Epilepsy & Behavior 24 (2012) 131133

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Brief Communication

Correction of vitamin D deciency improves seizure control in epilepsy: A pilot study

Andrs Holl a, Zsa Clemens b,, Anita Kamondi b, Pter Lakatos c, Anna Szcs b
a
National Institute for Medical Rehabilitation, H-1121 Budapest, Szanatrium u. 19, Hungary
b
National Institute of Neuroscience, H-1145 Budapest, Amerikai t 57, Hungary
c
Semmelweis University, 1st Department of Internal Medicine, H-1083 Budapest, Kornyi Sndor u. 2/a, Hungary

a r t i c l e i n f o a b s t r a c t

Article history: There is growing interest concerning the role of vitamin D in various medical conditions such as diabetes and
Received 16 January 2012 oncological, cardiovascular and central nervous system disorders. Although vitamin D deciency is known to
Revised 1 March 2012 be highly prevalent among epilepsy patients, only a single study, published nearly forty years ago, assessed
Accepted 3 March 2012
the effect of vitamin D on seizure control. Here, we measured serum 25-hydroxy-vitamin D (25(OH)D) levels
Available online 11 April 2012
and normalized it by administration of vitamin D3 in 13 patients with pharmacoresistant epilepsy. To see if
Keywords:
vitamin D3 has an impact on seizure frequency, we compared seizure numbers during a 90-day period
Vitamin D before and after treatment onset. We found that seizure numbers signicantly decreased upon vitamin D3
Hypovitaminosis D supplementation. Median seizure reduction was 40%. We conclude that the normalization of serum vitamin
Neurosteroids 25(OH)D level has an anticonvulsant effect.
Seizure control 2012 Elsevier Inc. All rights reserved.
Pharmacoresistant epilepsy

1. Introduction 2. Methods

Besides its well-known importance in bone health, there is growing
interest for widespread functions of vitamin D such as preventing
oncological [1] and cardiovascular diseases [2], infections [3] and dia-
betes [4] and lowering general mortality [5]. Poor vitamin D status
has also been implicated in the pathogenesis of dementias [6,7],
Parkinson's disease [8], multiple sclerosis [9] and schizophrenia [10].
Regarding epilepsy, several studies indicate increased risk for bone
loss in patients on antiepileptic medication as well as low levels of
serum 25(OH)D, the major circulating form of vitamin D3 [1113]. In
contrast to the above-mentioned antiepileptic drug-related studies,
fewer studies have addressed the relation between vitamin D and
epilepsy itself. There is one study addressing the effect of vitamin D
supplementation on seizures in a group of patients with pharmacore-
sistant epilepsy. This study [14], published nearly forty years ago,
showed that administration of vitamin D2 resulted in a seizure reduc-
tion of 30% on average. A few case studies [1518] suggested a link be-
tween maternal vitamin D deciency and newborn seizures eliminated
by vitamin D treatment. Since animal studies [1921] also support an
anticonvulsant effect of vitamin D, we asked the question whether
supplementation of vitamin D3, the physiological form of vitamin D,
may result in improved seizure control in patients with pharmacore-
sistant epilepsy. To assess this, serum 25(OH)D levels were measured
and corrected in 13 epilepsy patients, and corresponding changes in sei-
zure numbers were analyzed.
Corresponding author. Fax: + 36 1 255 8869.
E-mail address: clemenszsoa@gmail.com (Z. Clemens).
Thirteen consecutive epilepsy patients were recruited from two ep-
ilepsy outpatient clinics (National Institute of Neuroscience, Budapest,
Hungary; National Institute for Medical Rehabilitation, Budapest,
Hungary). Inclusion criteria were pharmacoresistance, keeping a reli-
able seizure diary, good compliance, lack of psychogenic seizures and
no change of antiepileptic medication during the previous 3 months.
Pharmacoresistance was dened as persisting seizures after a minimum
of two antiepileptic drugs [22]. In fact, all patients underwent several
failed trials of antiepileptic drug schedules. Upon patient selection,
we ascertained that patients had a reliable seizure diary kept either by
the patients themselves (n = 10) or their caregivers (n= 3). Seizure
data from pre-existing seizure diaries were used as a baseline. In
those cases where caretakers tracked seizures, these persons were the
same throughout the entire 6 months of the study. Ten patients had
localization-related epilepsy, two had LennoxGastaut syndrome, and
one patient was diagnosed with idiopathic generalized epilepsy. All pa-
tients were on antiepileptic polytherapy that was unchanged during the
entire study period. Patient characteristics are presented in Table 1. The
study was approved by the local ethics committee, and patients gave
written informed consent to participate in the study. The study was
performed in accordance with the ethical standards laid down in the
1964 Declaration of Helsinki.
Vitamin D status was assessed by measuring serum 25(OH)D
levels (Liaison, DiaSorin, Stillwater, MN, USA). In addition to this, the
following assessments were performed: complete blood count, renal
functions, serum antiepileptic drug levels, and calcium and phosphate
levels. Low levels of vitamin D were corrected according to the new
practice guideline on vitamin D deciency by Holick et al. [23].

