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COVID-19 and Seizures
Introduction
Over time as human civilization has grown, it has faced several pandemics over thousands of years. To name a few, lately, since the beginning of the 21st century, pandemics have included swine flu (H1N1) in 2009 and two novel coronaviruses—severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2015 —before the current novel coronavirus disease 2019 (COVID-19) infection caused by a beta-coronavirus (SARS-CoV-2) in 2019. Other than the common respiratory presentations for COVID-19, neurological presentations such as headaches, dizziness, stroke along with seizures have been described. Seizure occurrence is varied in the published literature, ranging from new onset seizures or new onset status epilepticus to the presence of electrographic seizures or nonepileptic spells.
Seizures in Coronavirus Infections
Over the last few decades, a variety of viral infections have been associated with neurologic manifestations including seizures and status epilepticus. These have been described in previous coronavirus pandemics such as MERS and the influenza A H1N1 pandemic. Seizures may also be seen in a variety of forms of viral encephalitis associated with upper respiratory infections such as influenza A H3N2 encephalitis. Prior studies have demonstrated that coronaviruses in particular are one of the most common viral respiratory illnesses responsible for febrile seizures in children.
Neurologic manifestations associated with coronavirus infections were first reported in a patient with SARS-CoV infection in 2003. More specifically, this patient presented with seizures. A second patient with documented SARS-CoV infection and seizures was reported in the literature shortly after. Both had SARS-CoV RNA in the cerebrospinal fluid (CSF). Additional studies found that up to 23% of hospitalized children with suspected encephalitis in the setting of the coronavirus infection had seizures. Similar reports of seizures associated with infections were reported with MERS. One study looking at 70 patients with MERS-CoV infection found that 26% of patients had altered mental status and 8.6% of infected patients had seizures.
In the early months of the COVID-19 pandemic, data regarding the incidence of seizures in COVID-19 infections was very scarce. Since then, numerous case reports have been published reporting seizures or status epilepticus associated with the SARS-CoV-2 infection ( Table 5.1 ). A study by Mao et al. on neurological presentations revealed that 0.5% of patients (1/214) had seizures, whereas another study reported clinical seizure-like events of concern in 63.3% of patients with COVID-19 infection.
Table 5.1
Summary of Patients With COVID-19 Infection Presenting With Seizures Or Status Epilepticus With Relevant Information Including Outcomes.
| Author, Publication Month and Year, and Country | Patient Age (Years), Gender, and Presentation | History of Epilepsy | Pertinent Medical History | Presentation of Seizure/Status Epilepticus | COVID-19 Diagnosis | Workup (Imaging, CSF) | EEG Findings | Outcome |
|---|---|---|---|---|---|---|---|---|
| Vollono et al., May 2020; Italy | 78, F, R face and limb twitching | Yes | Postencephalitic epilepsy (HSV-1) | Myoclonic jerks of R face, upper, and lower extremities | NP (+) | MRI: gliosis and atrophy involving L temporoparietal lobe | Semirhythmic, irregular, high amplitude delta waves in L Fr-C-T regions consistent with SE | Treated with valproic acid, midazolam, lopinavir-ritonavir, hydroxychloroquine. Discharged in stable condition |
| Somani et al., June 2020: USA | 73, F, dyspnea and confusion | No | L frontal skull base encephalocele and hydrocephalus requiring ventriculoperitoneal shunt | Face and arm myoclonus, worsening mentation 1 day after presentation | TA (+) | MRI and CSF deferred | Continuous b/l independent PDs over b/l hemispheres with evolution into recurrent sz from alternating hemispheres consistent with myoclonic SE | EEG improved with levetiracetam, lacosamide, phenytoin, and midazolam. Care was withdrawn due to organ failure |
| 49, F, altered mentation, witnessed sz | No | Conversion disorder and schizoaffective disorder | R facial twitching and head version to R, followed by GTC sz | NP (−) on admission. After 3 days, repeat NP (+) | MRI unremarkable. CSF deferred | Multiple sz (4–6/h) from midline and L Fr-C regions | Seizures resolved with levetiracetam, multiple doses of lorazepam, and propofol | |
| Hepburn et al., May 2020; USA | 82, M, dyspnea and altered mentation x 10 days | No | CKD and COPD | R eyelid and facial twitching on hospital day 5 | NP(+) | MRI deferred due to pacemaker, CSF deferred due to coagulopathy | Multiple sz from b/l Fr-T regions (L > R), progressing to focal SE, most were NC | Seizures resolved with levetiracetam. However, care was withdrawn given persistent respiratory failure |
| 76, M, fever, encephalopathy | No | L3-S1 laminectomy 5 days prior and asthma on benralizumab | Worsening encephalopathy and L upper extremity clonic activity following surgical drainage of epidural abscess | NP(+) | MRI: chronic white matter hyperintensities. CSF deferred | 3 focal sz arising from R C-P region x 30 s each | Seizures resolved with levetiracetam | |
