FULL-LENGTH ORIGINAL RESEARCH

Vitamin D deficiency and its risk factors in Malaysian

children with epilepsy
*Choong Yi Fong, *Ann Nie Kong, †Bee Koon Poh, ‡Ahmad Rithauddin Mohamed,
‡Teik Beng Khoo, *§Rui Lun Ng, *Mazidah Noordin, §Thiyagar Nadarajaw, and *Lai Choo Ong

Epilepsia, 57(8):1271–1279, 2016

doi: 10.1111/epi.13443

SUMMARY
Objective: Long-term use of antiepileptic drugs (AEDs) is a significant risk factor for
vitamin D deficiency in children with epilepsy. The aims of our study were to evaluate
the prevalence and risk factors for vitamin D deficiency among Malaysian children with
epilepsy.
Methods: Cross-sectional study of ambulant children with epilepsy on long-term AEDs
for >1 year seen in three tertiary hospitals in Malaysia from April 2014 to April 2015.
Detailed assessment of pubertal status, skin pigmentation, sunshine exposure behav-
ior, physical activity, dietary vitamin D and calcium intake, anthropometric measure-
ments and bone health blood tests (vitamin D, alkaline phosphatase, calcium,
phosphate, and parathyroid hormone levels) were obtained on all patients. Vitamin D
deficiency was defined as 25-hydroxy vitamin D [25(OH)D] levels ≤35 nmol/L and
insufficiency as 25(OH)D levels of 36–50 nmol/L.
Results: A total of 244 children (146 male) participated in the study. Ages ranged
between 3.7 and 18.8 years (mean 12.3 years). 25(OH)D levels ranged between 7.5
and 140.9 nmol/L (mean 53.9 nmol/L). Vitamin D deficiency was identified in 55
Dr. Choong Yi Fong patients (22.5%), and a further 48 (19.7%) had vitamin D insufficiency. Multivariate
is a consultant logistic regression analysis identified polytherapy >1 AED (odds ratio [OR] 2.16, 95%
pediatric neurologist confidence interval [CI] 1.07–4.36), age >12 years (OR 4.16, 95% CI 1.13–15.30), Indian
and associate ethnicity (OR 6.97, 95% CI 2.48–19.55), sun exposure time 30–60 min/day (OR 2.44,
professor at the 95% CI 1.05–5.67), sun exposure time <30 min/day (OR 3.83, 95% CI 1.61–9.09), and
University of Malaya, female (OR 2.61, 95% CI 1.31–5.20) as statistically significant (p < 0.05) risk factors for
Kuala Lumpur, vitamin D deficiency.
Malaysia. Significance: Despite living in the tropics, a high proportion of Malaysian children with
epilepsy are at risk of vitamin D deficiency. Targeted strategies including vitamin D
supplementation and lifestyle advice of healthy sunlight exposure behavior should be
implemented among children with epilepsy, particularly for those at high risk of having
vitamin D deficiency.
KEY WORDS: Antiepileptic drug, Anticonvulsant, Bone health, Pediatric, Nutrition.

Vitamin D is a prohormone that is essential for bone

Accepted May 24, 2016; Early View publication July 5, 2016.
*Division of Pediatric Neurology, Department of Pediatrics, Faculty of
Medicine, University Malaya, Kuala Lumpur, Malaysia; †Nutritional
Sciences Program, Faculty of Health Sciences, University Kebangsaan
Malaysia, Kuala Lumpur, Malaysia; ‡Pediatric Neurology Unit, Pediatric
Institute, Hospital Kuala Lumpur, Malaysia, Malaysia; and §Pediatric
Department, Hospital Sultanah Bahiyah, Alor Setar, Kedah, Malaysia
Address correspondence to Choong Yi Fong, Consultant Pediatric Neu-
rologist and Associate Professor, Division of Pediatric Neurology, Depart-
ment of Pediatrics, Faculty of Medicine, University of Malaya, 50603
Kuala Lumpur, Malaysia. E-mail: cyfong@ummc.edu.my
Wiley Periodicals, Inc.
© 2016 International League Against Epilepsy
health during childhood and adolescence.1–3 Vitamin D suf-
ficiency plays an important role in effective bone mineral-
ization and also enables bone mass accrual during the
childhood period.2,3 Dietary sources of vitamin D only
account for <10% of vitamin D requirements.4 The major
source of vitamin D is from exposure to sunlight.2 In addi-
tion, the other important extrinsic factors influencing vita-
min D levels include dietary vitamin D and calcium intake,
physical activity, and intake of medications that can affect
vitamin D levels.1,5 Vitamin D insufficiency is recognized

