Brain Injury

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ibij20

Neurological manifestations in COVID-19: a

systematic review and meta-analysis

Tzy Harn Chua , Zheyu Xu & Nicolas Kon Kam King

To cite this article: Tzy Harn Chua , Zheyu Xu & Nicolas Kon Kam King (2020) Neurological
manifestations in COVID-19: a systematic review and meta-analysis, Brain Injury, 34:12,
1549-1568, DOI: 10.1080/02699052.2020.1831606

To link to this article: https://doi.org/10.1080/02699052.2020.1831606

Published online: 19 Oct 2020.

Submit your article to this journal

Article views: 563

View related articles

View Crossmark data

Citing articles: 2 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ibij20
BRAIN INJURY
2020, VOL. 34, NO. 12, 1549–1568
https://doi.org/10.1080/02699052.2020.1831606

REVIEW

Neurological manifestations in COVID-19: a systematic review and meta-analysis

a
Tzy Harn Chua , Zheyu Xub, and Nicolas Kon Kam Kingc,d
a
Department of Pathology, Singapore General Hospital, Singapore, Singapore; bDepartment of Neurology, National Neuroscience Institute, Singapore,
Singapore; cDepartment of Surgery, Yong Loo Lin School of Medicine, Singapore, Singapore; dNeuro Asia Care, Mount Elizabeth Hospital, Singapore,
Singapore

ABSTRACT ARTICLE HISTORY

Objective: Following the outbreak of coronavirus 2019 (COVID-19), there is strong evidence of neurolo­ Received 7 August 2020
gical involvement in these patients. We aimed to determine the clinical characteristics of neurological Revised Vxx xxx xxxx
manifestations in COVID-19. Accepted 29 September 2020
Method: A systematic review of studies reporting neurological manifestations published between KEYWORDS
1 December, 2019 and 11 May, 2020 was performed. Studies were grouped based on neurological COVID-19; neurological;
manifestation. Pooled analyses of individual patient’s clinical characteristics and olfactory and gustatory Guillain-Barré syndrome;
dysfunction prevalence were performed. encephalitis; cerebrovascular
Results: Of 486 studies identified, 48 were included. 70 patients with 73 neurological manifestations were
reported. 39 (53.4%) patients had stroke, 18 (24.7%) had Guillain-Barré syndrome and variants, 11 (15.1%)
had meningitis, encephalitis, encephalopathy, or myelitis, and five (6.8%) had seizures. They had a mean
age of 61.9 ± 17.7 years (60.6% male). Neurological disease occurred 8.1 ± 6.8 days from initial symptoms.
Average mortality rate was 17.8%. Stroke has a mortality rate of 25.6%. Olfactory and gustatory dysfunc­
tion occurred in 59.9% and 57.5%, respectively.
Conclusions: Stroke is the most frequently reported neurological manifestation in COVID-19 and has the
highest mortality rate. Neurological manifestations tend to develop one to two weeks after the onset of
respiratory disease. There is significant morbidity and mortality associated with COVID-19 neurological
manifestations.

Introduction were published after the abovementioned reviews. These new

In December 2019, COVID-19 was first detected in patients
with pneumonia in Wuhan, China (1,2). Since then, more than
14 million cases have been detected in regions including Asia-
Pacific, Europe, Middle East, and America (3), at the time of
writing.
COVID-19 primarily involves the respiratory system, com­
monly manifesting with fever and cough (4). Strong evidence
suggests that it can affect other organs (5). The angiotensin-
converting enzyme II (ACE2) receptor, which is expressed in
the lungs, vascular endothelia, kidneys and intestine, has been
identified as the receptor utilized by the virus to gain entry to
human cells (2,6). Neurological manifestations of COVID-19
have been reported to range between 13.9 and 36.4% (7,8).
Other coronavirus infections, including Severe Acute
Respiratory Syndrome (SARS) (9) and Middle East
Respiratory Syndrome coronavirus (MERS-CoV) (10) were
also associated with neurological manifestations. While the
prevalence of neurological manifestations in SARS is unknown,
17.4% of MERS-CoV patients were reported to have neurolo­
gical manifestations (10).
Initial systematic and scoping reviews described possible
associations of neurological manifestations with COVID-19
(7,11–13). Currently, there is strong evidence for neurological
involvement in COVID-19. Furthermore, there is convincing
evidence of anosmia and ageusia in COVID-19, many of which
findings in this field have implications for disease screening
and detection. As such, it is timely and of great importance to
determine the clinical characteristics of these neurological
manifestations. Hence, this systematic review aims to provide
a comprehensive review of what is currently known of the
neurological manifestations in COVID-19.
Methods
Search strategy
In accordance with the PRISMA statement (14), the literature
search was conducted on 11 May, 2020, with the following
search terms: “COVID OR COVID-19 OR sars-cov” AND
“neuro OR neurology OR neurological OR nervous”, through
the PubMed electronic database and Google Scholar search
engine.
Inclusion and exclusion criteria
Inclusion criteria included: 1) published in English, 2) pub­
lished from 1 December, 2019 onwards, 3) reported clinical
neurological manifestations including signs and symptoms of
demyelinating disease, meningitis, encephalitis, encephalopa­
thy, myelitis, cerebrovascular disease, seizures, olfactory and
gustatory dysfunction, 4) COVID-19 diagnosis using PCR

CONTACT Nicolas Kon Kam King Nicolas.k@neuroasiacare.com Neuro Asia Care, Mount Elizabeth Hospital, Singapore 228510, Singapore
© 2020 Taylor & Francis Group, LLC
1550 T. H. CHUA ET AL.

assay, and 5) peer-reviewed. Exceptions were made for articles Statistical analysis
uploaded in preprint servers that were already cited by peer-
Continuous variables were expressed as means and standard
reviewed articles. Reference lists of full-text articles were
deviations. Categorical variables were expressed as propor­
reviewed to allow snowballing of articles.
tions. Pooled analysis of clinical characteristics including age,
Exclusion criteria included: 1) published in a language other
sex, onset from initial symptoms to neurological disease, and
than English, 2) basic science studies, 3) letters, correspon­
clinical outcome was performed. Pooled prevalence of olfac­
dence or commentaries that did not report clinical neurological
tory and gustatory dysfunction was performed. Means and
manifestations, 4) pediatric population, and 5) studies that
standard deviations were compared using one-way ANOVA
only reported nonspecific neurological symptoms including
while proportions were compared using Chi-square test. All
headache, dizziness, nausea, and vomiting. For multiple studies
statistical analyses were conducted using Statistical Package for
reporting a similar population of patients, the older study was
the Social Sciences for Windows (SPSS Statistics version 23.0;
excluded.
IBM Corp, Armonk, NY, USA).

Data collection
Clinical characteristics including age, sex, onset from initial
symptoms to neurological disease, neurological symptoms and
signs, imaging findings, selected blood findings, neurophysio­
logic findings, CSF findings, and clinical outcomes were col­
lected from the articles.
Results
Study characteristics
There were 469 records identified through PubMed (Figure 1),
with 29 articles identified from Google Scholar search engine.
After screening and excluding articles that did not meet

Figure 1. PRISMA flow diagram.

 BRAIN INJURY 1551

inclusion criteria, 48 articles were included. They comprised of GBS and variants
two (4.2%) prospective studies, 5 (10.4%) retrospective studies,
Study findings have been summarized in Table 2. Twelve
one (2.1%) case-control study, one (2.1%) cross-sectional
studies (15–26) reported GBS and variants in COVID-19.
study, seven (14.6%) case-series, 19 (39.6%) case reports, and
There were 18 patients with a mean age of 59.3 ± 14.8 years,
13 (27.8%) letters to the Editors, correspondence or rapid
consisting of 12 males (66.7%). 38.9% were 61 to 70 year-old,
communication.
followed by 22.2% above 70 year-old and another 22.2% aged
51 to 60 year-old (Table 1). Initial symptoms included fever
Clinical characteristics of neurological manifestations and cough. Out of 18 patients, 17 (94.4%) presented with prior
respiratory symptoms and of these 17 patients, 16 (94.1%)
There were 73 neurological presentations in 70 COVID-19
presented with sensory or motor symptoms typical of GBS
patients, 39 (53.4%) had stroke, 18 (24.7%) had Guillain-
and variants (paresthesia, hypoesthesia, rapidly progressive
Barré Syndrome (GBS) and variants, 11 (15.1%) had meningi­
weakness in the ocular, facial, or limb muscles) while one
tis, encephalitis, encephalopathy and myelitis (MEEM), and
(5.9%) presented with a brief loss of consciousness, without
five (6.8%) had seizures. Two patients who had MEEM were
evidence of respiratory failure. There was an average of
also included in the group with seizures while one patient with
8.0 ± 5.2 days from onset of initial symptoms to the develop­
GBS and variants were included in the group with seizures.
ment of neurological presentation (Table 1).
These patients had a mean age of 61.9 ± 17.7 years. Majority
Six (33.3%) out of 18 patients had normal cerebrospinal
were males (60.6%). Overall, two-third (66.6%) were above
fluid (CSF) (15,17,19,22,25), nine (50.0%) had abnormal CSF
61 year-old, with 25 (36.2%) patients above 70 year-old, and
(16,18,19,23–26), and three (16.7%) did not have CSF reported
21 (30.4%) patients were 61 to 70 year-old (Table 1). There was
(15,20,21). Seven (77.8%) out of nine abnormal CSFs had
a higher proportion of younger patients aged 30 to 40 year-old
increased protein levels with normal cell counts (18,19,23–
in the stroke group (five patients, 13.5%), when compared to
25). Out of 11 CSFs that were sent for detection of COVID-
the other age groups. Eleven (16.4%) out of 67 patients did not
19, all samples were negative for COVID-19.
have respiratory symptoms before developing neurological
Fifteen (83.3%) patients received intravenous immunoglo­
symptoms. Mean duration from onset of initial respiratory
bulin (15–21,23–26), one (5.6%) received steroids (22), two
symptoms to development of neurological disease was
(11.1%) did not require treatment (15,19), and no patient
8.1 ± 6.8 days, and there were 13 (17.8%) deaths (Table 1).
received plasmapheresis. Five (27.8%) out of 18 patients
Of these 13 deaths, 10 (76.9%) were above 70 year-old, one
required mechanical ventilation at the onset of neurological
(7.7%) was between 61 and 70 year-old and one (7.7%) was
symptoms (17,21,22,24,25), seven (38.9%) did not require
between 30 and 40 year-old. Both patients had stroke. The age
mechanical ventilation (15,16,19,25), and six (33.3%) patients’
of one patient who died was not reported. Outcomes were not
ventilation requirements were not reported (18,23,25,26).
reported in 25 (34.2%) patients. There was a statistically sig­
Notably, two studies (15,19) reported four patients who
nificant (p = .004) association between outcomes and the
presented with neuro-ophthalmological manifestations includ­
different neurological diseases (Table 1). In particular, stroke
ing diplopia, ptosis, reduced eye abduction, as well as neuro­
and seizure had a higher mortality rate when compared to the
logical manifestations including limb paresthesia, reduced
other manifestations, and the presentation of stroke was more
deep tendon reflexes, and gait instability. In United States,
delayed than the other manifestations (Figure 2).