| Pilato et al., July 2020; USA | 71, M, presyncopal episode, developed fever and URI symptoms after admission | No | Recent liver transplant | Developed agitation, eye twitching, and rhythmic movements involving head, mouth, and neck | NP(+) | MRI: periventricular white matter hypodensities | Generalized PDs, generalized delta/theta slowing, decreased voltage L hemisphere. After 32 days, EEG-multiple independent b/l Fr-T sz with R face twitching | Seizures controlled with levetiracetam, phenobarbital, and lacosamide. Patient deceased after cardiac arrest |
| 57, M, prolonged seizure in the setting of fever | Yes | R temporal lobe epilepsy, TBI, and stroke | Persistent decreased level of consciousness | NP(+) | Neuroimaging N/A | R posterior quadrant PDs, focal, NC SE. After 18 days, EEG-R posterior-quadrant lateralized PDs | Seizures resolved with propofol infusion and up-titration of home medications | |
| Sohal et al., May 2020; USA | 72, F, hypoglycemia, shortly after developed respiratory failure and altered mental status | No | ESRD on hemodialysis and diabetes mellitus | On day 3, developed multiple episodes of tonic clonic movements of all extremities for several minutes | NP (+) | MRI and CSF deferred | 6 L T sz, interictal—L T sharp waves | Treated with midazolam infusion, levetiracetam, and valproate. Patient deceased after cardiac arrest |
| Flamand et al., August 2020; France | 80, F, respiratory distress, fever x 2 days | No | Altered mental status and clonic movements of L foot | Initial NP(−), repeat on day 25 NP(+) | MRI and CSF studies normal | days 6 & 8—EEG-repetitive epileptiform discharges with quasi-rhythmic spatiotemporal evolution in bi-frontal regions. Days 18 and 21—EEG periodic triphasic activity | Seizures improved with valproate, lacosamide, and clobazam. Patient deceased on hospital day 25 | |
| Balloy et al., August 2020; France | 59, M, fever, dyspnea, and cough prompting intubated for respiratory failure | No | Atrial fibrillation | Impaired level of consciousness and behavioral disturbance following weaning of midazolam | Initial NP (−), repeat TA (+) | MRI and CSF PCR negative, including CSF SARS-CoV-2 RNA | Predominantly frontal runs of rhythmic delta discharges with superimposed spikes x 5–6 min | Improved on levetiracetam and clobazam |
| Moriguchi et al., May 2020; Japan | 24, M, fever, URI x 9 days | No | None | GTC sz x 1 min | NP(−), CSF(+) | MRI: DWI hyperintensity-R lateral ventricle wall, R MTL CSF: SARS-CoV-2 RNA (+), 12 WBCs (mononuclear predominant), OP-320 mm H 2 O |
N/A | Treated with levetiracetam, ceftriaxone, vancomycin, acyclovir, steroids, and favipravir |
| Kadono et al., June 2020; Japan | 44, M, anosmia, left hand and face numbness. | Yes | Cerebral venous sinus thrombosis complicated by hemorrhagic infarct and epilepsy, status post-R Fr-T decompression 6 months prior | Intermittent L hand and face twitching that secondarily generalized | NP(+) | CTH with worsening R temporal lobe edema. MRI with no new stroke. CSF deferred | N/A | Episodes resolved with levetiracetam. Treated with hydroxychloroquine and azithromycin |
| Lyons et al., June 2020; Ireland | 20, M, myalgias and lethargy x 3 days, then GTC sz at home | No | None | GTC sz | NP(−), repeat after 2 days NP(+) | MRI unremarkable. CSF with lymphocytic pleocytosis (21 cells/mm, 99% mononuclear cells), CSF SARS-CoV-2 PCR(−) | EEG after discharge-normal | Treated with levetiracetam, ceftriaxone, vancomycin, and acyclovir |
| Haddad et al., May 2020, USA | 41, M, dry cough, fever, and confusion x 6 days | No | Well-controlled HIV on dolutegravir-lamivudine and recurrent HSV on chronic suppressive therapy | Worsening mentation followed by GTC sz | NP(+) | MRI unremarkable. CSF with no WBCs | Diffuse slowing, no epileptiform activity | Clinically improved with hydroxychloroquine and azithromycin |
| Karimi et al., March 2020; Iran | 30, F, dry cough fever x 5 days | No | None | GTC sz in sleep 2 days prior to presentation, followed by recurrent (5) szs every 8 h | NP(+) | MRI and CSF studies normal. CSF SARS-CoV-2 PCR negative | N/A | Treated with phenytoin, levetiracetam, chloroquine, and lopinavir-ritonivir |
(−), negative; (+), positive; b/l, bilateral; C, central; CKD, chronic kidney disease; CTH, computed tomography of head; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CSF, cerebrospinal fluid; DWI, diffusion weighted images; EEG, electroencephalogram; ESRD, end-stage renal disease; F, female; Fr, frontal; GTC, generalized tonic clonic; HSV, herpes simplex virus; L, left; M, male; MRI, magnetic resonance imaging; MTL, mesial temporal lobe; N/A, not available; NC, nonconvulsive; NP, nasopharyngeal swab PCR; OP, opening pressure; R, right; P, parietal; PCR, polymerase chain reaction; PD, periodic discharges; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE, status epilepticus; sz, seizure; T, temporal; TA, tracheal aspirate PCR; TBI, traumatic brain injury; URI, upper respiratory infection; x = lasting for; WBC, white blood cells.
