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 Journal of the Neurological Sciences 414 (2020) 116884

Contents lists available at ScienceDirect

Journal of the Neurological Sciences

journal homepage: www.elsevier.com/locate/jns

Review Article

The neurology of COVID-19 revisited: A proposal from the Environmental T

Neurology Specialty Group of the World Federation of Neurology to
implement international neurological registries
Gustavo C. Romána,b, , Peter S. Spencerc, Jacques Reisd, Alain Buguete, Mostafa El Alaoui Farisf,
⁎

Sarosh M. Katrakg, Miguel Láinezh, Marco Tulio Medinai, Chandrashekhar Meshramj,

Hidehiro Mizusawak, Serefnur Öztürkl, Mohammad Wasaym, on behalf of the WFN
Environmental Neurology Specialty Group
a
Environmental Neurology Specialty Group of the World Federation of Neurology (ENSG-WFN), London, UK
b
Department of Neurology, Neurological Institute, Houston Methodist Hospital, 6560 Fannin Street, Suite 802, Houston, TX 77030, USA
c
Department of Neurology, School of Medicine, Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, USA
d
Université de Strasbourg, 67000 Strasbourg, France and Association RISE, 67205 Oberhausbergen, France
e
General (r) French Army Health Services, Malaria Research Unit, UMR 5246 CNRS, Claude-Bernard Lyon-1 University, 69622 Villeurbanne, France
f
World Congress of Neurology, Marrakesh WCN2011, Moroccan Foundation Against Neurological Disease, Neurology, Mohammed V University of Rabat, Rabat, Morocco
g
Neurology Department, Jaslok Hospital & Research Center, Professor Emeritus GMC and Sir JJ Group of Hospitals, Mumbai, India
h
Spanish Neurological Society, Department of Neurology, University Clinic Hospital, Catholic University of Valencia, 46010, Valencia, Spain
i
Latin America, WFN, Pan American Federation of Neurological Societies (PAFNS), Neurology and Epileptology, Faculty of Medical Sciences, National Autonomous
University of Honduras, Tegucigalpa, Honduras
j
Indian Academy of Neurology. Nagpur, India
k
World Congress of Neurology, Kyoto WCN2017, National Center of Neurology and Psychiatry (NCNP), Japan, Department of Neurology and Neurological Science,
Graduate School of Medical and Dental Sciences, Tokyo, Japan
l
Turkish Neurological Society, Department of Neurology, Selcuk University Faculty of Medicine, Konya, Turkey
m
Pakistan International Neuroscience Society, Neurology, Aga Khan University, Karachi, Pakistan

ARTICLE INFO ABSTRACT

Keywords: A comprehensive review of the neurological disorders reported during the current COVID-19 pandemic de-
Coronaviruses monstrates that infection with SARS-CoV-2 affects the central nervous system (CNS), the peripheral nervous
Coronavirus disease 2019 system (PNS) and the muscle. CNS manifestations include: headache and decreased responsiveness considered
COVID-19 neurological complications initial indicators of potential neurological involvement; anosmia, hyposmia, hypogeusia, and dysgeusia are
Endotheliitis
frequent early symptoms of coronavirus infection. Respiratory failure, the lethal manifestation of COVID-19,
Environmental neurology, MERS
responsible for 264,679 deaths worldwide, is probably neurogenic in origin and may result from the viral in-
MERS-CoV
Neuroepidemiology vasion of cranial nerve I, progressing into rhinencephalon and brainstem respiratory centers. Cerebrovascular
Neuropathology disease, in particular large-vessel ischemic strokes, and less frequently cerebral venous thrombosis, intracerebral
Pandemic hemorrhage and subarachnoid hemorrhage, usually occur as part of a thrombotic state induced by viral at-
SARS tachment to ACE2 receptors in endothelium causing widespread endotheliitis, coagulopathy, arterial and venous
SARS-CoV-1 thromboses. Acute hemorrhagic necrotizing encephalopathy is associated to the cytokine storm. A frontal hy-
SARS-CoV-2 poperfusion syndrome has been identified. There are isolated reports of seizures, encephalopathy, meningitis,
Viral neurotropism
encephalitis, and myelitis. The neurological diseases affecting the PNS and muscle in COVID-19 are less frequent
Zoonosis
and include Guillain-Barré syndrome; Miller Fisher syndrome; polyneuritis cranialis; and rare instances of viral
myopathy with rhabdomyolysis. The main conclusion of this review is the pressing need to define the neurology
of COVID-19, its frequency, manifestations, neuropathology and pathogenesis. On behalf of the World
Federation of Neurology we invite national and regional neurological associations to create local databases to
report cases with neurological manifestations observed during the on-going pandemic. International neuroepi-
demiological collaboration may help define the natural history of this worldwide problem.

⁎
Corresponding author at: Department of Neurology, Neurological Institute, Houston Methodist Hospital, Houston, TX 77030, USA.
E-mail address: gcroman@houstonmethodist.org (G.C. Román).

https://doi.org/10.1016/j.jns.2020.116884
Received 29 April 2020; Accepted 30 April 2020
Available online 07 May 2020
0022-510X/ © 2020 Published by Elsevier B.V.
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