Table 1. Clinical characteristics of neurological manifestations; SD, standard deviation; No., number of.
GBS and Meningitis, Encephalitis,
variants Encephalopathy Myelitis Stroke Seizure Overall p-value
Age
Number of patients 18 9 37 5 69 -
Mean age ± SD (years) 59.3 ± 14.8 57.1 ± 17.6 66.1 ± 17.8 48.8 ± 21.0 61.9 ± 17.7 0.113
< 30 year-old, No. (%) 1 (5.6) 1 (11.1) 1 (2.7) 1 (20.0) 4 (5.8) 0.456
30–40 year-old, No. (%) 2 (11.1) 1 (11.1) 5 (13.5) 1 (20.0) 9 (13.0)
41–50 year-old, No. (%) 0 (0.0) 1 (11.1) 2 (5.4) 0 (0.0) 3 (4.3)
51–60 year-old, No. (%) 4 (22.2) 0 (0.0) 2 (5.4) 1 (20.0) 7 (10.1)
61–70 year-old, No. (%) 7 (38.9) 4 (44.4) 9 (24.3) 1 (20.0) 21 (30.4)
> 70 year-old, No. (%) 4 (22.2) 2 (22.2) 18 (48.6) 1 (20.0) 25 (36.2)
Sex
Number of patients 18 11 37 5 71 -
Number of males (%) 12 (66.7) 7 (63.6) 22 (59.5) 2 (40.0) 43 (60.6) 0.746
Onset duration
Number of patients 15 11 37 4 67 -
Mean number of days from onset of initial symptoms to development 8.0 ± 5.2 6.5 ± 5.6 9.0 ± 8.0 5.0 ± 1.6 8.1 ± 6.8 0.576
of neurological disease, mean ± SD, days
Outcomes
Number of patients 18 11 39 5 73 -
Improvement in neurological symptoms, No. (%) 10 (58.6) 7 (63.6) 6 (15.4) 3 (60.0) 26 (35.6) 0.004
Worsening of or persistence in neurological symptoms, No. (%) 2 (11.1) 1 (9.1) 0 (0.0) 1 (20.0) 4 (5.5)
ICU or stroke unit admission, No. (%) 2 (11.1) 1 (9.1) 2 (5.1) 0 (0.0) 5 (6.8)
Death, No. (%) 1 (5.6) 1 (9.1) 10 (25.6) 1 (20.0) 13 (17.8)
Not reported, No. (%) 3 (16.7) 1 (9.1) 21 (51.8) 0 (0.0) 25 (34.2)
1552 T. H. CHUA ET AL.
Figure 2. Scatter plot of the duration from initial COVID-19 symptoms to development of neurological disease and mortality rate in the neurological manifestations;
MEEM, meningitis, encephalitis, encephalopathy, myelitis; GBS, Guillain Barre syndrome.
two patients (15) demonstrated enlargement of left oculomotor
nerve and enhancement of optic nerve sheaths on magnetic
resonance imaging (MRI) of the brain, respectively (15). In the
first patient, ophthalmological examination showed left
mydriasis, mild ptosis and limited depression and adduction
while the second patient had normal visual acuity and pupils.
Two (50.0%) patients were treated presumptively for Miller-
Fisher syndrome, with intravenous immunoglobulin [0.4 g/kg
for 5 days in Gutierrez-Ortiz et al. (19) and 2.0 g/kg for 3 days
in Dinkin et al. (15)]. The patient reported in Gutierrez-Ortiz
et al. (19) was positive to anti-ganglioside antibody GD1b-IgG
while the anti-ganglioside antibody panel was negative in
Dinkin et al. (15) One patient was diagnosed with polyneuritis
cranialis, with bilateral six nerve palsies, absent deep tendon
reflexes with normal limb strength. All four patients showed
improvement in neurological symptoms.
Ten out of 18 (58.6%) patients had an improvement in neuro­
logical symptoms (15,19,21–23,25,26), two (11.1%) had
a worsening of or persistence in neurological symptoms (18,25),
two (11.1%) were admitted to Intensive Care Unit (ICU) or stroke
unit (17,25), and there was one (5.6%) death (16).
Meningitis, encephalitis, encephalopathy, myelitis (MEEM)
Study findings have been summarized in Table 3. Thirteen studies
(8,27–38) reported 49 patients. Meningoencephalitis was reported
in five patients (28,31,34,35). Three other patients were reported
to have encephalopathy/encephalitis (36), rhombencephalitis (32),
and myelitis (33). Three studies reported that 13 (22.4%) patients
presented with encephalopathic features (37), 16 (7.5%) presented
with impaired consciousness (8), and nine (9.9%) presented with
confusion (38). Etiologies of encephalopathy and impaired con­
sciousness were not reported.
Of eight CT brain, two (25.0%) showed neurological involve­
ment including symmetric hypoattenuation within bilateral
medial thalami (30) and bilateral basal ganglia and paraventricular
lacunar infarction (33). The other six (75.0%) CT were normal.
Of 24 MRI brain performed in 24 patients, 22 (91.7%)
showed neurological involvement including hyperintensity
along the wall of inferior horn of right lateral ventricle (28),
hemorrhagic rim-enhancing lesions in bilateral thalami, medial
temporal lobes and subinsular regions (30). Eight (62.0%) out
of 13 ICU patients had leptomeningeal enhancement and 11
(100.0%) out of 11 patients had bilateral frontotemporal hypo­
perfusion on MRI brain (37).
Of 15 patients with CSF tested, eight (53.3%) were abnormal
(27,28,34,35,37). 25.0% (two out of eight) of the abnormal CSFs
had elevated protein levels with normal cell count (27,37). Four
(50.0%) out of eight had elevated cell count (28,34,35). One (8.3%)
out of 12 CSFs was positive for COVID-19 (28). Four (26.7%)
CSFs were sent for bacterial culture and were all negative
(30,32,34). CSFs were sent for herpes simplex virus testing in
four (26.7%) patients (27,28,30,35) and were all negative. CSF
was sent for varicella zoster virus testing in two (13.3%) patients
(28,30) and both were negative. One patient (6.7%) (30) was tested
for West Nile virus while another patient (6.7%) (27) was tested for
cytomegalovirus and respiratory syncytial virus; the CSFs were
negative. Two (13.3%) patients were negative for unspecified viral
pathogens (34). Oligoclonal bands with the same pattern in serum
were reported in two (13.3%) patients (37). Investigation for other
sources of pathogen in the CSF was not reported in three studies
(29,31,33).
Ten electroencephalograms (EEG) were performed. Three
(30.0%) of these EEGs showed slowing of brain activity (27,37)
and focal status epileptics (34). The other EEGs showed nonspe­
cific changes (37).
Treatments were reported in 10 patients (27,28,30,31,33–
36). Antiviral medications including ganciclovir, lopinavir,
ritonavir, acyclovir, ribavirin, umifenovir, and favipiravir
were used in seven (70.0%) patients (27,28,31,33–35).
Antibiotics including ceftriaxone, vancomycin, meropenem,
Table 2. GBS and variants; NR, not reported; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; CT, computed tomography; NCS, nerve conduction study; EMG, electromyography; IVIG, intravenous immunoglobulin; M,
male; F, female.
Number of Age
Study (Study type) patients (years)
[City, country] (diagnosis) [Sex] Onset Neurological Symptoms/Signs Imaging/physiological/blood findings CSF Outcome
Dinkin et al. (15) 2 (cranial neuropathies) Patient 1–36 [M] Patient 1 – four days after fever, cough and Patient 1: Patient 1:
(Case series) Patient 2–71 [F] myalgias ptosis, diplopia, distal Brain MRI: T2
[New York City, Patient 2 – several days after cough and fever paresthesia, mydriasis; hyperintensity and
United States] hyporeflexia, enlargement of left
hypesthesia and gait oculomotor nerve
ataxia Negative to anti-
Patient 2: ganglioside antibody
painless diplopia for Patient 2:
two days and inability Brain MRI:
to abduct right eye enhancement of
optic nerve sheaths
and posterior Tenon
capsules
Patient 1: NR Patient 1: improvement three
Patient 2: normal Partial days later
Patient 2:
Improvement of
diplopia at two
weeks after
discharge
Alberti et al. (16) 1 (GBS) 71 [M] Several days after low Limb paresthesia followed by distal Head CT: normal Protein: 54 mg/dL; white Death due to
(Case report) grade fever weakness evolving to a flaccid NCS: absence of sural nervy sensory nerve blood cells: 9 cells//μL; progressive
[Monza, Italy] tetraparesis over three days action potential and tibial nerve compound negative PCR for respiratory failure
Examination: limb weakness, glove-and- muscle action potential (CMAP); increased COVID-19
stocking hypesthesia; absent deep common peroneal CMAP distal latency
tendon reflexes
Camdessanche et al. 1 (GBS) 64 [M] Eleven days after Paresthesia in limbs, developing to a flaccid NCS: demyelinating pattern Protein: 1.66 g/L; normal ICU admission due to
(17) cough and fever severe tetraparesis in three days; EMG: no rest activity; during muscle cell count; respiratory failure
(Case report) dysphagia contraction, only one single motor unit was
[Saint-Etienne, Examination: weakness in limbs; absent recorded with a firing rate up to 25 Hz
France] tendon reflexes; absent vibration
sensation
El Otmani et al. (18) 1 (GBS) 70 [F] Three days after dry Two-day history of rapidly progressing NCS: reduction or absence of electrical potential Protein: 1 g/L; normal cell No neurological
(Case report) cough weakness and paresthesia in all limbs in both motor and sensory nerves in all limbs count; negative PCR for improvement after
[Casablanca, Examination: quadriplegia, hypotonia, EMG: diffuse and abundant fibrillation COVID-19 one week of
Morocco] areflexia and bilateral positive Lasègue potentials at rest treatment
sign
Gutiérrez-Ortiz et al. 1 (Miller Fisher Patient Patient 1 – five days Patient 1: Patient 1: Patient 1: Patient 1:
(19) Syndrome) 1–50 after cough, Two-day history of vertical diplopia, gait Head CT: normal Opening pressure of Resolution of
(Case report) 1 [M] malaise, headache, instability, anosmia and ageusia Positive to anti-gangliosides antibody GD1b- 11 cm H2O neurological features
[Madrid, Spain] (Polyneuritis Patient and fever Examination: broad-based gait, absent IgG Protein: 80 mg/dL except anosmia and
cranialis) 2–39 Patient 2 – three deep tendon reflexes; Right hypertropia Patient 2: White blood cell count: ageusia
[M] days after fever, in all fields of gaze, left eye nystagmus Head CT: normal 0 Patient 2: Complete
diarrhea Patient 2: Negative PCR for neurological recovery
acute diplopia, ageusia COVID-19 after two weeks
Examination: esotropia, severe abduction Patient 2:
deficits and fixation nystagmus; absence Opening pressure of
of deep tendon reflexes 10 cm H2O
BRAIN INJURY

Protein: 62 mg/dL
White blood cell count:
2 (all monocytes)
Negative PCR for
COVID-19
1553

(Continued)
 1554

Table 2. (Continued).
Number of Age
Study (Study type) patients (years)
[City, country] (diagnosis) [Sex] Onset Neurological Symptoms/Signs Imaging/physiological/blood findings CSF Outcome
T. H. CHUA ET AL.

