key: cord-0743005-kj2iszoc
authors: Anand, Pria; Al-Faraj, Abrar; Sader, Elie; Dashkoff, Jonathan; Abdennadher, Myriam; Murugesan, Rubachandran; Cervantes-Arslanian, Anna M.; Daneshmand, Ali
title: Seizure as the presenting symptom of COVID-19: A retrospective case series
date: 2020-07-21
journal: Epilepsy Behav
DOI: 10.1016/j.yebeh.2020.107335
sha: 4296aa3240c9f1bb224748a0540d897f1510177b
doc_id: 743005
cord_uid: kj2iszoc

Abstract Background Coronavirus Disease 2019 (COVID-19) has rapidly become a global pandemic, with over 1.8 million confirmed cases worldwide to date. Preliminary reports suggest that the disease may present in diverse ways, including with neurological symptoms, but few published reports in the literature describe seizures in patients with COVID-19. Objective To characterize the risk factors, clinical features, and outcomes of seizures in patients with COVID-19. Methods Retrospective case series. Cases were identified through a review of admissions and consultations to the neurology and neurocritical care services between April 1, 2020, and May 15, 2020. Setting A tertiary care, safety-net hospital in Boston, MA. Participants Patients presenting with seizures and COVID-19 during the study period. Results Seven patients met inclusion criteria (5 female, 71%). Patients ranged in age from 37 to 88 years (median 75 years). Three patients had a prior history of well-controlled epilepsy (43%), while 4 patients had new-onset seizures, including 2 patients with prior history of remote stroke. Three patients had no preceding symptoms of COVID-19 prior to presentation (57%), and in all cases, seizures were the symptom that prompted presentation to the emergency department, regardless of prior symptoms of COVID-19. Conclusions Provoking factors for seizures in patients with COVID-19 may include metabolic factors, systemic illness, and possibly direct effects of the virus. In endemic areas with community spread of COVID-19, clinicians should be vigilant for the infection in patients who present with seizures, which may precede respiratory symptoms or prompt presentation to medical care. Early testing, isolation and contact tracking of these patients can prevent further transmission of the virus.

J o u r n a l P r e -p r o o f 5 stroke epilepsy and one patient with epilepsy following cardiac arrest. Four patients had newonset seizures, including 2 patients with prior history of remote stroke, one patient with Parkinson's disease, and one with end-stage renal disease on hemodialysis. Home anti-epileptic medications included valproic acid, phenytoin, levetiracetam, and zonisamide prescribed for epilepsy, and lorazepam prescribed for anxiety in one patient without epilepsy.

Features of COVID-19: Presenting symptoms of COVID-19 included cough, fatigue, ageusia, fever, shortness of breath, and emesis in 4 patients (57%). Symptoms began 2-18 days prior to presentation with seizure. Three patients had no preceding symptoms of COVID-19 prior to presentation (43%). In all cases, COVID-19 was identified based on characteristic clinical features and positive nasopharyngeal PCR testing for SARS-CoV-2. Fever was noted in 5 cases (71%), and lymphopenia was noted in 4 (57%). D-dimer, C-reactive protein, and ferritin were elevated in all 7 patients. Chest imaging was abnormal in all 7 patients, and 4 patients (57%) had severe respiratory failure requiring intubation. One patient is deceased, while a second patient remains intubated, requiring ongoing respiratory support. The remaining 5 patients (71%) have been discharged from the hospital and returned to baseline neurologic function without recurrent seizures.

Seizure onset and semiology: In all 7 patients, seizures prompted presentation to the emergency department in spite of prior symptoms of COVID-19. Five patients (71%), had generalized tonicclonic seizures, while 2 patients had focal seizures characterized by gaze deviation, head version, and unilateral motor symptoms. Four patients developed focal post-ictal deficits that subsequently resolved. J o u r n a l P r e -p r o o f 6 Imaging and CSF findings: Non-contrast enhanced head CT was obtained in all cases and showed no new abnormalities in any of the cases. Arterial or venous vessel imaging was obtained in 3 cases (43%) without cerebral venous sinus thrombosis or large-vessel occlusion in any of the cases. MRI brain with and without contrast (Figure 1 ) was obtained in just one case and revealed gyriform restricted diffusion in the cortex of the bilateral frontal lobes and extensive abnormal FLAIR signal hyperintensity involving the subcortical U-fibers, periventricular white matter, bilateral cerebellar white matter, and bifrontal cortices. CSF studies were obtained for one patient (7) and demonstrated a normal protein and <1 nucleated cell/μL.

