Daniel J. Correa, MD, MSc
Since the first reports of COVID-19 emerged, it became clear that beyond the respiratory and multi-system organ failure, with resultant mortality, SARS-CoV-2/ COVID-19 infection often involved brain and nerves.1-6
In a report of 214 patients from Wuhan, China published in JAMA Neurology
, neurological involvement was more common in severely affected patients with COVID-19 (45.5%) than those with less severe illness (30.2%), and included acute stroke, impaired consciousness, muscle injury, and rarely seizures (1 patient), or peripheral neuropathies.1
A retrospective comparison of patients who either had recovered and were discharged or were deceased showed more prevalent impairment of consciousness among those who were eventually deceased (22%) compared with those who recovered (1%).2
Altered mental status has been recognized as a neurological manifestation of acutely ill patients admitted with COVID-19; the multiple metabolic or cardiorespiratory disturbances, the progressing viral infection, cytokine storm, or coagulopathies contribute to the abnormal mental status. Awareness and recognition of neurological involvement is essential to guide treatment decisions as the pandemic unfolds.
While there were several case reports of seizures (new onset or re-emergent) in patients with COVID-19,7
a report published in Epilepsia
on a larger group of 304 patients from Hubei, China concluded that “there was no evidence suggesting an additional risk of acute symptomatic seizures in people with COVID-19.”8
Our experience has been somewhat different. In our hospital network in New York, which was at the epicenter of the COVID-19 pandemic in the United States, we encountered numerous patients with neurological manifestations, including patients with seizures. Whether direct transmission of the virus to the central nervous system (CNS) also plays a role in the CNS manifestations or seizures is unclear.
Offering quality care for patients with seizures and epilepsy during the COVID-19 pandemic has been the preoccupation of many physicians treating these patients and consensus recommendations have been made.9
The electroencephalogram (EEG) is one of the main tools used in the evaluation of patients with seizures and epilepsy. Limiting the risk of infection to the EEG technologists, while also offering adequate EEG studies for patients with seizures is important, and using simplified EEG montages has been proposed.10
Mental status changes prompting an EEG of COVID-19-positive patients included new encephalopathy and poor recovery after discontinuation of sedation
Suspicion for new clinical seizures among patients without prior epilepsy prompted EEG requests
Epileptiform discharges appeared in 40.9% of patients with COVID-19 who had EEG, with frontal sharp waves as the predominant pattern.
Future studies need to establish whether COVID-19 increases the risk for epileptiform abnormalities and seizures/epilepsy, and to investigate pathogenesis
We focused on whether medically indicated EEGs performed in acutely ill patients under investigation (PUIs) for COVID‐19 reported epileptiform abnormalities and whether they are more prevalent in patients with COVID‐19 than patients without COVID-19 (COVID-19 negative). Use of the rapid response 8-channel headband EEG that can be quickly applied by healthcare personnel11,12
allowed us to perform EEG studies in critically ill patients and minimize exposure to the virus. Full montage EEGs have been used as well, but on a more limited number of patients. Our team published13
this retrospective analysis of the initial adult cases evaluated in our hospital network, performing EEGs on adult patients admitted with suspicion of COVID‐19 and medical indications for EEG, including altered mental status and/or seizure‐like events.
We included 28 COVID‐19 PUIs (age 30‐83 years), of whom 22 tested positive for SARS-CoV-2 (63.6% males) and 6 tested negative (33.3% male). The majority were severely ill, being intubated for acute respiratory failure (63.6% vs 100% in COVID-19 positive vs negative) and were already under sedatives or on antiseizure medications (86.4% vs 100% in COVID-19 positive vs negative).
Seizure-like events were reported and we observed epileptiform EEG abnormalities in the COVID-19 positive patients, and a significant proportion of these were in patients with no prior history of epilepsy. Seizure-like behaviors prompting EEG investigation were common (63.6%) in COVID-19-positive patients who had EEGs and sporadic epileptic abnormalities were seen in 40.9%, predominantly appearing as frontal sharp waves. In contrast, among the 6 COVID-19-negative patients, only 2 had clinical seizure-like events and 1 (16.7%) had epileptiform abnormalities. These epileptiform discharges did not appear to correlate with renal insufficiency or hepatic dysfunction or with sedatives and antiseizure medications, all of which were commonly present. There were no electrographic seizures in this initial series. However, many patients had already been started on antiseizure medications before the EEG due to clinical suspicion for seizures.