1. Introduction capacity of coronaviruses to infect humans and to jump across species

[15–17], most likely from bat reservoirs [18–20].
Coronavirus disease 2019 (COVID-19) is a severe acute respiratory Ten years later, in 2012, another outbreak of a highly pathogenic
syndrome (SARS) caused by the SARS-CoV-2 coronavirus that since coronavirus, MERS-CoV [21,22], caused 2494 confirmed cases and 858
December 2019 reached pandemic proportions causing in 5 months deaths according to WHO data (case-fatality rate: 34.4%) particularly in
more than 3 million confirmed cases worldwide and over 260.000 Saudi Arabia [23]. MERS may have also originated from bats [20] and
deaths [Johns Hopkins University Coronavirus Resource Center: utilized camels and dromedaries as intermediary hosts [24,25]. Evi-
https://coronavirus.jhu.edu]. Recent publications [1–3] have described dence of camel-to-human infection occurred initially in the Arabian
neurological manifestations in COVID-19 involving the central nervous Peninsula [26] followed by viral spread that included nosocomial in-
system (CNS), peripheral nervous system (PNS) and muscle, as well as fections [23].
early alterations of olfaction and taste [4]. The Environmental Neu- The current COVID-19 pandemic emerged in December 2019 in
rology Specialty Group of the World Federation of Neurology concluded Wuhan, China. A zoonotic origin of the etiological agent, SARS-CoV-2,
that the potential neurological involvement in COVID-19 is a topic of was confirmed with viral isolation from reservoirs in bats that infected
major importance that necessitates a global effort to obtain the neu- as intermediate host the Malayan pangolin (Manis javanica) and other
roepidemiological and clinical data required to quantify the magnitude wildlife used for food in China [27,28]. These outbreaks have solidly
of the problem, to define the full range of the neurological disease and confirmed the high infectivity and lethality of the coronaviruses that
to encourage neuropathological, physiopathological and therapeutic pose serious threats to Public Health around the world.
research. We proposed the creation of international COVID-19 neuro-
logical registries to collect and assemble data on acute, chronic and any 2.1. Taxonomy and structure
long-latency effects on the infection on the nervous system [5]. This
followed the example of the Spanish Neurological Society (Sociedad The coronaviruses (CoV) are members of the Coronavirinae sub-
Española de Neurología, SEN) [www.sen.es] that, in the midst of one of family. The Torovirinae plus the coronaviruses comprise the
the most severe outbreaks of COVID-19 in Europe, managed to imple- Coronaviridae family in the order Nidovirales [21]. CoVs are classified in
ment a registry of de novo acute and subacute neurological manifes- four different genera: alpha, beta, gamma, and delta-CoV according to
tations in patients with confirmed SARS-CoV-2 infection. their phylogenetic links and genomic structures. The Coronaviridae
We provide in this review updated information on the known neu- members MERS-CoV, SARS-CoV-1, and SARS-CoV-2 all belong to the
rological consequences of coronavirus infection in severe acute re- beta-coronavirus (β-CoV) genus and share highly homologous genomic
spiratory syndrome (SARS) and Middle East respiratory syndrome sequences [21].
(MERS), as well as selected published data on nervous system injury The coronaviruses are enveloped single-stranded ribonucleic acid
observed in animal models. We conclude with a current review of (RNA) viruses with the largest known RNA genome, ranging from 26.2
neurological manifestations reported in patients with COVID-19. Future to 31.7 kilobases [21]. The genome contains a 5′ cap and is composed of
research will define issues of congenital involvement –such as seen in six to ten open reading frames (ORFs). There are three main viral
maternal infections with Zika virus– or long-latency brain disorders proteins in the envelope of the virion: the spike protein (S), the mem-
following in utero, perinatal or early childhood infections. While pre- brane protein (M) and the envelope protein (E). The spike glycoprotein
sently unknown in COVID-19, we should be alert to the possibility of mediates virus entry and determines the range of potential hosts, cell
tardive disorders comparable to measles-associated Subacute Sclerosing tropism and disease pathogenesis [29]. SARS-CoV-1 and SARS-CoV-2
Panencephalitis or Progressive Rubella Panencephalitis; as well as long- use angiotensin-converting enzyme 2 (ACE2) as receptor to infect ci-
term neurological disease, for example late Parkinsonism that occurred liated bronchial epithelial cells and type II pneumocytes [20], which
among survivors of Encephalitis Lethargica [6] during the 1918–1920 explains the severity of the pulmonary involvement. SARS-CoV-2 has a
influenza pandemic [7] and, more recently, the increased risk of nar- higher affinity than SARS-CoV-1 for the ACE2 receptor, which is present
colepsy observed in 2009–2010 after the swine flu pandemic due to in neurons and endothelial cells indicating that SARS-CoV-2 may have
influenza A with concurrent vaccination using a monovalent H1N1 higher neuroinvasive potential compared to previous coronaviruses
influenza vaccine [8]. [30]. MERS-CoV uses dipeptidyl peptidase 4 (DPP4) receptor and the
carcinoembryonic antigen–related cell-adhesion molecule 5
2. Coronaviruses (CEACAM5) cofactor ligand to infect unciliated bronchial cells [20].
After binding to the receptor, viruses fuse their envelope with the host
According to Henry [9], the name “coronavirus,” from the Latin cell membrane and the nucleocapsids reach the target cell. The fusion
corona (crown), was coined in 1967 by June Almeida [10] based on involves large conformational changes of the spike protein [31].
ultrastructural images resembling the solar corona that she obtained of
human cold viruses and the avian infectious bronchitis virus [11]. Since 3. Animal models of neurotropic coronavirus infections
then, a large number of avian, feline, canine, porcine, bovine and
equine coronaviruses of veterinary interest has been described as Four decades of research on respiratory coronaviruses have de-
etiological agents of respiratory and enteric diseases [12]. A cor- monstrated the capacity of these viruses to go beyond the respiratory
onavirus characterized as porcine hemagglutinating encephalomyelitis system to enter the nervous system and establish persistent brain in-
virus (PHEMV) causes respiratory symptoms and encephalomyelitis in fection of animals with or without induction of neurological illness
pigs. It was first isolated in 1962 in Canada [13] but became an en- [30,32]. There is abundant experimental animal evidence that cor-
demic worldwide zoonosis reported as late as 2015 at animal fairs in onaviruses can reach the brain via spillage from the lungs to the cir-
Michigan and Ohio, USA [14]. culatory system or by axonal transport and transneuronal spread from
Coronaviruses were considered minor human pathogens until the olfactory and trigeminal nerve endings in the nasal epithelium [30,32].
2002–2003 outbreak of SARS in Guangdong, China, that eventually Some coronaviruses experimentally can spread from airway mechan-
affected 8096 people and caused at least 774 deaths worldwide (mor- oreceptors and chemoreceptors to the medullary cardio-respiratory
tality rate 9.6%), according to the World Health Organization (WHO). centers [33]. Viruses can also access the nervous system via the cir-
SARS-CoV (now called SARS-CoV-1) [15,16] originated in bats (Rhi- cumventricular organs [34] that normally lack a blood-brain barrier
nolophus affinis) and reached humans via badgers (Melogale moschata), (BBB) and via dorsal root ganglia and autonomic (including cardiac)
Himalayan palm civets (Paguma larvata), and raccoon dogs (Nyctereutes ganglia [35] both of which have no blood-nerve barrier (BNB). Indeed,
procyonoides) [17]. This SARS epidemic outbreak demonstrated the the previously mentioned swine coronavirus PHEMV can establish

2
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

ganglionic infection of sensory neurons in dorsal root ganglia after 4.1. SARS in China 2002–2003
peripheral inoculation [35].
Since SARS-CoV-2 can infect the vascular endothelium of peripheral In 2007, Gu and Korteweg [46] reported a dozen autopsies of SARS
organs (kidney lung, heart, kidney, and liver) this raises the question of patients; using RT-PCR on postmortem tissue they demonstrated SARS-
BBB/BNB disruption by direct infection of the endothelium of neural CoV-1 viral RNA and genomic sequences in the cytoplasm of hy-
vasculature. Varga and colleagues [36] demonstrated SARS-CoV-2 pothalamic and cerebral cortical neurons of confirmed SARS cases.
causes infection of endothelial cells and endotheliitis; thereby, systemic Brain edema and focal degeneration of neurons was found together
vascular endotheliitis promotes vasoconstriction, edema and a pro- with ultrastructural confirmation of viral infection of neurons and glial
coagulate state [37] with important implications relevant to cere- cells by SARS-CoV-1. Neuropathological changes included degeneration
brovascular stroke. According to Flammer et al. [38] the vascular en- and necrosis of neurons, extensive glial cell hyperplasia, and cellular
dothelium is an active paracrine, endocrine, and autocrine organ that is infiltrates, but demyelination was not present. Xu and colleagues [47]
indispensable for the regulation of vascular tone and the maintenance isolated a SARS coronavirus strain from brain tissue of a patient with
of vascular homoeostasis. Endothelial microvascular dysfunction leads SARS and symptoms of severe CNS involvement. Pathologic examina-
to vasoconstriction with subsequent organ ischemia, inflammation with tion of the brain revealed necrosis of neurons and gliosis. In addition,
associated tissue edema, and a pro-thrombotic state [37,38]. En- by immunostaining tissue sections they showed that a monokine in-
dothelial dysfunction is also an important factor for atherosclerosis duced by interferon-Γ (Mig) was expressed in glial cells along with
[37,38] infiltration of CD68+ monocytes/macrophages and CD3+ T lympho-
Experimental studies with the mouse hepatitis virus (MHV) illus- cytes in the brain parenchyma. Blood levels of interferon-Γ–inducible
trate the potential neurological effects of infection with a neurotropic protein 10 and Mig in the blood were highly elevated but other cyto-
coronavirus [39]. Neurotropic MHV strains induce an acute en- kines and chemokines were normal [47].
cephalitis in mice, while animals that survive the acute infection dis- SARS-CoV meningoencephalitis was demonstrated using RT-PCR in
play chronic brain demyelination, which has been used to model mul- CSF to detect viral RNA in two patients with severe respiratory symp-
tiple sclerosis (MS) [40]. Of interest, Yeh et al. [41] used reverse toms and generalized seizures admitted to the hospital during the se-
transcriptase polymerase chain reaction (RT-PCR) to demonstrate vere outbreak of SARS in Hong Kong [48]; one was a 59-year-old
human coronavirus (HCoV OC43) RNA in the cerebrospinal fluid (CSF) woman in status epilepticus [49] and the second patient was a 32-year-
and nasopharyngeal secretions of a 15-year-old boy with acute eleva- old pregnant woman [50].
tion of circulating anti-HCoV antibodies and evidence on Magnetic Involvement of the PNS was also reported in SARS occurring
Resonance Imaging (MRI) of the brain of demyelinating lesions diag- 2–3 weeks after onset of infection with features of axonal peripheral
nosed as Acute Disseminated Encephalomyelitis (ADEM), although MS neuropathy [51,52]. A myopathy with elevated creatinine kinase was
could not be ruled out. Moreover, human coronavirus RNA has been also reported [53]. Focal myocyte necrosis in skeletal muscle was found
demonstrated in CSF [42] and in brains of patients with MS [43,44]. in SARS autopsy cases [46,53,54], probably caused by diffuse vasculitis
Arbour and colleagues [45] using RT-PCR demonstrated the presence of [50]. A single case of olfactory neuropathy occurring 3 weeks after
HCoV RNA in 44% of brain tissue samples from 90 patients with neu- infection with SARS-CoV-1 was reported in Taiwan [55].
ropathology-proven MS. In a cohort of 206 SARS patients in Singapore [56] 5 had large-
vessel strokes (2.4% or about 1 in 42 SARS infections); 4 of them were
critically ill and 3 died. There was concern of enhanced thrombosis risk
4. Neurological involvement in SARS and MERS patients from using intravenous immunoglobulin (IVIg) given the observed
higher incidence of deep venous thrombosis and pulmonary embolism.
During the epidemic outbreaks of SARS in China and MERS in Saudi A Canadian study of 22 health-care workers assessed 13–36 months
Arabia, neurological signs and symptoms were reported in small num- after the 2003 outbreak of SARS found that chronic post-SARS-CoV
bers of patients infected with the respiratory coronaviruses SARS-CoV-1 infection was characterized by persistent fatigue, diffuse myalgia,
and MERS-CoV respectively. Neuropathological data from those pa- weakness, depression, and non-restorative sleep with associated REM-
tients are also available in limited cases, as described below. related apneas/hypopneas, an elevated sleep EEG cyclical alternating
pattern, and alpha EEG sleep anomaly [57]. These disorders