Electrographic findings: Twenty-four hour electroencephalography (EEG) was obtained in 2 cases. One patient (patient 6) had moderately slow background activity, with frequent sharp waves and focal epileptiform discharges in the right parieto-occipital region and occasional independent sharp waves in the right posterior temporal region. There were also frequent generalized sharp waves with triphasic morphology and right greater than frontal predominance.

The second patient (patient 7) had moderate to severe encephalopathy, with frequent short runs of generalized rhythmic delta activity (GRDA). Her clinical status epilepticus had resolved by the time of EEG.

Although systemic infection may be a trigger for breakthrough seizures in patients with a history of epilepsy, to date, few cases in the literature describe seizures in patients with COVID-19, including one in a critically ill patient, one in a patient with a history of epilepsy after prior viral J o u r n a l P r e -p r o o f 7 encephalitis, and 2 in patients with a COVID-19 encephalitis based on SARS-CoV-2 detection in the cerebrospinal fluid. 1,2,9-10 One large cohort from China's Hubei Province found that of 304 patients with COVID-19, including 84 with brain insults or metabolic imbalances, none had seizures and 2 had "seizure-like symptoms" in the setting of hypocalcemia, concluding that the virus does not carry an increased risk of seizure. 5 Notably, no patients with underlying epilepsy were included in the cohort. Three patients had a prior history of well-controlled epilepsy, while 4 patients had new-onset seizures, including 2 patients with prior history of remote stroke. In one case, valproic acid levels were found to be subtherapeutic, which may have precipitated seizures in conjunction with infection. Although the etiology for subtherapeutic levels was unclear, reports from prior coronavirus epidemics suggested that breakthrough seizures may occur at higher rates in the pandemic setting, as patients may avoid hospitals and pharmacies and have more difficulty obtaining their prescribed antiepileptic therapies. 4 Among patients with underlying epilepsy, respiratory infections can also be a frequent precipitant of breakthrough seizures, particularly in children. 5 Ancillary testing was limited in all cases, in part because of concerns regarding viral transmission to healthcare workers and other patients. Just one patient, who presented with status epilepticus following hemodialysis, had a brain MRI during her hospitalization. This study was markedly abnormal, with gyriform diffusion restriction and extensive leukoencephalopathy.

Etiologic considerations included sequelae of her prolonged status epilepticus or possible viral encephalitis, although CSF studies showed no evidence of inflammation or infection. EEG was obtained in just 2 cases and revealed epileptiform discharges in one case and findings suggestive of encephalopathy in the other.

Experience with prior pandemic RNA viruses suggest that both new-onset and breakthrough seizures may be a common presenting manifestation of viral illness. 8 In some cases, these may be a manifestation of encephalitis, while in others, they may reflect metabolic derangements, severe systemic illness, an inability to obtain medications, or gastrointestinal symptoms impeding absorption of oral medications. Because of prior reports regarding thromboembolic and hemorrhagic events in patients with COVID-19, seizures may also represent the presenting symptom of cerebral venous sinus thrombosis or intracerebral hemorrhage in some cases.

Regardless of etiology, COVID-19 should be considered in the differential diagnosis for patients presenting with seizures during the pandemic, as early consideration may lead to earlier detection and appropriate precautions.

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. 

Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study

Acute cerebrovascular disease following COVID-19: a single center, retrospective, observational study

A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2

The frequency and precipitating factors for breakthrough seizures among patients with epilepsy in Uganda

New-onset acute symptomatic seizure and risk factors in Corona Virus Disease

Central nervous system manifestations of COVID-19: A systematic review

Seizures associated with coronavirus infections

Focal status epilepticus as unique clinical feature of COVID-19: A case report