key: cord-0906654-tkku4s9a
authors: Khedr, Eman M; Shoyb, Ahmed; Mohammaden, Mahmoud; Saber, Mostafa
title: Acute Symptomatic Seizures and COVID-19: Hospital-Based Study
date: 2021-05-05
journal: Epilepsy Res
DOI: 10.1016/j.eplepsyres.2021.106650
sha: ff68dc47cef383dafad2871834bafe9f3adbdad9
doc_id: 906654
cord_uid: tkku4s9a

BACKGROUND AND PURPOSE: post COVID-19 seizures are relatively rare. The aim of the present study was to estimate the frequency of acute symptomatic seizures among patients with COVID-19 and to discuss possible pathophysiological mechanisms. MATERIAL AND METHODS: Out of 439 cases with COVID-19 that were admitted to Assiut and Aswan University hospitals during the period from 1 June to 10 August 2020, 19 patients (4.3%) presented with acute symptomatic seizures. Each patient underwent computed tomography (CT) or magnetic resonance imaging (MRI) of the brain and conventional electroencephalography (EEG). Laboratory investigations included: blood gases, complete blood picture, serum D-Dimer, Ferritin, C-reactive protein, renal and liver functions, and coagulation profile. RESULTS: Of the 19 patients, 3 had new onset seizures without underlying pathology (0.68 % out of the total 439 patients); 2 others (0.46%) had previously diagnosed controlled epilepsy with breakthrough seizures. The majority of cases (14 patients, 3.19%) had primary pathology that could explain the occurrence of seizures: 5 suffered a post COVID-19 stroke (3 ischemic and 2 hemorrhagic stroke); 6 patients had COVID-related encephalitis; 2 patients were old ischemic stroke patients; 1 patient had a brain tumor and developed seizures post COVID-19. CONCLUSION: acute symptomatic seizure is not a rare complication of post COVID-19 infection. Both new onset seizures and seizures secondary to primary brain insult (post COVID encephalitis or recent stroke) were observed.

In addition to systemic and respiratory symptoms, it has recently been reported that 36.4% (78/214) of patients with COVID-19 develop neurological symptoms (Mao et al., 2020) , of which anosmia and headache are the most common whereas seizures and stroke are relatively rare (Whittaker et al., 2020) . The proposed mechanisms of CNS involvement could be attributed to retrograde movement from the olfactory nerve, entry into CNS through circulating lymphocytes or entry through permeable blood brain barrier (BBB) (Moriguchi et al., 2020; Ye et al., 2020) .

Given that patients with COVID-19 may have hypoxia, multiorgan failure, and severe metabolic and electrolyte derangements, it is plausible to expect clinical or subclinical acute symptomatic seizures to occur in some cases (Emami et al., 2020; Nalleballe et al., 2020; Romero-Sánchez et al., 2020) . Only a few studies had been conducted to investigate the underlying mechanism of seizures associated COVID-19 (Emami et al., 2020; Hepburn et al., 2020; Nikbakht et al., 2020; Sohal and Mansur, 2020) .

The aim of the present study is to estimate the frequency of seizures among Egyptian patients with COVID-19 and to discuss possible pathophysiological mechanisms.

This was an observational, retrospective cohort study sampled from all patients with suspected COVID-19 who were sufficiently ill to be admitted during the period of 1 June to 10 August 2020 to the largest two University hospitals in Upper Egypt (Assiut University Hospitals and Aswan University hospital). Evidence of SARS-CoV-2 infection was defined as: 1-Cases with definite COVID-19 if patients came with clinical symptoms of infection and PCR of respiratory samples (eg, nasal or throat swab) was positive. 2-Cases with probable COVID-19 if clinical symptoms and chest CT was consistent with COVID-19 plus one or 2 laboratory investigations were positive J o u r n a l P r e -p r o o f (lymphopenia, high serum ferretin and D-Dimer Level) but PCR was negative or unavailable. Unfortunately it was not possible to sample CSF in these situations.

All patients who had "seizure" as a presenting manifestation of their illness were recruited and included in the study. The data of clinical manifestations of COVID-19 and the associated comorbidities were recorded. A chest CT was taken to demonstrate the ground-glass opacities of the lungs with consolidation and laboratory investigations including blood gases, complete blood picture, serum D-Dimer, Ferritin, C-reactive protein, renal, liver functions, coagulation profile. CT and/or MRI brain scan and EEG were performed in each patient. Unfortunately it was not possible to sample CSF in these situations.

The primary outcome 1-Estimation of the frequency of seizures either primary or secondary.

2-Determination of the type of seizures associated with COVID-19, complications with serial seizures or status epilepticus and correlation with laboratory and imaging studies.

Written informed consent was obtained from conscious patients or from first degree relatives of the others. The Local Ethical Committee of the Faculty of Medicine, Assiut and Aswan University/Egypt approved the study.