1271

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C. Y. Fong et al.
Key Points
• Vitamin D deficiency is prevalent among Malaysian
children with epilepsy
• Children with additional risk factors of >1 AED, low
sunshine exposure, Indian ethnicity, female, and age
>12 years are more likely to have vitamin D
deficiency
• In children with epilepsy, vitamin D supplementation
and lifestyle advice of healthy sunlight exposure need
to be provided
as a global problem, with a high number of children having
vitamin D insufficiency worldwide even in sun-rich Asian
countries like Malaysia, Thailand, Indonesia, and Vietnam.6
Long-term use of antiepileptic drugs (AEDs) is a signifi-
cant risk factor for vitamin D deficiency and impaired bone
health in children with epilepsy.7–10 Hepatic cytochrome
P450 (CYP) enzyme–inducing AEDs affect bone health by
increasing hepatic metabolism of vitamin D.8 Other non–
enzyme-inducing AEDs like sodium valproate can impact
bone health via direct effects on bone cells, resistance to
parathyroid hormone, and inhibition of calcitonin secre-
tion.7,8 Treatment of vitamin D deficiency in these children
is important as it will optimize bone health and can result in
reduction of rate of premature osteoporotic fractures when
they are adults.11,12 There are now recommendations of
periodic vitamin D blood monitoring and vitamin D supple-
mentation in children on long-term AEDs.8,10,13 Despite
these recommendations, a survey among pediatric neurolo-
gists in the United Kingdom highlighted that issues related
to bone health in children on long-term AEDs are often
overlooked.14 Currently in Malaysia, it is not a routine
practice for children on long-term AEDs to receive vitamin
D supplementation, and there is no guideline on vitamin D
supplementation in these children.
Malaysia is a tropical country in Southeast Asia located
at the Equator that is sunny all year round and receives on
average 6 h of sunshine per day. There are two studies to
date evaluating vitamin D status among healthy Malaysian
children, which showed high prevalence of vitamin D defi-
ciency of 20–35% even among normal healthy children.6,15
Currently there are no prevalence data of vitamin D defi-
ciency in children with epilepsy in Malaysia or from other
countries in the tropical Asian region. In addition, there are
no studies to date that have concomitantly and comprehen-
sively evaluated the other potential extrinsic risk factors
(sunshine exposure, dietary vitamin D intake, dietary cal-
cium intake, and physical activity) that can affect vitamin D
status in children with epilepsy.
The aims of this study, therefore, were to evaluate
the prevalence and potential risk factors for vitamin D
Epilepsia, 57(8):1271–1279, 2016
doi: 10.1111/epi.13443
15281167, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.13443 by Nat Prov Indonesia, Wiley Online Library on [30/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
deficiency in children on long-term AEDs in a tertiary hos-
pital–based Malaysian epilepsy population.
Methods
Patient recruitment
A cross-sectional study was conducted on all children
with epilepsy who were ambulant, aged between 3 and
18 years old, and on long-term (>1 year) AEDs. Patients
were recruited from April 2014 to April 2015 at tertiary
pediatric clinics in Hospital Sultanah Bahiyah Alor Setar
(HSBAS) Kedah at latitude 6°N, the Paediatric Neurology
clinic in University Hospital Medical Centre (UMMC)
Kuala Lumpur at latitude 3°N, and the Pediatric Neurology
clinic in Pediatric Institute Hospital Kuala Lumpur (PIHKL)
at latitude 3°N. Ethical approval to conduct this study was
given by the University Malaya Medical Center Medical
Ethics Committee (Ref: 1004.3) and Malaysia Medical
Research and Ethics Committee (Ref: NMRR-13-892-
16933).
Exclusion criteria were defined as the following: (1) pres-
ence of hepatic, skeletal, renal, or endocrine disorders; (2)
current and prior intake of vitamin D or calcium supple-
ments within the last 6 months; (3) patients who were non-
ambulant or unable to walk independently both indoors and
outdoors; or (4) patients who were fed by nasogastric tube
or gastrostomy. Parents/caregiver of all patients eligible for
the study were given a verbal explanation of the project,
provided with a patient information sheet, and written con-
sent was obtained for all participants.
Data collection
Clinical data were obtained using a standard proforma
sheet, which included the following:
(1) Demographic data of potential risk factors for vitamin
D status: age, sex, ethnicity, skin pigmentation and
pubertal status. Pubertal status was assessed using the
Tanner staging: pubertal onset was defined for girls with
breast stage ≥stage two and for boys with testicular vol-
ume >4 ml.16 Skin pigmentation was measured using
the Fitzpatrick’s classification, which has six types of
skin pigmentation ranging from type one (lightest) to
type six (darkest).17
(2) Epilepsy history: seizure frequency, AED chronology,
AED regimen (enzyme inducing AED included carba-
mazepine, phenobarbitone, phenytoin, oxcarbazepine,
and topiramate; and nonenzyme-inducing AED
included sodium valproate, clobazam, lamotrigine,
gabapentin, levetiracetam, zonisamide, and vigabatrin),
number of regular AEDs the patient was on, and length
of time on AED treatment.
(3) Anthropometry measurements: Weight was measured
in light clothing using calibrated TANITA digital scale
Model 330 (TANITA, Japan) accurate to 0.1 kg. Height
 15281167, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.13443 by Nat Prov Indonesia, Wiley Online Library on [30/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1273
Vitamin D Deficiency in Malaysian Epilepsy Patients

