European Journal of Cardiovascular Medicine

Seizures are a transient event of brain activity due to abnormal, excessive and or synchronous neuronal activity. The epileptic seizures are categorized into two generalized and focal seizures. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate seizures and by the neurobiological, cognitive, psychologic, and social consequences of this condition. Epileptic syndrome is a disorder that manifests 1 or more specific seizure types and has a specific age of onset and a specific prognosis (1).  Febrile seizures are common in children below 5 years of age, with an occurrence of 3-4% (2). The incidence of febrile seizure is higher in developing countries due to the prevalence of malnutrition, infection and infestation, with an incidence of 10-17% (3,4)

Several trace elements are said to play a major role in convulsions by their coenzyme activity or their ability to influence ion channels and receptors. 

Many studies have shown that role of zinc, iron, and magnesium plays a significant role in febrile convulsions. Zinc (Zn) acts as a cofactor for glutamic acid decarboxylase, which is the enzyme that maintains production of GABA in the central nervous system. A few studies have shown that decreased levels of Zn in CSF are also associated with febrile seizures. In the CNS, zinc acts as a neurosecretory product or co - cofactor. Zinc is highly concentrated in the synaptic vesicles of a specific contingent of neurons called zinc-containing neurons. Zinc slows the release rate of glutamate or increases the storage capacity of glutamate. Zinc also stimulates the activity of pyridoxal kinase, which is involved in the synthesis of pyridoxal phosphate from pyridoxal. Hence, decreased levels of Zinc concentration can result in a lowering of GABA levels, which can precipitate seizures (5). Recent studies, like Lalithkumar et al, indicate that serum Zn levels were low in febrile seizures, and Ganesh et al conducted a study in Chennai evidences that deficiency of zinc can play a significant role in febrile seizures. Another report by Garty on 66 patients at Schneider children's hospital, there was no difference in zinc levels between patients with febrile seizures and the control group. Therefore, about the importance of seizures, possible contributing factors, including serum zinc level, this study is conducted to compare the serum zinc levels in children with seizures, including simple febrile seizures and atypical febrile seizures, in comparison with febrile children without seizures

Study design and setting: A hospital-based case-control study to determine serum zinc level in children admitted with acute seizure and comparison with children without seizures in a tertiary care Centre. Sample size was calculated using the OpenEPI software. Study subjects: All children admitted to the department of paediatrics, diagnosed with seizures, will be taken up after a detailed clinical history and detailed clinical examination and treatment history by using a questionnaire. Children were included in this study after obtaining consent from parents and assent from the children. Inclusion criteria • Children diagnosed with seizures • Age group 5 months to 12 years Exclusion criteria • Children on Zn supplementation • Children with chronic illness or acquired illness are excluded Sampling method and Sample size: Taking the mean serum zinc levels in the study done by Ehsanipour et al, with a 95% confidence interval and with a power of 80%, the required sample size is 36. The sample size is then inflated by 10% to include children with seizures. Hence sample of 40 cases was taken, and a comparison was done with 40 children of the same age and sex matched controls without seizure. Study Period and Study Tool: Three millilitres of whole blood were collected by venipuncture under strict aseptic precautions and sent to the biochemistry laboratory for assessment of serum zinc levels. Determination of serum zinc levels was done by the calorimetric method. The principle being zinc in an alkaline medium reacts with nitro PAPS to form purple colored complex. The intensity of colour formed is directly proportional to the amount of zinc present in the sample. Prior to inclusion of the children in the study, a detailed history of presenting complaints was recorded by our history, including duration of fever, time of onset of seizures, type of seizures, duration of seizures, and past and family history of seizures. In addition, a history suggestive of any triggering factors for febrile episode-like cough, cold, nasal discharge, ear discharge, burning micturition or crying during micturition was also recorded. Vital signs, namely heart rate, respiratory rate, and blood pressure, were measured and recorded. The axillary temperature was recorded in all children with a mercury thermometer placed in the axilla for three minutes. Anthropometric measurements, namely weight, height, mid-arm circumference and head circumference, were recorded. This was followed by general examination and systemic examination in detail. Those children who showed features of any chronic congenital or acquired illness were excluded. Statistical analysis: The collected data were entered in Epi Info software and analyzed using SPSS software. Student T t-test and chi-square test were used for the statistical analysis. Odds ratio with a 95% confidence interval was calculated with P value <0.05 was considered statistically significant.

