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Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu
Original Article
abstract
BACKGROUND: Our aim was to evaluate the prevalence and risk factors of vitamin D deciency and the changes of
vitamin D level among children with epilepsy on antiepileptic drugs. METHODS: The levels of serum 25-hydroxy
vitamin D were measured at the start of antiepileptic drugs and at 6- to 12-month intervals in children with
epilepsy taking antiepileptic drugs in Pusan National University Childrens Hospital. Vitamin D deciency was
dened as 25-hydroxy vitamin D levels <20 ng/mL and insufciency between 21 and 29 ng/mL. RESULTS: A total of
143 children (103 boys and 40 girls) with the mean age of 7.4 5.4 years were included. The mean follow-up
duration was 1.8 0.8 years. At the start of antiepileptic drugs and the last follow-up, vitamin D deciency or
insufciency was recognized in 56.6% (81 of 143) and 79.0% (113 of 143), respectively (P < 0.01). The mean value of
initial 25-hydroxy vitamin D was 31.1 14.7 ng/mL, which was signicantly decreased to 20.2 14.9 ng/mL
(P < 0.01) in the last follow-up. Polytherapy (16.0 13.6 ng/mL), longer duration of 2 years (23.5 9.1 ng/mL),
tube feeding (18.2 14.5 ng/mL), and overweight with body mass index of eighty-fth percentile or greater
(17.0 12.1 ng/mL) had a signicant negative effect for the longitudinal change of 25-hydroxy vitamin D. Age,
etiologies, seizure outcomes, and type of antiepileptic drugs (enzyme-inducing versus nonenzyme-inducing anti-
epileptic drugs) did not affect the longitudinal decrease of 25-hydroxy vitamin D. CONCLUSIONS: A high proportion of
these children on antiepileptic drugs had hypovitaminosis D and a signicant decrease between the initial and the
last follow-up. Polytherapy and longer duration of antiepileptic drugs, tube feeding, and overweight were inde-
pendently associated with longitudinally signicant decrease of 25-hydroxy vitamin D.
Keywords: vitamin D, hypovitaminosis D, child, epilepsy, antiepileptic drug
Pediatr Neurol 2015; 52: 153-159
2015 Elsevier Inc. All rights reserved.
0887-8994/$ - see front matter 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2014.10.008
154 Y.-J. Lee et al. / Pediatric Neurology 52 (2015) 153e159
FIGURE 1.
(A) The longitudinal change of the mean of 25OHD levels in children with epilepsy taking AEDs showed a signicant decline from 31.1 14.7 ng/mL to
20.2 14.9 ng/mL during the mean 1.8-year follow-up period (10.9 14.5 ng/mL; P < 0.01). (B) The distribution of the levels of 25OHD was tilted to the
low end of the spectrum. The rate of the hypovitaminosis D status of <20 ng/mL signicantly increased from 20.3% (29 of 143) to 61.5% (88 of 143) between
the baseline and the last follow-up (P < 0.01). 25OHD, 25-hydroxyvitamin D; AEDs, antiepileptic drugs.
156 Y.-J. Lee et al. / Pediatric Neurology 52 (2015) 153e159
26.1 28.8
22 23.1
18.6
15
(E) Tube feeding Oral feeding (F) BMI >85% BMI <85%
36.8 (p<0.01)
(p=0.01) 32.9
30 30.1
23.6
20.4
18.7 15.9
12 ng/mL), and a girl experienced a femur fracture (25OHD, mean 10.9 14.5 ng/mL between the baseline and the last
9 ng/mL). Bone mineral density was not performed. Their 25OHD in our tertiary hospital-based population of pediatric
fractures have been naturally healed. epilepsy on long-term AEDs (mean duration, 1.8 0.8 years).
Polytherapy (two or more AEDs) and longer duration
Discussion (2 years) of AEDs, tube feeding, and elevated BMI of
eighty-fth percentile or greater were independently asso-
We discovered a high proportion of vitamin D deciency ciated with longitudinally signicant decrease of 25OHD
(61.5%; 88 of 143) or insufciency (17.5%; 25 of 143) before and after the AED treatment. Our study included a
status with a longitudinally signicant decrease of the large number of children with long-term follow-up to
Y.-J. Lee et al. / Pediatric Neurology 52 (2015) 153e159 157
TABLE 2.
Univariate and Multivariate Regression Analysis of the Factors Associated With Longitudinal Decrease Between the Baseline and the Last 25OHD
evaluate the vitamin D status (numbers of children on ranging from 4% to 75%.3-5,16,17 These inconsistent results
long-term AEDs participated in previous reports ranged could be inuenced by multiple factors, including seasonal
between 38 and 125 children).2-5,16,17 It can be considered as variation, diverse place of residence, different inclusion
the rst longitudinal study from the baseline to the last criteria for the duration of AED treatment, different exclu-
follow-up, and not as a cross-sectional study, for the sion criteria of children who may have underlying disorders
hypovitaminosis D in pediatric epilepsy on AEDs. We also affecting bone metabolism, and dissimilar cutoff values for
investigated the risk factors for the hypovitaminosis D the hypovitaminosis D (<10 or <20 ng/mL). We have tried
through a comparison between patients with longitudinally to reduce these confounding factors by measuring 25OHD
signicant decrease of 25OHD and with unnoticeable levels including all children with epilepsy on AEDs for at
change (D-25OHD < 10 vs 10 ng/mL). least 1 year, excluding the children with any intrinsic con-
Data from 12- to 19-year-old American adolescents from dition or disease of impaired bone health, and using a recent
the National Health and Nutrition Examination Survey denition for the vitamin D deciency (<20 ng/mL) and
revealed striking differences in the prevalence, depending insufciency (21 to 29 ng/mL). Our patients had a consid-
on the inconsistent cutoff values. When the denition of erable change of the prevalence of vitamin D deciency or
vitamin D deciency was changed from <11 to <20 ng/mL, insufciency between the baseline (56.6%) and the last
the prevalence increased from 2% to 14%. Vitamin D levels follow-up (79.0%) during the AED treatment. The preva-
are also affected by age, sex, geographic location, use of lence of hypovitaminosis D among healthy children in our
supplements, and BMI, which make it complicated to dene hospitals region has not been investigated until now.