was measured using wall-mounted SECA bodymeter corrected calcium, alkaline phosphatase, phosphate and
Model 208 (SECA, Germany) accurate to 0.1 cm with- parathyroid hormone (PTH) levels. To ensure uniformity
out shoes. Body mass index (BMI) was calculated as and accuracy of measurement of 25(OH)D and PTH, all
weight (kg) divided by height squared (m2). Anthropo- serum 25(OH)D and PTH levels were measured using the
metric status of participants were classified based on the same electrochemiluminescence immunoassay autoana-
World Health Organization (WHO) growth standards lyzer Cobas e411 (Roche, Basel, Switzerland) in a quality-
using height-for-age and BMI-for-age indicators.18,19 controlled accredited laboratory. The interassay coefficient
At enrollment, each participant was interviewed in person of variance (CV) of 25(OH)D was 3.0% at 170.5 nmol/L
or via the primary caregiver (for children <7 years old) by a (68.2 ng/ml) and 3.6% at 57 nmol/L (22.8 ng/ml). The
trained interviewer using structured questionnaires includ- interassay CV of PTH was 6.2% at 20.2 ng/ml and 4.1% at
ing the following: 58 ng/ml.
At present there is no international consensus as to a defi-
(1) Children’s physical activity questionnaire (cPAQ) was
nition of optimal vitamin D states. The American Academy
used to assess physical activity levels of children with
of Pediatrics (AAP), Institute of Medicine (IOM), and Euro-
epilepsy that was specifically developed and validated
pean Society of Pediatric Gastroenterology, Hepatology and
into a physical activity questionnaire for Malaysian
Medicine suggest 50 nmol/L (20 ng/ml) as the cut-off for
children.20,21 The interviewer-administered cPAQ
deficiency.1 Other reviews have defined vitamin D defi-
assessed three domains as follows: activities in relation
ciency as ≤37.5 nmol/L (15 ng/ml) and vitamin D insuffi-
to school, organized activities, and unorganized activi-
ciency as 37.6–50 nmol/L (16–20 ng/ml).4 In Malaysia the
ties. Children recalled activities from the past week and
accepted level of vitamin D deficiency among children is
reported habitual physical activity, including school
≤37.5 nmol/L and insufficiency as 37.6–50 nmol/L, hence
activities, all forms of transportation, physical education
the latter definition were used in this study. Our laboratory
sessions, activities in sports and other clubs, leisure time
reference values for PTH were between 1.0 and 7.0 pmol/L
activities, and work activities. Components of these
and phosphate values were between 0.78 and 1.65 mmol/L.
physical activities were assessed by calculating the
Reference values for the calcium and alkaline phosphatase
metabolic intensity using the metabolic component of
were based on recognized international age-dependent ref-
physical activity (METPA) scores in metabolic equiva-
erence values.26
lent–minute/week and calculating the mechanical bone
strain using mechanical component of physical activity
Statistical analysis
(MECHPA) scores in Peak Strain Score/week.20
The sample size calculation for vitamin D deficiency for
(2) Dietary intake was assessed using a modified diet his-
our cohort was performed based on healthy Malaysian chil-
tory questionnaire that recalls intake over the past
dren prevalence of 20%.6 The sample size required (with
7 days.22 Household measures were used to estimate
0.1 confidence interval width and 95% confidence interval)
portion sizes. Analysis of dietary intake of vitamin D
is 246 patients.
(lg/day) and calcium intake (lg/day) was performed
All data was entered into an SPSS database for analy-
using the Nutritionist Pro Software (Axxya System,
sis. Univariate analysis included Student t-test (or Fisher’s
First Databank, Inc, San Bruno, CA, U.S.A.) based on
exact test for cell values <5) for continuous data and chi-
Nutrient Composition of Malaysian Foods23 and the
square test for categorical data. Each patient’s vitamin D
United States Department of Agriculture (USDA) Stan-
status was classified as nondeficient or deficient. Bivariate
dard Reference Database for vitamin D content of
analysis of the individual risk factors against these two
foods. Total nutrient intake values were compared with
vitamin D status was performed using the chi-square test
the Recommended Nutrient Intakes (RNI) for
to identify candidate variables for the multivariable
Malaysia.24
model. The risk factors that showed an association with
(3) Sunshine exposure behavior was assessed using a ques-
25(OH)D status (defined as a p-value < 0.05) were
tionnaire adapted from Barger-Lux and Heaney.25 Par-
entered into a multiple logistic regression model to deter-
ticipants were asked about their outdoor activities over
mine which potential risk factors independently influ-
the previous week in terms of type of activity, daily
enced vitamin D deficiency. At this step, multicollinearity
duration (in minutes), and frequency (per week) and
diagnostics was done by checking the variance inflation
usual skin exposure to sun (face, wrist, hands [up to
factor (VIF) and tolerance to check for interaction
short sleeve], hands and arms, lower legs [up to short
between different variables. Variance inflation factor
pants level], and whole legs [up to underpants level]).
(VIF > 10) and tolerance below 1 were used to indicate
the problem of multicollinearity among the predictor vari-
Blood sampling and biochemical analyses
ables. All the predictor variables did not violate the VIF
Venous blood was taken and analysis was performed to
and tolerance conditions and were included in multiple
determine 25-hydroxyvitamin D (25(OH)D), albumin-

