the
later: bilateral acute moderate small therapeutic Persistent left temporal
posterior cerebral vessel disease and anticoagulation occlusion of the stem and
artery territory established cortical left M2 MCA cerebral
infarcts despite infarcts, in arterial branches peduncle
therapeutic border zone
anticoagulation territories
Tissue plasminogen activator, No, no, LMWH No, no, LMWH No, no, LMWH No, no, LMWH No, no, LMWH No, no, aspirin 7 Yes, no, aspirin 5 Aspirin 10 days
mechanical ventilation, anti- days then days then then LMWH
thrombotic therapy switched to switched to
apixaban LMWH
Outcome status Rehabilitation unit Rehabilitation unit Remains static in ICU Died Rehabilitation Rehabilitation Stroke unit Rehabilitation
(Day 31) unit unit unit
Page 33 of 63 Brain

ACA = anterior cerebral artery F = female; ICU = intensive care unit; LMWH = low molecular weight heparin; M = male; MCA = medial cerebral artery; NK = not known; NR = no result; PCA = posterior cerebral
artery; PE = pulmonary embolism.
Page 34 of 63
Brain
figure 1
figure 2
Brain
Page 35 of 63
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Figure 3
Page 37 of 63 Brain

51x45mm (300 x 300 DPI)

The Emerging Spectrum of COVID-19 Neurology: Clinical, Radiological and Laboratory Findings

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Brain Page 2 of 63

The emerging spectrum of COVID-19 neurology: clinical,

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*These authors contributed equally to this work.

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1 University College London, Queen Square Institute of Neurology, London, UK

2 Darent Valley Hospital, Dartford, Kent, UK

3 UK Dementia Research Institute, London, UK

4 UK Dementia Research Institute

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7 University of Liverpool, Brain Infections Group, Liverpool, Merseyside, UK

8 Wexham Park Hospital, Berkshire, UK

10 Watford General Hospital, Watford, Hertfordshire, UK

11 King’s College Hospital, Denmark Hill, London, UK

12 Northwick Park Hospital, Harrow, London, UK

13 Lister Hospital, Stevenage, Hertfordshire, UK

14 Imperial College London, London, UK

15 Barts and The London NHS Trust, London, UK

16 UCL, Department of Physiology, London, UK

17 Guy’s and Saint Thomas' Hospitals NHS Trust, London, UK

18 University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe

Correspondence to: Dr Michael S. Zandi PhD FRCP

University College London Queen Square Institute of Neurology

London WC1N 3BG

Running title: The emerging spectrum of COVID-19 neurology

Keywords: COVID-19; SARS-CoV-2; encephalitis; ADEM

Abbreviations: ADEM = acute demyelinating encephalomyelitis; COVID-19 = coronavirus

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Here we describe the detailed emerging spectrum of neurological disorders encountered in 43

Materials and methods

probable or possible COVID-19, which were likely to be associated with COVID-19 on

The probability of COVID-19-related neurological disease was determined using WHO

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Vignette A: acute parainfectious encephalopathy with psychosis

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Vignette B: post-infectious probable brainstem and cortical autoimmune

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Vignette C: ADEM with haemorrhage in a critically ill patient

Vignette D: acute haemorrhagic leukoencephalopathy form of ADEM

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Vignette E: sequential para-infectious involvement of central and

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Vignette F: ischaemic stroke with concurrent pulmonary embolism

A 58-year-old male (Patient 27), previously independent in a high-risk occupation for

Peripheral nervous system

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Summary of key features

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The neurological complications of SARS-CoV2 have similarities to those described in the

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neuropathological studies or development of accurate CSF viral markers and serological

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Stroke associated with a generalized thrombotic predisposition in COVID-19 is of particular

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infectious inflammation including autoantibody production to neuronal antigens, and the

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Collectively, these cases presented a considerable challenge to diagnose with MRI,