Table 1
SARS: pathological findings (According to Gu & Korteweg, 2007 [46]).
Organs/Tissue Pathology # Cases

Central nervous system Edema and degeneration of neurons, positive neurons by in situ hybridization 12
Skeletal Muscles Myofiber necrosis and atrophy, few regenerative myofibers 13
Heart Edema and atrophy of myocardial fibers 22
Respiratory tract Diffuse alveolar damage with varying degrees of acute exudative features including edema, hyaline membranes, organization, and fibrosis. 63
Macrophagic or mixed cellular infiltration, multinuclear giant cells, atypical reactive pneumocytes, and vascular injury. Positive in situ
hybridization in pneumocytes, lymphocytes, and macrophages
Spleen and lymph nodes Lymphocyte depletion in spleen and lymph nodes with architectural disruption. Splenic white pulp atrophy. Positive in situ hybridization signals 25
in immune cells
Digestive tract Intestines: No obvious pathology, nonspecific lesions. Depletion of mucosal lymphoid tissue. Positive in situ hybridization signals in mucosal 19
epithelial cells
Liver: No specific pathology. In some cases, necrosis and apoptosis 20
Urogenital tract Kidneys: acute tubular necrosis, in varying degrees and other non-specific features. Positive in situ hybridization signals in the epithelial cells of 21
the distal tubules
Bone marrow In some cases, reactive hemophagocytosis 9
Adrenal gland Necrosis and infiltration of monocytes and lymphocytes 14
Thyroid gland Destruction of follicular epithelial cells, several apoptotic cells 5
Testes Germ cell destruction, apoptotic spermatogenetic cells 7

Modified from The American Journal of Pathology, Vol. 170, No. 4, April 2007

3
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

Table 2
The Neurology of COVID-19 due to SARS-CoV-2.
Neurologic diagnosis Features City/Country Author [Ref]

Central nervous system symptoms

Headache 6% to 8% (all patients) Wuhan, China Various [66,68,69]
6.5% (all patients) Beijing, China Tian et al. [70]
13% (stroke patients) Wuhan, China Chen et al. [71]
Li et al. [62]
Agitation & Delirium 69% agitation (58 ICU patients) Strasbourg, France Helms et al. [91]
65% delirium (58 ICU patients)
67% pyramidal tract signs
Impaired Consciousness 22% (fatal cases vs. 1% non-fatal cases) Wuhan, China Chen et al. [71]
14.8% (severe cases vs. 2.4% non-severe cases) Wuhan, China Mao et al. [3]
Anosmia, hyposmia 5.1% (cases from 3 hospitals) Wuhan, China Mao et al. [3]
85.6% (cases from 12 hospitals) Europe Lechien et al. [4]
Dysgeusia 5.6% (cases from 3 hospitals) Wuhan, China Mao et al. [3]
88% (cases from 12 hospitals) Europe Lechien et al. [4]

Central nervous system diseases

Cerebrovascular Disease 2.4% (6/214) Wuhan, China Mao et al. [3]
Ischemic stroke 5 Wuhan, China Li et al. [62]
Hemorrhagic stroke 1 China (6 case- Aggarwal et al. [84]
5.8% (13/221) series) Helms et al. [91]
Large-vessel ischemic stroke 11 Strasbourg, France Oxley et al. [129]
Hemorrhagic stroke 1 New York, US
Cerebral sinus thrombosis 1
1% to 6% (pooled analysis)
23% (3/13 ICU patients from 2 hospitals)
Ischemic strokes 3
Large-vessel ischemic strokes
Frontotemporal hypoperfusion 58 ICU patients with severe COVID-19, 45 survived (33% had frontal lobe Strasbourg, France Helms et al. [91]
behavioral signs)
11/11 CBF-ASL-MRI frontotemporal hypoperfusion
Arterial & Venous Thromboses 184 patients from 3 hospitals The Netherlands Klok et al. [92]
31% thrombotic complications including pulmonary embolism in 81% China Zhang et al. [93]
27% venous thromboses Zurich, Varga et al. [36]
3.7% arterial thromboses Switzerland
3 patients with multiple arterial thromboses of legs, hands, brain, associated with
anticardiolipin IgA and anti–β2-glycoprotein-I IgA and IgG antibodies
3 patients with multiple arterial thromboses and multi-organ failure due to
coronavirus attachment to ACE2 receptors, viral invasion of endothelial cells,
resulting in lymphocytic endotheliitis
Subarachnoid hemorrhage 1 patient with Immune thrombocytopenic purpura France Zulfiqar et al. [94]
Acute Hemorrhagic Necrotizing Brain MRI showed bilateral hemorrhagic rim-enhancing lesions in the thalami, Detroit, USA Poyiadji et al. [61]
Encephalopathy medial temporal lobes, and subinsular regions, probably associated with cytokine
storm syndrome
Meningoencephalitis Seizures, neck rigidity, CSF pleocytosis (12/μ/L). CSF-RT-PCR positive for SARS- Japan Moriguchi et al. [102]
CoV-2.
Encephalopathy Decreased level of consciousness with COVID-19. Negative CSF & CT brain; EEG: Florida, USA Filatov et al. [103]
diffuse encephalopathy Wuhan, China Ye et al. [104]
Confusion, myalgias, meningeal signs, CSF opening pressure 220 mmHg, normal
CT brain.
Seizures Recurrent generalized tonic-clonic seizures; normal CT/MRI, CSF-RT-PCR Iran Karimi et al. [105]
negative for SARS-CoV-2
Myelitis COVID-19 pneumonia, high fever (40 °C), acute flaccid paraplegia Wuhan, China Zhao et al. [113]

