Original Article
Vitamin D Deficiency in Children With Newly Diagnosed Idiopathic Epilepsy
Journal of Child Neurology 1-5 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814566627 jcn.sagepub.com
Fatma Mujgan Sonmez, MD1, Ahsen Donmez, MD2, Mehmet Namuslu, MD3, Metin Canbal, MD4, and Emel Orun, MD2
Abstract Several studies have shown a link between vitamin D deficiency and epilepsy. This study includes 60 newly diagnosed idiopathic epilepsy patients and 101 healthy controls (between the ages of 5 and 16). Each group was also divided into two subgroups according to seasonal changes in terms of months of longer versus shorter daylight. We retrospectively evaluated the levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-OH vitamin-D3 in the study participants. Levels below 20 ng/ml were defined as vitamin D deficiency and levels of 20-30 ng/ml as insufficiency. There were no significant differences in age, gender distribution and levels of calcium, phosphorus, alkaline phosphatase and parathyroid hormone between the groups. The level of 25-OH vitamin-D3 in the patient group was significantly lower when compared to the control group (p < 0.05) (14.07 + 8.12 and 23.38 + 12.80 ng/ml, respectively). This difference also held true when evaluation was made according to seasonal evaluation (12.38 + 6.53 and 17.64 + 1.14 in shorter daylight and 18.71 + 9.87 and 30.82 + 1.04 in longer daylight). Keywords vitamin D deficiency, idiopathic, epilepsy, children, season Received March 24, 2014. Received revised October 26, 2014. Accepted for publication December 3, 2014.
Vitamin D (calciferol) is a fat-soluble seco-steroid synthesized in the skin from 7-dehydrocholesterol (as hormone) or ingested with food (as vitamin).1,2 Vitamin D undergoes bioactivation by double hydroxylation in the liver and kidney. Subsequently, it is metabolized to the active form, 1,25-dihydroxycholecalciferol (calcitriol, vitamin D3).1-4 Active vitamin D has several biological roles such as the regulation of mineral and bone metabolism, tissue proliferation, differentiation, and apoptosis, and it also has some effects on the cardiovascular and immune systems.4,5 Vitamin D3 initiates biological responses via binding to the vitamin D receptor,2,6 which is widely distributed in 38 tissues including brain neurons, glial cells, macrophages, the spinal cord, and the peripheral nervous system.7 Vitamin D3 and its receptors also play important roles in the brain, including regulation of cell growth and differentiation processes and neuroprotective and mood-stabilizing effects.8 Previous studies provide contradictory data on whether children with epilepsy have a greater risk of vitamin D deficiency and low bone-mineral density than healthy control subjects. Despite ongoing research, many areas of vitamin D metabolism and bone health in persons with epilepsy remain poorly understood. Diet, physical exercise, body weight, skin color, and sun exposure are also likely to play a significant role.9 In the literature, most studies have focused on the adverse effects of antiepileptic drugs on vitamin D metabolism or bone
turnover.10-16 In contrast to studies investigating antiepileptic drugs, there are only 2 studies about the effect of vitamin D supplementation on drug-resistant seizures.17,18 Some animal studies have shown that the vitamin D system may be involved in epilepsy.19-21 To our knowledge, our study is the first to investigate the blood vitamin D levels in children with newly diagnosed idiopathic epilepsy. Because of the high prevalence of vitamin D deficiency in our region,22 we also evaluated the levels in a healthy control group and compared the 2 groups according to seasonal changes (months of higher vs lower solar exposure)
Methods This study was carried out in the Department of Pediatric Neurology with the approval of the Hospital Ethics Committee (Number:
1
Department Department 3 Department 4 Department 2
of of of of
Child Neurology, Turgut Ozal University, Ankara, Turkey Pediatrics, Turgut Ozal University, Ankara, Turkey Biochemistry, Turgut Ozal University, Ankara, Turkey Family Medicine, Turgut Ozal University, Ankara, Turkey
Corresponding Author: Fatma Mujgan Sonmez, MD, Department of Child Neurology, Turgut Ozal University, Alparslan Turkes Caddesi, No: 57 Emek, Ankara 06560, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at UNIV OF MARYLAND BALTIMORE CO on February 3, 2015
2
Journal of Child Neurology
99950669/717). Epilepsy type was classified according to the recommendations of the International League Against Epilepsy.23
Subjects This study included 60 patients (34 females, 26 males; mean age ¼ 9.6 + 3.2 years, range ¼ 5-16 years) with idiopathic epilepsy observed between the dates of September 2011 and November 2012 and 101 healthy children (53 females, 48 males; mean age ¼ 9.49 + 3.3 years, range ¼ 5-16 years). Results of neurologic examination and magnetic resonance imaging (MRI) were normal in all patients and none of the patients had any other disease. Patients with symptoms and signs of illnesses other than epilepsy (eg, metabolic, skin, liver, gastrointestinal, bone or renal disease, mental retardation, cerebral palsy), a history of status epilepticus, previous use of any antiepileptic drugs, dietary restrictions, or a family history of osteoporosis, and those using any medications that might affect bone metabolism (nonsteroidal anti-inflammatory drugs, calcium, vitamin D, or steroids) were excluded from the study. The control group included healthy children who were admitted to the pediatric outpatient clinic for checkup before undertaking athletic or school activities. The patients and control groups were divided into 2 subgroups according to seasonal changes in terms of months of longer versus shorter daylight, and all parameters were evaluated and compared among the patients and control groups and subgroups. We retrospectively investigated the clinical and laboratory records of the patients and evaluated the levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-OH vitamin D3. Vitamin D3 levels below 20 ng/mL were defined as vitamin D deficiency and levels of 20 to 30 ng/mL as vitamin D insufficiency.