Predisposition to Seizures in COVID-19 Infection
Similar to other coronaviruses, the SARS-CoV-2 virus has been found to be neurotropic and to have neuroinvasive properties. The SARS-CoV-2 virus has an affinity to the angiotensin-converting enzyme 2 (ACE2) receptor found on the cells of multiple organs, including cells of the central nervous system. Binding of the virus to this receptor allows for entry of the virus into these cells. The specific mechanism responsible for seizure development in infected patients remains unclear; however, it is likely multifactorial in nature. Contributing factors are thought to include direct neuroinvasion leading to focal cerebral injury, breakdown of the blood–brain barrier, and cerebral blood flow dysfunction. Additional factors likely include an inflammatory cascade leading to accumulation of inflammatory mediators, activation of glutamate receptors, and neuronal hyperexcitability. The possibility of a cytokine storm mechanism via activation of the ACE2 signaling pathway has also been hypothesized for seizure occurrence. Given that the SARS-CoV-2 infection can lead to severe organ dysfunction, seizures may also occur with metabolic derangements, in the setting of other associated conditions such as renal, hepatic, and hypoxemic respiratory failure.
Encephalopathy is one of the most common neurologic manifestations of COVID-19 infection. However, some studies did not reveal any seizure activity on EEG. In addition to encephalopathy, a few cases of suspected SARS-CoV-2 associated encephalitis have been reported. In one case series of encephalopathy with encephalitis diagnosed by increased CSF levels of anti-S1 IgM and abnormal CSF cytokines, consistent with direct central nervous system involvement by SARS-CoV-2, though with undetectable CSF RNA, two of the three patients exhibited multifocal myoclonus. Overall, this promotes the possibility that mechanisms including peri-infectious inflammation mediated by antibodies, complement, vasculopathy, or altered neurotransmission, other than direct brain infection, might account for the cause.
Even with an increasing amount of data regarding seizures and COVID-19 infection, the question of whether or not concurrent SARS-CoV-2 infection further increases the risk of seizures in patients with a known history of epilepsy remains. Overall, evidence at this point demonstrates that the risk of seizures is not significantly increased in patients with epilepsy. The majority of cases of seizure associated with COVID-19 infection were in patients with no previously known history of epilepsy.
Certain epilepsy syndromes where seizures may be triggered by fever, such as Dravet syndrome, may theoretically have worsening of their seizure frequency during COVID-19 infection. However, in a study from Spain that assessed the impact of national lockdown on patients in developmental and epileptic encephalopathies from the caregiver’s perspective, epilepsy remained stable in 86% of cases, and of the 14.1% of patients with increased seizure frequency, one had status epilepticus. Patients with epileptic encephalopathies may be at higher risk of seizures in the setting of COVID-19 infection due to factors that include triggers, antiseizure medications, and additional comorbid medical conditions, including respiratory disease.
A multicenter retrospective study in China performed during the early COVID-19 pandemic (January to February 2020) demonstrated no cases of new onset seizure or status epilepticus in 304 patients diagnosed with COVID-19 infection, even though patients had multiple risk factors including prior stroke, traumatic brain injury, central nervous system infection, and severe metabolic disturbances. None of these patients had a history of epilepsy. This suggests that even in the presence of underlying risk factors, infection with SARS-CoV-2 did not increase the risk of seizure occurrence. However, no routine or long-term EEG was recorded in that cohort due to risk of virus exposure, so the presence of subclinical seizures could have gone unnoticed. Several reports of ischemic stroke associated with a suspected hypercoagulable state have been documented in COVID-19 infection. Although it is reasonable to believe that this would result in an associated risk of poststroke epilepsy, there have been no reports of this at the time of publication.
Since the publication of whole genome sequence analysis on January 5, 2020, the SARS-COV2 genome has remained largely unchanged in some regions while others have shown diversity, and 198 filtered recurrent mutations in the SARS-CoV-2 genome have been revealed until the date of this publication. Genomic mutations are sometimes known to be associated with variable clinical features. There are no studies published thus far, relating neurological manifestations to this, let alone occurrence of seizures in those who are infected.
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