Vitamin D status of pediatric epilepsy patients and evaluation of affecting factors

doi:10.21203/rs.3.rs-4624819/v1

Anti-seizure medication that is used in patients with epilepsy is one of the significant risk factors associated with abnormal vitamin D status in these patients. We aimed to identify risk factors related to hypovitaminosis D in pediatric patients treated with anti-seizure medications.

Method. A cross-sectional retrospective cohort study was conducted on 127 pediatric epilepsy patients who received anti-seizure drugs from December 2021 to December 2022. Demographic data, seizure types, diet, physical activity, duration, and types of anti-seizure medications were analyzed.

Results; Among the 127 patients in this study, 53% were male, and the mean age was 9,1 ± 4.6 years (range: 2–17). The mean serum 25(OH)D level at baseline in winter/autumn was 24.2 ± 14.2 ng/mL; 47.0% of the patients were 25(OH) D deficient, 23% 25(OH)D insufficient, and 30% had a vitamin D level within the normal range. Vitamin 25(OH) D level was 27,6 ± 12,2 in the epilepsy group with non-enzyme-induced anti-seizure drugs, 21,76 ± 19,7 in enzyme-induced anti-seizure drugs, and 13,96 ± 7,9 in the group with combined anti- seizures drugs (p < 0.001).

Conclusion: : The number of anti seizures drugs, treatment with enzyme-induced anti-seizure drugs, long duration of epilepsy, abnormal magnetic resonance imaging, and etiology play an important role on vitamine D level

Epilepsy

Pediatric patients

Vitamin D

It is mainly accepted nowadays that vitamin D deficiency is a problem that concerns almost everyone worldwide, and it affects not only the musculoskeletal system but also many acute and chronic diseases (1). Despite its importance, it is noticed that one billion people worldwide are vitamin D insufficient or deficient (2). Recent studies have shown that vitamin D deficiency is more frequent in epileptic patients treated with anti- seizures drugs (ASDs), especially drugs that induce cytochrome p450 enzymes (3).

ASDs are categorized according to their ability to induce the hepatic cytochrome P450 enzymes: Enzyme-induced anti-seizure drugs (EIASDs) such as phenytoin, phenobarbital, carbamazepine, eslicarbazepine acetate, primidone, oxcarbazepine and topiramate > 200 mg/day) and non-enzyme-induced anti-seizure drugs ( Non-EIASDs ) as valproate, lamotrigine, gabapentin, levetiracetam, clobazam, pregabalin, zonisamide, lacosamide, perampanel, topiramate ≤ 200 mg/day and benzodiazepines) (4).

EIASDs can induce the cytochrome P450 enzymes, responsible for vitamin D catabolism, and consequently convert vitamin D into inactive metabolites (5, 6). The resulting hypovitaminosis leads to hypocalcemia and an increase in parathyroid hormone levels, increasing bone turnover with higher susceptibility to osteopenia and bone fractures. More, there are also other major factors related to vitamin D status that has to be taken into account as insufficient exposure to the sun, geographical factors, skin pigmentation, inadequate diet, underlying diseases such as malabsorption syndromes, liver, and chronic kidney diseases(7, 8)

So in this study, we aimed to study and screen for vitamin D deficiency and insufficiency among pediatric epilepsy patients, identify the risk factors associated with vitamin D deficiency/ insufficiency and explore the relationship between EIASDs/Non-EIASDs and vitamin D status.

The medical records of patients aged 2 to 17 years approached Diyarbakır Children's Hospital from December 20121 to December 2022 were retrospectively reviewed to detect the following ICD-10 codes: G40.0 Epilepsy · G40.1 epilepsy · G41.2 Complex partial epilepsy · G41.8 Other epilepsy · G41.9 Epilepsy unspecified. The patients with the above ICD codes who adhered to the same anti-seizure medication for at least one year with reliable seizure records were included in the study. Demographic and clinical variables comprised of age, gender, weight, height, body mass index (BMI), age of onset of epilepsy, type of seizure, etiology, predisposing genetic factors, diet, sun exposure, living in the city or urban area, and vitamin D levels were recorded, The exclusion criteria were: changes in the ASDs schedule prior to the study, intake of vitamin D supplementation or medication interfering with vitamin D metabolism six months before the study, using other drugs in addition to ASDs, history of hypercalcemia, nephrolithiasis, parathyroid disease or gastric surgery, cerebral palsy and inability to walk. Clinical and demographic data were collected through a questionnaire during consultation and follow-up visits and from clinical files. Epilepsy type and etiology were considered according to the International League Against Epilepsy (ILAE) classification. Epilepsy was considered refractory when two suitable with maximum tolerable doses of ASDs schedules failed to achieve seizure freedom. Our study was approved by the ethics committee of Health Sciences University Gaziyaşargil Training and Research Hospital, 03-03-2023 with the approval number 353.