The present case–control study was conducted in a tertiary care Hospital for a year's duration and included a total of 80 children aged 5 months to 12 years. Of these, 40 children presented with seizures and constituted the case group, while 40 age- and sex-matched febrile children without seizures served as controls. The demographic distribution showed that the majority of participants in both groups were between 1 and 5 years of age (72.5%), followed by infants under one year (25%) and only 2.5% above five years, indicating that seizures occurred predominantly in younger children.

Table 1 – Age group

Gender distribution revealed a male predominance in both cases and controls. In the seizure group, 24 (60%) were males and 16 (40%) females, yielding a male-to-female ratio of 1.25:1. A similar distribution was observed in the control group, signifying no gender difference between the two groups in recruitment but reaffirming the higher seizure incidence among boys.

Table 2 – Gender distribution

Age-wise distribution of zinc levels further highlighted this trend. Among infants (<1 year) with seizures, 60% had reduced zinc levels, while none of the infants in the control group showed deficiency. In the 1–5-year age group, 51.7% of cases had low zinc values compared to only 13.8% among controls. This consistent disparity across all age brackets supports the hypothesis that zinc deficiency may contribute to lowering seizure threshold in susceptible children.

Table 3 – Age group with serum Zn distribution

Gender-specific analysis of zinc levels revealed that among seizure cases, 62.5% of males and 37.5% of females had low zinc levels. Conversely, in the control group, low zinc levels occurred only in 16% of females and none of the males. Mean serum zinc levels in male seizure cases were 51.33 ± 26.44 µg/dl, while females demonstrated relatively higher values (71.86 ± 26.77 µg/dl). In the control group, mean zinc levels were 103.04 ± 39.46 µg/dl for males and 98.93 ± 39.59 µg/dl for females. Thus, zinc deficiency was more prominent among males in the seizure population, although both genders showed significantly lower levels compared to controls.

Table 4 – Gender with serum Zn level

The mean serum zinc level across all seizure cases was 59.6 µg/dl, markedly lower than the control mean of 101.4 µg/dl. Statistical analysis using the student’s t-test revealed a highly significant difference between the two groups (p = 0.0001), reinforcing the strong association between low serum zinc and seizures in children.

Table 5- Age group and serum Zn levels among cases and controls

When the seizure cases were categorized based on aetiology, simple febrile seizures constituted the majority (57.5%), followed by atypical febrile seizures (27.5%) and other seizure types (15%). Mean zinc levels were lowest in simple febrile seizure cases (52.3 ± 27.7 µg/dl), followed by atypical febrile seizures (60.9 ± 21.3 µg/dl). Both subgroups demonstrated statistically significant differences compared to controls (p = 0.0001). However, in children with other seizure etiologies, although mean zinc levels (67.7 ± 40.1 µg/dl) were lower than in controls, the difference was not statistically significant (p = 0.0600). This indicates that zinc deficiency has a stronger association with febrile seizures than with non-febrile seizure disorders

Table 6 – Serum Zn level frequency in both groups

Serum zinc levels were classified as low (<60 µg/dl), normal (60–120 µg/dl), and high (>120 µg/dl). Among children with seizures, 21 (52.5%) had low serum zinc levels, whereas only 4 (10%) of the controls demonstrated low levels. Normal serum zinc values were observed in 45% of cases and 62.5% of controls. Elevated zinc levels were rare in the seizure group (2.5%) but were observed in 27.5% of controls. These findings clearly indicate that low zinc levels were significantly more common among children with seizures, suggesting a strong association between zinc deficiency and seizure occurrence.

Electrolyte analysis among seizure cases showed mean values of sodium (136.2 mEq/L), potassium (4.17 mEq/L), chloride (96.9 mEq/L), and calcium (9.8 mg/dl), all within normal ranges, ruling out electrolyte disturbances as contributing factors in most cases and strengthening the role of zinc deficiency as an independent association

Table 7 – Serum Zn level comparison in the cause of Seizure in the case group

Table 8 – Mean Zn levels among cases and controls

Table 9 – Test of significance

Overall, the study's results consistently demonstrate that serum zinc levels are significantly lower in children presenting with seizures, particularly febrile seizures, compared to age- and sex-matched febrile controls without seizures. The findings support the hypothesis that zinc deficiency may play a contributory role in seizure pathogenesis, particularly by influencing neuronal excitability and GABAergic neurotransmission.

The present case–control study was undertaken to determine whether serum zinc levels differ significantly between children presenting with seizures and age- and sex-matched febrile controls without seizures. Zinc, a crucial trace element involved in neurotransmission and enzymatic pathways, has been repeatedly suggested in the literature as a potential contributor to seizure threshold modulation. Given the biological plausibility that zinc deficiency may reduce GABA synthesis and alter neuronal excitability, this study aimed to evaluate whether hypozincemia is associated with seizure occurrence in the pediatric population.

