COVID-19-associated seizure

Seizure refers to an episode of symptoms due to abnormally excessive or synchronous neuronal activity in the brain followed by return to normal state. Seizures manifest as abnormal uncontrolled shaking movements that involve much of the body with loss of consciousness, shaking movements of part of the body with variable level of consciousness or a subtle momentary loss of consciousness. As COVID-19 (caused by SARS-Cov2) is now known to have several neurological complications, seizure is one of the complications seen in a few cases so far. Brain waive activity can be seen on EEG to confirm diagnosis since structural changes are very rarely seen on brain imaging. Anti-seizure medications are used for symptomatic treatment of seizure along with treatment of COVID-19.

• First case of seizure in COVID-19 patient was a result of meningitis/encephalitis caused by SARS-CoV2 and documented by Moriguchi et al in late February 2020 ^[1].
• After that, more cases were reported with acute seizures as a complication of COVID-19.^[2][3]
• In early February 2020, seizurelike activity was reported in two COVID-19 patients but the cause was acute anxiety disorder and electrolyte imbalance instead of viral damage by SARS-Cov-2^[4]
• To view the historical perspective of COVID-19, click here.

• There is no established classification for COVID-19 associated seizure.

• Neurological complications caused by COVID-19 are through direct or indirect pathways.
• This includes hematogenous pathway, neuronal retrograde dissemination through olfactory bulb, entry into to glial cells and neurons via ACE2 receptor and impairment of gas exchange in lungs leading to anemia, hence increasing anaerobic metabolites in brain resulting in cellular and interstitial edema ^[5]
• Seizures in a patient with COVID-19 may be due to primary virus infection or due to reactivation of the latent virus.
• Infiltration of the brain tissue by the virus and subsequent production of toxins by the virus is one of the several mechanisms that can cause seizures in a COVID-19 patient. ^[6]
• Production of inflammatory mediators by the brain may also trigger seizures.
• Inflammatory cytokines that are released as a result of inflammatory cascade provoked by COVID-19 include interleukin 2,6,7, and 10, TNF-α and granulocyte colony-stimulating factor. Consequently, activation of glutamate receptors by the cytokines causes neuronal hyperexcitability and development of seizures. ^[6]

• Cause of COVID-19-associated seizure is viral infection by SARS-CoV-2 and its consequences which include:^[8]
  • Hypoxia
  • Metabolic derangement
  • Organ failure
  • Cerebral damage.^[9]
  • To view causes of COVID-19, click here.

• For further information about the differential diagnosis, click here.
• To view the differential diagnosis of COVID-19, click here.

• More data is required to comment on epidemiology and demographics of COVID-19-associated seizure.
• One study, specifically investigated the neurological manifestations of COVID-19 and documented CNS manifestations in 25% of the patients (headache (13%), dizziness (17%), impaired consciousness (8%), acute cerebrovascular problems (3%), ataxia (0.5), and seizures (0.5%)]^[10]

• Several risk factors of seizure in COVID-19 patients were considered in a multicenter restrospective study from Jan 18th to FEb 18th, 2020 in China.^[11]
• Risk factors that were studied include acute cerebrovascular disease, traumatic brain injury (TBI), central nervous system (CNS) infection, shock, hypoxia, severe metabolic disturbance, multiple‐organ dysfunction syndrome, sepsis, and exposure to drugs or toxic substances.
• According to the study, hypoxia and imipenem were shown to be important risk factors, among several others, for seizure in a COVID-19 patient.
• To view the risk factors of COVID-19, click here.

• There is insufficient evidence to recommend routine screening for COVID-19 associated seizure.

Natural History

• Seizure activity in a patient with or without COVID-19 usually lasts for a few seconds to less than 5 minutes with return to normal after the seizure episode.
• If seizure episode lasts for more than 5 minutes it is called status epilepticus.
• This is followed by a period of confusion, called postictal period that can last 3-15 minutes and sometimes hours.