According to the Endocrine Society Guidelines, Vitamin D status is defined as a deficiency when a 25(OH)D level is below or equal to 20 ng/mL and vitamin D insufficiency when a 25(OH)D level in the range of 21–29 ng/ml. All vitamin D levels were evaluated in the same laboratory liquid chromatography-tandem mass spectroscopy method in our patients with epilepsy aged 2–17 years old from December 2021 to December 2022; serum levels of 25(OH)D were routinely obtained as part of our standard clinical care for patients with epilepsy. In addition, complete blood count, renal functions, serum antiepileptic drug levels, and calcium, magnesium, and phosphate levels were assessed (3, 4).

Statistical Analysis

Categorical variables were expressed as numbers and percentages, whereas continuous variables were summarized as mean and standard deviation. To compare categorical variables between the A.S.D. types, Pearson Chi-Square Test or Fisher's Exact Test was used depending on whether the expected value problem arises or not. The normality of distribution for continuous variables was confirmed with the Shapiro-Wilk test. For the comparison of vitamin D levels between two groups (gender, living area, etc.), the Student's t-test or Mann-Whitney U test was used depending on whether the statistical hypotheses were fulfilled or not. For comparison of vitamin D levels between more than two groups (ASDs types, epilepsy type, MRI) Oneway ANOVA or Kruskal Wallis test was used depending on whether the statistical hypotheses were fulfilled or not. For normally distributed data, regarding the homogeneity of variances, Tukey or Games&Howell tests were used for multiple comparisons of groups. For nonnormally distributed data, Bonferroni adjusted Mann Whitney U test was used for multiple comparisons of groups. To evaluate the correlations between measurements, Pearson Correlation Coefficient or Spearman Rank Correlation Coefficient was used depending on whether the statistical hypotheses were fulfilled or not. Linear regression analysis was applied to determine the most effective predictors of vitamin D levels. All analyses were performed using IBM SPSS Statistics Version 20.0 statistical software package. The statistical level of significance for all tests was considered to be 0.05.

SPSS. referansı: IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.

Among the 127 patients in this study, 53% were male, and the mean age was 9,1 ± 4.6 years (range: 2–17). The mean serum 25(OH)D level at baseline in winter/autumn was 24.2 ± 14.2 ng/mL; 47.0% of the patients were 25(OH) D deficient, 23% 25(OH)D insufficient, and 30% registered a vitamin D level within the normal range. vitamin 25(OH) D level was 27.6 ± 12,2 in the non-EIASDs group, 21,76 ± 19,7 in EIASDs, and 13,96 ± 7,9 in the group with combined ASDs (P < 0.001).

Details of all clinical and demographic features of the patients are shown in Table 1. The lifestyle habits of the total patients are shown in Table 2. Model parameter estimates are shown in Table 3. Comparison of vitamin D levels according to the seasons and vitamin D parameters according to variables are shown in Tables 4 and 5. Figure 1. shows vitamin D levels in autumn/winter and summer/spring in ASDs ( non-EIASDs, EIASDs, and combined) groups.

Table 1. Clinical and demographic profile of the patients in ASDs groups.

