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CORRESPONDENCE

Letter: Neurological Implications of COVID-19 and Lessons Learned From Prior Epidemics and Pandemics

Daou, Badih J MD; Koduri, Sravanthi MD; Palmateer, Gregory BS; Thompson, B Gregory MD; Chaudhary, Neeraj MD; Gemmete, Joseph J MD; Pandey, Aditya S MD

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doi: 10.1093/neuros/nyaa186

To the Editor:

We performed a literature review on viral epidemics and pandemics, including the severe acute respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS), influenza H1N1, and the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the goal of identifying the neurological symptoms, signs, and complications of these infections within the context of the COVID-19 pandemic (Figure).

fig1
FIGURE.:
Flow diagram of study selection criteria and results.

Of 16 articles that included 8042 patients with H1N1, neurological involvement was reported in 1286 patients (15.99%). Excluding headaches, 771 patients had neurological involvement (9.6%) (Table 1). Of 8 articles consisting of 1128 patients with MERS, 323 patients (28.6%) had neurological findings and 170 patients (15.07%) without headache. Of 5 articles with 1251 patients with SARS, 187 patients (14.95%) were reported to have neurological involvement and 6.2% (n = 78) with the exclusion of headache. Of 17 articles on 5335 patients with COVID-19, 744 patients were reported to have neurological signs, symptoms, or sequelae (13.9%) to date, with a rate of 2.47% when headache was excluded (n = 132) (Table 2).

TABLE 1. - Summary of Literature Reviewa
Study and year Number of patients Summary of neurological findings
H1N1
 Wilking et al, 201418 365 Seizure: 17, encephalitis: 4, meningitis: 4, encephalopathy: 3, meningismus: 3, focal hemorrhagic brain lesions: 2, brain infarction: 1, sensorineural hearing loss: 1
 Frobert et al, 201119 181 Seizure: 8, encephalitis: 2, encephalopathy: 1, basilar artery thrombosis: 1, myasthenic crisis: 1, decreased consciousness: 1
 Ekstrand et al, 201020 303 Seizure: 12, status epilepticus: 7, encephalopathy: 9, headache: 3, focal neurological findings: 5, myositis: 1, aphasia: 6
 Glaser et al, 201221 2069 Encephalopathy/encephalitis: 29, seizure: 44, meningitis: 3, Guillain-Barré syndrome: 1
 Jain et al, 200922 272 Headache: 92
 Tokuhira et al, 201223 81 Seizure: 19, encephalopathy: 14, neurologic long-term complications: 5
 Dominguez-Cherit et al,200924 58 Weakness: 41, headache: 33
 Kumar et al, 200925 168 Altered level of consciousness: 17
 Archer et al, 200926 100 Headache: 62
 Kwon et al, 201227 1389 Seizures: 22, meningitis: 1, encephalopathy: 2
 Cao et al, 200928 426 Headache: 83
 Libster et al, 201029 251 Headache: 6, seizures: 3
 Louie et al, 200930 1088 Headache: 211, altered mental status: 60
 Kedia et al, 201131 307 Seizure: 17, encephalopathy: 7
 Stein et al, 201032 478 Headache: 51, seizure: 41, meningitis or encephalitis: 5
 Khandaker et al, 201233 506 Seizure: 38, encephalitis/encephalopathy 5, confusion/disorientation: 5, loss of consciousness: 5, paralysis/Guillain-Barré syndrome: 2.
MERS
 Arabi et al, 201434 12 Headache: 2, altered consciousness: 1
 Noorwali et al, 201535 261 Headache: 59, altered consciousness: 53, focal neurological deficit: 10
 Saad et al, 201436 70 Confusion: 18, headache: 9, seizure: 6
 Arabi et al, 201737 330 Altered consciousness: 70, headache: 34
 Choi et al, 201638 186 Headache: 38, altered consciousness: 10
 Assiri et al, 201339 47 Headache: 6
 Shalhoub et al, 201840 32 Altered consciousness: 2, headache: 5
 Aleanizy et al, 201741 190 No neurological symptoms or complications reported
SARS
 Choi et al, 200342 267 Headache: 89, dizziness: 48, confusion: 2
 Umapathi et al, 20045 206 Large artery cerebral infarctions: 5
 Tsai et al, 200543 664 Polyneuropathy: 3, large artery ischemic stroke: 5
 Leung and Chiu, 200444 64 Headache: 18, dizziness: 12, altered consciousness: 3
 Lien et al, 200845 50 Headache: 2
COVID-19
 Mao et al, 202046 214 Dizziness: 36, headache: 28, altered consciousness: 16, acute cerebrovascular disease: 6, ataxia: 1, seizure: 1, hypogeusia: 12, hyposmia: 11, hypopsia: 3, neuralgia: 5
 Xu et al, 202047 62 Headache: 21
 Chen et al, 202048 274 Headache: 3, dizziness: 21, altered consciousness: 26
 Wu et al, 202049 80 Headache: 13
 Lian et al, 202050 788 Headache: 75
 Wang et al, 202051 69 Headache: 10, dizziness: 5
 Guan et al, 202052 1590 Headache: 205, altered consciousness: 20
 Arentz et al, 202053 21 Seizure: 1
 Wan et al, 202054 135 Headache: 24
 Chu et al, 202055 54 Unspecified
 Huang et al, 202056 34 Headache: 2
 Yang et al, 202057 149 Headache: 13
 Yang et al, 200258 52 Headache: 3
 Guan et al, 202059 1099 Headache: 150
 Korea Centers for DiseaseControl and Prevention60 28 Headache: 3
 Huang et al, 202061 41 Headache: 3
 Zheng et al, 202062 645 Headache: 67
aAll studies were retrospective, except Howlett et al, 2018, which was prospective.

