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).
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 |
a
All 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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