	Total	ASDs type			P
	Total	Non-EIASDs	EIASDs	Combined
	N=127	N=82	N=24	N=21
Age, Mean±SD	9.1±4.6	9.0±4.6	8.0±5.1	10.8±3.9	0.138
Gender, n (%) Male Female	67 (%53) 60 (%47)	46 (%56) 36 (%44)	9 (%38) 15 (%62)	12 (%57) 9 (%43)	0.250
Weight, Mean±SD	38.9±18.4	39.4±19.3	33.2±16.0	43.9±16.1	0.140
Height, Mean±SD	132.6±28.8	133.1±28.0	125.4±35.2	139.0±23.1	0.282
BMI, Mean±SD	21.1±4.3	21.1±4.5	20.4±3.1	21.9±4.6	0.474
Epilepsy type, n (%) Focal Generalized Combined Unknown	57 (%45) 58 (%46) 2 (%2) 10 (%8)	17 (%21) 56 (%68) 0 (%0) 9 (%11)	23 (%96) 0 (%0) 0 (%0) 1 (%4)	17 (%81) 2 (%10) 2 (%10) 0 (%0)	<0.001^a,b
Etiology, n (%) Structural Genetic Unknown Other	30 (%24) 17 (%13) 76 (%60) 3 (%2)	11 (%14) 8 (%10) 60 (%74) 2 (%2)	6 (%25) 7 (%29) 10 (%42) 1 (%4)	13 (%62) 2 (%10) 6 (%29) 0 (%0)	<0.001^b,c
MRI., n (%) Normal Encephalomalazic Locomalazic Cortical dysplasia Other	94 (%74) 13 (%10) 8 (%6) 4 (%3) 8 (%6)	70 (%85) 5 (%6) 2 (%2) 2 (%2) 3 (%4)	17 (%71) 5 (%21) 1 (%4) 0 (%0) 1 (%4)	7 (%33) 3 (%14) 5 (%24) 2 (%10) 4 (%19)	<0.001^b,c
EEG., n (%) Normal Epileptic	2 (%2) 124 (%98)	0 (%0) 82 (%100)	2 (%8) 22 (%92)	0 (%0) 20 (%100)	0.059
Age of onset, Mean±SD	6.1±4.2	6.3±4.2	5.3±4.3	6.4±4.2	0.563
Duration of disease, Mean±SD	3.0±2.1	2.7±1.8	2.8±2.2	4.3±2.6	0.021^b,c
Number of seizures in last three months, n (%) 0 >1	82 (%65) 45 (%35)	56 (%68) 26 (%32)	17 (%71) 7 (%29)	9 (%43) 12 (%57)	0.073
Number of ASDs, n (%) 1 2 >3	82 (%65) 24 (%19) 21 (%17)	54 (%66) 22 (%27) 6 (%7)	22 (%92) 2 (%8) 0 (%0)	0 (%0) 16 (%76) 5 (%24)	<0.001^a,b,c

SD: Standard Deviation

a: p<0.05 for NEIAEDs vs EIAEDs

b: p<0.05 for NEIAEDs vs Both

c: p<0.05 for EIAEDs vs Both

Table 2

Lifestyle habits and laboratory measurements in ASD groups.
	Total	ASDs type			P
	Total	Non-EIASDs	EIASDs	Combined
	N = 127	N = 82	N = 24	N = 21
Living in a city, n (%)	96 (%76)	63 (%77)	15 (%62)	18 (%86)	0.177
Diet, n (%) Normal Vegetarian	125 (%98) 2 (%2)	82 (%100) 0 (%0)	23 (%96) 1 (%4)	20 (%95) 1 (%5)	0.155
Physical activity, n (%) < 1 hr. / week > 1 hr. / week	15 (%12) 112 (%88)	9 (%11) 73 (%89)	3 (%12) 21 (%88)	3 (%14) 18 (%86)	0.910
Sun exposure, n (%) < 1 hr. / week > 1 hr. / week	13 (%10) 114 (%90)	8 (%10) 74 (%90)	2 (%8) 22 (%92)	3 (%14) 18 (%86)	0.831
Vitamin D level in autumn, Mean ± SD	24.2 ± 14.2	27.6 ± 12.2	21.7 ± 19.7	13.9 ± 7.9	<0.001^a,b
Vitamin D level in summer, Mean ± SD	23.2 ± 16.4	26.1 ± 13.2	22.8 ± 29.2	14.2 ± 9.2	<0.001^a,b
Vitamin D level in autumn, n (%) Deficiency (25(OH)D ≤ 20 ng/mL) Insufficiency (25(O.H.)D: 21–29 ng/mL) Normal values (25(OH)D ≥ 30 ng/mL)	60 (%47) 29 (%23) 38 (%30)	25 (%31) 25 (%31) 32 (%39)	17 (%71) 2 (%8) 5 (%21)	18 (%86) 2 (%9) 1 (%5)	< 0.001^a,b
Vitamin D level in summer, n (%) Deficiency (25(OH)D ≤ 20 ng/mL) Insufficiency (25(O.H.)D: 21–29 ng/mL) Normal values (25(OH)D ≥ 30 ng/mL)	43 (%54) 18 (%22) 19 (%24)	19 (%36) 18 (%35) 15 (%29)	10 (%83) 0 (%0) 2 (%17)	14 (%88) 0 (%0) 2 (%12)	< 0.001^a,b
Ca, Mean ± SD	10.1 ± 1.3	10.1 ± 1.5	9.9 ± 0.5	10.0 ± 0.6	0.737
Mg, Mean ± SD	2.15 ± 0.58	2.10 ± 0.59	2.2 ± 0.64	2.32 ± 0.48	0.251
PO4, Mean ± SD	5.07 ± 0.47	5.08 ± 0.49	5.02 ± 0.44	5.10 ± 0.43	0.829