Peripheral nervous system & muscle

Neuritic pain 8.9% Wuhan, China Mao et al. [3]
Guillain-Barré syndrome First case in China 61-year-old woman Shanghai, China Zhao et al. [108]
First case in USA 54-year-old man USA Virani et al. [109]
Three cases from northern Italy Italy Toscano et al. [110]
Miller Fisher Syndrome, Polyneuritis 50-year-old man with diplopia due to external ophthalmoplegia, ataxia and Madrid, Spain Gutiérrez-Ortiz et al. [112]
Cranialis areflexia Bangkok, Thailand Sriwijitalai & Wiwanitkit
Neurosensory hearing loss 39-year-old man with diplopia from bilateral abducens palsy, global areflexia but [113]
no ataxia
Old woman from Thailand
Myalgia 36% early symptom in > 1200 COVID-19 patients Wuhan, China Several
26–51% muscle fatigue Wuhan, China [62,68,69]
Huang et al. [63]
Myopathies 10.7% (19.3% severe vs. 4.8% non-severe) Wuhan, China Mao et al. [3].
Rhabdomyolysis 33% have increased creatine kinase China Several [64–66]
Early sign in 2 case reports Wuhan, China Jin & Tong [121]
Suwanwongse et al. [122]

Irreversible respiratory failure

Case-fatality rates (CFR) 81% of 72,314 COVID-19 infections are mild but 20% or 8255 are severe (CFR China Wu & McGoogan [124]
8.0% - 14.8%) or critical (CFR 49%) Worldwide Several [67,69,74,80,106]
Neurogenic respiratory failure due to viral brainstem invasion could explain the
dismal prognosis

4
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

conceivably may have been related to viral particles and viral genome induced by the viral infection. However, given the growing reports of
sequences isolated from the cytoplasm of neurons in the hypothalamus neurological disease of COVID-19, with others [2,67], we consider it
[47,58]. critical to define the direct neurotropic effect as well as the indirect
Table 1 summarizes the pathological lesions produced by SARS- virus-induced secondary impact of SARS-CoV-2 infection on the ner-
CoV-1 including, in addition to respiratory tract lesions and pneumonia vous system. We updated the review of published reports as of April 30,
with severe alveolar damage, viral injury in mucosal cells of the in- 2020, including a number of pre-publication articles, and describe
testine, acute tubular necrosis, vasculitis and lymphocyte depletion in below the available data on the neurology of COVID-19. Table 2 sum-
spleen and lymph nodes [46]. According to Guo et al. [54], the pa- marizes this information.
thology of SARS is the result of direct injury caused by the coronavirus
infection of target cells, as well as indirect injury from immune re- 5.1. Headache and alterations of consciousness
sponses, circulatory dysfunction, and hypoxia. The exact route of SARS-
CoV-1 infection of the human brain is unknown. Infected monocytes/ During the early symptomatic phase of SARS-CoV-2 infection
macrophages migrating across the blood–brain barrier (BBB) might be in > 1200 patients reported from hospitals in Wuhan [62–66,68,69],
involved [54]. fever occurred in 88%–92%; cough in 67%–69%, fatigue in 26%–51%,
In summary, there is solid evidence of involvement of nervous and 36% had myalgia. In a cohort of 262 confirmed cases from Beijing
system and muscle in human infection by SARS-CoV-1 based on neu- hospitals [70] 6.5% had headache, compared with 6%–8% in Wuhan
ropathological studies. However, clinical series of SARS patients with and 13% developed cerebrovascular disease (CVD) [62]. Chen et al.
neurological manifestations are unavailable. [71] studied the initial symptoms in a cohort of 113 fatalities of COVID-
19 compared with 161 patients who recovered; early alteration of
4.2. MERS-CoV in Saudi Arabia consciousness occurred significantly more often in fatal cases (22%)
compared with 1% among those who recovered. Mao et al. [3] also
According to Senga et al. [59], following the prodromal symptoms found impaired consciousness in 14.8% of 214 patients hospitalized due
of fever, chills, cough, and dyspnea present in > 70% of patients, ap- to severe disease compared with 2.4% in non-severe infections.
proximately one-third of the cases infected with MERS-CoV had Therefore, early onset of headache and decreased responsiveness are
myalgia, malaise, and gastrointestinal symptoms. Arabi et al. [60] indicators of potential neurological involvement in COVID-19 patients.
provided the only report of neurological involvement in 3 fatal cases
observed during the epidemic outbreak of MERS in Saudi Arabia in 5.2. Alterations of smell and taste
June 2012.
The first patient was a 74-year-old man with a 3-day history of The absence or diminished ability to smell (anosmia, hyposmia) or
ataxia, vomiting, confusion, fever, and left hemiparesis; he became to taste normally (hypogeusia, dysgeusia) is a common symptom among
comatose and required respiratory support. CSF was normal and ne- COVID-19 patients around the world [4,72–74] and it has been sug-
gative for MERS-CoV. MRI showed multiple bilateral non-enhancing gested that anosmia could indicate the neurotropic potential of the
areas of signal hyperintensity on T2/FLAIR in the periventricular, deep coronavirus to invade the brain [75]. Among 214 patients with COVID-
white matter, subcortical area, corpus callosum, bilateral brachium 19 from 3 hospitals in Wuhan, China [3] hypogeusia was reported in
pontis, midbrain as well as in the left cerebellum and upper cervical 5.6% and hyposmia in 5.1%. A much higher incidence of these dis-
cord. The second patient was a 57-year-old man who presented with orders has been described in European patients. A multi-center study
flu-like illness, fever and a gangrenous toe who developed facial pa- involving 12 European hospitals conducted by the Young-Otolar-
ralysis, respiratory distress, became comatose and required intubation. yngologists of the International Federation of Oto-rhino-laryngological
MRI showed bilaterally deep watershed lesions, and scattered foci in Societies (YO-IFOS) [4] recruited 417 patients with mild-to-moderate
the cortical and subcortical regions of the temporal, parietal, and oc- COVID-19 and found olfactory dysfunction in 85.6% and gustatory
cipital lobes. The third patient was a 45-year-old man with cough, dysfunction in 88%; both symptoms were often associated, and early
dyspnea, rigors, fever, and diarrhea. He was conscious and had no focal olfactory recovery occurred in 44% [4]. In severe COVID-19 cases, al-
neurological signs. He developed septic shock and respiratory failure. terations of smell and taste occurred before any other complaints in
MRI showed confluent non-enhancing T2WI/FLAIR hyperintensities 11.8% of the cases. According to Xydakis [72], the American Academy
within the white matter of both cerebral hemispheres and along the of Otolaryngology—Head and Neck Surgery and the British Association
corticospinal tract. CSF showed white cell count of 2 cells/mm3, protein of Otorhinolaryngology have recommended adding anosmia-dysgeusia
0.85 g/L with negative RT-PCR for MERS-CoV. to the list of primary screening symptoms for SARS-CoV-2 infection.
Although not recognized as such by the authors, the brain MRI These symptoms often occur in the absence of nasal congestion or
images are highly suggestive of acute hemorrhagic necrotizing en- rhinorrhea in patients with mild or no constitutional symptoms [73,74].
cephalopathy (AHNE), a condition recently reported during the COVID- Because of the frequent occurrence of anosmia-dysgeusia, Li and
19 epidemic outbreak in the USA [61]. In summary, there is almost colleagues [75] suggested that viral neurotropism of SARS-CoV-2 could
complete absence of clinical information on the neurology of MERS and result in invasion of the olfactory nerve (cranial nerve I) [30,75], the
no pathological data are available, except for a single postmortem olfactory brain and then the brain stem causing the irreversible re-
needle biopsy of the brain with normal results. spiratory failure typical of severe COVID-19. The neurotropism of cor-
onaviruses has been demonstrated before. In 2007, Suzuki et al. [76]
5. Neurological disease in COVID-19: central nervous system were able to identify coronaviruses in the nasal discharge of patients
who failed to recover olfaction after a cold. Animal models have shown
As indicated earlier, a few reports issued from the original epidemic that the nasal route is a well-recognized pathway for neurotropic
outbreak in Wuhan, China [1–3], emphasize the occurrence of neuro- viruses to reach the brain [32,33,71,77]. Given the importance of the
logical involvement in patients with SARS-CoV-2. A systematic review ACE2 receptor in the pathogenesis of SARS-CoV-2 neurotropism, Net-
published in the Journal of the Neurological Sciences [1] found only 6 land and colleagues [78] using mice transgenic for human ACE2 de-
articles [3,62–66] from December 2019 to March 2020 addressing the monstrated that the virus enters the brain through the olfactory bulb
neurology of COVID-19 and concluded that these complications have and uses rapid transneuronal spread to reach olfactory cortex, basal
not been studied appropriately, particularly because they may remain ganglia and midbrain (dorsal raphe) nuclei, dorsal motor nucleus of the
unrecognized in patients with severe illness. Also, it is unclear if some vagus, nucleus tractus solitarii and area postrema causing neuronal
of the conditions listed here are simply concurrent or if they are death in the absence of encephalitis. A similar pattern of brain invasion