Data was coded, tabulated and recorded on a PC using the Statistical package for Social Science (SPSS 25). Number and percent or means ± standard deviation (SD) were used to represent data. The level of significance was set at P < 0.05. ground-glass opacity in CT chest; the remaining patient had a normal CT chest. One patient had anemia, thrombocytopenia, one had lymphopenia and the third one had normal laboratory data. (Table 1) Post COVID-19: Previously diagnosed, controlled epilepsy with breakthrough seizures Two patients had a history of previously diagnosed, controlled epilepsy and had been seizure-free for up to 2 years prior to infection but had a recurrence of their seizures post COVID-19. One of them had fever, fatigue, cough, dyspnea and confusion for 4 days followed by serial seizures. The other one had fever for only 2 days before developing generalized seizures. Details of PCR and CT chest and laboratory data are illustrated in table 1.

Post-COVID-19: Acute stroke (ischemic and hemorrhagic stroke as documented by CT/MRI brain) presenting with seizure onset J o u r n a l P r e -p r o o f Three patients had a recent ischemic stroke with seizure onset after COVID-19 infection. All had fever, cough and sputum; one had additional dyspnea as constitutional symptoms for 3 to 7 days. Onset of seizure was coincident with stroke in all cases. One patient had generalized seizures and the other 2 had focal seizures with secondary generalization. Two patients had HTN and cardiovascular disease (CVD); one of them also had renal impairment. The third patient had raised liver enzymes. All 3 patients had a negative PCR for COVID-19 but they had bilateral ground-glass opacities on chest CT. All patients had raised D-dimer, anemia and leukocytosis; 2 of them had lymphopenia.

Of the two patients who had acute cerebral hemorrhage, one had fever, myalgia, cough and headache for 2 days followed by repeated focal seizures and disturbed consciousness with and left hemiplegia. The other patient had fever, headache, cough, dyspnea and confusion for 3 days before having generalized seizures and left hemiplegia. Other details are illustrated in table 2.

Six patients developed seizures in the context of COVID-19 related encephalitis. All of them had fever and 5 of them had headache and cough; these constitutional symptoms lasted between 2 to 6 days before seizures developed. One patient had visual hallucinations and another one had meningeal signs. All 6 patients had generalized seizures and 2 of them developed status epilepticus; one of these had serial seizures.

All were transferred to ICU. MRI brain scans with contrast showed a combination of diffuse cerebral oedema, leptomeningeal enhancement with T2 and FLAIR hyperintensities in the frontal lobes and/or bilateral medial temporal lobes and thalami. One patient had a comorbid pineal body tumor and hydrocephalus. EEG showed diffuse slowing of the background activity with bilateral periodic sharp waves and epileptiform discharges. One patient was 4 months pregnant. Other details are illustrated in table 3.

J o u r n a l P r e -p r o o f Two patients had a history of old ischemic stroke confirmed by CT brain. One patient had fever, cough and dyspnea as constitutional symptoms for 4 days while the other had no constitutional symptoms. One patient presented with focal seizures with secondary generalization and the other presented with generalized seizures complicated by serial seizures. The remaining patient had an old parafalcine meningioma as documented by brain MRI. After admission to hospital she had disturbed consciousness for 1 day and then developed frequent generalized seizures complicated by status epilepticus. PCR, comorbidities, CT chest and laboratory data are illustrated in table 4.

Severe acute respiratory syndrome Coronavirus-2 (SARS)-CoV-2 was first reported in Wuhan, China and officially named COVID-19 by the WHO on February 2020. The primary target cells for SARS-CoV-2 are the epithelial cells of the respiratory and gastrointestinal tract, which contain angiotensin converting enzyme 2 (ACE2), which is the portal of the virus to enter the cell . The ACE2 is expressed in the brain, particularly in the brain stem and in the regions responsible for regulation of cardiovascular function; expression of ACE2 has been found in both neurons and glia (Gowrisankar and Clark, 2016) . In present study we found 19 (4.3%) patients who presented with seizures mostly after constitutional symptoms of COVID-19, which was higher than other studies (Romero-Sánchez et al., 2020) . In a study from Spain, during March 2020, of 841 patients hospitalized with confirmed COVID-19, seizures occurred in 6 (0.7%) patients, 2 of which followed intracranial hemorrhages; 1 patient had encephalitis and 1 patient was previously diagnosed with epilepsy (Romero-Sánchez et al., 2020) . In Wuhan, China, from January to February 2020, of 214 patients with confirmed COVID-19, seizures occurred in only 1 (0.5%) patient. In the USA, from January to June 2020, of 40,469 patients with confirmed COVID-19, only 258 (0.6%) patients had seizures (Nalleballe et al., 2020) . All these cases were newly-developed seizures "without underlying pathology" or occurred in known epileptic patients, or were secondary to primary brain injury (ischemic or hemorrhagic stroke) post COVID-19.