Sedaghat et al. (20) 1 (GBS) 65 [M] Two weeks after Acute ascending quadriparesis; facial Cervical spine and brain MRI: normal except Not performed NR
(Case report) Covid-19 diagnosis paresis mild herniation of two intervertebral discs
[Sari, Iran] Examination: weakness in four limbs, NCS: decreased amplitude at compound
absent deep tendon reflexes, reduction muscle action potential; no response at
sensation, bifacial nerve palsy sensory nerve action potential
EMG: decreased recruitment
Virani et al. (21) 1 (GBS) 54 [M] Ten days after Two-day history of numbness and weakness Thoracic and lumbar spine MRI: normal Not performed Improvement in
(Case report) nonproductive in lower limb; urinary retention EMG: not performed respiratory status (off
[Pittsburgh, cough Examination: absent deep tendon mechanical
United States] reflexes in lower limbs; weakness in all ventilation on day 4
limbs of IVIG therapy)
Lower limb weakness
persisted, requiring
physical
rehabilitation.
Zanin et al. (22) 1 (demyelinating 54 [F] Several days after anosmia and ageusia Loss of consciousness EEG: two seizures from
(Case report) lesions) Examination: GCS 12 right frontotemporal
[Brescia, Italy] (E3, M6, V3); nil region and diffusing
sensorimotor deficits in homologous
contralateral
hemisphere
Brain MRI: alteration
of periventricular
white matter,
hyperintensity in
T2WI
Normal; negative Transferred to Rehabilitation
PCR for COVID-19 on day twelve of
hospitalization
Coen et al. (23) 1 (GBS) 70+ [M] Ten days after dry Paraparesis, distal allodynia Spine MRI: excluded myelopathy Albuminocytologic Transferred to
(Letter to the cough Examination: bilateral lower limb flaccid NCS: sensorimotor demyelinating dissociation without Rehabilitation on day
Editors) paresis, absent deep tendon reflexes in polyneuropathy with sparing of sural nerve intrathecal IgG eleven of
[Geneva, all limbs; nil sensory deficits synthesis; negative PCR hospitalization
Switzerland] for COVID-19
Padroni et al. (24) 1 (GBS) 70 [F] Three weeks after One-day history of weakness, upper and NCS: reduced amplitude in distal compound Protein: 48 mg/dL NR
(Letter to the Covid-19 diagnosis lower limb paresthesia, and gait muscle action potentials White blood cells:
Editors) difficulties. 1 × 10^6/L
[Ravenna, Italy] Examination: symmetric distal upper and Negative microbiologic
lower limbs weakness, absent deep testing
tendon reflexes
(Continued)
Table 2. (Continued).
Number of Age
Study (Study type) patients (years)
[City, country] (diagnosis) [Sex] Onset Neurological Symptoms/Signs Imaging/physiological/blood findings CSF Outcome
Toscano et al. (25) 5 (GBS) Patient 1: Five to ten days after Patient 1: Flaccid areflexic tetraplegia Patient 1: Patient 1: Patient 1: persistence of
(Correspondence) 77 [F] symptoms evolving to facial weakness, upper-limb Spine MRI: enhancement of caudal nerve protein, 101 mg/dl; upper-limb
[Pavia, Italy] Patient including fever, paresthesia and respiratory failure roots white-cell, 4 per mm3; weakness, dysphagia,
2: 23 cough, anosmia Patient 2: Facial diplegia, generalized EMG: axonal variant of GBS, with sparing of negative PCR for and
[M] and/or ageusia areflexia, lower limb, paresthesia and sural nerve COVID-19 lower-limb
Patient ataxia Patient 2: Patient 2: paraplegia at one
3: 55 Patient 3: Flaccid tetraparesis and facial Brain MRI: bilateral enhancement of facial protein, 123 mg/dl; no month follow-up
[M] weakness, areflexia and respiratory nerve cells; negative PCR for Patient 2: decrease in
Patient failure EMG: axonal sensory-motor damage COVID-19 ataxia and
4: 76 Patient 4: Flaccid areflexic tetraparesis involving lower limbs, with sparing of sural Patient 3: mild decrease in
[M] and ataxia nerve, decrease in facial nerve cMAP protein, 193 mg/dl; no facial
Patient Patient 5: Facial weakness, flaccid amplitude cells; negative PCR for weakness at one
5: 61 areflexic paraplegia and respiratory Patient 3: COVID-19 month follow-up
[M] failure Spine MRI: enhancement of caudal nerve Patient 4: Patient 3: ICU
roots normal protein; no admission due to
EMG: severe axonal neuropathy cells; negative PCR for neuromuscular
Patient 4: COVID-19 respiratory failure
Brain MRI: normal Patient 5: and
Spine MRI: normal protein, 40 mg/dl; flaccid tetraplegia at
Patient 5: white-cell, 3 per mm3; one month follow-up
EMG: conduction blocks and demyelination negative PCR for Patient 4: mild
COVID-19 improvement but
unable to stand at
one month follow-up
Patient 5: NR
Zhao et al. (26) 1 (GBS) 61[F] Nil prior symptoms One-day history of lower limb weakness. NCS: delayed distal latencies and absent Not performed Weakness resolved and
(Correspondence) Examination: symmetric weakness and F waves tendon reflexes
[China] areflexia in lower limbs, with progressive returned by day 30.
weakness after admission. Reduced
sensation to light touch and pinprick.
BRAIN INJURY
1555
1556 T. H. CHUA ET AL.
moxifloxacin and amoxicillin were used in five (50.0%) patients
(27,28,33–35). Steroids were used in two (20.0%) patients
(28,33). Intravenous immunoglobulin was used in two
(20.0%) patients (30,33). Anti-epileptic medications including
levetiracetam were started in three (30.0%) patients (27,28,35).
Ye et al. reported the management of encephalitis with sup­
portive management including mannitol infusion (36).
After exclusion of three studies (8,37,38) for purpose of
a pooled analysis, there were 11 patients included for analysis.
Of nine patients with age reported, the mean age was
57.1 ± 17.6 year-old. Four (44.4%) were 61 to 70 year-old and
two patients (22.2%) were above 70 year-old. The remaining
patients were 50 year-old and younger. Seven out of 11 were
males (63.6%) and mean duration from onset of initial symp­
toms to development of neurological disease was 6.5 ± 5.6 days
(Table 1). Two patients did not have respiratory symptoms
prior to hospital presentation (29,35).
Of 11 patients, seven (63.6%) patients had improvement in
neurological symptoms. One (9.1%) experienced a worsening
of or persistence in neurological symptoms, one (9.1%) was
admitted to the intensive care unit (ICU) or stroke unit and
there was one death (9.1%).
Stroke
Study findings have been summarized in Table 4. Twelve
studies (8,37,39–48) from Asia, North America, Europe
reported stroke in 46 patients. Four out of 46 (8.7%) were
diagnosed with hemorrhagic strokes while the remaining
were diagnosed with ischemic stroke. CT was performed in
19 (41.3%) patients, MRI in eight (17.4%). Two CSF samples
were tested for COVID-19 (40) and both were negative.
Amongst 37 patients with age reported, 22 were males (59.5%)
and mean age was 66.1 ± 17.8 year-old. There were 18 (48.6%)
patients above 70 year-old, nine (24.3%) were 61 to 70 year-old,
two (5.4%) were 51 to 60 year-old, two (5.4%) were 41 to 50 year-
old, five (13.5%) were 30 to 40 year-old and one (2.7%) was below
30 year-old. The mean duration from onset of respiratory symp­
toms to development of neurological disease was 9.0 ± 8.0 days
(Table 1). Six (13.0%) out of 46 patients did not have respiratory
symptoms before admission. 15 (32.6%) patients had COVID-19
symptoms before presenting with signs and symptoms suggestive
of stroke. Presenting symptoms were not reported in 22 (47.8%)
patients and three (6.5%) were asymptomatic for stroke (37).
These three patients initially underwent MRI brain for unex­
plained encephalopathic manifestations (37). Five (10.9%) out of
these 46 patients developed stroke during admission (37,43,46).
Out of 39 patients, 6 (15.4%) patients had improvement in
neurological symptoms, 2 (5.1%) was admitted to ICU or
stroke unit, 10 (25.6%) died and outcomes were not reported
in 21 (51.8%) patients.
Seizure
Study findings have been summarized in Table 5. Seven studies
(8,22,28,34,49–51) reported occurrence of seizures in COVID-
19 patients. Lu et al. (51) reported that none of the 304 patients
had seizures while Mao et al. (8) reported only one patient
(0.5%) that presented with seizure.
Of the four case reports and one letter to the Editors
(22,28,34,49,50), these five patients had a mean age of
48.8 ± 21.0 years, with two males (40.0%) and mean duration
from onset of initial symptoms to development of seizure was
5.0 ± 1.6 days (Table 1). Two patients had meningoencephalitis
(28,34) and one patient (22) had GBS variant disease with
hypoxia. The patient in Karimi et al. (49) had a fever up to
38.8 degrees Celsius. The cause of seizure was not determined
in Sohal et al. although the authors mentioned that the patient
was persistently febrile throughout admission (50).
CT brain was done in three (60.0%) patients (22,28,50),
which did not show acute abnormalities. MRI brain was done
in four (80.0%), which showed underlying encephalitis (28)
and demyelinating lesions (22). MRI was normal in Karimi
et al. (49) and Bernard-Valnet et al. (34). EEG was performed
in three (60.0%) patients (22,34,50), which showed seizure
activity. CSFs were analyzed for four patients (22,28,34,49).
CSF was normal in two patients (22,49) while the CSF in
Moriguchi et al. (28) and Bernard-Valnet et al. (34) showed
increased cell count. Three (75.0%) out of four CSF samples
were negative for COVID-19 virus (22,34,49).
Three (60.0%) patients had improvement in neurological
symptoms, one (20.0%) had a worsening of or persistence in
neurological symptoms and there was one (20.0%) death.
Olfactory and gustatory dysfunction
Study findings have been summarized in Table 6. Twelve
studies (8,19,52-61) reported olfactory dysfunction including
anosmia, hyposmia, and gustatory dysfunction including ageu­
sia, hypogeusia and dysgeusia. Based on a pooled analysis of
data from Lechien et al. (52), Luers et al. (53), and Mao et al.
(8), out of 703 patients, 421 patients (59.9%) reported olfactory
dysfunction while 404 patients (57.5%) reported gustatory
dysfunction.
Lechien et al. reported that amongst 357 patients with
olfactory dysfunction, 11.8% experienced the dysfunction
before COVID-19 symptoms, 22.8% occurred at the same
time as COVID-19 symptoms and 65.4% occurred after the
COVID-19 symptoms (52). 72.6% recovered within first 8 days
after disease resolution (52). Due to heterogeneity of the data
available from the studies, further pooled analysis with regards
to onset duration and prognosis was not performed.
Discussion
In this systematic review, we have reviewed the current litera­
ture of the neurological manifestations in COVID-19. In our
pooled analysis of 703 patients, olfactory dysfunction occurred
in 59.9% while gustatory dysfunction occurred in 57.5%. In the
separate series, patients had a mean age of 61.9 ± 17.7 years and
were predominantly male (60.6%). Onset of neurological dis­
ease was an average duration of 8.1 ± 6.8 days from initial
COVID-19 symptoms. The mortality rate was 17.8%, with
majority of deaths occurring in those aged above 70. Stroke
has the highest mortality rate of 25.6%.
Neurological complications were rarely described in SARS
and MERS-CoV. In SARS, three patients developed polyneuro­
pathy following initial illness and five patients developed large
Table 3. Meningitis, encephalitis, encephalopathy, myelitis; NR, not reported; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; CT, computed tomography; NCS, nerve conduction study; EEG, electro-encephalography;
ICU, intensive care unit; GCS, Glasgow coma scale; M, male; F, female.
Study Age
(Study type) Number of patients (years)
[City, country] (Diagnosis) [Sex] Onset Neurological Symptoms/Signs Imaging/physiological/blood findings CSF Outcome
Filatov et al. (27) 1 (Encephalopathy) 74 [M] One day after fever Headache, altered mental status and Head CT: no acute abnormalities Protein: 68 Remained in ICU
(Case report) and cough fever. EEG: bilateral slowing and focal slowing in the left 4 white blood cells
[Boca Raton, Examination: encephalopathic temporal region with sharply countered waves
United States]
Moriguchi et al (28). 1 (Meningo- 24 [M] One week after fever, Altered consciousness and transient Head CT: normal Pressure: more than 320 Impaired
(Case report) encephalitis) fatigue and generalized seizure Brain MRI: hyperintensity along the wall of inferior mmH2O; consciousness
[Yamanashi, headache Examination: GCS 6 (E4 V1 M1); horn of right lateral ventricle 10 mononuclear cells, on day 15
Japan] neck stiffness 2 polymorphonuclear
cells
Positive PCR for
COVID-19
Paniz-Mondolfi 1 (Encephalopathy) 74 [M] Nil prior symptoms Confusion, fever Head CT: patchy subcortical and periventricular NR Died on day 11
et al. (29) hypodensities unchanged from a scan done six
(Case report) months earlier
[New York City,
United States]
Poyiadji et al. (30) 1 (Encephalopathy) NR [F] Nil prior symptoms Three-day history of cough, fever and Head CT: symmetric hypoattenuation within bilateral Traumatic LP; negative NR
(Case report) altered mental status medial thalami bacterial culture;
[Detroit, United Brain MRI: hemorrhagic rim enhancing lesions negative for HSV-1,
States] within bilateral thalami, medial temporal lobes, and HSV-2, VZV and West
subinsular regions Nile virus.
Yin et al. (31) 1 (Meningo- 64 [M] Ten days after cough Lethargy and unresponsiveness Head CT: no significant abnormalities Pressure of 200 cm H2O Discharged to
(Case report) encephalitis) and fever Examination: lethargy and Protein: 275.5 mg/L quarantine facility
[Nanjing, China] irritability; ankle clonus; Babinski Cell count: 1 x 10^6/L
sign and Chaddock sign; positive Negative PCR for
Brudzinski sign and straight leg COVID-19
raise test
Wong et al. (32) 1 (Rhombencephalitis) 40 [M] Three days after Unsteady gait,
(Case report) admission for a ten- diplopia,
[Telford, United day history of fever oscillopsia, limb
Kingdom] and dyspnea on ataxia, altered
exertion sensation
Examination:
facial weakness,
reduced tongue
movements;
upbeat
nystagmus; limb
ataxia
Brain and cervical rhombencephalitis/myelitis Protein: 423 mg/L Discharged on day
spine MRI: eleven of admission
inflammatory
Zhao et al. (33) 1 (Myelitis) 66 [M] More than five days Weakness in lower limbs, urinary and Head CT: bilateral basal ganglia and paraventricular Not performed Discharged to
(Case report) after fever bowel incontinence lacunar infarction and brain atrophy Rehabilitation
[Wuhan, China] Examination: 3/5 power in upper facility with
limbs; 0/5 power with a lower limb
BRAIN INJURY