5
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

was demonstrated in human brains from patients with SARS-CoV-1 receptors and thrombocytopenia [89,90]. The risk of ischemic stroke is
infection [42,79]. It has been proposed that viral neurotropism could linked to SARS-CoV-2 infection among critically ill elderly patients with
explain the severity of respiratory failure in COVID-19 [75] and the vascular risk factors, such as hypertension, diabetes mellitus, hyperli-
absence of dyspnea [80]. Mutations of the S protein of the coronavirus pidemia, smoking and history of previous stroke or transient ischemic
[81] or variations in population genetics for expression of ACE2 [82] attacks (TIA). Increased serum levels of D-dimer could enhance the risk
could determine the divergences in the pattern of respiratory problems of thrombosis and embolism [89,90].
in COVID-19.
5.4. Frontotemporal hypoperfusion
5.3. Cerebrovascular disease
Helms and her colleagues [91] from Strasbourg, France, reported 58
COVID-19 may increase the risk for venous and arterial throm- patients with severe COVID-19 treated in two Intensive Care Units
boembolism associated with inflammation, hypoxia, immobilization, (ICUs). Neurologic findings were encountered in 84% at the time of ICU
and diffuse intravascular coagulation. admission including agitation (69%); corticospinal tract signs (67%),
Only three clinical series of stroke in patients with COVID-19 are such as brisk tendon reflexes, ankle clonus, and bilateral extensor
currently available [3,62,84]. plantar responses; delirium in 65% (based on the Confusion Assessment
A report by Mao et al. [3] described 214 patients with acute COVID- Method for the ICU, CAM-ICU); and, hyperthermia with a fever >
19 in Wuhan included 58.9% (mean age 58.7 years) severe cases and 38.5 °C. About 12% had past neurological history of TIA, epilepsy, and
41.1% (mean age 49.9 years) non-severe patients. In total, 78 patients mild cognitive impairment (MCI). Lumbar punctures were performed
(36.4%) had neurological involvement occurring more often in the se- on 7 patients; in all CSF showed no cells and CSF RT-PCR was negative
vere disease group. Six patients (2.4%) had acute cerebrovascular dis- for SARS-CoV-2; a single case had elevated CSF protein and IgG levels.
ease, 5 of them severe cases (5.5%) that occurred 9 days after onset MRI showed cerebral ischemic strokes in 3/13 (23%) cases, two
(range = 1–18 days). Computed tomography (CT) of the brain con- asymptomatic patients each had small acute ischemic strokes and 1 had
firmed 4 ischemic strokes and 1 cerebral hemorrhage. Stroke patients a subacute stroke, probably preexisting. Linear and nodular enhance-
with severe infection were older, had more underlying vascular risk ment of leptomeningeal spaces on FLAIR and T1 was noted post-con-
factors, especially hypertension, and showed fewer typical symptoms of trast in 8/13 (62%) patients. Notably, arterial spin labeling (ASL)-per-
COVID-19, such as fever and cough. fusion MRI demonstrated bilateral frontotemporal hypoperfusion in 11/
Also in Wuhan, Li and colleagues [62] reported 221 patients and 11 patients. Electroencephalography showed diffuse bifrontal slowing
found 11 (5%) cases with ischemic strokes mainly from large-vessel consistent with encephalopathy in 1 out of 8 cases. Of interest, 33% of
occlusion. A 32-year-old man had cerebral sinus thrombosis and an- the 45 survivors presented a dysexecutive syndrome suggestive of
other had cerebral hemorrhage (62-year-old man). Stroke affected more frontal lobe involvement, with alterations of attention, orientation and
women (6/11) who were significantly older (71.6 ± 15.7 years) vs. poorly organized movements on command.
52.1 ± 15.3 years in the group without stroke; more vascular risk
factors were present including history of hypertension, diabetes, and 5.5. Arterial and venous thromboses, subarachnoid hemorrhage, and
previous cerebrovascular disease. Stroke patients had leukopenia and coagulopathies
the values of C-reactive protein (CRP) were higher (mean = 51.1 mg/L,
range = 1.3–127.9 mg/L) than in non-stroke cases (12.1 mg/L, Evaluation of 184 patients with COVID-19 at three Dutch hospitals
0.1–212.0 mg/L); also, a hypercoagulable tendency was reflected in [92] found a high incidence (31%) of thrombotic complications, in-
significant elevation of D-dimer values (mean = 6.9 mg/L, cluding 3 patients with stroke. Venous thrombosis occurred in 27%
range = 0.3–20.0 mg/L) vs. 0.5 mg/L (range = 0.1–20.0 mg/L) in non- (95%CI 17–37%) and arterial thromboses in 3.7% (95%CI 0–8.2%).
stroke cases (p < .001). Therapy included anti-platelet treatment in 6 Pulmonary embolism was the most frequent thrombotic complication
cases and anticoagulation in 5. A total of 5 patients with stroke died (n = 25, 81%). Advanced age and coagulopathy, defined as sponta-
(38% mortality). neous prolongation of PT/PTT (prothrombin time > 3 s or activated
A first report on 393 patients with confirmed COVID-19 from two partial thromboplastin time > 5 s), were independent predictors of
hospitals in the disease epicenter of New York City, USA was recently thrombotic complications. The authors recommended applying strict
published [83] but cerebrovascular disease was not mentioned. How- pharmacological thrombosis prophylaxis in all COVID-19 patients ad-
ever, strokes from large-vessel occlusion in younger subjects with re- mitted to ICU.
latively mild COVID-19 in New York have been reported [129]. Zhang and colleagues [93] reported 3 patients from China (ages
Aggarwal et al. [84] conducted a pooled analysis of the literature on 65–70 years) with severe COVID-19 infection who developed multiple
the effect on COVID-19 prognosis of either new acute stroke or previous arterial thromboses associated with anticardiolipin IgA antibodies as
history of stroke. The analysis included 6 studies from China ranging in well as anti–β2-glycoprotein-I IgA and IgG antibodies with negative
size from 52 to 1099 patients. Cerebrovascular disease occurred in 1% lupus anticoagulant. Patient 1 had ischemia in the lower limbs bilat-
to 6% of the cohorts corresponding to a non-statistically significant erally as well as in two fingers of the left hand; CT of the brain showed
increase of about 2.5-fold in odds of developing severe COVID-19 bilateral cerebral infarcts in multiple vascular territories, involving
among patients with stroke compared with those without. frontal, parietal, occipital lobe and bilateral basal ganglia, brain stem,
A number of countries have issued stroke guidelines during the and bilateral cerebellar hemispheres. Patient 2 had multiple cerebral
COVID-19 pandemia. After the first patients with COVID-19 were infarctions in the right frontal lobe and bilateral parietal lobe. Patient 3
hospitalized in Singapore [85], Christopher et al. [86] provided re- had multiple cerebral infarctions in bilateral frontal lobes, right frontal,
commendations for the early recognition and treatment of stroke in parietal, temporal and occipital lobes, and bilateral cerebellar hemi-
patients infected with SARS-CoV-2, including the potential use of in- spheres.
travenous thrombolysis (TPA) or Endovascular Therapy (EVT) with Zulfiqar and associates [94] from France, reported a 65-year-old
mechanical thrombectomy in COVID-19 patients. A similar consensus woman with SARS-CoV-2 infection with viral pneumonia confirmed by
was published in India [87]. chest CT. She developed lower-extremity purpura, epistaxis, and pro-
In China, Jin et al. [88] encouraged neurologists to consider both gressive thrombocytopenia with normal PT/PTT. One week later, she
ischemic and hemorrhagic strokes as potential complications of COVID- complained of right frontal headache without fever, vomiting, or focal
19. Intracerebral bleed and subarachnoid hemorrhage may be linked to neurologic deficits. CT of the brain showed a small subarachnoid he-
arterial hypertension induced by binding of SARS-CoV-2 to ACE2 morrhage in the right frontal lobe. The platelet count had decreased to

