Prepared on behalf of the American Epilepsy Society by:
B. Keith Day, MD, PhD
Assistant Professor, Neurology
Director, Epilepsy Fellowship
Washington University School of Medicine in St. Louis
R. Edward Hogan, MD
Director, Adult Epilepsy Center
Washington University School of Medicine in St. Louis
The COVID-19 outbreak continues to evolve, currently with spread to the United States, which is now the epicenter of the pandemic. In all areas of medicine, there is a critical need for accurate information to inform an appropriate response to the outbreak. However, our current understanding of COVID-19 is limited by reports of the pathogen only in its earliest stages of evolution. Realizing both the need for and limitation of current information, this summary provides a focused summary of pertinent clinical diagnostic information about neurological involvement of SARS-CoV-2 virus and COVID-19, especially in relationship to patients with seizures and epilepsy.
There are multiple factors which influence frequency of epileptic seizures, including systemic and environmental factors.1 COVID-19 therefore may exacerbate epileptic seizures from associated systemic effects not directly related to SARS-CoV-2 virus CNS infection. Reports of seizures in COVID-19 patients should be interpreted in this context. As detailed below, cohort studies of patients with COVID-19 show that neurological complications are relatively uncommon, and occur with increased frequency in patients with more severe systemic illness.2;3 Lack of early neurological signs and symptoms suggest absence of early direct CNS infection by the SARS-CoV-2 virus. Later neurological manifestations of COVID-19 could be related to either systemic complications of severe infection, or direct CNS infection by SARS-CoV-2 virus, which is uncertain from available data.
Two Cohort Studies of Clinical Manifestations of COVID-19
In a retrospective study of 1099 patients with laboratory-confirmed COVID-19 in China, Guan et al2 reported presenting symptoms. The cohort included both hospitalized and outpatient subjects. There were no reported definitive neurological signs or symptoms on presentation. Additionally, seizures and epilepsy were not listed among coexisting disorders before COVID-19 infection. The reported presenting symptoms of headache (13.6%), fatigue (38.1%), and myalgia or arthralgia (14.9%), theoretically neurologically related, are more typically related to systemic effects of the associated viral infection. Additionally, there were no reported neurological signs. In a retrospective case series, Mao et al3 reviewed 214 COVID-19 confirmed hospitalized patients in Wuhan, China, reporting on 74 of whom had neurological signs or symptoms. Comparing patients with severe and non-severe COVID-19 infections as defined by international guidelines for community-acquired pneumonia, patients with severe infection were more likely to have CNS manifestations of disease. Specifically, impaired consciousness and acute stroke were more common in severe cases. There was a single case of epilepsy, in the severe group. Additionally, there were associated hypogeusia and hyposmia in 5.6% and 5.1% of patients, respectively, which showed no difference in occurrence between the severe and non-severe groups. Muscle injury was reported in 10.7%.
Taken together, these two studies show that initial neurological involvement is rare, especially in mild COVID-19 cases, but that neurological involvement can occur in more severe cases later in the disease course. Epilepsy and seizures are an uncommon complication of COVID-19.
Expert Consensus of COVID-19 Care for Neurology
In an expert consensus of neurologists from China,4 there are reported COVID-19 related neurological signs and symptoms. These include stroke, headache, seizures, impaired consciousness, and myalgias. A few patients developed symptoms of neuropathy, e.g. paresthesia, and bowel/bladder function disturbance. The report stresses that a significant number of patients present without fever, which is confirmed in other studies.5 Other clinical directives include the importance of treating clinical signs and symptoms appropriately if testing results for SARS-CoV-2 are ambiguous or unavailable, and that some patients had leukopenia before onset of symptoms.
Potential Concerns for SARS-COV-2 CNS Infection
Despite findings from early studies, there is great heterogeneity of neurological presentation for individual patients with viral illnesses, so a minority of COVID-19 patients may present with neurological signs and symptoms. SARS‐CoV-2 has been reported in the brains from both patients and experimental animals,4;6 supporting that clinical manifestations may be related to direct SARS-CoV infection. There are reported cases of COVID-19 presentations with primarily neurologic signs and symptoms, including new-onset seizures,7 as well as a case report of presumptive COVID-19-assoicated acute necrotizing hemorrhagic encephalopathy.8 Several case reports outline seizures and epilepsy during COVID-19 infections.