hyporeflexia; sensory level at T10 power of 1/5

to pinprick; reduced tendon
reflexes
(Continued)
1557
 1558
T. H. CHUA ET AL.

Table 3. (Continued).
Study Age
(Study type) Number of patients (years)
[City, country] (Diagnosis) [Sex] Onset Neurological Symptoms/Signs Imaging/physiological/blood findings CSF Outcome
Bernard-Valnet et al. 2 (Mening- Patient 1: Patient 1: five days Patient 1: tonic-clonic seizure; Patient 1: Patient 1: Patient 1: resolution
(34) oencephalitis) 64 [F] after mild asthenia, disorientation, attention deficit, Brain MRI: normal Proteins: 466 mg/L of symptoms after
(Letter to the Patient myalgia, cough verbal and motor perservations, EEG: non-convulsive, focal status epilepticus Cells: 17/mm^3 4 days
Editors) 2: 67 [F] Patient 2: 17 days bilateral grasping Patient2: Negative PCR for Patient 2:
[Lausanne, after mild Patient 2: headache, drowsiness, Brain MRI: normal COVID-19 discharged with
Switzerland] respiratory confusion; examination: Patient 2: resolution of
symptoms disorientation, bilateral grasping, Proteins: 461 mg/L symptoms after
left hemianopia, sensory Cells: 21/mm^3 72 hours
hemineglect Negative PCR for
COVID-19
Duong et al. (35) 1 (Meningo- 41 [F] Nil prior symptoms Headache, fever and new-onset Head CT: normal Protein: 100 Mental status
(Letter to the encephalitis) seizure; disorientation and 70 white blood cells improved by day
Editors) hallucination during with 100% five but
[Los Angeles, hospitalization lymphocytes hallucinations
United States] Examination: neck stiffness; persisted
photophobia intermittently
Ye et al. (36) 1 (Encephalitis) NR [M] Ten days after Confusion; Examination: nuchal Head CT: normal Pressure: 220 mmHg Discharged after
(Letter to the development of rigidity, positive Kernig and Protein: 0.27 g/L 17 days of
Editors) fever, dyspnea and Brudzinski signs White blood cells: hospitalization
[Nanjing, China] myalgia 0.001 x 10^9/L
Negative PCR for
COVID-19
Helms et al. (37) 13 (22.4%) with NR [NR] Admitted to ICU due NR Brain MRI: leptomeningeal enhancement in 8 patients Elevated protein and IgG NR
(Correspondence) encephalopathic to ARDS (62%); bilateral frontotemporal hypoperfusion in 11 in 1 out of 7 patients
[Strasbourg, features patients (out of 11 perfusion imaging performed); No cells in all patients
France] cerebral ischemic stroke in 3 patients (23%) Oligoclonal bands
EEG: 1 out of 8 patients had diffuse bifrontal present in 2 patients
slowing Negative PCR assay
for COVID-19in all
patients
Table 4. Stroke; NR, not reported; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; CT, computed tomography; ICU, intensive care unit; GCS, Glasgow coma scale; M, male; F, female.
Study Number of
(Study type) patients Age (years)
[City, country] [Type of stroke] [Sex] Onset Neurological Symptoms/Signs Imaging findings Relevant blood findings Outcome
Mao et al. (8) 6 (2.8%) NR [NR] NR NR NR NR One died of respiratory
(Retrospective) [5- Ischemic failure
[Wuhan, China] 1-
Hemorrhagic]
Li et al. (39) 13 (5.9%) 71.6 ± 15.7 10 days (IQR: 1–29) NR NR Platelet count: 142.0 x 10^9/L Eight survived; five died
(Retrospective) [12- Ischemic [7 F, 6 M] after symptoms of D-dimer: 6.9 mg/L
[Wuhan, China] 1- COVID-19
Hemorrhagic]
Al Saiegh et al. (40) 2 Patient Patient 1: One week Patient 1: Headache and loss of Patient 1: NR Patient 1: Discharged to
(Case series) [1- Ischemic 1–31 [M] after malaise, fever, consciousness CT: subarachnoid hemorrhage Rehabilitation facility
[Philadelphia, 1- Patient cough and arthralgia Patient 2: altered mental status Patient 2: Patient 2: NR
United States] Hemorrhagic] 2–62 [F] Patient 2: Ten days CT: hemorrhagic conversion
after discharge for and obstructive
left middle cerebral hydrocephalus
artery occlusion
Avula et al. (41) 4 [all ischemic] Patient 1: Patient 1: two days Patient 1: fever, respiratory distress, Patient 1: Patient 1: Patient 1: terminally
(Case series) 73 [M] after dyspepsia, altered mental status CT: left MCA territory infarct Platelet count: 182/mm^3 extubated
[New York, Patient 2: nausea, vomiting Patient 2: fever, facial droop, Patient 2: D-dimer: NR Patient 2: Care
United States] 83 [F] Patient 2: nil prior slurred speech; examination: left CT: hypodensity in right Patient 2: withdrawn
Patient 3: symptoms facial droop and slurred speech, frontal lobe Platelet count: 138/mm^3 Patient 3: terminally
80 [F] Patient 3: frequent left-sided hemineglect, Patient 3: D-dimer: NR extubated
Patient 4: falls in past week Patient 3: left-sided weakness; CT: acute right MCA stroke Patient 3: Patient 4: discharged to
88 [F] Patient 4: nil prior examination: left hemiplegia, Patient 4: Platelet count: 380/mm^3 Rehabilitation facility
symptoms aphasia MRI: acute infract in left D-dimer: 13966 ng/mL
Patient 4: right arm weakness and medial temporal lobe Patient 4:
numbness Platelet count: 176/mm^3
D-dimer: 3442 ng/mL
Gonzalez-Pinto et al. 1 [Ischemic] 36 [F] Nil prior symptoms Aphasia and right hemiplegia CT: infarct in the territory of left NR Died 72 hours after
(42) middle cerebral artery admission
(Case report)
[Bilbao, Spain]
Moshayedi et al. 1 [Ischemic] 80 [M] Five days after dyspnea Aphasia, right-sided weakness and MRI: acute infract in left insular, Normal platelet counts NR
(43) right sided facial droop temporal, parietal, and frontal Activated partial thromboplastin time >
(Case report) lobe 85.5 while on heparin
[Los Angeles]
Sharifi-Raszavi et al. 1 [Hemorrhagic] 79 [M] Three days after fever Loss of consciousness; examination: CT: intracerebral hemorrhage in Platelet count: 210 x 10^9/L NR
(44) and cough GCS 7, bilateral extensor plantar right hemisphere International normalized ratio (INR): 1
(Case report) reflexes Partial thromboplastin time: 64 seconds
[Sari, Iran]
Zhai et al. (45) 1 [Ischemic] 79 [M] One week after cough Right limb weakness; examination: CT: lacunar infarction Coagulation: normal Able to walk and
(Case report) non-fluent speech, tongue communicate with near
[Wuhan, China] deviation fluent language on day
twelve
BRAIN INJURY

(Continued)
1559
 1560

Table 4. (Continued).
Study Number of
(Study type) patients Age (years)
[City, country] [Type of stroke] [Sex] Onset Neurological Symptoms/Signs Imaging findings Relevant blood findings Outcome
Beyrouti et al. (46) 6 [All ischemic] Patient 1: Patient 1: 15 days after Patient 1: aphasia, right Patient 1: MRI: left vertebral Patient 1: Positive anti-cardiolipin IgM; NR
(Letter to the 64 [M] cough, dyspnea, homonymous hemianopia artery thrombus positive anti–β2-glycoprotein I IgM and
T. H. CHUA ET AL.