6
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

2000 per cubic millimeter and she was treated with platelet transfusion, metalloprotease-9 without vessel wall disruption. AHNE may also occur
prednisolone and eltrombopag with good results. A meta-analysis by following vaccination, in particular with the DPTw (diphtheria-tetanus-
Lippi et al. [95] confirmed the association of thrombocytopenia with pertussis whole cell) vaccine [99]. COVID-19 fatalities have been as-
severe COVID-19. sociated with a hyperinflammatory syndrome manifested by a growing
In Zurich, Switzerland, Varga and her colleagues [36] reported HScore [101] decreasing platelet counts, cytopenias, hyperferritinemia,
endothelial viral infection by SARS-CoV-2 and endotheliitis in post- and increased levels of IL-2, IL-7, granulocyte-colony stimulating factor,
mortem examinations of three patients (71-year-old man, renal trans- interferon-γ-inducible protein 10, monocyte chemo-attractant protein
plant recipient, with history of coronary artery disease and arterial 1, TNF-α and macrophage inflammatory protein 1-α [100]. Proposed
hypertension; 58-year-old woman, obese with history of hypertension; treatments include steroids, IVIg, and selective cytokine blockade with
69-year-old hypertensive man). In addition to the severe respiratory anakinra, tocilizumab, or Janus kinase (JAK) inhibition [99,100].
failure typical of COVID-19, they all developed multisystem organ
failure and vascular complications including myocardial infarction and 5.7. Encephalopathy, meningitis, encephalitis, and seizures
mesenteric ischemia requiring small intestine resection. Pathology ex-
amination demonstrated lymphocytic endotheliitis in lung, heart, As reviewed earlier [3,65], decreased level of consciousness is a
kidney, small intestine and liver. Viral inclusions were revealed by neurological manifestation indicative of a severe COVID-19 prognosis.
electron microscopy indicating direct viral infection of endothelial cells The causes may range from metabolic encephalopathy associated with
accompanied by accumulation of mononuclear inflammatory cells. The severe hypoxia, post-ictal state following seizures, to acute cere-
authors [36] postulate that this mechanism could explain the wide- brovascular disease caused by endotheliitis and subsequent hematolo-
spread endothelial dysfunction associated with apoptosis and multi- gical changes or a cytokine storm resulting in AHNE.
organ vascular involvement observed in severe COVID-19 infections. There are few reports of meningitis or encephalitis with demon-
Treatments targeted to halt viral replication or to modify ACE2 re- stration of SARS-CoV-2 in CSF or brain. In Japan, Moriguchi et al. [102]
ceptors [96–98] could have beneficial effects in COVID-19. reported the case of a 24-year-old man admitted with headache, fever,
As mentioned earlier [20,84], SARS-CoV-2 infects the host by using fatigue and seizures. On examination, he was in a post-ictal state and
the ACE2 receptors present in the upper airway passages and the had neck rigidity. CT brain showed no brain edema or lesions. CSF
pneumocytes in the alveolar epithelial lining, but also expressed in showed 10 mononuclear and 2 polymorphonuclear cells per μ/L. CSF-
endothelial cells in lung, heart, kidney, intestines, and in brain, where it RT-PCR was positive for SARS-CoV-2 but the nasal swab test was ne-
may protect neurons against ischemic injury [97,98]. ACE2 is the en- gative. Brain MRI showed hyperintense DWI/FLAIR images on the right
zyme that physiologically counters the activation of the renin-angio- mesial temporal lobe and the inferior horn of the right ventricle con-
tensin-aldosterone system (RAAS) degrading angiotensin II to angio- sistent with encephalitis and ventriculitis.
tensin- (1–7), attenuating vasoconstriction and sodium retention [97]. Filatov et al. [103] reported a second case of encephalopathy from
The use of ACE inhibitors (ACEI) and angiotensin-receptor blockers Florida, USA, affecting a 74-year-old man with a previous stroke who
(ARBs) during the COVID-19 pandemic was the topic of an extensive became poorly responsive with COVID-19. CSF was normal and CSF-
review by Vaduganathan and colleagues [97] who concluded that ACE2 RT-PCR was negative. Brain imaging showed no new lesions and EEG
may be beneficial and that the withdrawal of RAAS inhibitors in high- was consistent with diffuse encephalopathy. He developed respiratory
risk cardiovascular patients may be harmful. This is in agreement with failure and required intubation and respiratory support.
the results of a retrospective, multi-center study in Hubei province, In Wuhan, China, Ye et al. [104] reported a male COVID-19 patient
China [99], which included 1128 hypertensive patients with COVID-19 with fever, shortness of breath and myalgias who became confused.
demonstrating that the use of ACEI/ARB was associated with lower risk Meningeal signs were positive and extensor plantar responses were
of all-cause mortality. elicited. Lumbar puncture showed an opening pressure of 220 mmHg
and normal cells, protein and glucose. CSF was negative for SARS-CoV-
5.6. Acute hemorrhagic necrotizing encephalopathy 2 and the brain CT was normal. The patient recovered and was dis-
charged from the hospital. Two consecutive SARS-CoV-2 swab tests
Poyiadji et al. [61] from Detroit, Michigan, USA, described brain- were negative.
imaging findings in a woman in her late fifties who presented with In Iran, Karimi et al. [105] reported a previously healthy 30-year-
COVID-19 infection, demonstrated by a positive nasopharyngeal RT- old woman with COVID-19 who was admitted to hospital with re-
PCR test for the SARS-CoV-2 virus. CSF showed no bacterial growth and current generalized tonic-clonic seizures. CSF and brain MRI were
was negative for Herpes simplex 1–2 virus (HSV), varicella-zoster virus normal. CSF-RT-PCR for SARS-CoV-2 was negative. Seizures were
(VZV), and West Nile virus. Coronavirus could not be tested in the CSF. treated and the patient was discharged.
CT brain demonstrated bilateral and symmetric hypoattenuation within In summary, the paucity of reports of encephalitis or meningitis in
the medial thalami with normal CT angiogram and CT venogram. Brain COVID-19 is unexpected given the high neurotropic potential of SARS-
MRI showed bilateral hemorrhagic rim-enhancing lesions in the tha- CoV-2 [106]. The few cases of meningoencephalitis conceivable may be
lami, medial temporal lobes, and subinsular regions. The authors con- the consequence of the extremely high fatality rate of respirator-de-
cluded that the patient presented acute hemorrhagic necrotizing en- pendent COVID-19 patients, perhaps caused by direct injury of the re-
cephalopathy (AHNE). This rare condition is usually considered a spiratory centers in the brainstem. Detailed post-mortem neuropatho-
parainfectious disease [99]; it has been associated with influenza A logical studies [107] should answer this dilemma.
(H1N1) and influenza B, parainfluenza, VZV, human herpes viruses
HHV-6 and HHV-7, enteroviruses, the novel reovirus strain serotype 2 6. Neurological disease in COVID-19: peripheral nervous system &
(MRV2Tou05), rotaviruses, HSV, rubella, coxsackie A9, and measles muscle
viruses, among which H1N1 and HHV-6 are the most common [99].
AHNE is not an encephalitis and the CSF usually shows no pleocytosis. Compared with the reports of CNS involvement in COVID-19 the
It is generally accepted that AHNE may be caused by a “cytokine storm” bibliography describing PNS and muscle pathology is more limited.
[100] resulting in elevation of proinflammatory cytokines including
interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-10, IL-15, 6.1. Guillain-Barré syndrome
IL-1β, soluble TNF receptor, and interferon-gamma (IFN-γ), plus lym-
phocytes, in particular CD56+ natural killer (NK) cells leading to brain Zhao et al. [108] from Shanghai, China, reported the first case of
injury through alterations of the BBB by trypsin and matrix Guillain-Barré syndrome (GBS) associated with COVID-19 in a 61-year-