SD: Standard Deviation

a: p < 0.05 for NEIAEDs vs EIAEDs

b: p < 0.05 for NEIAEDs vs Both

c: p < 0.05 for EIAEDs vs Both

Table 3

Model parameter estimates.
Vitamin D level in winter/autumn (Adjusted R²: 0.335)
Variable	Estimate
Number of ASDs	-6.944
Living in rural	10.416
Non-EIASDs use	8.134
BMI	-0.606
D vitamin level in summer/spring (Adjusted R²: 0.230)
Variable	Estimate
Number of ASDs	-7.033
Age	-0.773
BMI	-1.180

Table 4

Comparison of vitamin D levels according to the seasons
	N	D vitamin level		P
	N	in winter/autumn	in summer/spring	P
Total	80	23,0 ± 12,9	23,2 ± 16,4	0,901
Non-EIASDs	52	27,4 ± 17,8	26,1 ± 13,2	0,053
EIASDs	12	15,1 ± 8,8	22,8 ± 29,2	0,371
Combined	16	14,6 ± 8,9	14,2 ± 9,2	0,696

Table 5

Vitamin D parameters according to variables
		D vitamin level
		N	Autumn	P	N	Summer	P
Type of Therapy
	Monotherapy	75	28.1 ± 14.8	< 0.001	44	27.2 ± 17.9	0.002
	Combined therapy	52	18.6 ± 11.2		36	18.3 ± 13.0
Number of ASDs
	1	76	28.4 ± 15.0		45	28.1 ± 18.7
	2	40	19.5 ± 10.7	< 0.001^e	27	17.9 ± 10.2	0.001^e
	> 3	11	12.6 ± 6.2		8	13.5 ± 10.4

e: p < 0.05 for No. of AEDs is 1 vs No. of AEDs is 2 and p < 0.05 for No. of AEDs is 1 vs No. of AEDs is 3+

To assess the risk factors with an effect on 25(OH)D serum level, six independent variables were seen to be statistically significant: number of ASDs (p = 0.001), type of ASDs (p = 0.01), and duration of epilepsy(p = 0,021), epilepsy type (p = 0,001), etiology (p = 0,001), MRI (p 0,001).

Due to the high belief that vitamin D is normal/ high in sunny seasons, a test for vitamin D level was done in 127 patients in winter/autumn but the same test was done in only 80 patients in summer/spring. According to ASDs type, epilepsy type, duration of disease, MRI findings, and etiology were found to be different between the groups. Accordingly, The EIASDs and combined groups had more patients with focal-type seizures, while the Non-EIASDs group had more patients with generalized type. Disease duration and the number of attacks in the last three months were higher in the combined group compared to the other two groups (Non-EIASDs and EIASDs). The percentage of patients with normal MRI findings was higher in the Non-EIASDs and EIASDs groups compared to the combined group. In terms of etiology, the rate of patients with structural etiology was higher in the combined group than in the other two groups.