Epilepsia, 57(8):1271–1279, 2016

doi: 10.1111/epi.13443

1274
C. Y. Fong et al.
logistic regression. Odds ratios (OR) along with 95% con-
fidence interval (CI) were calculated and a p-value < 0.05
was considered statistically significant. Statistical analysis
was performed using Statistical Package for Social
Sciences for Windows version v22.0 (SPSS Inc., Chicago,
IL, U.S.A.).
Results
Participants’ characteristics
A total of 256 ambulant epilepsy patients on long-term
AEDs were identified and recruited during this study period.
From these 256 patients, 12 patients had incomplete data
(2 patients did not have complete anthropometric measure-
ments, 4 patients did not have diet history questionnaire per-
formed, and 6 patients did not have complete bone health
blood tests performed). Hence 244 patients were finally
included in the study, with 43 patients (17.6%) from
HSBAS, 99 (40.6%) patients from UMMC, and 102
(41.8%) patients from PIHKL.
The patient’s age ranged from 3.7 to 18.8 years, with
mean of 12.3 years (SD 3.85). The weight ranged from 12
to 117.7 kg with a mean of 42.5 kg (SD 18.17). The
patient’s BMI-for-age was normal in 120 (49.2%), over-
weight in 47 (19.3%), and obese in 40 (16.4%). In the
majority of our cohort; 202 (82.8%) were not stunted
(height-for-age ≥ 2 SD), and the remainder 42 patients
(17.2%) had height-for-age < 2 SD. Details of the partici-
pant’s anthropometry, blood laboratory values, pubertal
status, and lifestyle behavior (sunshine exposure, physical
activity, vitamin D intake and calcium intake) are presented
in Table 1.
In our cohort, the 25(OH)D levels ranged between 7.5
and 140.9 nmol/L, with a mean of 58.8 nmol/L (SD 25.5).
Vitamin D deficiency was present in 55 patients (22.5%),
and a further 48 patients (19.7%) had vitamin D insuffi-
ciency. The characteristics of the participants (244 patients)
with their individual vitamin D status are presented in
Tables 1 and 2. Significant differences (p < 0.05) were
noted between ethnic groups, with Indians having lower
median 25(OH)D values of 47.5 nmol/L (interquartile
range [IQR] 23.9) than Malays (59.5 nmol/L, IQR 36.6)
and Chinese (68.2 nmol/L, IQR 23.9).
Abnormally elevated PTH levels (range 7.5–73.2
pmol/L) were seen in 22 patients, with 4 patients having 25
(OH)D insufficiency and a further 8 having a 25(OH)D defi-
ciency. Abnormally high ALP levels (range: 321–568 IU/
L) were seen in 20 patients, with 7 having 25(OH)D insuffi-
ciency and a further 2 having 25(OH)D deficiency. Abnor-
mally low calcium level (range 1.81–2.19 mmol/L) was
seen in 37 patients, with 8 patients having 25(OH)D insuffi-
ciency and a further 7 with 25(OH)D deficiency. Abnor-
mally low phosphate levels (range 0.6–0.72 mmol/L) were
seen in three patients, with two patients having 25(OH)D
deficiency. None of the blood laboratory markers had a
Epilepsia, 57(8):1271–1279, 2016
doi: 10.1111/epi.13443
15281167, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.13443 by Nat Prov Indonesia, Wiley Online Library on [30/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
statistically significant association with vitamin D defi-
ciency on our bivariate analysis.
Factors predicting vitamin D status
In the bivariate analysis of potential risk factors predict-
ing 25(OH)D deficiency, sex, age, ethnicity, number of
AEDs, duration of AED treatment, duration of daily sun
exposure, and daily dietary calcium intake showed a
statistically significant association (p < 0.05) with 25(OH)
D deficiency (Table 1 and 2). The multiple logistic regres-
sion model including these seven potential risk factors
resulted in sex, age, ethnicity, number of AEDs, and dura-
tion of sun exposure as the remaining risk factors that
demonstrated statistically significant (p < 0.05) increased
risk of 25(OH)D deficiency (Table 3). 25(OH)D deficiency
was significantly greater in female compared with male
patients (OR 2.61, 95% CI 1.31–5.20); children on AED
polytherapy (>1 AED) compared to children on one AED
(OR 2.16, 95% CI 1.07–4.36); Indian ethnicity when com-
pared to Chinese ethnicity (OR 6.97, 95% CI 2.48–19.55);
and duration of sun exposure with the risk increasing in chil-
dren with lower daily sun exposure, that is, 30–60 min/day
sun exposure compared with >60 min/day sun exposure
(OR 2.44, 95% CI 1.05–5.67) and <30 min/day sun expo-
sure compared with >60 min/day sun exposure (OR 3.83,
95% CI 1.61–9.09).
Discussion
In this Malaysian hospital-based population of children
on long-term AEDs seen at three tertiary hospitals, we found
a high prevalence of vitamin D deficiency and insufficiency.
Fifty-five patients (22.5%) had frank vitamin D deficiency
and a further 48 (19.7%) had vitamin D insufficiency.
Children with epilepsy on AED polytherapy (>1 AED),
reduced daily sunlight exposure, female sex, adolescent
age >12 years old, and Indian ethnicity were at greater risk
of having vitamin D deficiency.
This is the largest pediatric epilepsy study to date evaluat-
ing vitamin D status in children on long-term AEDs (num-
ber of children on AED recruited in previous pediatric
epilepsy studies ranged between 34 and 198 children) and
the first to be conducted in the tropical Asian region.10,27
The other strength of our study is that we are the first to
explore comprehensively potential confounding factors of
lifestyle and dietary intake that may affect vitamin D status,
which have not been addressed by previous epilepsy studies.
We attempted to maintain a homogenous cohort of epilepsy
patients by excluding patients who are nonambulant due to
potential confounders associated with being nonambulant
and the difficulty of accurately assessing lifestyle behavior
in this subgroup of patients.
There are only two studies to date of published preva-
lence rates of vitamin D deficiency (≤37.5 nmol/L) among
healthy school children in Malaysia.6,15 A study in 2008 of
 15281167, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.13443 by Nat Prov Indonesia, Wiley Online Library on [30/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1275
Vitamin D Deficiency in Malaysian Epilepsy Patients