7
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

old woman who had returned from Wuhan; she did not report fever or fever, vertical diplopia, perioral paresthesias, anosmia, ageusia, and
respiratory symptoms but complained of weakness of both legs and unsteadiness. He had a broad ataxic gait and global areflexia. On
severe fatigue. On examination she had symmetric weakness and are- neuroophthalmologic examination he showed right hypertropia in all
flexia of both legs and feet (Medical Research Council, MRC 4/5) that fields of gaze, severe limitation of adduction and down-gaze move-
progressed over the next 3 days (MRC 3/5). Lymphocytopenia and ments of right eye, plus left eye nystagmus on left gaze consistent with
thrombocytopenia were noted. CSF cell counts were normal with ele- right internuclear ophthalmoparesis and right fascicular oculomotor
vated protein (124 mg/dL). Nerve conduction studies showed delayed palsy. Anti-ganglioside antibody GD1b-IgG was positive as well as the
distal latencies and absent F waves consistent with demyelinating SARS-CoV-2 test. CSF showed no cells and a protein of 80 mg/dL. CSF-
neuropathy. With a diagnosis of GBS she was treated with IVIg. On day RT-PCR was negative for COVID-19. He was diagnosed with Miller
8, oropharyngeal swabs were positive for SARS-CoV-2, suggesting a Fisher syndrome (external ophthalmoplegia, ataxia and areflexia) with
parainfectious profile for GBS, instead of the classic postinfectious one. good response to IVIg.
In the U.S., a 54-year-old male with confirmed COVID-19 and a Patient 2 was a 39-year-old man with acute onset of diplopia. He
history of fever, cough and Clostridium difficile colitis of recent onset had history of diarrhea and fever, ageusia, and overall fatigue; he tested
developed difficulty breathing and weakness and diminished reflexes of positive for COVID-19. Neuroophthalmologic exam was consistent with
arms and legs eventually diagnosed as GBS [109]. bilateral abducens palsy. He had global areflexia but no motor weak-
Toscano and colleagues [110] reported 5 patients with GBS from ness. All CSF tests were negative including SARS-CoV-2; CT brain was
three hospitals in northern Italy during the COVID-19 outbreak. Patient normal. Two weeks later he had made spontaneous recovery of the
1: A 77-year-old woman with abrupt onset of paresthesias in legs and diplopia, the ageusia and the areflexia. He was diagnosed with poly-
hands that progressed in 36 h to areflexic tetraplegia without bulbar neuritis cranialis or with incomplete Miller Fisher syndrome sine ataxia.
signs. Seven days earlier she had fever, cough, and had developed As with the GBS patient reported above, the cranial nerve involvement
pneumonia positive for SARS-CoV-2. NCV/EMG confirmed an axonal appears to be parainfectious (not due to direct viral neurotropism) but
variant of GBS. The first CSF was normal but the second one showed immune-mediated with presence of GD1b antibodies and positive re-
high protein (101 mg/dL); CSF-RT-PCR was negative twice. During IVIg sponse to IVIg.
treatment, she developed bulbar symptoms with dysphagia and tongue A single case of de novo neurosensory hearing loss was reported in a
weakness, which required assisted ventilation. Patient 2: A 23-year-old woman with COVID-19 from Thailand [113].
man with a 2-day history of mastoid pain, complete facial weakness,
ageusia and leg paresthesias. Ten days earlier, the patient had fever and 6.3. Myelitis
sore throat. On exam he had complete bilateral facial palsy, areflexia
and sensory ataxia. EMG confirmed lower-extremity axonal sensory- Zhao et al. [114] from Wuhan, China, reported a case of a 66-year-
motor neuropathy with sural nerve sparing and decreased facial nerve old man with fever and fatigue for two days from COVID-19 pneu-
cMAP. CSF protein was high (1123 mg/dL) with negative virus test and monia. After high fever at night (40 °C), he developed acute flaccid
anti-ganglioside antibodies. He was treated with IVIg with some im- paralysis of the legs along with urinary and bowel incontinence. He had
provement. Patient 3: A 55-year-old man with 10 days of fever, cough decreased strength in the arms (MRC 3/5) with normal bilateral re-
and COVID-19 pneumonia; he developed neck pain, paresthesias in the flexes in upper extremities and flaccid paralysis in the legs (MRC 0/5)
4 limbs and lower leg weakness. On day 12, he developed areflexic with bilateral hyporeflexia but without pathologic reflexes. Sensation
tetraparesis with severe axonal neuropathy. CSF showed elevated pro- was intact in the arms but was globally impaired in both legs with a T10
tein (123 mg/dL) and a negative coronavirus test. He developed facial sensory level. CT brain revealed basal ganglia and paraventricular la-
diplegia and respiratory failure with IVIg and required assisted venti- cunar infarctions. CSF and MRI were not done due to pandemic pre-
lation due to neuromuscular impairment. Patient 4: A 76-year-old man ventive measures. A possible cytokine storm in response to SARS-CoV-2
with a 5-day history of cough and anosmia evolving into COVID-19 infection was diagnosed based on the high fever, leukocytosis, low
pneumonia. He was admitted with low-back pain and leg weakness that serum iron (1.80 μmol/L, normal = 10.6–36.7 μmol/L), elevated serum
progressed rapidly to areflexic tetraparesis. CSF was normal with a ferritin (> 2000 ng/mL, normal = 21.81–274.6 ng/mL) and high levels
negative virus test. IVIg treatment produced motor improvement more of CRP, serum amyloid protein, procalcitonin, and interleukin-6. Fol-
evident in the arms but he was still unable to walk. Patient 5: A 61-year- lowing treatment, muscle strength in both upper limbs recovered (MRC
old man with a one-week history of asthenia, anosmia and ageusia. 4/5) with minimal improvement in the legs (MRC 1/5). Possible in-
Noticed problem climbing stairs and leg paresthesias and was unable to fectious causes of myelitis were ruled out [115], including Mycoplasma
stand up on awakening. He had generalized areflexia and paraparesis. pneumoniae [116], Chlamydia pneumoniae, Epstein–Barr virus (EBV),
COVID-19 oropharyngeal test was negative and CSF was normal with influenza A-B virus, parainfluenza virus, adenovirus, coxsackieviruses,
negative coronavirus CSF-RT-PCR. Anti-ganglioside antibodies were cytomegalovirus (CMV), and respiratory syncytial virus. Tuberculosis
negative. On the second day of IVIg therapy, he developed flaccid tet- infection was negative. The authors postulated that myelitis was the
raplegia with facial weakness and dysphagia; he eventually required result of direct SARS-CoV-2 given that ACE2 receptors are expressed on
tracheostomy and assisted ventilation. Serum SARS-CoV-2 antibodies the surface membranes of spinal cord neurons [117] combined with a
were positive on admission. In sum, GBS occurred 5 to 10 days after cytokine storm syndrome [99,100].
onset of COVID-19 symptoms, a typical interval. Clinical neurophy-
siology was consistent with axonal-type GBS in 3 cases and demyeli- 6.4. Myasthenia Gravis (MG)
nating-type in 2 patients. Post-Gadolinium MRI showed enhancement
of caudal nerve roots in 2 patients and the facial nerve in one. All pa- The International MG/COVID-19 Working Group [118] published
tients were treated with IVIg and Patients 1 and 3 received two cycles. the guidance for the management of myasthenia gravis (MG) and
A similar treatment was used in GBS patients during the MERS outbreak Lambert-Eaton myasthenic syndrome (LEMS) during the COVID-19
[111]. pandemic.