Additional Studies Specifically Aimed at Defining the Relationship Between COVID-19, Seizures, and Epilepsy
Lu Lu et al.10 specifically collected data about new-onset acute symptomatic seizures between January and February 2020 at 42 hospitals in the Hubei province, the epicenter of COVID-19 in China. They enrolled 304 patients, none with a prior history of epilepsy, 108 with severe disease. Patients presented with acute cerebrovascular disease, and systemic disorders which could provoke seizures, but without seizures, febrile seizures, or episodes of status epilepticus. Two patients had seizure-like events, diagnosed as seizure mimics due to acute stress reaction and hypocalcemia. The authors concluded that COVID-19 poses minimal risk for acute symptomatic seizures, though a significant portion of severely ill patients had increased potentially provocative risk factors. A limitation of this study was lack of routine or long-term EEG recordings to investigate these seizure-like episodes or to assess for subclinical seizures. In general, there is currently limited EEG testing and reported EEG findings for COVID-19 positive patients. Helms et al.11 reported EEG data on a subset of 58 of 64 patients admitted to two ICU’s in France with severe COVID-19 and ARDS. Eight patients underwent EEG, all of whom had non-specific findings with no epileptiform discharges or seizures.
There are currently three case reports of special interest. Dugue et al.12 reported a COVID-19 positive 6-week-old male presenting with cough, fever, and two brief episodes of sustained upward gaze and bilateral leg stiffening, which were clinically consistent with febrile seizures. SARS-CoV-2 RNA and rhinovirus C sequences were detected by nasopharyngeal and anal swabs, but SARS-CoV-2 RNA was not detected in CSF, serum, or plasma. Long-term EEG was abnormal due to excessive sharp transients and focal slowing but did not capture typical events or seizures. Brain MRI was normal. Laboratory data was notable for leukopenia. Possibly, COVID-19 contributed to the febrile systemic response provoking seizures; however, rhinovirus could have similarly done so, and there was no definitive confirmation of ictal events as seizures.
In the second case, Vollono et al.13 reported a 78-year-old female with a history of herpes encephalitis and medically well-controlled seizures who presented with EEG-supported focal status epilepticus with right-sided motor symptoms which resolved with additional medical treatment. There were no reported anti-seizure medication serum levels. She was afebrile, her chest X-ray was normal, and there were no acute findings on brain MRI. However, her labs revealed lymphopenia and thrombocytopenia. She had a history of second-degree contact with three SARS-CoV-2 positive people and developed a fever hours after presentation. Her RT-PCR of naso- and oropharyngeal swab samples were positive for SARS-CoV-2. She did not have a lumbar puncture. She was treated with resolution of her fever and no further seizures or additional serious medical problems. Her home seizure medications included valproic acid, which can cause blood cell dyscrasias, but her lymphopenia and subsequent fever were suggestive of a mounting systemic response that triggered breakthrough seizures prior to developing the fever and in the absence of pulmonary involvement. There was no direct evidence of CNS viral infection. However, from presented information, medication non-compliance was also a possible etiology.
For the third case, Moriguchi et al.14 reported a 24-year-old man with no past history of seizures who developed headache, fatigue, fever, and sore throat. On Day 5, he had a normal chest X-ray. On Day 9, he presented with altered mental status, and had a generalized seizure en route to the hospital. He had neck stiffness on exam. Labs showed leukocytosis (neutrophil dominant, lymphocytes relatively decreased). Chest CT showed ground glass opacities. He had a lumbar puncture with an elevated opening pressure, and CSF studies revealed 12 nucleated cells (no RBCs). SARS-CoV-2 RT-PCR was negative for his nasopharyngeal swab samples but positive in CSF. He had multiple seizures requiring intubation. He was diagnosed with meningitis and viral pneumonia. Brain MRI was consistent with right lateral ventriculitis and encephalitis with hyperintense right mesial temporal changes. He was under treatment for pneumonia and encephalitis at the time of publication. This was the first reported case of meningitis/encephalitis with new-onset seizures in the setting of SARS-CoV-2 positive CSF and significant pulmonary disease despite negative nasopharyngeal swab testing.
Epidemiology of COVID-19 in Pediatric Patients
Dong et al.15 reported a retrospective nationwide Chinese epidemiological case series of 2135 patients <18 years old with COVID-19 in January and early February 2020. Severity of illness was divided into asymptomatic, mild, moderate, severe, and critical; and severity was determined based on clinical case review for 2133 patients. Disease severity definitions did not include neurological symptoms other than patients in the critical group could have encephalopathy. History of epilepsy or presence of seizures was not included in the presented data. Patients were subdivided by age into 5 groups: < 1-year-old (infants), 1-5 years old, 5-10 years old, 11-15 years old, and >15 years old. Less than 6% of children in the study were assessed to be severe or critical, which was significantly less than in adult patients with COVID-19. However, children less than 6 years old, especially infants were over-represented in the severe and critical groups (59.8% with 29.5% infants, and 69.2% with 53.8% infants, respectively). From another perspective, the proportion of severe and critical cases within each age group was 10.6% for infants, 7.3% for 1-5 year-old children, and ~3-4% for the remaining older children’s groups. There was one death as of 2/8/2020, a 14-year-old boy from Hubei province.