Complications

• Complications of COVID-19-associated seizure include:
  • Headache
  • Tiredness
  • Difficulty speaking
  • Difficulty breathing (due to blockage of airway)
  • Abnormal behavior
  • Psychosis
  • Injury to tongue due to bite during seizure activity
  • Trauma due to sudden fall and/or loss of consciousness

Prognosis

• In general, after the first seizure, subsequent seizure episodes can be predicted using EEG and brain imaging.^[12]
• Prognosis of seizure in a COVID-19 patient is not known.
• However, if left untreated, seizure caused by acute brain event is known to have low risk of recurrence but higher risk of death compared to those with epilepsy. ^[13]

• The diagnosis of COVID-19-associated seizure is made through electroencephalogram (EEG, brain waive activity).^[14]

• Other diagnostic tests include:
  • CT scan brain
  • MRI brain
  • Blood test
  • Lumbar puncture
  • Toxicology screening

Common symptoms:

• Staring
• Jerking movements of the arms and legs
• Stiffening of the body
• Loss of consciousness
• Breathing problems

• Falling suddenly for no apparent reason, especially when associated with loss of consciousness
• Not responding to noise or words for brief periods
• Appearing confused or in a haze

Less common symptoms:

• Nodding of head rhythmically, associated with lack of awareness
• Periods of rapid eye blinking

• Physical examination of a patient with COVID-19-associated seizure include:

• Vital signs: Tachycardia may be present.

• Finding a bite to the side of the tongue (when present, is helpful in making the diagnosis).

• Postictal drowsiness or confusion.

• Postictal levels of the following may be elevated in a patient with seizures:
  • Prolactin (within 20 minutes after a convulsive event)
  • Lactate (within 1 to 2 hours)
  • Ammonia (within several hours)
  • Creatine kinase (especially 24 to 48 hours postictally)
  • To view the laboratory findings on COVID-19, click here.

• There are no typical ECG findings associated with seizures in a COVID-19 patient.
• To view the electrocardiogram findings on COVID-19, click here.
  

• There are no x-ray findings associated with COVID-19 associated seizure.
• To view the x-ray finidings on COVID-19, click here.
  

• There are no typical echocardiographic findings for seizure related to COVID-19.
• To view the echocardiographic findings on COVID-19, click here.
  

• CT brain may show structural lesions but majority of patients will show nothing.
• To view the CT scan findings on COVID-19, click here.

• MRI brain may show structural lesions but majority of patients will show nothing.
• To view the MRI findings on COVID-19, click here.
  

• There are no other imaging findings associated with seizure related to COVID-19.
• To view other imaging findings on COVID-19, click here.
  

• To view other diagnostic studies for COVID-19, click here.
  

• Development of seizures in a COVID-19 patient requires urgent treatment.^[15][16][8]
• After the cause of seizure is determined, medical therapy should be aimed at treating the cause immediately (for example, hypoxia, fever, metabolic imbalance).
• Anti-seizure medication (levetiracetam 50-60 mg/kg/day) is often necessary.
• Anti-epileptics therapy with mannitol has been documented in decreasing cerebral edema.
• For a single seizure less than 5 min rescue treatment with benzodiazepine is not needed.
• Intravenous antiseizure medication are used with caution in COVID-19 patients due to the adverse effects (e.g., Phenytoin, Phenobarbital and Lacosamide in respiratory and cardiac problems) and drug interactions (e.g., Carbamazepine, Phenytoin, Phenobarbital and Valproic acid).
• Brivaracetam and Levetiracetam have less adverse effects and drug interactions.
• In patients with more than one seizure (either shorter or longer than 5 min) and in status epilepticus rescue treatment with benzodiazepines in addition to ASM is needed.

• Surgical intervention is not recommended for the management of COVID-19 associated seizure.

• There are no established measures for the primary prevention of seizures associated with COVID-19.

• There are no established measures for the secondary prevention of seizures associated with COVID-19.

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