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

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 Review

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

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. 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, seizures, and to a lesser extent meningoencephalitis, more severe necrotizing encephalopathy, cerebral edema, and stroke, 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,, neuropathy, Guillain-Barré syndrome, postinfluenza myositis, and postviral Parkinsonism.

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.

Furthermore, the ACE2 receptor, which is present in the nervous system and the skeletal system, was identified as the functional receptor for SARS-CoV-2. There is also some speculation that invasion into the CNS and damage to the medullary cardiorespiratory centers may lead to worsening respiratory symptoms. Also, with the prior SARS epidemic, multiple human brain specimens demonstrated direct infection of neuronal cells within the cerebral cortex and hypothalamus.

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.

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.