Also important for the pediatric population is the possible association of COVID-19 with Kawasaki Disease.16
Early evidence on COVID-19 shows neurological complications are most associated with severe cases. Additionally, seizures and epilepsy do not appear to be a predisposing factor for COVID-19. Importantly, because most pediatric patients with COVID-19 do not develop severe disease,9 pediatric patients are likely at relatively decreased risk of seizures due to COVID-19. However, younger children, especially infants, develop severe disease at a higher rate15 and may be at heightened risk for seizures within the pediatric group; further investigation is needed.
So far, there is no objective evidence from cohort studies that seizures are worsened in COVID-19 patients. Individual case reports provide helpful details of seizures during the clinical course of COVID-19 infection, but overall leave open the question as to whether systemic complications or direct CNS SARS-CoV-2 virus infection cause seizures. However, there are no cohort studies focusing on patients with a history of epilepsy, which would greatly predispose to seizures in the setting of an infection. Clinical experience with seizures and epilepsy in general indicates that exacerbation of seizures, especially from systemic effects of severe COVID-19 infections, will be a major concern. Given this likelihood, all caregivers of patients with epilepsy should take extra care to assist their patients in preventing potential COVID-19 infection.
- Theodore WH, Porter RJ. Precipitation of epileptic seizures is influenced by the type of epileptic syndrome, patient variability, and environmental factors. Epilepsy: 100 Elementary Principles. London: W.B. Saunders Co. Ltd., 1995:25-8.
- Guan WJ, Ni ZY, Hu Y et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020: https://doi.org/10.1056/NEJMoa2002032
- Mao L, Jin H, Wang M et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurology 2020: DOI: https://doi.org/10.1001/jamaneurol.2020.1127
- Hu B, Mao L. Expert consensus on clincial prevention and control of new coronavirus infections of neurology (first edition). 2020: https://mp.weixin.qq.com/s/ZQfQTNsow4luZ6NBjmw9Mw, accessed 3/30/2020
- Guan WJ, Zhong NS. Clinical Characteristics of Covid-19 in China. Reply. N Engl J Med 2020: https://doi.org/10.1056/NEJMc2005203
- 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: DOI: https://doi.org/10.1002/jmv.25728
- Talan J. COVID-19: Neurologists in Italy to colleagues in US: Look for poorly-defined neurologic conditions in patients with the coronavirus. Neurology Today. 2020. https://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=920, accessed 4/3/2020
- Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features. Radiology 2020: DOI: https://doi.org/10.1148/radiol.2020201187
- Fauci AS, Lane C, Redfield RR. Covid-19 - Navigating the uncharted. N Engl J Med 2020;382:1268-9. https://doi.org/10.1056/NEJMe2002387
- Lu L, Xiong W, Liu D, et al. New-onset acute symptomatic seizure and risk factors in Corona Virus Disease 2019: A Retrospective Multicenter Study. Epilepsia 2020: https://doi.org/10.1111/epi.16524
- Helms J, Kremer S, Merdji H, et al. Neurologic Features in Severe SARS-CoV-2 Infection. NEJM 2020. Correspondence DOI: 10.1056/NEJMc2008597
- Dugue R, Cay-Martinez KC, Thakur K, et al. Neurological manifestations in an infant with COVID-19. Neurology. 2020 https://doi.org/10.1212/WNL.0000000000009653
- Vollono C, Rollo E, Romozzi M, et al. Focal status epilepticus as unique clinical feature of COVID-19: A case report. Seizure. 78 (2020):109-112. https://doi.org/10.1016/j.seizure.2020.04.009
- Moriguchi T, Norikazu H, Goto J, et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. International Journal of Infectious Disease. 94 (2020): 55-58. https://doi.org/10.1016/j.ijid.2020.03.062
- Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics 145(6): June 2020. https://doi.org/10.1542/peds.2020-0702
- Jones VG, Mills M, Suarez D, et al. COVID-19 and Kawasaki Disease: Novel virus and novel case. Hosp Pediatr 2020: DOI: 10.1542/hpeds.2020-0123