In our study, 80 children aged 6 months to 12 years were evaluated, comprising 40 seizure cases and 40 controls. The two groups were comparable with respect to age and sex distribution, minimising confounding. Most children belonged to the 1–5-year age group, which is consistent with the peak incidence of febrile seizures documented globally. The male predominance seen in our study mirrors previous research findings, suggesting a biological predisposition or gender-related vulnerability.

The mean serum zinc level among seizure cases was found to be significantly lower (59.6 µg/dl) compared to controls (101.4 µg/dl), with a highly significant p-value (<0.0001). More than half of the seizure cases (52.5%) had zinc levels below 60 µg/dl, compared with only 10% of controls, indicating a strong association between seizures and low zinc levels. These findings are in agreement with several earlier studies. Studies by Lalith Kumar et al (6), Ganesh et al. (7), and Vidyasagar et al (8) reported similarly reduced zinc levels in patients with febrile seizures compared to those with febrile controls. Ganesh et al., for instance, reported mean serum zinc levels of 32.17 µg/dl in simple febrile seizure cases compared to 87.6 µg/dl in controls, demonstrating a strong correlation between zinc deficiency and seizure predisposition. Our results strongly reinforce this association.

On analysing zinc levels among different types of seizures, both simple febrile seizures and atypical febrile seizures showed significantly lower zinc levels when compared with controls, again with statistically significant p-values (<0.0001). This highlights that zinc deficiency is not limited to typical febrile seizures but also found in atypical forms, which are often longer in duration, focal, or recurrent within the same febrile episode. The findings support the hypothesis that zinc deficiency may reduce seizure threshold irrespective of the specific febrile seizure subtype. However, in children with other seizure aetiologies (non-febrile or idiopathic), the difference in zinc levels was not statistically significant (p = 0.060), suggesting that zinc’s contribution may be more relevant in fever-related seizure mechanisms rather than all seizure types.

The biological basis for this association may lie in zinc’s regulatory role in glutamate and GABA neurotransmission. Zinc acts as a cofactor for glutamic acid decarboxylase, the enzyme vital for GABA synthesis. A decrease in zinc levels could diminish GABA production, leading to reduced inhibitory control and enhanced neuronal excitability. Zinc also modulates NMDA receptors, providing an inhibitory effect; therefore, deficiency may facilitate excitatory neurotransmission. Studies cited in the literature have shown increased sensitivity of GABA-A receptors to zinc modulation in epilepsy models, emphasizing zinc’s critical neuromodulatory functions.

Several comparable studies strengthen our findings. Ehsanipour et al (9) observed significantly lower zinc levels in febrile convulsion groups compared to both febrile and non-febrile controls. Kumaravel et al (10) similarly reported significantly lower zinc and selenium levels in children with febrile convulsions. Vidyasagar et al., in contrast, did not find as big a difference, possibly owing to regional dietary variations or methodological differences. Pannersevam et al (11) conducted a study in Chennai, showing that low levels of serum zinc in the febrile seizure group, which is similar to our study. Regardless, the collective evidence—including the present study—supports zinc as an important biochemical factor influencing seizure susceptibility.

An important observation from our study is that zinc levels were not related to age or gender among cases, indicating that deficiency, when present, exerts a similar effect across subgroups. This finding is in line with studies by Ganesh et al. and Vidyasagar et al., which also did not report any significant demographic influence on serum zinc levels.

Although this study provides strong evidence of reduced serum zinc levels in children with seizures, particularly febrile seizures, there are certain limitations. The sample size, though statistically adequate, was relatively small for subgroup analysis. Additional biochemical parameters, such as serum copper or magnesium, which also influence seizure activity, were not included due to financial constraints. Moreover, a dietary assessment, which could have clarified the cause of zinc deficiency, was not undertaken.

Despite these limitations, the findings hold significant clinical relevance. The demonstration of markedly reduced serum zinc levels in children with febrile seizures suggests that zinc supplementation could potentially serve as a preventive strategy, especially in high-risk groups. Given the safety, low cost, and established immune benefits of zinc, its role as a prophylactic agent merits exploration through larger, multicentric trials.

In conclusion, this study provides compelling evidence that zinc deficiency is significantly associated with febrile seizures. Further research with larger cohorts is recommended to confirm these findings and explore the potential therapeutic value of zinc supplementation. Limitations of the study The study’s small sample size limits generalizability, and financial constraints restricted evaluation of additional micronutrients, preventing comprehensive biochemical correlation with seizure aetiology and zinc status.

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