Assays Spectrophotometric analysis of serum calcium, phosphorus, and alkaline phosphatase levels were carried out using a commercial kit according to manufacturer’s instructions and measurements were made with a Roche Integra 800 spectrophotometer. Vitamin D was quantified by high performance liquid chromatography (Vertical Mark of Column device by UFLC-SHIMADZU, features by VertiSep GES C18 high-performance liquid chromatography Column, ImmuChrom GmbH lot number VD130218F). Serum levels of parathyroid hormone were measured using the Siemens Centaur XP chemiluminescence immunoassay system.
Statistics Statistical analyses were performed using the Statistical Package for the Social Sciences Software (SPSS 16.0). In each group, conformity of the measured values to the normal distribution was analyzed using the Kolmogorov-Smirnov test. Descriptive statistics were given. The chi-square test was used to compare categorical data. One-way analysis of variance was used to compare these parameters among the months with higher or shorter periods of daylight. Post hoc and least significance difference tests were used to asess the homogeneity of the variances. A value of P < .05 was considered statistically significant.
Table 1. Seizure Type and EEG Findings of the Patients. Seizure type
n
%
Simple partial Complex partial GTC Tonic Clonic Atonic Absence Total
20 4 22 2 3 7 2 60
33 6.8 36.7 3.4 5 11.7 3.4 100
EEG findings
n
%
Epileptiform activity Focal 12 20.0 Generalized 40 66.6 Paroxysmal abnormality Focal 5 8.3 Generalized 2 3.4 Normal 1 1.7 Total 60 100
Abbreviation: GTC, generalized tonic clonic.
Results The study included 60 patients (34 females, 26 males) aged between 5 and 16 years (mean ¼ 9.6 + 3.2 years). The control group included 101 healthy children (53 females, 48 males) aged between 5 and 16 years (mean ¼ 9.5 + 3.3 years). There was no statistically significant difference between the patient and control groups with respect to mean age. Epilepsy types were generalized in 36 (60%) patients and partial in 24 (40%) patients; partial seizures were simple and complex in 20 (73%) and 4 (6.8%) patients, respectively (Table 1). The patient and control groups were divided into 2 subgroups according to months of longer and shorter daylight for evaluation and exclusion of seasonal factors. The shorter daylight period was accepted as October to the end of May. The longer daylight period was defined as June to September (the summer holiday period for children in Turkey). The shorter and longer daylight groups included 44 (73%) and 16 (27%) children, respectively, in the patient group (mean ages ¼ 8.9 + 2.2 and 9.4 + 3.5) and 57 (56%) and 44 (44%) children, respectively, in the control group (mean ages ¼ 9.3 + 3.1 and 9.7 + 3.5). There was no statistically significant difference in age between the patient and control groups according to the seasonal subgroups (P > .05) (Table 2). There was no statistically significant difference between the patient and control groups with respect to the levels of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone (P > .05) (Table 2). Forty-eight of the 60 epilepsy patients (80%) and 51 of the 101 controls (50.5%) had vitamin D deficiency. Of these 48 epilepsy patients, vitamin D deficiency was detected in 39 (88.6%) and 9 (56.2%) of the patients in the shorter and longer daylight groups, respectively. These values in the control group were 45 (78.9%) and 6 (13.7%) in the shorter and longer daylight groups, respectively.