Editors) Patient 2: fever, myalgia Patient 2: Acute confusion, Patient 2: CT: right parietal IgG; Lupus anticoagulant: positive
[London, United 53 [F] Patient 2: 24 days incoordination cortical and left cerebellar Patient 2: Lupus anticoagulant: positive
Kingdom] Patient 3: after cough, Patient 3: Dysarthria, right facial infract Patient 3: Lupus anticoagulant: negative
85 [M] dyspnea, fever droop and weakness Patient 3:CT: thrombus in left Patient 4: Lupus anticoagulant: positive
Patient: Patient 3: 10 days Patient: 4: Dysarthria, left facial posterior cerebral artery Patient 5: Lupus anticoagulant: positive
4: 61 [M] after cough droop and weakness Patient: 4: MRI: infraction in Patient 6: Lupus anticoagulant: positive
Patient 5: Patient: 4: nil prior Patient 5: Dysarthria, left facial right corpus striatum
83 [M] symptoms droop, weakness and Patient 5: CT angiogram:
Patient 6: Patient 5: 15 days sensory inattention thrombotic occlusionof right
73 [M] after fever, cough, Patient 6: Aphasia, right facial middle cerebral artery
dyspnea droop, right-sided weakness Patient 6: MRI: infraction in
Patient 6: 8 days right thalamus, left pons,
after dyspnea and right occipital lobe and right
tachypnea cerebellar hemisphere
Helms et al. (37) 3 [All ischemic] NR [NR] NR Asymptomatic MRI: two patients had a small NR NR
(Correspondence) acute ischemic stroke; one
[Strasbourg, patient had a subacute
France] ischemic stroke
Oxley et al. (47) 5 [All ischemic] Patient 1: Patient 1: one week Patient 1: dysarthria, numbness and Patient 1: CT angiogram: partial Patient 1: Platelet count: 427,000/mm^3 Patient 1: discharged to
(Correspondence) 33 [F] after cough, weakness in left limbs infraction of right middle PT: 13.3 seconds; aPTT: 25.0 seconds rehabilitation facility
[New York City, Patient 2: headache, and chills Patient 2: dysphasia, right cerebral artery Fibrinogen: 501 mg/dL; D-dimer: Patient 2: discharged
United States] 37 [M] Patient 2: no prior hemiplegia, dysarthria, sensory Patient 2: CT angiogram: 460 ng/ml home
Patient 3: symptoms deficit infarction in the territory of Patient 2: Platelet count: 299,000/ Patient 3: admitted to
39 [M] Patient 3: no prior Patient 3: left homonymous the left middle cerebral artery mm^3 Intensive Care Unit for
Patient 4: symptoms hemianopia, left hemiplegia, Patient 3: CT angiogram: PT: 13.4 seconds; aPTT: 42.7 seconds multiorgan failure and
44 [M] Patient 4: two hours ataxia infarction in the territory of Fibrinogen: 370 mg/dL; D-dimer: 52 ng/ respiratory failure
Patient 5: after onset of Patient 4: global dysphasia, right the right posterior cerebral ml Patient 4: admitted to
49 [M] lethargy hemiplegia, gaze preference artery Patient 3: Platelet count: 135,000/ stroke unit
Patient 5: eight Patient 5: left hemiplegia, Patient 4: CT angiogram: mm^3 Patient 5: discharge to
hours after fever, dysarthria, facial weakness infarction in the territory of PT: 14.4 seconds; aPTT: 27.7 seconds rehabilitation facility
cough and lethargy left middle cerebral artery Fibrinogen: 739 mg/dL; D-dimer:
Patient 5: CT angiogram: 2230 ng/ml
infarction in the territory of Patient 4: Platelet count: 372,000/
right middle cerebral artery mm^3
PT: 12.8 seconds; aPTT: 26.9 seconds
Fibrinogen: 443 mg/dL; D-dimer:
13800 ng/ml
Patient 5: Platelet count: 255,000/
mm^3
PT: 15.1 seconds; aPTT: 37.0 seconds
Fibrinogen: 531 mg/dL; D-dimer:
1750 ng/ml
(Continued)
Table 4. (Continued).
Study Number of
(Study type) patients Age (years)
[City, country] [Type of stroke] [Sex] Onset Neurological Symptoms/Signs Imaging findings Relevant blood findings Outcome
Zhang et al. (48) 3 [All ischemic] Patient 1: Patient 1: 18 days after NR Patient 1: CT: Infarctions in Patient 1: Platelet count: 78,000/mm^3 NR
(Correspondence) 69 [M] fever, cough, bilateral frontal parietal PT: 17.0 seconds; aPTT: 43.7 seconds
[Beijing, China] Patient 2: dyspnea, diarrhea, occipital lobe, basal ganglia, Fibrinogen: 4.15 g/L; D-dimer: >
65 [F] headache brain 21.0 mg/L
Patient 3: Patient 2: 33 days stem, cerebellar hemispheres Patient 2: Platelet count: 79,000/mm^3
70 [M] after fever, cough, Patient 2: CT: Infarctions in PT: 17.2 seconds; aPTT: 45.3 seconds
dyspnea right frontal and bilateral Fibrinogen: 4.42 g/L; D-dimer: 2.84 mg/
Patient 3: 10 days parietal lobe L
after fever, fatigue, Patient 3: CT: Infarctions in Patient 3: Platelet count: 180,000/
dyspnea, headache frontal lobe, right frontal mm^3
parietal temporal occipital PT: 15.1 seconds; aPTT: 47.6 seconds
lobe, and bilateral Fibrinogen: 6.42 g/L; D-dimer: 3.23 mg/
cerebellar hemispheres L
Anticardiolipin IgA, anti–
β2-glycoprotein I IgA and IgG present in
all three patients; lupus anti-coagulant
was not detected in any patients
BRAIN INJURY
1561
 1562

Table 5. Seizure; NR, not reported; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; CT, computed tomography; EEG, electro-encephalography ICU, intensive care unit; GCS, Glasgow coma scale; M, male; F, female.
T. H. CHUA ET AL.

Study Number Age

(Study type) of (years)
[City, country] patients [Sex] Onset Neurological Symptoms/Signs Imaging/physiological/blood findings CSF Outcome
Mao et al. (8) 1 (0.5%) NR [NR] NR Limb twitching, foaming in the mouth, NR NR
(Retrospective) loss of consciousness
[Wuhan,
China]
NR
Karimi et al. (49) 1 30 [F] Five days after cough; three New-onset generalized tonic-clonic seizures Brain MRI: normal Normal protein, Fever and seizure
(Case report) days after fever and glucose controlled after one
[Sari, Iran] fatigue Five cell counts (all week
lymphocytes)
Negative PCR for
COVID-19
Moriguchi et al. 1 24 [M] One week after fever, fatigue Altered consciousness and transient generalized seizure Brain MRI: hyperintensity along the Pressure: more than Impaired consciousness
(28) and headache Examination: GCS 6 (E4 V1 M1); neck stiffness wall of inferior horn of right lateral 320 mmH2O; on day 15
(Case report) ventricle; 10 mononuclear
[Yamanashi, cells, 2
Japan] polymorphonuclear
cells
Positive PCR for
COVID-19
Sohal et al. (50) 1 72 [M] Three days after admission Tonic-clonic movements of four limbs Head CT: no acute infarcts or NR Died on day 5 of
(Case report) for hypoglycemia and hemorrhage admission
[Brooklyn, respiratory failure EEG: six left temporal seizures and
United States] left temporal sharp waves which
were epileptogenic
Zanin et al. (22) 1 54 [F] Several days after anosmia Loss of consciousness EEG: two seizures originating from the Normal; negative PCR Transferred to
(Case report) and ageusia Examination: GCS 12 (E3, M6, V3); nil sensorimotor deficits right frontotemporal region for COVID-19 Rehabilitation on
[Brescia, Italy] Brain MRI: alteration of day12 of
periventricular white matter, hospitalization
hyperintensity in T2WI
Bernard-Valnet 1 64 [F] Five days after mild asthenia, Tonic-clonic seizure; disorientation, attention deficit, verbal Brain MRI: normal Proteins: 466 mg/L Resolution of symptoms
et al. (34) myalgia, cough and motor perservations, bilateral grasping; alternating EEG: non-convulsive, focal status Cells: 17/mm^3 after 4 days
(Letter to the with psychotic symptoms epilepticus (97% lymphocytes)
Editors) Negative PCR assay
[Lausanne, for COVID-19
Switzerland]
Table 6. Olfactory and gustatory dysfunction; NR, reported; SD, standard deviation; IQR, interquartile range; M, male; F, female.
Study Age Neurological
(Study type) (years) Symptoms
[City, country] Number of patients [Sex] Determination of disorder Onset /Signs Imaging findings CSF findings Outcome
Lechien et al. (52) Olfactory dysfunction: NR [NR] sQOD-NS questionnaire 11.8% appeared before initial Anosmia: 284 NR NR Olfactory: 72.6% recovered within 8 days
(Prospective) 357 (85.6%) Smell and taste component of symptoms; (79.6%) following resolution of disease
[Belgium; France; Gustatory the National Health and 65.4% after initial symptoms Hyposmia (73 Gustatory: NR
Spain; Italy] dysfunction: 342 Nutrition Examination Survey 22.8% occurred concurrently (20.4%)
(88.8%) with initial symptoms Phatosmia:
12.6%
Parosmia:
32.4%
Ageusia/
hypogeusia:
78.9%
Dysgeusia:
21.1%
Luers et al. (53) Olfactory dysfunction: NR [NR] Standardized two-section Olfactory dysfunction occurred Olfactory NR NR NR
(Prospective) 53 (74.0%) questionnaire 3.56 ± 3.07 days following dysfunction:
[Cologne, Gustatory initial symptoms; 53 (74.0%)
Germany] dysfunction: 50 Gustatory dysfunction Gustatory
(69.0%) occurred 3.38 ± 3.06 days dysfunction:
Both: 49 (68.0%) following initial symptoms 50 (69.0%)
Both: 49
(68.0%)
Mao et al. (8) Olfactory dysfunction: NR Self-reported NR Olfactory NR NR NR
(Retrospective) 11 (5.1%) dysfunction:
[Wuhan, China] Gustatory 11 (5.1%)
dysfunction: 12 Gustatory
(5.6%) dysfunction:
12 (5.6%)
Beltran-Corbellini Olfactory and/or Mean: 52.6 Unspecified questionnaire Presenting symptoms: 11 Anosmia: 14 NR NR 12 (40.0%) patients reported complete
et al. (54) gustatory (SD: 17) (35.5%) (45.7%) recovery after 7.4 ± 2.3 days, and 5
(Case-control) dysfunction: 31 [19 M Acute: 21 (67.7%) Hyposmia: 9 (16.7%) partial recovery after
[Madrid, Spain] (39.2%) (61.9%)] Subacute: 10 (32.3%) (29.0%) 9.1 ± 3.6 days.
Dysomia: 2
(6.5%)
Ageusia: 14
(45.2%)
Hypogeusia: 7
(22.6%)
Dysgeusia: 8
(25.8%)
Giacomelli et al. (55) Olfactory and/or 56 (IQR Unspecified questionnaire 12 (20.3%) had symptoms Anosmia: 0 NR NR NR
(Cross-sectional) gustatory 47–60) before admission; Hyposmia: 3
[Milan, Itlay] dysfunction: 20 [NR] 8 (13.5%) experienced (5.1%)
(33.9%) during hospitalization Ageusia: 1
(1.7%)
Dysgeusia: 5
(8.5%)
Mixed taste
BRAIN INJURY