6.2. C. Miller Fisher syndrome, polyneuritis cranialis 6.5. Myopathies

Gutiérrez-Ortiz and her colleagues [112] from Madrid, Spain, re- As mentioned earlier, fatigue occurred in 26%–51% of patients with
ported two patients with clinical manifestations of PNS involvement in COVID-19 in China [63], 36% had myalgia and increased creatine ki-
COVID-19. Patient 1 was a 50-year-old man with a 2-day history of nase (CK) was present in 33% of patients [64–66]. There are no reports

8
G.C. Román, et al. Journal of the Neurological Sciences 414 (2020) 116884

of electromyography or muscle histopathology. Viral myositis occurred well as risk factors for severe outcomes including death, and timing and
with MERS [119] and SARS [42,47–49]. Rhabodomyolysis was re- intensity of infectiousness determined by viral shedding studies.
ported in patients with acute renal failure during SARS [120] and there There is an urgent need to understand the neurotropic potential of
are two reports [121,122] during COVID-19. Guidon and Amato [123] SARS-CoV-2 and the frequency of these complications; the traditional
published a guide for the management of immune therapies and sup- methods of neurology including the time-honored clinicopathological
port groups for patients with neuromuscular disorders during the correlation should provide much-needed answers. The Environmental
COVID-19 emergency. Neurology Specialty Group of the World Federation of Neurology
(ENSG-WFN) issued an appeal [5] to neurological societies around the
7. Conclusions globe to develop national or regional COVID-19 neuroepidemiological
databanks. Neurologists and physicians at the front line of this pan-
We conclude from this comprehensive review of current literature demic are asked to report to each society all cases of new-onset, acute,
that patients with COVID-19 frequently suffer substantial neurological delayed and long-latency neurological disorders associated with SARS-
involvement. According to the analysis of 72,314 cases from China CoV-2 infection during the current COVID-19 pandemic. The worldwide
[124], the large majority of SARS-CoV-2 infections (81%) are mild and response to this pandemic encourages us to believe that regional neu-
subjects recover entirely, while about 20% (8255 cases) develop re- rologists and physicians, government authorities, and scientists with
spiratory symptoms ranging from severe (case-fatality rate, CFR expertise in Public Health, epidemiology, infectious diseases, virology,
8.0%–14.8%) to critical (CFR 49%) particularly among elderly subjects neurosciences and other relevant fields will be willing to advise and
with multiple risk factors. However, many severe cases occur in young assist neurological societies to achieve the goal of creating national and
people after trivial symptoms of the infection [125]. regional databases. This will also encourage much needed peer-re-
Although the a priori impression is that CNS injury occurs pre- viewed publications on the neurology of COVID-19. We will work to
dominantly as a result of metabolic and inflammatory responses oc- assure that the results of the national registries are collected, posted and
curring in elderly patients admitted to intensive care units (ICU), a become freely available at the WFN website [https://wfneurology.org].
direct viral attack might be a more likely explanation for the extremely This global effort should help the world understand the neurological
high mortality. Vincent & Taccone [126] point out that once old age, impact of COVID-19.
frailty, disability, comorbidities, or lack of personnel and equipment are
discounted, most ICU patients can be supported by invasive mechanical Authors' contribution
ventilation until the lungs recover [127]. This is not to the case with
COVID-19. This paper is the result of a Delphi-type consensus of the listed
We hypothesize that SARS-CoV-2, like other human coronaviruses, members of the Environmental Neurology Specialty Group of the World
has neurogenic properties that result in anosmia in 85.6% of the cases Federation of Neurology (ENSG-WFN) with the participation of all au-
[4] occurring shortly after the virus reaches ACE2 receptors in the nasal thors via e-mail and telephone. Jacques Reis, Gustavo Román, Peter
epithelium at the time of contagion. Given the relative absence of nasal Spencer, and Alain Buguet coordinated the meetings. Initial data col-
congestion and rhinorrhea [66,67], anosmia likely results from viral lection and drafts by Peter Spencer, manuscript redirection and litera-
presence in the olfactory bulbs [69]. In about half of the cases (44%), ture review by Gustavo Román; final drafts by Gustavo Román with
the defense mechanisms control the infection and early olfactory re- additional contributions from all other authors. Miguel Láinez provided
covery occurs [4]. In some of the remaining patients, the viral neuro- valuable input on the experience of the registry and database of the
tropism of SARS-CoV-2 probably invades the brain via axonal transport Spanish Neurological Society during the outbreak. All authors provided
and transneuronal spread from the olfactory nerves to the rhinence- input for the scientific content of the paper and submitted bibliographic
phalon finally reaching the brainstem causing the irreversible re- references, suggestions, and edits.
spiratory failure of severe COVID-19, typically characterized by lack of
dyspnea [74]. Declaration Competing of Interest
Concurrently, the virus proliferates and attaches to ACE2 receptors
present in the upper airway and in pneumocytes in the alveolar epi- The authors are all members of the Environmental Neurology
thelial lining, as well as in endothelial cells of the lungs, heart, kidney, Specialty Group (ENSG) of the World Federation of Neurology and
and intestine [91–93], resulting in generalized endotheliitis [91] that declare no competing interests.
causes severe pneumonia, multi-organ collapse including heart failure,
hepatorenal syndrome, coagulopathy and thrombotic state. Widespread Acknowledgements
viral invasion of the vascular endothelium apparently may increase the
risk of blood clots that leads to concomitant cardiovascular and cere- Prof. Roman's research is funded by the Blanton Endowed Chair, the
brovascular events, perhaps the most serious complications of COVID- Wareing Family Research Fund and the David Cabello Research Fund at
19 infection. The immune response to the viral proliferation has been Houston Methodist Hospital.
poorly studied but includes the effects of the cytokine storm syndrome
[100]. While the acute and residual effects of SARS-CoV-2 infection References
have come into focus, as of this writing there are no reports of the long-
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