Discussion Based on biological effects, a normal 25-OH vitamin D level is 30 ng/dL. The World Health Organization defines vitamin D
Downloaded from jcn.sagepub.com at UNIV OF MARYLAND BALTIMORE CO on February 3, 2015
Sonmez et al
3
Table 2. Mean Age and Standard Deviations of the Biochemical Bone Parameters and 25-OH-Vitamin D Levels According to Groups and Seasons. Total Patient (n ¼ 60)
Control (n ¼ 101)
Age (year) 9.03 + 2.94 9.49 + 3.26 Calcium (mg/dL) 9.70 + 0.39 9.79 + 0.42 Phosphorus 4.68 + 0.52 4.65 + 0.56 (mg/dL) Alkaline 200.01 + 71.20 195.45 + 75.41 phosphatase (U/L) Parathyroid 44.37 + 22.12 43.85 + 37.26 hormone 25-OH vitamin 14.07 + 8.12a 23.38 + 12.80b D (ng/mL) a,b
Shorter daylight P
Patient (n ¼ 44)
.293 .709 .683
8.89 + 2.75 9.69 + 0.41 4.65 + 0.53
Control (n ¼ 57) 9.32 + 3.10 9.78 + 0.40 4.54 + 0.56
.354 205.08 + 71.31 197.78 + 70.6
Longer daylight P
Patient (n ¼ 16)
Control (n ¼ 44)
P
.500 .354 .112
9.44 + 3.55 9.74 + 0.35 4.75 + 0.52
9.70 + 3.48 9.81 + 0.46 4.79 + 0.53
.790 .478 .538
.533 193.42 + 76.17 194.54 + 75.30 .947
.692
46.57 + 24.35
53.10 + 46.1
.292
39.95 + 16.86
31.86 + 13.96 .349
.001
12.38 + 6.53c
17.64 + 1.14d .009
18.71 + 9.87e
30.82 + 1.04f .000
p < 0.005.
c,d
p < 0.05. p < 0.0001. c,e p: 0.031. d,f p: 0.000. e,f
deficiency as a serum 25-OH vitamin D level of
Vitamin D Deficiency in Children With Newly Diagnosed Idiopathic Epilepsy
Journal of Child Neurology 1-5 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814566627 jcn.sagepub.com
Fatma Mujgan Sonmez, MD1, Ahsen Donmez, MD2, Mehmet Namuslu, MD3, Metin Canbal, MD4, and Emel Orun, MD2
Abstract Several studies have shown a link between vitamin D deficiency and epilepsy. This study includes 60 newly diagnosed idiopathic epilepsy patients and 101 healthy controls (between the ages of 5 and 16). Each group was also divided into two subgroups according to seasonal changes in terms of months of longer versus shorter daylight. We retrospectively evaluated the levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-OH vitamin-D3 in the study participants. Levels below 20 ng/ml were defined as vitamin D deficiency and levels of 20-30 ng/ml as insufficiency. There were no significant differences in age, gender distribution and levels of calcium, phosphorus, alkaline phosphatase and parathyroid hormone between the groups. The level of 25-OH vitamin-D3 in the patient group was significantly lower when compared to the control group (p < 0.05) (14.07 + 8.12 and 23.38 + 12.80 ng/ml, respectively). This difference also held true when evaluation was made according to seasonal evaluation (12.38 + 6.53 and 17.64 + 1.14 in shorter daylight and 18.71 + 9.87 and 30.82 + 1.04 in longer daylight). Keywords vitamin D deficiency, idiopathic, epilepsy, children, season Received March 24, 2014. Received revised October 26, 2014. Accepted for publication December 3, 2014.
