Epilepsy Seizures in Hyponatremic COVID-19/SARS-CoV-2: A Comprehensive Single-Center Analysis

Introduction

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.

Materials and Methods

Study Design

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).

Ethical Statement

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.

Patient Inclusion

The study included only hyponatremic adults diagnosed with COVID-19, as confirmed by RT-PCR tests (Rotor-Gene, Qiagen, USA). The patients in the study consisted only of those who received levetiracetam as routine therapy for the prevention of their epilepsies before COVID-19. Epilepsy patients using other drugs with the Area Under Curve (AUC) measuring without levetiracetam were excluded. the model's diagnostic ability. The logistic Participants were divided into two groups: those who experienced epilepsy seizures (seizure group) and those who did not (non-seizure group) during COVID-19 illness.

Data Collection and Seizure Classification

Clinical data, including demographic data, medical history, epilepsy seizure occurrence, and laboratory findings, were collected from electronic medical records. The variables of interest included age, gender, history of epilepsy, comorbidity profiles, and specific treatments administered. Seizures were classified as either new-onset or pre-existing based on the medical history and clinical presentation. For the treatment of new-onset seizures, midazolamwas administered following established guidelines. Patients with a history of epilepsy were only included if they were not currently using levetiracetam to ensure uniformity in the study. Laboratory parameters, including sodium, potassium, chloride levels, and other biochemical markers, were measured using standard laboratory procedures.

Statistical Analysis

Statistical analyses were performed using SPSS (IBM Corp., Armonk, NY, USA). A P-value of less than 0.05 indicated significance in all tests. All continuous variables, representing measurements that inherently exhibit a range of values, such as age, were expressed as mean ± standard deviation. Chi-square test presented categorical variables representing distinct categories or classifications as numbers and percentages. Regarding continuous data, the independent t-test and ANOVA were used. Logistic regression was utilized to explore the correlation between active COVID-19 and the occurrence of seizures. For the specific task of assessing the predictive value of sodium levels for epileptic seizures, Receiver Operating Characteristic (ROC) analysis was conducted, model assessed COVID-19, epilepsy seizures, and various clinical and laboratory parameters.

Results

Demographic Characteristics

The present study revealed no difference in the age of patients with and without epilepsy seizures during COVID-19, with averages of 64.6 (±19.6) and 68.7 years (±16.5), respectively (p=0.127). Gender distribution between male and female patients in both groups also showed no difference (p=0.725). The history of epilepsy did not differ between those with and without seizures (p=0.511). However, a notable variance was observed in the prevalence of comorbidities. As seen in Table-1, patients with seizures had a higher incidence of multiple comorbidities (p=0.002).

COVID-19 Infection and Clinical Details

A significant correlation was found between active COVID-19 and the occurrence of epilepsy seizures (p=0.001). Likewise, antiepileptic treatment history was more common in patients who experienced seizures (p=0.001). The mortality, represented as exitus, showed a significant difference, lower in patients with seizures (p=0.001).

Laboratory Parameters

In terms of laboratory parameters (Table-1), there were no differences in C-reactive protein, Albumin, Calcium, Magnesium, Vitamin D, Folat, Vitamin B₁₂, Triiodothyronine, Thyroxine, Thyroid Stimulating Hormone, International Normalized Ratio, Glucose, Blood Urea Nitrogen, Creatinine, D-Dimer, Ferritin, Lactate Dehydrogenase, Alanine Amino transferase, Aspartate Aminotransferase, Hemoglobin, and pH levels between the two groups. However, Sodium, Potassium, Chloride, Neutrophils, and White Blood Cell counts showed differences between groups (P=0.005, 0.046, 0.002, 0.028, 0.053, respectively).

ROC Analysis for Natrium Levels

Upon analysis of the ROC generated from sodium data for predicting epileptic seizures (Figure-2), the model demonstrated moderate discrimination capability with an AUC of 0.319. This performance indicates an improvement over random chance, as evidenced by the asymptotic significance (p=0.002). A cutoff value of sodium below 130.2 mmol/L yielded a sensitivity of 71% and specificity of 74.3%. The 95% confidence interval for the AUC (0.232- 0.407) suggests uncertainty in the model's predictive accuracy across populations.

Logistic regression

In this logistic model, we observed an overall fit, evidenced by a Nagelkerke’s R(2) value of 0.153, indicating that the model explains 15.3% of the variance in the occurrence of seizures. Sodium stands out as a unique predictor within the model. The negative coefficient, marked at -0.131, implies that an increase in sodium levels correlates with a decreased probability of experiencing seizures. The Exp(B) value of 0.878 suggests that for each unit increase in sodium, the likelihood of having a seizure decreases by 12.2%. Evaluating the model's predictive accuracy, the classification table reveals an overall correct classification rate of 78.2%.

Discussion

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.

Conclusion

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.