In the present study; only 3 patients (0.68%) developed new onset seizures without underlying pathology. It could be contributed to direct entry of the virus to the CNS via olfactory nerve or the affected sensory or motor neurons lead to release of proinflammatory cytokines (TNF-α, IL-6, IL-1B), nitric oxide, prostaglandin E2, and free radicals, and causes chronic inflammation neural hyper-excitability, seizure, and death (Huang et al., 2020a; Tufan and Avanoğlu Güler, 2020) . SARS-CoV-2 triggers a systemic inflammatory storm (peripherally) with a massive release of cytokines, chemokines, and other inflammation signals which causes a significant disruption of the blood brain Barrier (BBB) leading to neuroinflammation, neuronal apoptosis and seizures (Steardo et al., 2020) . The accumulation of inflammatory markers also may lead to local cortical irritation that precipitates seizures (Hepburn et al., 2020) . High levels of glutamate released from ischemic or hypoxic cells into the extracellular spaces may activate AMPA and NMDA receptors leading to neuronal apoptosis or death (Prentice et al., 2015) . Decreased GABA receptors may also lead to hyper-excitability of neural networks and seizure (Galanopoulou, 2008) . In the present study the 2 (0.46%) patients who previously had well-controlled epilepsy and experienced breakthrough seizures. Seizures exacerbation in controlled epileptic patients could be attributed to factors such as fever and hypoxemia which may trigger the seizures and sometimes introduce complications such as serial seizures or status. Stress also might be an independent precipitant for triggering seizures in some epileptic patients (Huang et al., 2020b ).

On the other hand the incidence of seizure following acute stroke is rare, in the present study 5 patients had post-COVID-19 acute stroke (3 ischemic and 2 hemorrhagic) associated with seizure onset. The Incidence of acute ischemic stroke was approximately 5% in hospitalized patients with severe disease in W uhan, China . COVID-19 leads to hypoxemia and excessive secretion of inflammatory cytokines, which contributes to the occurrence of ischemic stroke (Zhai et al., 2020) and increases the incidence of seizure (Hepburn et al., 2020) . The incidence of seizures following spontaneous intracerebral hemorrhage reportedly ranges from 2.8-18.7% (Woo et al., 2012) . Seizures after hemorrhagic strokes are thought to be due to irritation by products of blood metabolism. The exact pathophysiology is unclear, but an J o u r n a l P r e -p r o o f associated ischemic area secondary to hemorrhage is thought to play a part.

Hemosiderin deposits are thought to cause irritability after a hemorrhagic stroke (Silverman et al., 2002) . About 11.5% of stroke patients are at risk of developing poststroke seizures within five years (Myint et al., 2006) . The occurrence of seizure in old stroke patients could occur due to changes in neuronal excitability and gliotic scarring (Myint et al., 2006) . In present study, 2 patients had a history of old stroke and newlydeveloped seizures following COVID-19. The occurrence of seizure in old stroke patients in the present study may be unrelated to COVID-19 infection, but one patient had fever and hypoxemia and the other was dependent on tramadol and stopped suddenly while in the hospital which could potentially explain seizure occurrence.

The occurrence of seizures associated encephalitis or brain tumors are common. The incidence of encephalitis related to SARS-CoV-2 is debated, with only case reports available (Moriguchi et al., 2020; Pilotto et al., 2020; Wong et al., 2020) (Glantz et al., 2000) . Seizures exacerbation in patient with brain tumor could be attributed to fever and hypoxemia of COVID-19 which may trigger the seizures. Wu, Y., Xu, X., Chen, Z., Duan, J., Hashimoto, K., Yang, L., Liu, C., Yang, C., 2020. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, behavior, and immunity 87, 18-22.

Ye, M., Ren, Y., Lv, T., 2020. Encephalitis as a clinical manifestation of COVID-19. Brain, behavior, and immunity 88, 945-946.

Zhai, P., Ding, Y., Li, Y., 2020. The impact of COVID-19 on ischemic stroke. 15, 78. 

GABA(A) receptors in normal development and seizures: friends or foes?

Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors

Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures

Acute Symptomatic Seizures in Critically Ill Patients with COVID-19: Is There an Association? Neurocritical care

COVID-19 outbreak: The impact of stress on seizures in patients with epilepsy

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

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

Post-stroke seizure and post-stroke epilepsy

Spectrum of neuropsychiatric manifestations in COVID-19

How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Multiple sclerosis and related disorders 46, 102535

Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases. Oxidative medicine and cellular longevity

Neurologic manifestations in hospitalized patients with COVID-19: The ALBACOVID registry

Poststroke seizures

Neuroinfection may contribute to pathophysiology and clinical manifestations of COVID-19

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

Neurological Manifestations of COVID-19: A systematic review and current update