The novel coronavirus spread rapidly across the world in late 2019 and became a pandemic in early 2020. The most common symptoms observed were fever, dry cough, loss of taste and smell, and shortness of breath. Other rare complications can include the cardiovascular, gastrointestinal, or nervous systems. Among the neurological complications, epileptic seizures are a topic of particular interest due to their relatively unknown and widespread etiology. It is understood that the entry or production of pro-inflammatory cytokines during COVID-19 infection can lead to neurotransmitter modulation and ion channel dysfunction, resulting in neuronal hyperexcitability, which manifests as seizures. To our knowledge, we present the first case in Sub-Saharan Africa of a patient with COVID-19 who presented to our institution with an epileptic seizure followed by confusion. Our case highlights the need to extend our differential diagnosis to include COVID-19 infection in patients with seizures.
Coronavirus disease 2019 (COVID-19) caused by the novel coronavirus (SARS-COV-2) has spread rapidly across the world since late 2019. It remains a significant global health threat in many parts of the world, due to new variables that have increased virulence or transmissibility and reduced the effectiveness of public health and social preventive measures. The main symptoms of infected patients include fever, dry cough, pain, body aches, chills, lethargy, loss of appetite, loss of sense of smell, and senescence. . Some patients may also have cardiovascular complications such as heart failure, clotting disorders, irregular heart electrical activity, and gastrointestinal complications such as loss of appetite, nausea, diarrhea, vomiting, and abdominal pain. . In particular, a minority of patients may present with neurological symptoms such as headache, paresthesia, loss of smell, advanced age, dizziness, delirium, ischemic/hemorrhagic stroke, encephalitis, and seizures. [3,4]. While the exact mechanisms of seizures are not yet fully understood, the consensus is that they are caused by neuronal hyperexcitability following ion channel dysfunction. This may result from increased excitatory neurotransmitters such as aspartate or glutamate or decreased gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter . Other possible causes include electrolyte imbalance, hypo or high blood sugar, acute nerve cell damage from infection, inflammation, head trauma, stroke, fever, and hypoxia. . To our knowledge, we present the first observed case of a patient with a seizure caused by COVID-19 in Kenya.
A 33-year-old patient with no other medical comorbidities presented to our institution with a 48-hour history of sudden dizziness preceded by an episode of profuse sweating. Twenty-four hours after the onset of his symptoms, he had a tonic-clonic seizure, lasting about one minute, with both urinary and fecal incontinence. There were no episodes of biting the tongue, moving the eye, or frothing in the mouth. He looked confused for about three minutes, according to the family, after which he felt a sense of exhaustion. His wife reported a seizure and a family member recorded it in part.
When presented to the emergency room, he had a tachycardia of 123 beats per minute, his respiratory rate was regular and a normal temperature of 36.5 °C. His neurological examination, in particular, was within normal limits. The remainder of the physical examination was unremarkable. He denied any travel history or exposure to patients.
Preliminary laboratory analysis showed a glucose level of 133 mg/dL, and a white cell count of 6.98 x 103μl (normal neutrophil count), hemoglobin 14.5 g/dl and platelets 159 μl. Its extended electrolytes were also within normal limits. Creatinine was slightly elevated at 117 μmol/L with normal potassium 3.82 mmol/L, urea 4.4 mmol/L and sodium 144 mmol/L. HBA1c was reported at 6.1%. Its CRP was slightly elevated at 16 mg/dL, and procalcitonin was reported at 0.11 ng/mL. Its D-dimer was also slightly elevated at 2.0 μg/mL. Urine toxicants were negative for any illegal drugs. His RT-PCR was reported to be positive for COVID-19 24 hours after presentation. A high-resolution computed tomography (HRCT) scan of his chest was suggestive of atypical pneumonia with lung involvement of 10 percent (Fig. 1).
Subsequent lumbar puncture showed a white cell count and zero red cell count. Cerebrospinal fluid (CSF) protein and glucose levels were within normal limits, and cultures were reported as negative. CSF cultures for tuberculosis (TB) were also negative, and COVID-19 PCR of CSF was not performed. The electroencephalogram (EEG) was reported as normal, and the subsequent brain MRI was reported as unremarkable (Fig. 2). A 2D echocardiogram showed 55-60% of normal ejection with no abnormalities of the wall and normal valve function.