Table 1. Patient demographics and lifestyle characteristics with associated vitamin D status
Vitamin D status of patients
(% within individual variable)
Nondeficient: Deficient:
No. of 25(OH)D 25(OH)D
Risk factor patients (%) >37.5 nmol/L (%) ≤ 37.5 nmol/L (%) p-Value
Gender
Male 146 (59.8) 122 (83.6) 24 (16.4) 0.005*
Female 98 (40.2) 67 (68.4) 31 (31.6)
Age
3–9 years 53 (21.7) 49 (92.5) 4 (7.5) 0.002*
9–12 years 60 (24.6) 49 (81.7) 11 (18.3)
>12 years 131 (53.7) 91 (69.5) 40 (30.5)
Ethnicity
Malay 128 (52.5) 103 (80.5) 25 (18.3) 0.007*
Chinese 60 (24.6) 51 (85.0) 9 (15.0)
Indian 56 (23.0) 35 (62.5) 21 (37.5)
Puberty status
Prepuberty 143 (58.6) 117 (81.8) 26 (18.2) 0.052
Achieved puberty 101 (41.4) 72 (71.3) 29 (28.7)
BMI status
Underweight 37 (15.2) 98 (81.7) 22 (18.3) 0.466
Normal 120 (49.2) 28 (75.7) 9 (24.3)
Overweight 47 (19.3) 34 (72.3) 13 (27.7)
Obese 40 (16.4) 29 (72.5) 11 (27.5)
Height-for-age Z-score
≥ 2.00 SD 202 (82.8) 157 (77.7) 45 (22.3) 0.829
< 2.00 SD 42 (17.2) 32 (76.2) 10 (23.8)
Skin pigmentation
Type 1 and 2 59 (24.2) 48 (81.4) 11 (18.6) 0.632
Type 3 and 4 115 (47.1) 89 (77.4) 26 (22.6)
Type 5 and 6 70 (28.7) 52 (74.3) 18 (25.7)
METPA weekly score (MET-min/week)
Tertile 1 (0–880) 82 (33.6) 59 (72.0) 23 (28.0) 0.342
Tertile 2 (881–1,795) 81 (33.2) 65 (80.2) 16 (19.8)
Tertile 3 (1,796–5,895) 81 (33.2) 65 (80.2) 16 (19.8)
MECHPA weekly score (PSS/week)
Tertile 1 (0–3) 93 (38.1) 67 (72.0) 26 (28.0) 0.269
Tertile 2 (4–7) 72 (29.5) 59 (81.9) 13 (18.1)
Tertile 3 (8–18) 79 (32.4) 63 (79.7) 16 (20.4)
Average daily sunlight exposure
<30 min/day 52 (21.3) 33 (63.5) 19 (36.5) 0.007*
30–60 min/day 77 (31.6) 58 (75.3) 19 (24.7)
>60 min/day 115 (47.1) 98 (85.2) 17 (14.8)
Daily body parts exposed to sun
Hands (up to short sleeve level) and face 133 (54.4) 100 (75.2) 33 (24.8) 0.353
More than hands (up to short 111 (45.5) 89 (80.2) 22 (19.8)
sleeve level) and face
Dietary vitamin D intake
Meets RNI (≥5 lg) 14 (5.7) 10 (71.4) 4 (28.8) 0.578
Does not meet RNI 230 (94.3) 179 (77.8) 41 (22.2)
Dietary calcium intake
Meets RNI 29 (11.9) 27 (93.1) 2 (6.9) 0.032*
Does not meet RNI 215 (88.1) 162 (75.3) 53 (24.7)
N = 244.
BMI, body mass index (kg/m2); METPA, metabolic component of physical activity; MET, metabolic equivalent; MECHPA, mechanical component of physical
activity; PSS: peak strain score; RNI: recommended nutrient intake.
*p-Value significant at <0.05.