As the number of ASDs used increases, the vitamin D level decreases. However, it is not clear whether this is the effect of the drug or the fact that the severity of the disease is higher in patients who use multiple drugs. Therefore, it is necessary to be careful when generalizing and analyzing the results.

Our study underlines the importance of vitamin D difference/insufficiency in pediatric patients with epilepsy on ASDs and which group should be monitored closely (9, 10). This study revealed a high rate of vitamin D deficiency/insufficiency (70%) in winter/autumn and 76% in summer/spring among pediatric epilepsy patients with ASDs, supporting the results of previous reports and our results were alining Napakjira Likasitthananon et al. study’s result that was conducted in Thailand, which showed two-thirds of pediatric epilepsy patients had hypovitaminosis D despite the living in the tropical zone. This fact can underline the effect of ASDs on vitamin D metabolism. Reem Al Khalifah et al. study showed almost the same results in Saudi children with epilepsy that received ASDs (3, 11).

Considering the risk factors affecting vitamin D levels, the type of ASDs was found to affect vitamin D levels EIASDs were accompanied by lower 25( OH )D levels, supporting the results of Inês Antunes Cunha et al. studies’ results. Which was conducted on a total of 92 adult patients (44.6% males), with a mean age of 41.0 ± 14.8, in the study showed 56.5% were vitamin D deficient and 22.8% were vitamin D insufficient, which means that 79.3% of patients in total had abnormal levels of vitamin D (4).

In total agreement with some studies' results, a higher number of ASDs was associated with lower levels of vitamin D. This result, however, can be explained by the fact that our pediatric patients who on more than one ASDs were taking a combination of Non-EIASDs and EIASDs and, as a result, were likely to be affected by vitamin D deficiency related to EIASDs disagreeing with Inês Antunes Cunha et al. studies’ results which showed a higher level of vitamin D in the group who used a higher number of ASDs which was explained by the most patient who used more than one drug were on Non-EIASDs in that study (4). In a study which was conducted in the tropical area of Malaysia, polytherapy > 1 ASDs, age > 12, Indian ethnicity, inadequate sun exposure time, and being female were found to be statistically significant risk factors for vitamin D deficiency in pediatric patients with epilepsy ( 12). In another study conducted by J H Baek et al., vitamin D levels were lower in patients who had taken anticonvulsants for more than two years as compared to those who had taken them for less than two years. The same study concluded that those taking oxcarbazepine(EIASDs) had significantly lower vitamin D levels than patients taking valproic acid ( Non-EIASDs), which was in line with our results to some extent (13). In our study, the number of ASD.s and BMI were found to affect the level of D vitamin in all seasons, while age was found to affect the level of vitamin D in summer/spring. These results could be explained by the lower number of patients with vitamin D levels in summer/spring due to the high belief that vitamin D is normal/ high in sunny seasons. Living in a rural area affected vitamin D levels in winter/autumn. This situation could be due to the exposure to the sun in rural areas in winter /autumn.than in the city centers. Seasons can play a role in vitamin D levels. Everyone can expect to have a higher level of vitamin D in summer, but our results showed that there was insufficient in all seasons despite sun exposure for more than one hour a week which could be due to the use of ASDs. However, only 55% of patients had vitamin D screening tests in summer/ spring. In contrast, all the patients had a test for vitamin D v in the winter /autumn seasons for probable vitamin D insufficiency or deficiency due to shorter sun exposure. So, our results could be different if larger samples of vitamin D were investigated in all seasons. In addition, ineffective sun exposure could play a role in vitamin D levels in summer due to the use of clothes and sunscreen glasses to avoid strong exposure to ultraviolet sun rays in this very sunny area of our study. In fact, exposure to direct sun rays is low in all seasons. In addition to that, ASDs certainly played a role in vitamin D levels.

In another study conducted in a sunny city in Australia, analysis of that study identified children with > 2 ASDs or with underlying genetic etiologies were more likely to have vitamin D deficiency. A high percentage of children with long-term ASDs in Australia are at risk of vitamin D deficiency/insufficiency despite living in the subtropics; these results matched our study that was conducted in one of the sunniest cities in Turkey in this study(14).