and olfactory
disorders: 11
(18.7%)
(Continued)
1563
 1564

Table 6. (Continued).
Study Age Neurological
(Study type) (years) Symptoms
[City, country] Number of patients [Sex] Determination of disorder Onset /Signs Imaging findings CSF findings Outcome
T. H. CHUA ET AL.

Gilani et al. (56) Olfactory dysfunction: 5 Mean: 39 Self-reported Presenting symptoms of Covid- Anosmia in all NR NR NR
(Case series) (SD: 2.9) 19: 2 (40.0%) patients
[Tehran, Iran] [2 M 2–4 days after initial
(40%)] symptoms: 3 (60.0%)
Gutiérrez-Ortiz et al. Olfactory and gustatory Patient Self-reported Patient 1 – five days after Patient 1: Patient 1: Patient 1: Patient 1:
(19) dysfunction: 1 1–50 development of cough, anosmia and Positive to Protein: anosmia and ageusia persisted
(Case report) Gustatory [M] malaise, headache, low back ageusia anti- 80 mg/dL Patient 2: Complete neurological
[Madrid, Spain] dysfunction: 1 Patient pain and fever Patient 2: gangliosides Negative recovery after two weeks
2–39 Patient 2- three days after ageusia antibody PCR for
[M] development of fever, GD1b-IgG COVID-19
diarrhea Patient 2: Patient 2:
Head CT: Protein:
normal 62 mg/dL
White
blood cell
count: 2 (all
monocytes)
Negative
PCR for
COVID-19
Ottaviano et al. (57) Olfactory dysfunction: 6 NR Olfactory test “Le Nez du Vin”; Two patients had olfactory loss Anosmia/ NR NR All but one patient complained of
(Letter to the [NR] Sino-nasal Outcome Test-22; one day after myalgia onset hyposmia/ hyposmia and hypogeusia after
Editors) Visual analog scale for smell ageusia/ 15 days
[Padova, Italy] and taste hypogeusia: 6
(100%)
Eliezer et al. (58) Olfactory dysfunction: 1 40+ [F] 5 odorants A few days after development Anosmia NR NR NR
(Letter to the of dry cough
Editors)
[Paris, France]
Passali et al. (59) Olfactory dysfunction: NR [NR] NR NR NR NR NR NR
(Letter to the 25–30% (total
Editors) number of patients
[Rome, Italy] not reported)
Mermelstein et al. Olfactory and/or 27 [NR] Self-reported Six days after development of Anosmia and NR NR Partial recovery at 7–13 days
(60) gustatory cough, sore throat, running hypogeusia
(Correspondence) dysfunction: 1 nose, headache
[Rio, Brazil]
Vaira et al. (61) Olfactory and/or NR [NR] History and physical examination NR Anosmia and/or NR NR NR
(Correspondence) gustatory ageusia
[Sassari, Italy] dysfunction: 62
(19.4%)

artery ischemic strokes (9). However, the prevalence of these
neurological complications in SARS is unknown. In MERS-
CoV2, three patients were reported to have developed hyper­
intense lesions in the white matter and subcortical areas of the
brain (62), and 4 (17.4%) out of 23 patients had developed
neurological complications including encephalitis and GBS
two to 3 weeks after onset of respiratory symptoms (10). As
COVID-19 shares highly similar genetic sequences with the
SARS-CoV (63), it is plausible that neurological complications
can also occur in COVID-19.
Two retrospective studies have provided insight into the
typical demographics of COVID-19: Guan et al. (64) in
a retrospective study of 1590 patients reported a mean age of
48.9 ± 16.3 years, with 57.3% males in China; whilst Lechien
et al. (65) reported a mean age of 39.2 ± 12.1 years, with 32.3%
males amongst 1420 patients in Europe. In contrast, our data
suggest that patients with neurological complications were
much older and were more likely to be male compared to
COVID-19 patients without neurological complications. Age
is a risk factor for more severe COVID-19 (66). Neurological
complications occurred more commonly in those with severe
infections (8). Furthermore, as age by itself is the strongest risk
factor for stroke; the high proportion of stroke reported as
a neurological complication in our series could have also dri­
ven this age difference observed in patients with neurological
complications when compared with patients without neurolo­
gical complications. Hence, there may potentially be an asso­
ciation amongst age, sex, severity of COVID-19, and
development of neurological disease.
In our pooled analysis, olfactory dysfunction was a common
complaint in COVID-19. However, most existing studies have
ascertained olfactory dysfunction only through questionnaires
rather than using more objective measures of smell, such as the
University of Pennsylvania Smell Identification Test (UPSIT).
Further large-scale studies using objective measures of olfac­
tory function will be necessary to clarify the nature and severity
of olfactory dysfunction in COVID-19. Anosmia had also been
reported in SARS-CoV (67), with animal studies demonstrat­
ing that the SARS-CoV virus enters the brain primarily via the
olfactory bulb (66). In COVID-19, the ACE2 receptor has been
implicated in virus entry into neurological tissue (63,68) with
entry of COVID-19 virus via the cribriform plate close to the
olfactory bulb suggested as a possible mechanism (68). As such,
invasion of COVID-19 near or in the olfactory bulb may
potentially be linked to the development of anosmia in these
patients.
GBS and variants are associated with a variety of viruses and
have been estimated to occur in 1.2% of Zika virus patients (69)
and 5.5–13.7% of Influenza patients (70). GBS and variants
were previously reported in three patients with SARS-CoV (9)
and one MERS-CoV patient (10). The development of GBS and
its variants is thought to be linked to molecular mimicry and
a cross-reactive immune response (71). Thus, COVID-19 may
similarly trigger a cross-reactive immune response, leading to
the development of GBS and variants (72). Higher inflamma­
tory biomarkers including C-reactive protein, procalcitonin
and inflammatory cytokines; and reduced CD4 + T cells num­
bers have been reported in COVID-19, which may contribute
BRAIN INJURY 1565
to immune dysregulation and the development of GBS and its
variants. These hypotheses warrant further research.
In meningoencephalitis, COVID-19 was detected in the CSF
of one patient but not in the remaining 11 tested. However, it is
not implausible for COVID-19 to directly infect the central
nervous system, due to breakdown of blood–brain barrier from
the interaction of COVID-19 with ACE2 receptors found in the
nervous system (73). Additionally, hypoxic injury and viremia
implicated in COVID-19 may also contribute to toxic ence­
phalopathy (73). With that said, encephalopathy secondary to
severe illness, organ failure and metabolic derangements
remain part of the differential diagnoses of meningoencepha­
litis that may be difficult to disentangle in a severely ill patient.
We have identified 37 patients (with age reported) who
presented with stroke, of which 15 (40.5%) were under the
age of 65 years; and 16.2% occurred below the age of
40 years. The proportion of strokes occurring below the age
of 65 in COVID-19 is higher than the reported 34.0% in the
general population (74). 32.6% of these patients had a prior
history of COVID-19 symptoms before presenting with stroke
symptoms while 13.0% did not have prior symptoms; 6.5%
were asymptomatic and 47.8% of patients did not have their
presenting symptoms reported. COVID-19 is associated with
a coagulopathy, that has been suggested to result in thromboin­
flammation and thrombosis (75). Deep vein thrombosis was
found in seven out of 12 patients (58.0%) and pulmonary
embolism was identified as the cause of mortality in four
(33.0%) patients in an autopsy series of 12 COVID-19 patients
(76). However, these complications could also result from
severe illness and immobility. In a small series of 9 patients,
88.9% were found to be positive for the antiphospholipid anti­
bodies (46,48), which may raise the possibility that COVID-19
is a prothrombotic state. However, a significant proportion
(66.7%) of patients in this series had prior history of stroke
and ischemic heart disease (46,48), and may already be at an
increased risk of cerebrovascular disease. Not all studies have
identified positive antiphospholipid antibodies in COVID-19
(77). The significance of positive antiphospholipid antibodies
in COVID-19 remains debatable as COVID-19 is a pro-
inflammatory state and transient elevations of antiphospholi­
pid antibodies can occur during acute infection, with recent
recommendations suggesting that antiphospholipid antibody
testing should not be routinely carried out in the context of
COVID-19 (77). Current evidence suggests that in addition to
the older COVID-19 patients, younger patients with COVID-
19 may also present more frequently with stroke, when com­
pared to the population baseline risk of stroke. It may also be
possible that COVID-19 by itself is a risk factor for developing
stroke, in both older and younger patients. With such baseline
risk in the population and high mortality rate, further research
is warranted in this area.
CSF yielded abnormal results in more than half the patients
in our series, however, the yield of COVID-19 PCR testing in
CSF is low. Only approximately half of the CSF samples were
abnormal for patients with GBS and variants, and MEEM.
Elevated protein in the presence of normal cell counts were
seen in 77.8% of abnormal CSF samples in GBS and variants,
whilst this finding was detected in 25.0% of the group of
1566 T. H. CHUA ET AL.
patients with MEEM. Half of patients with MEEM had elevated
cell count on CSF. In a series of five patients with unspecified
neurological symptoms with cortical signal abnormalities iden­
tified on brain imaging, four (80.0%) of five CSF samples had
an elevated total protein with normal cell count (78). Our
findings suggest that the yield of CSF testing for COVID-19
infection is low with only one (3.8%) out of 26 CSF samples
performed in our series testing positive. It has been suggested
that viral invasion of the neurological system may occur before
that of the respiratory system; with the peak of viral load
occurring during the asymptomatic phase, which decreases as
the respiratory and neurological complications manifest clini­
cally (79), and could account for the low yield of COVID-19
PCR testing in CSF. Thus, current evidence seems to suggest
that CSF PCR analysis for COVID-19 is low yield.
This study has several limitations. It comprised of studies that
are of poor quality and heterogeneous. Even after pooled analysis
was performed, the sample size is not sizable. Many studies had
incomplete neurological investigations performed. There was
incomplete data with regards to follow-up and long-term neu­
rological prognosis. However, as this is a rapidly evolving field,
there were few, if any large systematic prospective studies to
study the neurological complications of COVID-19. To the best
of our knowledge, at the time of writing, this study is the first
study to comprehensively describe the clinical characteristics of
the distinct neurological entities in COVID-19.
Conclusion
In COVID-19, stroke is the most reported neurological man­
ifestation, with mortality in 25.6%, although the number of
reported cases at present remains small. Other neurological
manifestations such as GBS and variants, MEEM remain rare,
but similarly appear to develop approximately one to two
weeks after the onset of COVID-19 respiratory disease, which
further supports the current notion that there is an association
between COVID-19 and neurological manifestations.
Olfactory and gustatory dysfunction appears to be common
in COVID-19 patients, but objective olfactory testing and long-
term follow up will be needed to determine its clinical signifi­
cance. Given that neurological manifestations is common in
COVID-19, and is associated with significant morbidity and
mortality. Greater awareness of these manifestations is needed.
Declaration of interests
The authors report no conflict of interest.
Data availability statement
The data supporting the findings of this study are available within the
article.
Funding
This research did not receive any specific grant from funding agencies in
the public, commercial, or not-for-profit sectors.
ORCID
Tzy Harn Chua http://orcid.org/0000-0001-6250-2004
References
1. World Health Organization. Rolling updates on coronavirus dis­
ease (COVID-19). Geneva (Switzerland); 2020 May 15 [accessed
2020 May 16]. https://www.who.int/emergencies/diseases/novel-
coronavirus-2019/events-as-they-happen.
2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B,
Shi W, Lu R, et al. A novel coronavirus from patients with pneu­
monia in China, 2019. N Engl J Med. 2020;382:727–33.
3. Johns Hopkins University. COVID-19 dashboard. Baltimore
(MD); 2020 July 14 [accessed 2020 July 14]. https://coronavirus.
jhu.edu/map.html.
4. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H,
Lei CL, Hui DSC, et al. Clinical characteristics of coronavirus
disease 2019 in China. N Engl J Med. 2020;382:1708–20.
5. Wadman M, Couzin-Frankel J, Kaiser J, Matacic C. A rampage
through the body. Science. 2020;368(6489):356–60.
6. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR,
Zhu Y, Li B, Huang CL, et al. A pneumonia outbreak associated
with a new coronavirus of probable bat origin. Nature.
2020;579:270–73.
7. Daou BJ, Koduri S, Palmateer G, Thompmson BG, Chaudhary N,
Gemmete JJ, Pandey AS. Letter: neurological implications of
COVID-19 and lessons learned from prior epidemics and
pandemics. Neurosurgery. 2020;87:E234–E238. doi:10.1093/neu­
ros/nyaa186.
8. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C,
Zhou Y, Wang D, et al. Neurologic manifestations of hospitalized
patients with coronavirus disease 2019 in Wuhan, China. JAMA
Neurol. 2020;77:683.
9. Tsai LK, Hsieh ST, Chang YC. Neurological manifestations in
severe acute respiratory syndrome. Acta Neurol Taiwan. 2005;14
(3):113–19.
10. Kim JE, Heo JH, Kim HO, Song SH, Park SS, Park TH, Ahn JY,
Kim MK, Choi JP. Neurological complications during treatment of
Middle East respiratory syndrome. J Clin Neurol. 2017;13
(3):227–33. doi:10.3988/jcn.2017.13.3.227.
11. Herman C, Mayer K, Sarwal A. 2020. Scoping review of prevalence
of neurologic comorbidities in patients hospitalized for
COVID-19. Neurology. 95(2):77–84. doi:10.1212/
wnl.0000000000009673.
12. Asadi-Pooya AA, Simani L. Central nervous system manifestations
of COVID-19: a systematic review. J Neurol Sci. 2020;413:116832.
doi:10.1016/j.jns.2020.116832.
13. Wilson MP, Jack AS. Central nervous system manifestations of
COVID-19: a systematic review. Clin Neurol Neurosurg.
2020;193:105866. doi:10.1016/j.clineuro.2020.105866.
14. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A,
Petticrew M, Shekelle P, LA S; PRISMA-P Group. Preferred report­
ing items for systematic review and meta-analysis protocols
(PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.
15. Dinkin M, Gao V, Kahan J, Bobker S, Simonetto M, Wechslert P,
Harpe J, Greer C, Mints G, Salam G, et al. COVID-19 presenting
with ophthalmoparesis from cranial nerve palsy. Neurology. 2020.
doi:10.1212/WNL.0000000000009700.
16. Alberti P, Beretta S, Piatti M, Karantzoulis A, Piatti ML, Santoro P,
Vigano M, Giovannelli G, Pirro F, Montisano DA, et al. Guillain-
Barré syndrome related to COVID-19 infection. Neurol
Neuroimmunol Neuroinflamm. 2020;7:e741.
17. Camdessanche JP, Morel J, Pozzetto B, Paul S, Tholance Y,
Botelho-Nevers E. COVID-19 may induce Guillain-Barré syn­
drome. Rev Neurol (Paris). 2020. doi:10.1016/j.neurol.2020.04.003.
18. El Otmani H, El Moutawakil B, Rafai MA, El Benna N, El
Kettani C, Soussi M, El Mdaghri N, Barrou H, Afif H. Covid-19
and Guillain-Barré syndrome: more than a coincidence! Rev
Neurol (Paris). 2020;176:518–19. doi:10.1016/j.neurol.2020.04.007.