the hypovitaminosis D and estimate the prevalence.18 Pre- Several studies commented on the effect of polytherapy
vious studies of vitamin D status in pediatric epilepsy have of AEDs on vitamin D status in pediatric epilepsy. A
reported a diverse prevalence of the hypovitaminosis D, German cross-sectional study4 reported that polytherapy
158 Y.-J. Lee et al. / Pediatric Neurology 52 (2015) 153e159
is associated with signicantly lower 25OHD levels is After the follow-up period, we instituted vitamin D
monotherapy. Bergqvist et al.5 reported a decline of supplementation in the children with vitamin D deciency.
approximately 7 ng/mL in 25OHD for each additional AED The oral vitamin D preparation used was sunny D drops
in children with refractory epilepsy. Other reports have11 cholecalciferol (D3, 400 IU/drop; GMP laboratories of
documented that, while the type of AEDs exerted no ef- America), and children took one drop (400 IU/day) of sunny
fect on vitamin D status or bone mineral density, poly- D drops according to the maintenance dose in children.
therapy exerted a negative impact on bone mineral Most of them showed an increase of 25OHD, although these
density. Our children with polytherapy or longer duration data are preliminary.
(longer than 2 years) of AEDs also had greater decline of Our study has limitations. First, we lack comprehensive
25OHD than those with monotherapy or shorter duration. dietary assessments and home backgrounds in our patients.
Because many AEDs induce hepatic CYP450 metabolism, Others have highlighted that diet plays an important role in
they result in an increased metabolism of vitamin D, determining vitamin D levels, and this should not be over-
leading to declining 25OHD levels, increased parathyroid looked.3,5 Second, we do not routinely examine the bone
hormone levels, and abnormally enhanced bone turn- mineral density in children with epilepsy. Therefore, we
over.19-25 However, even nonenzyme-inducing medica- cannot comment much regarding the potential impact of
tions were associated with poor bone health.19-23 low vitamin D levels on bone mineral density in our pa-
Therefore, hepatic enzyme induction is just one compo- tients. Nevertheless, current evidence has shown the asso-
nent of multifaceted mechanisms by which AEDs affect the ciation of low vitamin D levels with low bone mineral
health of bones. density in children.30 Last, we did not evaluate the effects of
Baer et al.10 studied vitamin D levels in relation to specic drugs. We just compared the effect between
ambulation in a large sample of children and documented enzyme-inducing and nonenzyme-inducing AEDs in chil-
that the risk of the hypovitaminosis D among non- dren undergoing monotherapy. Enzyme-inducing AEDs
ambulatory children was about twice that of ambulatory were not associated with the risk compared with others.
children (P < 0.01), even after adjusting for confounders. Nearly half of our patients had taken with new AEDs. These
Other studies excluded nonambulatory patients because of new AEDs, which are not potent hepatic enzyme inducers,
concerns about confounding results. We found that non- may have a lesser effect on 25OHD levels than old enzyme-
ambulatory children of epilepsy had a longitudinally greater inducing drugs. However, others have documented that
decrease of 25OHD than ambulatory children; however, oxcarbazepine24,31,32 and lamotrigine33 may inuence on
ambulation was not an independent risk factor in multi- 25OHD and/or bone mineral density.
variate model. We found that there is a longitudinally signicant
One study5 of children with intractable epilepsy on a decrease in 25OHD levels during the AED treatment and a
ketogenic diet reported that, before the diet therapy, 4% and high prevalence of hypovitaminosis D in children with ep-
51% had vitamin D deciency (25OHD of <11 ng/mL) and ilepsy. Polytherapy and longer duration of AEDs, tube
insufciency (<32 ng/mL), respectively. The levels of feeding, and elevated BMI were signicant as independent
25OHD were declined by approximately 0.5 ng/mL/mo risk factors for the longitudinal decrease of 25OHD. A high
during a 15-month ketogenic diet. In our study, both tube proportion of these children on AEDs are at further risk for
feeding and ketogenic diet were associated with the sig- bone injury due to seizures, comorbid neuromuscular
nicant decrease of 25OHD in a univariate model; however, dysfunction, and long-term AED treatment that affect the
only tube feeding was an independent risk factor (OR, 6.08; health of bones. Augmented concern and advice regarding
95% CI, 5.22 to 12.51). Generally, there is no need for addi- vitamin D status and bone health among children with
tional nutritional supplements when taking a liquid for- epilepsy are very important. Further studies evaluating the
mula (vitamin D, 2.5 mg/200 mL) or a ketogenic milk efcacy of vitamin D supplementation in these children is
(vitamin D, 3.2 mg/180 mL) for the tube-fed children necessary.
because it contains all the vitamins and minerals that are
required for physical growth based on the Dietary Reference This study was supported by a 2013 research grant from Pusan National University
Intake for Koreans (vitamin D, 5 mg/day in 1 year of age, Yangsan Hospital.
10 mg/day in >1 year of age). Nonetheless, children on tube
feeding, who might be exposed to poor eating capacity or
recurrent gastrointestinal disturbance, could be explained
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