TABLE 2. - Neurologic Complications by Viral Disease
Neurologic finding Number of patients Percent
H1N1
 Headache 541 6.73%
 Seizure 228 2.84%
 Encephalitis/encephalopathy(often grouped together) 76 0.95%
 Weakness 41 0.51%
 Altered level of consciousness 22 0.27%
 Meningitis 13 0.16%
 Speech difficulties 6 0.07%
 Cognitive and memory issues 5 0.06%
 Cranial nerve or focal deficit 5 0.06%
 Neurological long-termcomplications, not specified 5 0.06%
 Stroke 4 0.05%
 Guillain-Barré syndrome 3 0.04%
 Hearing impairment andtinnitus 1 0.01%
MERS
 Headache 147 13.03%
 Altered level of consciousness 136 12.06%
 Cognitive or memory issues 18 1.60%
 Cranial nerve or focal deficit 10 0.89%
 Seizure 6 0.53%
SARS
 Headache 109 8.71%
 Dizziness 60 4.80%
 Stroke 10 0.80%
 Altered level of consciousness 5 0.40%
 Neuropathy 3 0.24%
COVID-19
 Headache 620 11.74%
 Dizziness 62 1.17%
 Altered level of consciousness 62 1.17%
 Diminished taste sensation 12 0.23%
 Diminished smell 11 0.21%
 Stroke 6 0.11%
 Neuralgia 5 0.09%
 Seizure 2 0.04%
 Ataxia 1 0.02%

At this time, the neurological complications of COVID-19 are not fully understood, but reports of prominent neurological symptoms and complications are beginning to emerge.1 The current incidence of neurological findings with COVID-19 is relatively low, but as data from prior epidemics show, particularly prior coronavirus-related epidemics, the rate is likely to further increase. Neurological manifestations, including headache, dizziness, altered level of consciousness, focal neurological deficits, cranial nerve involvement,2 seizures, and to a lesser extent meningoencephalitis,3 more severe necrotizing encephalopathy,4 cerebral edema, and stroke,5 have been reported with the recent viral epidemics. Importantly, with prior epidemics (Table 3), there are also several reports of patients developing neurological sequelae months to weeks later, including cerebellitis,6,7 neuropathy,8 Guillain-Barré syndrome,9 postinfluenza myositis,10 and postviral Parkinsonism.11

TABLE 3. - Year Identified, Total Case Numbers, and Case Fatality Rates of SARS, H1N1, MERS, and COVID-19
Virus Year identified Number of countries affected Number of cases Number of deaths Case fatality rate
H1N1 2009 >214 0.7 to 1.4 billion 18 036 (confirmed) 284 000 (estimated) 0.03% (estimated)
SARS (SARS-CoV) 2002 26 8437 813 9.6%
MERS 2012 27 2499 861 34.5%
COVID-19 2019 >205 >2 million 33 509 4.8%

Coronaviruses are thought to disseminate to the central nervous system (CNS) through either hematogenous spread, retrograde neuronal dissemination, or direct invasion of the olfactory epithelium.12

Furthermore, the ACE2 receptor, which is present in the nervous system and the skeletal system,13 was identified as the functional receptor for SARS-CoV-2.14 There is also some speculation that invasion into the CNS and damage to the medullary cardiorespiratory centers may lead to worsening respiratory symptoms.15 Also, with the prior SARS epidemic, multiple human brain specimens demonstrated direct infection of neuronal cells within the cerebral cortex and hypothalamus.16

Additionally, there are reports of a hypercoagulable state in certain cases of COVID-19, placing patients at a higher risk of stroke, especially in the setting of acute illness and in the elderly population.17

Given the higher prevalence of neurological sequelae reported with prior coronavirus-related pandemics, COVID-19 has the potential of leading to similar if not worse neurological sequelae due to its enhanced virulence. Neurological sequelae can lead to significant morbidity and mortality within survivors, and a heightened attention to neurological findings is required in the ensuing weeks to months.

In conclusion, with the continuing spread of COVID-19 throughout the world and from what the experience from prior epidemics has shown us, neurological findings are likely to increase; therefore, continued monitoring and early recognition is imperative.

Disclosures

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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