19. Gutierrez-Ortiz C, Mendez A, Rodrigo-Rey S, Pedro-Murillo ES,
Bermejo-Guerrero L, Gordo-Manas R, de Aragon-gomez G, Miller
Fisher B-LJ. Syndrome and polyneuritis cranialis in COVID-19.
Neurology. 2020;95:e601–e605. doi:10.1212/
WNL.0000000000009619.
20. Sedaghat Z, Karimi N. Guillain Barre syndrome associated with
COVID-19 infection: a case report. J Clin Neurosci. 2020;76:233-35. .
21. Virani A, Rabold E, Hanson T, Haag A, Elrufay R, Cheema T,
Balaan M, Guillain-Barre BN. Syndrome associated with
SARS-CoV-2 infection. IDCases. 2020;20:e00771. doi:10.1016/j.
idcr.2020.e00771.
22. Zanin L, Saraceno G, Panciani PP, Renisi G, Signorini L,
Migliorati K, Fontanella MM. 2020. SARS-CoV-2 can induce
brain and spine demyelinating lesions. Acta Neurochir (Wien).
162(7):1491–94. doi:10.1007/s00701-020-04374-x.
23. Coen M, Jeanson G, Almeida LAC, Hubers A, Stierlin F, Najjar I,
Ongaro M, Moulin K, Makrygianni M, Leemann B, et al. Guillain-
Barré syndrome as a complication of SARS-CoV-2 infection. Brain
Behav Immun. 2020. doi:10.1016/j.bbi.2020.04.074.
24. Padroni M, Mastrangelo V, Asioli GM, Pavolucci L, Abu-Rumeileh
S, Piscaglia MG, Querzani P, Callegarini C, Foschi M. Guillain-Barré
syndrome following COVID-19: new infection, old complication?
J Neurol. 2020;1–3. doi:10.1007/s00415-020-09849-6.
25. Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P,
Cuzzoni MG, Franciotta D, Baldanti F, Daturi R, Postorino P,
et al. Guillain-Barre syndrome associated with SARS-CoV-2.
N Engl J Med. 2020;382:2574–76.
26. Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-Barré syndrome
associated with SARS-CoV-2 infection: causality or coincidence?
Lancet Neurol. 2020;19(5):383–84. doi:10.1016/S1474-4422(20)
30109-5.
27. Filatov A, Sharma P, Hindi F, Espinosa PS. Neurological complica­
tions of coronavirus disease (COVID-19): encephalopathy. Cureus.
2020;12:e7352.
28. Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J,
Ueno M, Sakata H, Kondo K, Myose N, et al. A first case of
meningitis/encephalitis associated with SARS-Coronavirus-2.
Int J Infect Dis. 2020;94:55–58.
29. Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J,
Lednicky J, Sordillo EM, Fowkes M. Central nervous system invol­
vement by severe acute respiratory syndrome coronavirus −2
(SARS-CoV-2). J Med Virol. 2020. doi:10.1002/jmv.25915.
30. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B.
COVID-19-associated acute hemorrhagic necrotizing encephalo­
pathy: CT and MRI features. Radiology. 2020;201187. doi:10.1148/
radiol.2020201187.
31. Yin R, Feng W, Wang T, Chen G, Wu T, Chen D, Lv T, Xiang D.
2020. Concomitant neurological symptoms observed in a patient
diagnosed with coronavirus disease 2019. J Med Virol. 92
(10):1782–84. doi:10.1002/jmv.25888.
32. Wong PF, Craik S, Newman P, Makan A, Srinivasan K,
Crwaford E, Dev D, Moudgil H, Ahmad N. Lessons of the month
1: a case of rhombencephalitis as a rare complication of acute
COVID-19 infection. Clin Med. 2020;20:293–94. doi:10.7861/
clinmed.2020-0182.
33. Zhao K, Huang J, Dai D, Feng Y, Liu L, Nie S. Acute myelitis after
SARS-CoV-2 infection: a case report. medRxiv. 2020. doi:10.1101/
2020.03.16.20035105.
34. Bernard-Valnet R, Pizzarotti B, Anichini A, Demars Y, Russo E,
Schmidhauser M, Cerutti-Sola J, Rosetti AO, Du Pasquier R. Two
patients with acute meningo-encephalitis concomitant to
SARS-CoV-2 infection. Eur J Neurol. 2020;27. doi:10.1111/
ene.14298.
35. Duong L, Xu P, Liu A. Meningoencephalitis without respiratory
failure in a young female patient with COVID-19 infection in
Downtown Los Angeles, early April 2020. Brain Behav Immun.
2020;87:33. doi:10.1016/j.bbi.2020.04.024.
36. Ye M, Ren Y, Lv T. Encephalitis as a clinical manifestation of
COVID-19. Brain Behav Immun. 2020;88:945–46. doi:10.1016/j.
bbi.2020.04.017.
BRAIN INJURY 1567
37. Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M,
Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana M,
et al. Neurologic features in severe SARS-CoV-2 infection. N Engl
J Med. 2020;382(23):2268–70. doi:10.1056/NEJMc2008597.
38. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J,
Liu Y, Wei Y, et al. Epidemiological and clinical characteristics of
99 cases of 2019 novel coronavirus pneumonia in Wuhan, China:
a descriptive study. Lancet. 2020;395(10223):507–13. doi:10.1016/
S0140-6736(20)30211-7.
39. Li Y, Wang M, Zhou Y, Chang J, Xian Y, Wang D, Mao L, Jin H,
Hu B. Acute cerebrovascular disease following COVID-19: a single
center, retrospective, observational study. SSRN Electron J. 2020.
doi:10.2139/ssrn.3550025.
40. Al Saiegh F, Ghosh R, Leibold A, Avery MB, Schmidt RF,
Theofanis T, Mouchtouris N, Philipp L, Peiper SC, Wang ZX,
et al. Status of SARS-CoV-2 in cerebrospinal fluid of patients
with COVID-19 and stroke. J Neurol Neurosurg Psychiatry.
2020;91:846–48.
41. Avula A, Nalleballe K, Narula N, Sapozhnikov S, Dandu V, Toom S,
Glaser A, Elsayegh D. COVID-19 presenting as stroke. Brain Behav
Immun. 2020;87:115–19. doi:10.1016/j.bbi.2020.04.077.
42. González-Pinto T, Luna-Rodríguez A, Moreno-Estébanez A,
Agirre-Beitia G, Rodriguez-Antiguedad A, Emergency
Room R-LM. Neurology in times of COVID-19: malignant
ischemic stroke and SARS-COV2 infection. Eur J Neurol.
2020;27. doi:10.1111/ene.14286.
43. Moshayedi P, Ryan TE, Mejia LLP, Nour M, Liebeskind DS. Triage
of acute ischemic stroke in confirmed COVID-19: large vessel
occlusion associated with coronavirus infection. Front Neurol.
2020;11:353. doi:10.3389/fneur.2020.00353.
44. Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracer­
ebral haemorrhage: causative or coincidental? New Microbes New
Infect. 2020;35:100669. doi:10.1016/j.nmni.2020.100669.
45. Zhai P, Ding Y, Li Y. The impact of COVID-19 on ischemic stroke:
a case report. Res Square Preprint Server. 2020. doi:10.21203/rs.3.
rs-20393/v1.
46. Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF,
Goh YY, Humphries F, Jager HR, Losseff NA, Perry RJ, et al.
Characteristics of ischaemic stroke associated with COVID-19.
J Neurol Neurosurg Psychiatry. 2020;91:889–91.
47. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, De
Leacy RA, Shigematsu T, Ladner TR, Yaeger KA, et al. Large-vessel
stroke as a presenting feature of COVID-19 in the young. N Engl
J Med. 2020;382:e60.
48. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H,
Ding X, Zhao H, Zhang H, et al. Coagulopathy and antiphospho­
lipid antibodies in patients with COVID-19. N Engl J Med.
2020;382:e38.
49. Karimi N, Razavi A, Rouhani N. Frequent convulsive seizures in an
adult patient with COVID-19: a case report. Iran Red Crescent
Med J. 2020;e102828. doi:10.5812/ircmj.102828.