It was initially loaded with Levetiracetam at a dose of 1 g and continued at a regular dose at 500 mg twice daily. He also received prophylactic enoxaparin at a dose of 40 mg subcutaneously once a day. The patient was well treated until the second day of hospital admission when the temperature began to rise by 38.5aC with persistent tachycardia of 120-130 beats per minute. Its oxygen saturation also decreased to less than 92%. Immediately started taking oral dexamethasone 6 mg daily and supplemented with oxygen (2 L) to maintain saturation at 92%. Within 72 hours, he was off oxygen, and no further seizures were reported during his hospital stay. He was discharged on the sixth day of the hospital to complete 14 days of self-isolation at home.
SARS-COV-2 can enter the nervous system via the hematopoietic pathway by affecting blood-brain barrier endothelial cells or leukocytes, eventually causing dissemination to other tissues. Alternatively, the virus can also enter the nervous system through the return of peripheral nerves via active axonal transmission. . SAR-COV-2, like SARS and MERS, is also believed to bind to the angiotensin-converting enzyme 2 (ACE2) receptor found in the meninges and the blood-brain barrier, making tissues susceptible to infection and ultimately leading to neuronal death. [7,8]. SAR-COV-2 can also enter the brain directly through the olfactory tract, bypassing the need for ACE2 receptors. . Once the virus invades the central nervous system (CNS), it causes reactive astrogliosis and stimulates microglia to trigger a large inflammatory cascade, resulting in a cellular storm.
Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), Interleukin 1 beta (IL-1B), Interleukin 6 (IL-6), free radicals, nitric oxide, and others are released, resulting in severe symptoms or Chronic inflammation that causes hyperexcitability of neurons and potentially leads to seizures . These cytokines exacerbate apoptosis and neuronecrosis in the central nervous system, and also stimulate glutamate release while inhibiting GABA release in the hippocampus and cerebral cortex (IL-1B, TNF-α) . In addition, using α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors, these cytokines increase calcium entry into neurons, resulting in to an overabundance of neurons. Excitability (TNF-α). Finally, they release different neurotoxic compounds through different autocrine/paracrine (IL-6) mechanisms. Moreover, IL-6, in particular, has been shown to contribute to the febrile response. This specific pro-inflammatory cytokine could play a role in neuroinflammation and appears to contribute to inflammatory signaling at the seizure threshold. . Some studies have also linked IL-6 to the development of seizures . Since COVID-19 is associated with an elevated level of IL-6 and fever, it can be assumed that this increases the likelihood of seizures in some patients.
It should be noted that there is no definitive association between COVID-19 and seizures. However, fear of infection, isolation that leads to stress, and elevated levels of cytokines are known to lower the seizure threshold and contribute to the development of seizures. [12,13]. Lu et al. He conducted a retrospective study looking at seizures among COVID-19 patients. They found that hypoxia, the most common complication in the group studied, can lead to hypoxic encephalopathy, causing seizures. . Hypoxia from COVID-19 has also been shown to lead to stroke, which can increase the development of seizures in some patients. . In addition, electrolyte abnormalities and some use of antibiotics can trigger seizures in patients .
In every COVID-19 patient who has seizures, it remains necessary to investigate the etiology of seizures further. This includes a careful review of their medication, a complete metabolic exam, a prolonged EEG scan (if available), and brain imaging. CSF analysis is also necessary for further investigation of acute viral causes of seizures . It should be noted that several studies have reflected on their inability to detect SARS-COV-2 virus in the CSF of COVID-19 patients. .
Our patient was initially treated with the anti-epileptic drug (AED) Keppra (Levetiracetam). While the exact mechanism of Levetiracetam’s anti-epileptic activity is not fully understood, studies have shown that it inhibits GABA inhibition. This presynaptic inhibitor inhibits glutamate secretion and exhibits inhibitory effects on calcium release, thus inhibiting the release of Ca2+-related neurotransmitters . Unlike other antiepileptics, Levetiracetam has the fewest number of interactions with other treatments associated with COVID-19 and is the preferred treatment option in patients suffering from seizures and COVID-19. . Usually, patients do not require prolonged anti-seizure therapy after the acute attack has resolved and if the attacks have not recurred [15,19]
After follow-up in clinic after 2 and 6 weeks, our patient performed well without reporting epileptic seizures. Its Levetiracetam has been discontinued, and it’s currently still doing quite well. Vaccinations for COVID-19 are recommended, about 12 weeks after initial infection, to help mitigate future infections.
One rare neurological complication of COVID-19 is seizures, which can occur due to neurotransmitter-induced neuronal hyperexcitability or electrolyte modulation due to an inflammation-induced cytokine storm during the body’s immune system response. Comprehensive examination is required to better understand the causes of seizures in patients with COVID-19. Treatment with drugs that reverse the upregulation/downregulation of these neurotransmitters or electrolytes, thereby restoring proper ion channel function in the central nervous system, can improve pathogenesis.