The predominance of frontal sharp waves, bilateral symmetric or asymmetric, raises the possibility of a frontal epileptiform focus or frontal dysfunction and a suggestion that this may be where SARS-CoV-2 virus enters the CNS (through the nasopharyngeal mucosa or the olfactory nerves). Similar pathways have been shown with intranasally delivered SARS-CoV or Middle East Respiratory Viral Syndrome coronavirus (MERS-CoV) entering the brains of mice, possibly via olfactory nerves14
or through the blood-brain barrier in other places. SARS-CoV may then spread to regions such as the brainstem, thalamus, or limbic regions.14
It has also been proposed that the rapid clinical decline of certain patients with COVID-19 may in some cases be precipitated by the neuroinvasive potential of the virus invading the CNS and leading to the rapid respiratory decline.3
However, in humans, COVID-19 has been very rarely detected by PCR in the cerebrospinal fluid (CSF), although CSF testing for COVID-19 has not been used extensively so far. There are rare case reports of patients with meningitis/encephalitis and/or seizures who test positive for COVID-19 in the CSF.4,15
For example, CSF detection of the virus was reported in a patient with a negative nasopharyngeal swab,15
but CNS entry of the virus does not happen in most COVID-19-positive patients. In a recent report of patients with severe COVID-19 infection, none of the 7 tested CSF samples revealed virus.6
Additionally, CNS viral infections or neuroinflammation may lower the threshold for seizures and potential development of epilepsy in certain individuals.16
Seizures have been variably reported in other types of viral encephalitides.17
Case reports of uncontrolled seizures have been reported in patients with MERS-CoV,18
children and adults with Influenza A H1N1 infection-related altered mental status,19
and Influenza A H3N2 encephalitis.20
The higher yield of epileptiform abnormalities in our cohort compared to other reports on severe COVID-19 infections6
could be related to the longer duration of EEG studies or other parameters that are worth investigating.
In summary, we describe the first preliminary report of high prevalence of new onset epileptiform abnormalities, particularly in the frontal lobes, among patients with severe COVID-19 infections with altered mental state or recent seizure-like symptoms.13
Future studies will be needed to investigate the neuropathological correlates of severe COVID-19. In addition, long-term, large, controlled follow-up studies are needed to validate our findings, test the specific effect of COVID-19, and elucidate the pathogenic mechanisms of COVID-19.
Daniel J. Correa, MD, MSc, is assistant professor in the Saul R. Korey Department of Neurology at Albert Einstein College of Medicine and is deputy chief of neurology at Montefiore Medical Center.
Aristea Galanopoulou, MD, PhD, is professor in the Saul R. Korey Department of Neurology (pediatric neurology) and professor in the Dominick P. Purpura Department of Neuroscience at Albert Einstein College of Medicine, and director of the Laboratory of Developmental Epilepsy.
1. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. doi:10.1001/jamaneurol.2020.1127
2. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.
3. 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;92(6):552-555. doi: 10.1002/jmv.25728
4. Zhou L, Zhang M, Wang J, Gao J. Sars-Cov-2: Underestimated damage to nervous system. Travel Med Infect Dis. 2020:101642.
5. Nataf S. An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID-19. J Med Virol. 2020;10.1002/jmv.25826. doi: 10.1002/jmv.25826
6. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020;382:2268-70.
7. Vollono C, Rollo E, Romozzi M, et al. Focal status epilepticus as unique clinical feature of COVID-19: A case report. Seizure. 2020;78:109-112.
8. Lu L, Xiong W, Liu D, et al. New onset acute symptomatic seizure and risk factors in coronavirus disease 2019: A retrospective multicenter study. Epilepsia. 2020;61(6):e49-e53. doi: 10.1111/epi.16524
9. French JA, Brodie MJ, Caraballo R, et al. Keeping people with epilepsy safe during the COVID-19 pandemic. Neurology. 2020:10.1212/WNL.0000000000009632.
10. Gelisse P, Rossetti AO, Genton P, Crespel A, Kaplan PW. How to carry out and interpret EEG recordings in COVID-19 patients in ICU? Clin Neurophysiol. 2020;S1388-2457(20)30176-0
11. Kamousi B, Grant AM, Bachelder B, Yi J, Hajinoroozi M, Woo R. Comparing the quality of signals recorded with a rapid response EEG and conventional clinical EEG systems. Clin Neurophysiol Pract. 2019;4:69-75.
12. Yazbeck M, Sra P, Parvizi J. Rapid response electroencephalography for urgent evaluation of patients in community hospital intensive care practice. J Neurosci Nurs. 2019;51:308-12.
13. Galanopoulou AS, Ferastraoaru V, Correa DJ, et al. EEG findings in acutely ill patients investigated for SARS‐CoV‐2/COVID‐19: A small case series preliminary report. Epilepsia Open. 2020;5:314-324.
14. 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;82:7264-7275.
15. Moriguchi T, Harii N, Goto J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 2020;94:55-58.
16. Barker-Haliski ML, Loscher W, White HS, Galanopoulou AS. Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy. Epilepsia. 2017;58 Suppl 3:39-47.
17. Misra UK, Tan CT, Kalita J. Viral encephalitis and epilepsy. Epilepsia. 2008;49 Suppl 6:13-8.
18. Mogi T, Toda H, Tatsuzawa Y, et al. Clinically mild encephalopathy with a reversible splenial lesion and nonconvulsive status epilepticus in a schizophrenic patient with neuroleptic malignant syndrome. Psychiatry Clin Neurosci. 2017;71:212.
19. Cunha BA, Fear GL, Chawla K. A rare case of influenza A in a hospitalized adult presenting with encephalitis and a seizure. ID Cases. 2018;12:153-155.
20. Yuan HT, Ho TH, Lee JT, Chen PC, Wang CW, Yang FC. Simply influenza A (H3N2)-associated encephalitis with seizure. Am J Emerg Med. 2019;37:1808 e1- e3.