50. Sohal S, Mossammat M. COVID-19 presenting with seizures.
IDCases. 2020;20:e00782. doi:10.1016/j.idcr.2020.e00782.
51. Lu L, Xiong W, Liu D, Liu J, Yang D, Li N, Mu J, Guo J, Li W,
Wang G, et al. New onset acute symptomatic seizure and risk
factors in coronavirus disease 2019: a retrospective multicenter
study. Epilepsia. 2020;61. doi:10.1111/epi.16524.
52. Lechien JR, Chiesa-Estomba CM, De Siati DR, Horoi M, Le
Bon SD, Rodriguez A, Dequanter D, Blecic S, El Afia F,
Distinguin L, et al. Olfactory and gustatory dysfunctions as
a clinical presentation of mild-to-moderate forms of the corona­
virus disease (COVID-19): a multicenter European study. Eur Arch
Oto-Rhino-L. 2020:1–11. doi:10.1007/s00405-020-05965-1.
53. Luers JC, Rokohl AC, Loreck N, Matos PAW, Augustin M,
Dewald F, Klein F, Lehmann C, Heindl LM. Olfactory and gusta­
tory dysfunction in coronavirus disease 19 (COVID-19). Clin
Infect Dis. 2020. doi:10.1093/cid/ciaa525.
54. Beltrán-Corbellini Á, JL C-G, Martínez-Poles J, Rodriguez-Jorge F,
Vatera-Villalba E, Gomez-Corral J, Gomez-Lopez A, Monreal E,
Parra-Diaz P, JL C-C, et al. Acute-onset smell and taste disorders in
1568 T. H. CHUA ET AL.
the context of Covid-19: a pilot multicenter PCR-based
case-control study. Eur J Neurol. 2020. doi:10.1111/ene.14273.
55. Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L,
Rusconi S, Gervasoni C, Ridolfo AL, Rizzardini G, et al. Self-
reported olfactory and taste disorders in SARS-CoV-2 patients: a
cross-sectional study. Clin Infect Dis. 2020;71:889–90.
56. Gilani S, Roditi R, Naraghi M. COVID-19 and anosmia in Tehran,
Iran. Med Hypotheses. 2020;141:109757. doi:10.1016/j.
mehy.2020.109757.
57. Ottaviano G, Carecchio M, Scarpa B, Marchese-Ragona R.
Olfactory and rhinological evaluations in SARS-CoV-2 patients
complaining of olfactory loss. Rhinology. 2020. doi:10.4193/
Rhin20.136.
58. Eliezer M, Hautefort C, Hamel AL, Verillaud B, Herman P,
Houdart E, Sudden EC. Complete olfactory loss function as
a possible symptom of COVID-19. JAMA Otolaryngol Head
Neck Surg. 2020. doi:10.1001/jamaoto.2020.0832.
59. Passali GC, Bentivoglio AR. Comment to the article “olfactory and
gustatory dysfunctions as a clinical presentation of mild-to-
moderate forms of the coronavirus disease (COVID-19):
a multicenter European study”. Eur Arch Oto-Rhino-L.
2020;277:2391–92. doi:10.1007/s00405-020-06024-5.
60. Mermelstein S. Acute anosmia from COVID-19 infection. Pract
Neurol. 2020;20:343–44. doi:10.1136/practneurol-2020-002583.
61. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and ageusia:
common findings in COVID-19 patients. Laryngoscope. 2020.
doi:10.1002/lary.28692.
62. Arabi YM, Harthi A, Hussein J, Bouchama A, Johani S, Hajeer AH,
Saeed BT, Wahbi A, Saedy A, AlDabbagh T, et al. Severe neurologic
syndrome associated with Middle East respiratory syndrome cor­
ona virus (MERS-CoV). Infection. 2015;43:495–501.
63. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of
SARS-CoV2 may play a role in the respiratory failure of
COVID-19 patients. J Med Virol. 2020. doi:10.1002/jmv.25728.
64. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, Liu XQ,
Chen RC, Tang CL, Wang T, et al. Comorbidity and its impact on
1590 patients with COVID-19 in China: a nationwide analysis. Eur
Respir J. 2020;55:2000547.
65. Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y,
Cabaraux P, Mat Q, Huet K, Plzak J, Horoi M, Hans S, et al.
Clinical and epidemiological characteristics of 1,420 European
patients with mild-to-moderate coronavirus disease 2019.
J Intern Med. 2020;288:335–44.
66. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe
acute respiratory syndrome coronavirus infection causes neuronal
death in the absence of encephalitis in mice transgenic for human
ACE2. J Virol. 2008;82:7264–75. doi:10.1128/JVI.00737-08.
67. Hwang CS. Olfactory neuropathy in severe acute respiratory syn­
drome: report of a case. Acta Neurol Taiwan. 2006;15(1):26–28.
68. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the
COVID-19 virus targeting the CNS: tissue distribution,
host-virus interaction, and proposed neurotropic
mechanisms. ACS Chem Neurosci. 2020;11(7):995–98.
doi:10.1021/acschemneuro.0c00122.
69. Barbi L, Coelho AVC, de Alencar LCA, Crovella S. Prevalence of
Guillain-Barre syndrome among Zika virus infected cases:
a systematic review and meta-analysis. Braz J Infect Dis. 2018;22
(2):137–41. doi:10.1016/j.bjid.2018.02.005.
70. Sivadon-Tardy V, Orlikowski D, Porcher R, Sharshar T,
Durand MC, Enouf V, Rozenberg F, Caudie C, Annane D,
Ven der Werf S, et al. Guillain-Barre syndrome and influenza
virus infection. Clin Infect Dis. 2009;48(1):48–56. doi:10.1086/
594124.
71. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis,
and treatment of Guillain-Barre syndrome. Lancet Neurol. 2008;7
(10):939–50. doi:10.1016/S1474-4422(08)70215-1.
72. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, Xie C, Ma K,
Shang K, Wang W, et al. Dysregulation of immune response in
patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020.
doi:10.1093/cid/ciaa248.
73. Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, Liu C, Yang C.
Nervous system involvement after infection with COVID-19 and
other coronaviruses. Brain Behav Immun. 2020. doi:10.1016/j.
bbi.2020.03.031.
74. Centers for Disease Control and Prevention. Hospitalization for
stroke in U.S. Hospitals, 1989–2009. Atlanta (GA); 2012 May
[accessed 2020 May 16]. https://www.cdc.gov/nchs/products/datab
riefs/db95.htm.
75. Connors JM, Levy JH. 2020. COVID-19 and its implications for
thrombosis and anticoagulation. Blood. 135(23):2033–40.
doi:10.1182/blood.2020006000.
76. Wichmann D, Sperhake JP, Lutgehetmann M, Steurer S, Edler C,
Heinemann A, Heinrich F, Mushimba H, Kniep I, Schroder AS,
et al. Autopsy findings and venous thromboembolism in patients
with COVID-19. Ann Intern Med. 2020;173:268–77.
77. Wool G, Gil M, Lee A, Key N, Sabath D, Leissinger C, Volod O,
Kreuziger LB. COVID-19 and aPL Antibodies: frequently asked
questions. Washington (DC); 2020 Apr 20 [accessed 2020 May 16].
https://www.hematology.org/covid-19/covid-19-and-apl-ab.
78. Kandemirli SG, Dogan L, Sarikaya ZT, Kara S, Akinci C,
Kaya D, Kaya Y, Yildirim D, Tuzuner F, Yildirim MS, et al.
Brain MRI findings in patients in the intensive care unit with
COVID-19 infection. Radiology. 2020:201697. doi:10.1148/
radiol.2020201697.
79. Panciani PP, Saraceno G, Zanin L, Reinisi G, Signorini L,
Battaglia L, Fontanella MM. SARS-CoV-2: “three-steps” infection
model and CSF diagnostic implication. Brain Behav Immun.
2020;87:128–29. doi:10.1016/j.bbi.2020.05.002.