The COVID-19/SARS-CoV-2 pandemic has unleashed unprecedented challenges in the medical field, particularly in understanding and managing its diverse clinical manifestations ( 1 – 3 ). The nexus between viral infections and neurological complications is well-established, yet SARS-CoV-2 has presented novel clinical challenges ( 4 , 5 ). One emerging concern is the neurological impact of COVID-19, especially in patients presenting with hyponatremia – a condition characterized by abnormally low sodium levels in the blood ( 6 – 8 ).

Hyponatremia intersection and neurological disorders, particularly within the context of the pandemic, presents a critical area of medical research ( 9 ). Hyponatremia, characterized by reduced sodium levels in the blood, is recognized as a significant risk factor in hospitalized patients and is known to extend hospital stays and increase resource utilization ( 10 ). Its correlation with epilepsy complications is an emerging field of study ( 11 ). Research has consistently shown that the improvement of hyponatremia is associated with decreased mortality ( 12 , 13 ). The link between low sodium levels and an increased likelihood of epileptic seizures has been documented, highlighting a transparent risk gradient associated with varying levels of hyponatremia ( 8 , 14 ). This concern is especially pertinent in epilepsy undergoing treatment with certain antiseizure medications, some of which have been identified as potential contributors to lowered sodium levels ( 15 , 16 ). Previous research has suggested that certain medicines, such as benzodiazepines and antipsychotics, might be linked to an increased risk of hyponatremia in epilepsy ( 14 , 17 ). Additionally, they have indicated a connection between the initiation of specific epilepsy treatments and a rise in hospitalizations due to hyponatremia ( 13 ).

Preliminary studies suggest an association between severe SARS-CoV-2 cases and an increased risk of seizures for patients with epilepsy. However, the role of hyponatremia as a contributing factor in these neurological outcomes remains underexplored. This study aims to delve deeper into the incidence and characteristics of epilepsy in patients with SARS- CoV-2 who develop hyponatremia. The study aimed to quantify the incidence of epilepsy seizures in patients with COVID-19-related hyponatremia.

This observational retrospective research aimed to compare clinical and laboratory parameters in patients who experienced epilepsy seizures (n:46) and those who did not (n:160), with a focus on epilepsy cases with hyponatremic COVID-19 positive (Figure-1).

The protocol was reviewed and approved by the Institutional Review Board of the University [18/10/2023 - 2017-KAEK-120/10/2023.G-74 ]. The Informed consent was waived due to the study's retrospective nature, following the ethical standards of the Declaration of Helsinki.

The present research explored the intricate relationship between epilepsy seizures and hyponatremia in COVID-19, uncovering critical insights into how the pandemic influences neurological complications. A standout finding is the pivotal role of sodium levels in predicting seizure occurrence. Contrary to demographic indicators, sodium emerged as a significant predictor, with lower levels associated with a higher likelihood of seizures in hyponatremic COVID-19 patients. This discovery underscores the potential of sodium as a critical parameter in understanding epilepsy in the context of the COVID-19 pandemic.

In COVID-19, various factors can contribute to the development of seizures. Common causes include fever, hypoxia or metabolic imbalances. However, these triggers are relatively rare and typically lead to a less severe form of seizures. As a result, these patients often respond well to treatment and have favorable outcomes. There are multiple theories regarding the specific mechanisms by which COVID-19 might lead to seizures. One debated theory suggests that a direct attack by the SARS-CoV-2 on the central nervous system might be responsible, based on clinical research demonstrating the virus's ability to affect the central nervous system ( 18 , 19 ). An epidemiological study in Salzburg revealed that seizures during the pandemic were comparable to the general incidence of seizures observed in the preceding five years ( 20 ). Another theory posits that seizures could be a consequence of the systemic inflammatory response triggered by SARS-CoV-2 ( 21 ). Inflammatory parameters, including C-reactive protein and erythrocyte sedimentation, are frequently elevated in these cases. Our research also involved a comprehensive analysis of these parameters concerning COVID-19, drawing on various studies that have established a connection between these factors and the disease. However, among all these parameters, hyponatremia was the most valuable predictor of seizures for SARS-CoV-2 positives. Some study highlighted a link between hyponatremia and COVID-19 related pneumonia ( 22 , 23 ). The occurrence of hyponatremia in these patients correlates with mortality, underscoring the importance of prompt identification and effective treatment to enhance outcomes ( 24 ). Notably, an analysis involving 4,452 patients, all confirmed SARS-CoV-2 positive, revealed that 30% experienced hyponatremia, with severe cases constituting 1% of this group ( 25 , 26 ). This electrolyte imbalance often results from multiple factors and represents the most prevalent electrolyte abnormality in clinical settings, linked to heightened mortality ( 27 , 28 ). A primary cause is the inappropriate secretion of antidiuretic hormone ( 29 ). Ho and associates documented the inaugural instance of COVID- 19-related hyponatremia presenting as new-onset seizures ( 30 ).

Our study underscores the critical role of hyponatremia in the context of epilepsy seizures. Despite no difference in demographic characteristics, the correlation between active COVID-19 and seizure occurrence was notable. Particularly striking is the association of hyponatremia with increased seizure risk. Laboratory analyses revealed that while most parameters did not differ significantly between groups, sodium stood out, indicating that hyponatremia could be a key predictor of seizure risk in COVID-19. The ROC for sodium reinforced this issue, demonstrating moderate effectiveness in using sodium levels to predict seizures. A lower sodium level threshold was associated with seizures, emphasizing the need for careful monitoring and management of sodium, especially for those with a history of epilepsy or at risk for seizures.

The study's strength is notably enhanced by including a cohort using levetiracetam for epilepsy management, reducing potential bias from varied antiepileptic drugs. This uniformity provides a more controlled environment to assess the interplay between hyponatremic COVID-19 positive cases and epilepsy seizures. Despite the strengths, the study faces limitations. While useful for explorations, the retrospective design may not capture the full spectrum of clinical nuances. Additionally, the study's reliance on a single-center cohort and relatively small sample can limit the generalizability, as it may not reflect diversity of populations. Despite its limitations, our research offers important insights into the intricate dynamics of epilepsy and hyponatremic COVID-19, paving the way for further research in this critical area of medicine.

Lower sodium showed a significant warner and predictor of seizure occurrence, with higher levels being protective against seizures, in contrast to clinical demographic factors. The model demonstrates moderate effectiveness in predicting seizures, with a notable strength in identifying non-seizure cases. Monitoring it in assessing and understanding the increased seizure risk of epilepsy in COVID-19-positive patients is essential, particularly for those experiencing hyponatremia. This observation marks a shift in focus from traditional indicators to natrium in the context of the pandemic.