7 to 12-year-old children in Kuala Lumpur showed that
35.3% have vitamin D deficiency, with 16.4% being
obese.15 The SEANUTS survey of 3,542 Malaysian
children aged 6 months to 12 years from six regions of
Malaysia between 2010 and 2011 showed 19.9% had vita-
min D deficiency, with 11.8% being obese.6 Our cohort
Epilepsia, 57(8):1271–1279, 2016
doi: 10.1111/epi.13443
 15281167, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.13443 by Nat Prov Indonesia, Wiley Online Library on [30/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1276
C. Y. Fong et al.

Table 2. Patient epilepsy characteristics with associated vitamin D status

Vitamin D status of patients
(% within individual variable)
Nondeficient: Deficient:
No. of 25(OH)D 25(OH)D
Risk factor patients (%) > 37.5 nmol/L (%) ≤ 37.5 nmol/L (%) p-Value
No. of AED therapy
1 AED 126 (51.6) 105 (83.3) 21 (16.7) 0.023*
≥2 AED 118 (48.4) 84 (71.2) 34 (28.8)
Duration of AED therapy
≤5 years 113 (46.3) 94 (83.2) 19 (16.8) 0.047*
>5 years 131 (53.7) 95 (72.5) 36 (27.5)
Type of AED at enrollment
Non-EIAED 125 (51.2) 100 (80.0) 25 (20.0) 0.622
EIAED 67 (27.5) 50 (74.6) 17 (25.4)
Both non-EIAED and EIAED 52 (21.3) 39 (75.0) 13 (25.0)
Type of AED 1 year prior to enrollment
Non-EIAED 127 (52.0) 101 (79.5) 26 (20.5)
EIAED 56 (23.0) 45 (80.4) 11 (19.6)
Both non-EIAED and EIAED 61 (25.0) 43 (70.5) 18 (29.5) 0.335
Type of AED 2 years prior to enrollment
Non-EIAED 117 (48.0) 92 (78.6) 25 (21.4) 0.795
EIAED 52 (21.3) 41 (78.8) 11 (21.2)
Both non-EIAED and EIAED 75 (30.7) 56 (74.7) 19 (25.3)
Type of AED 4 years prior to enrollment
Non-EIAED 103 (42.2) 85 (82.5) 18 (17.5) 0.205
EIAED 49 (20.1) 38 (77.6) 11 (22.4)
Both non-EIAED and EIAED 92 (37.7) 66 (71.7) 26 (28.3)
Intake of EIAED at enrollment
No 123 (50.4) 98 (51.9) 79.7 25 (45.5) 20.3 0.404
Yes 121 (49.6) 91 (48.1) 75.2 30 (54.5) 24.8
Intake of EIAED 1 year prior to enrollment
No 127 (52.0) 101 (53.4) 79.5 26 (47.3) 20.5 0.420
Yes 117 (48.0) 88 (46.6) 75.2 29 (52.7) 24.8
Intake of EIAED 2 years prior to enrollment
No 117 (48.0) 92 (48.7) 78.6 25 (45.5) 21.4 0.674
Yes 127 (52.0) 97 (51.3) 76.4 30 (54.5) 23.6
Intake of EIAED 4 years prior at enrollment
No 105 (43.0) 87 (46.0) 82.9 18 (32.7) 17.1 0.079
Yes 139 (57.0) 102 (54.0) 73.4 37 (67.3) 26.6
Seizure type
Focal 132 (54.1) 100 (75.8) 32 (24.2) 0.49
Generalized 112 (45.9) 89 (79.5) 23 (20.5)
Seizure frequency
At least one seizure weekly 57 (23.4) 38 (66.7) 19 (33.3) 0.084
At least one seizure monthly 65 (26.6) 55 (84.6) 10 (15.4)
Maximal 1–5 seizure/year 70 (28.7) 53 (75.7) 17 (24.3)
Seizure free 52 (21.3) 43 (82.7) 9 (17.3)
N = 244.
AED, antiepileptic drug; EIAED, enzyme-inducing antiepileptic drug.
*p-Value significant at <0.05.