The features of seizures also played a role in vitamin D levels, focal seizures, unknown features, or mixed types, which involved both focal and generalized seizures accompanied by lower vitamin D levels. Abnormal MRI and etiology were the other important factors that played a major role in indicating vitamin D level, which could be explained by the use of EIASD or the use of a higher number of ASDs. High frequency of seizure in the past three months was not associated with lower vitamin D levels in our study, disagreeing with Inês Antunes Cunha et al. results’ study conducted on adult patients, which showed an association between seizure frequency and lower vitamin D levels (4, 5, 13).

Concerning seizure type and duration of epilepsy, patients who had epileptic seizures for more than four years had lower vitamin D levels. This situation could be explained by the type of ASDs used by these patients, mostly EIASDs, and the high number of ASDs. On the other hand, the majority of seizure-free patients used only Non-EIASDs which could account for the higher levels of 25(OH) D observed in these patients. Napakjira Likasitthananon et al. study showed that more than two years of ASDs use was significantly associated with hypovitaminosis D ( 3). This situation could be due to different medications being simultaneously researched, and they could influence vitamin D levels through different and several mechanisms. At the same time, Na Dong et al. study showed that D vitamin level is lower in epileptic patients before even starting ASDs which underlines that the disease could also directly affects vitamin D metabolism or lower vitamin D can lead to more seizures as other neurosteroids vitamin D is claimed to exert its actions by many ways (15) Vitamin D plays several roles in modulation of cell proliferation, differentiation, neurotransmission and immune response in the central nervous system (16). Most studied are its genomic actions. These involve binding of 1,25(OH)D to the nuclear vitamin D receptor and regulating the expression of several proteins expressed in the nervous system, including neurotrophins such as neurotrophin-3, neurotrophin-4, and nerve growth factor and glial cell-derived neurotrophic factor as well as parvalbumin a calcium-binding protein, that inhibits the synthesis of the nitric oxide synthetase and prevents seizures (17).

Vitamin D deficiency is common with anticonvulsant therapy, especially EIASDs have a particular effect on vitamin D levels. Vitamin D is very important for bone health, and vitamin D deficiency may contribute to many disorders such as autoimmune, infections, cancer, degenerative, diabetic, and vascular diseases (18, 19).

Limitations of the study

Single centers, a limited number of patients, and the unavailability of vitamin D levels in all patients in summer/spring were considered the main limitations of our study.

This study underlines the high percentage of vitamin D deficiency/insufficiency among pediatric epilepsy patients. The shown risk factors for vitamin D deficiency/insufficiency were: the number of ASDs, treatment with EIASDs, long duration of epilepsy and thus long treatment period., abnormal MRI, and etiology, which can necessitate the use of a high number of ASDs. Hence vitamin D status of children treated with ASDs should be regularly monitored, and vitamin D supplements should be considered individually in these patients.

ASDs: Anti Seizures Drugs

EIASDs: Enzyme-Induced Anti-Seizure Drugs

Non-EIASDs: Non-Enzyme-Induced Anti-Seizure Drugs

BMI.; Body mass index

ILAE.: International League Against Epilepsy

MRI.: Magnetic Resonance Imaging

Acknowledgments; Not applicable.

Authors’ contributions: SB planned and coordinated the study, SNT. analyzed the literature, and SB was a major contributor to writing the manuscript study. Both authors read and approved the final manuscript.

Funding Nothing to declare. No funding has been received

Availability of data and materials At S.B. repository. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethical Approval and consent to participate: The study was conducted in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards and approved by the Clinical Research Ethics Committee of Gazi YşargilEducation & Research Hospital (2023:2023/353). Written informed consent was obtained from all the participants and/or legal guardians.

Consent for publication: Not applicable

Competing interests: The authors declare that they have no competing interest

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Vitamin D status of pediatric epilepsy patients and evaluation of affecting factors

Status:

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Abstract

Figures

Background

Material & Method

Statistical Analysis

Results

Discussion

Limitations of the study

Conclusion

Abbreviations

Declarations

References

Status:

Version 1