Vitamin D (calciferol) is a fat-soluble seco-steroid synthesized in the skin from 7-dehydrocholesterol (as hormone) or ingested with food (as vitamin).1,2 Vitamin D undergoes bioactivation by double hydroxylation in the liver and kidney. Subsequently, it is metabolized to the active form, 1,25-dihydroxycholecalciferol (calcitriol, vitamin D3).1-4 Active vitamin D has several biological roles such as the regulation of mineral and bone metabolism, tissue proliferation, differentiation, and apoptosis, and it also has some effects on the cardiovascular and immune systems.4,5 Vitamin D3 initiates biological responses via binding to the vitamin D receptor,2,6 which is widely distributed in 38 tissues including brain neurons, glial cells, macrophages, the spinal cord, and the peripheral nervous system.7 Vitamin D3 and its receptors also play important roles in the brain, including regulation of cell growth and differentiation processes and neuroprotective and mood-stabilizing effects.8 Previous studies provide contradictory data on whether children with epilepsy have a greater risk of vitamin D deficiency and low bone-mineral density than healthy control subjects. Despite ongoing research, many areas of vitamin D metabolism and bone health in persons with epilepsy remain poorly understood. Diet, physical exercise, body weight, skin color, and sun exposure are also likely to play a significant role.9 In the literature, most studies have focused on the adverse effects of antiepileptic drugs on vitamin D metabolism or bone
turnover.10-16 In contrast to studies investigating antiepileptic drugs, there are only 2 studies about the effect of vitamin D supplementation on drug-resistant seizures.17,18 Some animal studies have shown that the vitamin D system may be involved in epilepsy.19-21 To our knowledge, our study is the first to investigate the blood vitamin D levels in children with newly diagnosed idiopathic epilepsy. Because of the high prevalence of vitamin D deficiency in our region,22 we also evaluated the levels in a healthy control group and compared the 2 groups according to seasonal changes (months of higher vs lower solar exposure)
Methods This study was carried out in the Department of Pediatric Neurology with the approval of the Hospital Ethics Committee (Number:
1
Department Department 3 Department 4 Department 2
of of of of
Child Neurology, Turgut Ozal University, Ankara, Turkey Pediatrics, Turgut Ozal University, Ankara, Turkey Biochemistry, Turgut Ozal University, Ankara, Turkey Family Medicine, Turgut Ozal University, Ankara, Turkey
Corresponding Author: Fatma Mujgan Sonmez, MD, Department of Child Neurology, Turgut Ozal University, Alparslan Turkes Caddesi, No: 57 Emek, Ankara 06560, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at UNIV OF MARYLAND BALTIMORE CO on February 3, 2015
2
Journal of Child Neurology
99950669/717). Epilepsy type was classified according to the recommendations of the International League Against Epilepsy.23
Subjects This study included 60 patients (34 females, 26 males; mean age ¼ 9.6 + 3.2 years, range ¼ 5-16 years) with idiopathic epilepsy observed between the dates of September 2011 and November 2012 and 101 healthy children (53 females, 48 males; mean age ¼ 9.49 + 3.3 years, range ¼ 5-16 years). Results of neurologic examination and magnetic resonance imaging (MRI) were normal in all patients and none of the patients had any other disease. Patients with symptoms and signs of illnesses other than epilepsy (eg, metabolic, skin, liver, gastrointestinal, bone or renal disease, mental retardation, cerebral palsy), a history of status epilepticus, previous use of any antiepileptic drugs, dietary restrictions, or a family history of osteoporosis, and those using any medications that might affect bone metabolism (nonsteroidal anti-inflammatory drugs, calcium, vitamin D, or steroids) were excluded from the study. The control group included healthy children who were admitted to the pediatric outpatient clinic for checkup before undertaking athletic or school activities. The patients and control groups were divided into 2 subgroups according to seasonal changes in terms of months of longer versus shorter daylight, and all parameters were evaluated and compared among the patients and control groups and subgroups. We retrospectively investigated the clinical and laboratory records of the patients and evaluated the levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-OH vitamin D3. Vitamin D3 levels below 20 ng/mL were defined as vitamin D deficiency and levels of 20 to 30 ng/mL as vitamin D insufficiency.
Assays Spectrophotometric analysis of serum calcium, phosphorus, and alkaline phosphatase levels were carried out using a commercial kit according to manufacturer’s instructions and measurements were made with a Roche Integra 800 spectrophotometer. Vitamin D was quantified by high performance liquid chromatography (Vertical Mark of Column device by UFLC-SHIMADZU, features by VertiSep GES C18 high-performance liquid chromatography Column, ImmuChrom GmbH lot number VD130218F). Serum levels of parathyroid hormone were measured using the Siemens Centaur XP chemiluminescence immunoassay system.
Statistics Statistical analyses were performed using the Statistical Package for the Social Sciences Software (SPSS 16.0). In each group, conformity of the measured values to the normal distribution was analyzed using the Kolmogorov-Smirnov test. Descriptive statistics were given. The chi-square test was used to compare categorical data. One-way analysis of variance was used to compare these parameters among the months with higher or shorter periods of daylight. Post hoc and least significance difference tests were used to asess the homogeneity of the variances. A value of P < .05 was considered statistically significant.