when compared with the SEANUTS survey showed a
broadly similar proportion of vitamin D deficiency (22.5%
in our cohort); however, there was a slightly higher
proportion of our patients being obese (16.4%). Our vitamin
D deficiency prevalence results may not be directly
comparable with results of these two Malaysian surveys, as
the age group studied in the previous surveys was only up
to 12 years old compared to our study which was between 3
and 18 years old.
Epilepsia, 57(8):1271–1279, 2016
doi: 10.1111/epi.13443
Our study reemphasizes that long-term AED polytherapy
intake (>1 AED) is an important risk factor for children with
epilepsy to develop vitamin D deficiency. Our findings are
similar with those of other studies showing the negative
impact of AED polytherapy9,28 and support the results of
other studies showing that AED polytherapy exerted a nega-
tive impact on bone mineral density.29 This highlights the
importance for clinicians to avoid treating children with
AED polytherapy whenever possible due to adverse effects
 15281167, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.13443 by Nat Prov Indonesia, Wiley Online Library on [30/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1277
Vitamin D Deficiency in Malaysian Epilepsy Patients

study reiterates this and is the first Asian study to show that
Table 3. Results of multiple logistic regression model of
the key lifestyle determinants of vitamin D status in Malay-
risk factors for 25(OH)D level ≤37.5 nmol/L
sian pediatric epilepsy patients is sun exposure behavior
Adjusted odds Standard rather than dietary intake. Our cohort showed an increasing
Risk factor ratio (95% CI) error p-Value
risk of 25(OH)D deficiency among those with lower daily
Age group sunlight exposure. Our findings are similar with the pedi-
9–12 years 1.872 (0.462–7.592) 0.714 0.380
atric studies of vitamin D status in Qatar and Saudi Arabia,
compared
with 3–9 whereby the child’s reduced sun exposure behavior was
years shown to be associated with vitamin D insufficiency.30,31
>12 years 4.158 (1.130–15.301) 0.665 0.032* Studies have stated that under ideal conditions, 20–30 min
compared of daily sunlight exposure to minimum of 27–30% of body
with 3–9
surface area is sufficient for adequate vitamin D produc-
years
Sex tion.32,33 However, it has been shown that in South Asian
Female 2.610 (1.309–5.204) 0.352 0.006* adults with darker skin pigmentation (Fitzpatrick skin type
compared five), this recommendation is not sufficient and South
with male Asians would require longer sunshine exposure of approxi-
Number of AEDs
mately 51.4 min per day.34 Our Malaysian cohort of
Polytherapy 2.159 (1.069–4.362) 0.359 0.032*
compared to patients with 28.5% having dark skin pigmentation (Fitz-
monotherapy patrick skin type 5 or 6) further supports this study, empha-
Duration of treatment sizing that the standard 20–30 min of daily sunlight
AEDs >5 years 1.209 (0.579–2.524) 0.376 0.613 exposure is also not sufficient for Malaysians children with
compared
epilepsy. In our cohort, vitamin D deficiency rate of 36.5%
to ≤5 years
Ethnicity was present among children with <30 min daily sunlight
Malay compared 2.199 (0.864–5.597) 0.477 0.098 exposure compared to a vitamin D deficiency rate of 14.8%
with Chinese among children who have >60 min daily sunlight exposure.
Indian compared 6.967 (2.483–19.548) 0.526 0.000* Although there are concerns about the hazards and conse-
with Chinese
quences of excessive sun exposure, our study highlights that
Dietary calcium intake
<RNI compared 2.433 (0.417–14.200) 0.900 0.323 these concerns needs to be weighed against the potential risk
to ≥RNI that current sun avoidant lifestyles cause inadequate sun
Duration of daily sun exposure exposure, thereby increasing the risk of vitamin D
>60 min/day 2.440 (1.051–5.665) 0.430 0.038* deficiency.
compared with
Girls and the adolescent age group were also significant
30–60 min/day
>60 min/day 3.825 (1.610–9.085) 0.441 0.002* risk factors for vitamin D deficiency in our cohort of
compared with patients. Our study is consistent with results from Khor
<30 min/day et al. showing higher prevalence of vitamin D deficiency
AED, antiepileptic drug; RNI, recommended nutrient intake; CI, confidence among girls of 41% when compared with boys of 28.3%,
interval. and the Malaysian SEANUTS data with prevalence of vita-
*p-Value significant at <0.05.
min D deficiency among girls of 28% when compared with
boys of 12%.15,35 Other studies have also shown that vita-
min D insufficiency is more prevalent in Korean, Qatari,
to bone health. Our study is also the first to show that long- and Saudi Arabia adolescents.27,30,31 These two risk factors
term AED polytherapy intake is a risk factor independent of may be related to lifestyle behavioral factors. Teenage girls
the child’s lifestyle and dietary intake of vitamin D or cal- may opt to avoid the sun to maintain a fair skin tone, as it is
cium. Analysis of our polytherapy cohort of patients indi- culturally accepted in Southeast Asia that having fair skin is
cates that duration of treatment may be a factor, with the a mark of beauty. Adolescents may be also busier doing
polytherapy group on AEDs for a longer duration with a more indoor school academic work away from sunshine due
mean duration of AED treatment of 6.77 years (SD 4.01) to pressure to excel in academic performance in comparison
compared to a mean duration of AED treatment for the to younger children.
monotherapy group of 5.53 years (SD 3.92). AED type, in Our study is also the first to highlight the importance of
particular the presence of enzyme-inducing AED intake at the Indian ethnicity as a risk factor for vitamin D defi-
enrollment and up to 4 years prior to enrollment, did not ciency. Another recent study on healthy children showed
have an impact on vitamin D status (Table 2). that Malaysian Indians have lower 25(OH)D levels when
The primary source of vitamin D is made in the skin after compared to other ethnic groups.6 This is relevant when
exposure to sunlight (ultraviolet B radiation), and only formulating policies for vitamin D supplementation in
<10% of vitamin D is derived from dietary sources.4 Our many South East Asian countries with multiethnic
Epilepsia, 57(8):1271–1279, 2016
doi: 10.1111/epi.13443

1278
C. Y. Fong et al.
populations that include a sizeable proportion of Indians.
Although our Indian patients, who are mostly Southern
Tamil in origin, had darker skin pigmentation than other
Malaysian ethnicities (skin pigmentation type 5/6 seen
among 75% of Indians, 22% of Malays, and 0% of Chi-
nese), suggesting that skin pigmentation may be a con-
founding factor, this hypothesis was however not
supported by the results of our regression analysis. In
Southeast Asia due to lack of fortification of vitamin D,
there are very few types of foods that have high vitamin
D content, making it unlikely that there is an ethnicity dif-
ference in vitamin D intake.36 This was further supported
by the mean vitamin D intake among the three ethnicities
in our study, which was not significantly different (1.1 lg
among Malays, 2.6 lg among Chinese, and 1.2 lg among
Indians). Hence, the possibility of intrinsic genetic risk
factors among the Indians that may predispose to vitamin
D deficiency needs to be explored further.
In our study, a significantly high proportion of Malaysian
children with epilepsy did not achieve the recommended
vitamin D and calcium intake, with only 5.7% and 11.9%
meeting the recommended vitamin D and calcium intakes,
respectively. This is significantly lower when compared to a
previous Malaysian study, which showed that approxi-
mately 50% of Malaysian children did not achieve the rec-
ommended vitamin D and calcium intake.35 To date, there
are only a few studies in Italy, the United States, and India
that have assessed nutritional intakes in children with
epilepsy.37–39 These studies have shown that children
with intractable epilepsy are at risk of poor nutritional status
with decreased nutritional intake, and our study reaffirms
this. Despite vitamin D and calcium intake not appearing to
be a risk factor for 25(OH)D deficiency in our study, knowl-
edge that a high proportion of Malaysian children with epi-
lepsy have poor nutritional intake is invaluable. Clinicians
overseeing the care of Malaysian children with epilepsy
need to reinforce the importance of a healthy intake of vita-
min D and calcium to optimize bone health in these high-
risk patients.
We acknowledge there are limitations to our study. We
did not compare the 25(OH)D levels of our patients with
those of healthy controls. However, the finding of sub-
stantial rates of vitamin D deficiency in our cohort of
pediatric epilepsy patients who already have preexisting
risk of impaired bone health due to long-term AED intake
is important for clinicians. We were also unable to evalu-
ate bone mineral density (BMD) using dual-energy x-ray
absorptiometry (DXA) scanner in our cohort of patients
due to lack of DXA scanning facilities in two of the three
hospitals. Despite this lack of BMD data, previous studies
have shown an association of low vitamin D levels with
low BMD in children.40 The effect of sun exposure and
physical activity may also not be adequately obtained by
a retrospective questionnaire alone, and future studies
may consider measuring sun exposure directly by using
Epilepsia, 57(8):1271–1279, 2016
doi: 10.1111/epi.13443
15281167, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/epi.13443 by Nat Prov Indonesia, Wiley Online Library on [30/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
UV sensitive badges to collect reliable UV-B exposure
and pedometer for physical activity. Dietary assessment
may also be inaccurate given use of diet history question-
naires that are proxy-reported by third parties (namely
mothers or main caregivers), which can lead to biased
estimation of portion sizes.
Conclusion
Our study shows that vitamin D deficiency is prevalent
among Malaysian pediatric epilepsy patients. The key risk
factors of vitamin D deficiency in these children are lower
daily sun exposure behavior, Indian ethnicity, female gen-
der, adolescence age, and AED polytherapy. Our findings
highlight the importance of clinicians, being vigilant of
assessing vitamin D status among children with epilepsy in
Malaysia. We recommend targeted strategies including
vitamin D supplementation with the latest guidance recom-
mending that children on AEDs should be receiving two to
three times more vitamin D supplementation (1200–
3000 IU/day)1 and implementation of healthy sunlight
exposure behavior lifestyle advice for children with epi-
lepsy, particularly in those at high risk of having vitamin D
deficiency.
Acknowledgments
This research study received funding from the University of Malaya
research grant (UMRG 532-13HTM and P0026/2013A). We gratefully
thank all participating children and their parents for their full cooperation
toward this study. We also acknowledge the support of specialists, clinical
staff, and nurses of all the three participating clinics for their cooperation
and assistance.
Disclosure
None of the authors has any conflict of interest to disclose. We confirm
that we have read the Journal’s position on issues involved in ethical publi-
cation and affirm that this report is consistent with those guidelines.
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