Table 1. Seizure Type and EEG Findings of the Patients. Seizure type
n
%
Simple partial Complex partial GTC Tonic Clonic Atonic Absence Total
20 4 22 2 3 7 2 60
33 6.8 36.7 3.4 5 11.7 3.4 100
EEG findings
n
%
Epileptiform activity Focal 12 20.0 Generalized 40 66.6 Paroxysmal abnormality Focal 5 8.3 Generalized 2 3.4 Normal 1 1.7 Total 60 100
Abbreviation: GTC, generalized tonic clonic.
Results The study included 60 patients (34 females, 26 males) aged between 5 and 16 years (mean ¼ 9.6 + 3.2 years). The control group included 101 healthy children (53 females, 48 males) aged between 5 and 16 years (mean ¼ 9.5 + 3.3 years). There was no statistically significant difference between the patient and control groups with respect to mean age. Epilepsy types were generalized in 36 (60%) patients and partial in 24 (40%) patients; partial seizures were simple and complex in 20 (73%) and 4 (6.8%) patients, respectively (Table 1). The patient and control groups were divided into 2 subgroups according to months of longer and shorter daylight for evaluation and exclusion of seasonal factors. The shorter daylight period was accepted as October to the end of May. The longer daylight period was defined as June to September (the summer holiday period for children in Turkey). The shorter and longer daylight groups included 44 (73%) and 16 (27%) children, respectively, in the patient group (mean ages ¼ 8.9 + 2.2 and 9.4 + 3.5) and 57 (56%) and 44 (44%) children, respectively, in the control group (mean ages ¼ 9.3 + 3.1 and 9.7 + 3.5). There was no statistically significant difference in age between the patient and control groups according to the seasonal subgroups (P > .05) (Table 2). There was no statistically significant difference between the patient and control groups with respect to the levels of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone (P > .05) (Table 2). Forty-eight of the 60 epilepsy patients (80%) and 51 of the 101 controls (50.5%) had vitamin D deficiency. Of these 48 epilepsy patients, vitamin D deficiency was detected in 39 (88.6%) and 9 (56.2%) of the patients in the shorter and longer daylight groups, respectively. These values in the control group were 45 (78.9%) and 6 (13.7%) in the shorter and longer daylight groups, respectively.
Discussion Based on biological effects, a normal 25-OH vitamin D level is 30 ng/dL. The World Health Organization defines vitamin D
Downloaded from jcn.sagepub.com at UNIV OF MARYLAND BALTIMORE CO on February 3, 2015
Sonmez et al
3
Table 2. Mean Age and Standard Deviations of the Biochemical Bone Parameters and 25-OH-Vitamin D Levels According to Groups and Seasons. Total Patient (n ¼ 60)
Control (n ¼ 101)
Age (year) 9.03 + 2.94 9.49 + 3.26 Calcium (mg/dL) 9.70 + 0.39 9.79 + 0.42 Phosphorus 4.68 + 0.52 4.65 + 0.56 (mg/dL) Alkaline 200.01 + 71.20 195.45 + 75.41 phosphatase (U/L) Parathyroid 44.37 + 22.12 43.85 + 37.26 hormone 25-OH vitamin 14.07 + 8.12a 23.38 + 12.80b D (ng/mL) a,b
Shorter daylight P
Patient (n ¼ 44)
.293 .709 .683
8.89 + 2.75 9.69 + 0.41 4.65 + 0.53
Control (n ¼ 57) 9.32 + 3.10 9.78 + 0.40 4.54 + 0.56
.354 205.08 + 71.31 197.78 + 70.6
Longer daylight P
Patient (n ¼ 16)
Control (n ¼ 44)
P
.500 .354 .112
9.44 + 3.55 9.74 + 0.35 4.75 + 0.52
9.70 + 3.48 9.81 + 0.46 4.79 + 0.53
.790 .478 .538
.533 193.42 + 76.17 194.54 + 75.30 .947
.692
46.57 + 24.35
53.10 + 46.1
.292
39.95 + 16.86
31.86 + 13.96 .349
.001
12.38 + 6.53c
17.64 + 1.14d .009
18.71 + 9.87e
30.82 + 1.04f .000
p < 0.005.
c,d
p < 0.05. p < 0.0001. c,e p: 0.031. d,f p: 0.000. e,f
deficiency as a serum 25-OH vitamin D level of