1525-5050/$ see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2012.03.011
132 A. Holl et al. / Epilepsy & Behavior 24 (2012) 131133

Table 1 3.2. Seizure data

Patient characteristics. A = absence. AA = atypical absence. CPS = complex partial
seizure. IGE = idiopathic generalized epilepsy. LGS = LennoxGastaut syndrome.
LRE = localization-related epilepsy. SGTCS = secondarily generalized tonic-clonic seizure.
Among all patients, 10 exhibited decreased, two increased and one
SPS = simple partial seizure. TAS = tonic axial seizure. TMS = tonic motor seizure. unchanged seizure numbers following vitamin D3 supplementation.
Reduction of seizure numbers was signicant (p= 0.04) with a median
Patient Age Epilepsy duration Sex Epilepsy Seizure type
seizure number reduction of 40%. A seizure reduction of 50% was
(years) (years) syndrome
present in ve patients.
1 29 17 M LRE SPS, CPS
2 19 17 M LRE CPS, SGTCS
3 60 27 F LRE CPS 4. Discussion
4 28 22 F LRE SPS, TMS, SGTCS
5 29 10 F LRE CPS
6 57 33 M LRE CPS To our knowledge, this is the rst study assessing the effect of
7 32 29 F LRE SPS, CPS vitamin D3 supplementation on seizures in epilepsy patients. In a
8 29 24 M LGS AA, TAS previous study dating back to 1974, supplementation of vitamin D2
9 44 32 F IGE A resulted in decreased seizure frequency [14]. Animal studies also
10 41 38 F LRE CPS
suggest an anticonvulsant effect of vitamin D. In a rodent model,
11 60 40 F LRE CPS
12 43 42 M LRE CPS, SGTCS Siegel et al. [19] showed that vitamin D3 delivered to the hippocam-
13 38 38 F LGS AA, TAS pus elevates the threshold for chemically induced seizures while in-
creased seizure susceptibility was present in vitamin D receptor
knockout mice [20].
According to that guideline, 25(OH)D levels were considered normal
Here, we show that vitamin D3 supplementation results in improved
above 30 ng/ml. In those patients with low (b30 ng/ml) 25(OH)D
seizure control in patients with pharmacoresistant epilepsy. Ten (of 13)
levels, we administered an oral dose of 40,000200,000 IU bolus of
patients showed decreased seizure numbers during the 90 days
vitamin D3 in order to normalize vitamin D deciency, and then treat-
following treatment onset as compared to the baseline period. Among
ment was continued with a daily maintenance dose of 20002600 IU.
all patients, the median seizure reduction was 40%, and there was a
The patient with normal serum 25(OH)D levels was given a
non-signicant tendency for patients with larger proportional elevation
maintenance dose only. Exact dosage of vitamin D3 was dened by
of 25(OH)D levels exhibiting a larger proportional reduction in seizure
the endocrinologist member of the team (PL). The 25(OH)D levels
numbers (p=0.13, Spearman rank order correlation).
were rechecked 3 months after treatment onset to ascertain normaliza-
The exact mechanism by which vitamin D exerts its benecial
tion of serum levels and to exclude potential overdose.
effect in epilepsy is still to be explored. Vitamin D receptors as well
To evaluate the effect of vitamin D3 supplementation on seizure
as the 1-alpha-hydroxylase, the enzyme that produces 1,25(OH)D
numbers, seizure diaries were analyzed. In the statistical analysis,
(the active form of vitamin D), are distributed widely in the brain
we compared the total number of seizures during the 90 days before
[24]. It is suggested that the effect of vitamin D in the central nervous
and after treatment onset. Since seizure data showed non-normal
system is mediated by both calcemic and non-calcemic actions [25].
distribution across patients as well as outliers, we applied the non-
The latter include changes in gene expression in response to the
parametric sign test to assess changes in seizure numbers.
binding of 1,25(OH)D to the nuclear vitamin D receptor [26].
The main limitations of the study are the small patient number
3. Results and the lack of placebo control. Future studies are needed to conrm
these preliminary ndings in a larger sample of patients and by using
3.1. Serum 25(OH)D levels a double-blind, placebo-controlled design. It should also be investi-
gated whether a higher dosage of vitamin D3 would result in addi-
Median serum 25(OH)D level at baseline was 11.8 ng/ml (range: tional seizure reduction as well as to characterize the anticonvulsant
b434.2 ng/ml). Low (b30 ng/ml) serum 25(OH)D level was present effect of vitamin D3 in detail, e.g., its specicity in different epilepsy
in 12 patients, and b12-ng/ml levels were present in eight patients. syndromes, long-term effects and doseeffect relationships. It is
At the 3-month follow-up, serum levels were elevated signicantly also intriguing to speculate whether vitamin D deciency in epilepsy
(p= 0.001, sign test) and were within (or close to) the normal range is due to enzyme-inducing antiepileptic drugs only or whether
in all patients (median: 38 ng/ml, range: 23.345 ng/ml). Individual vitamin D deciency itself is an independent risk factor for developing
25(OH)D levels as well as seizure data for the 13 patients are presented epilepsy. Our study highlights the potential importance of screening
in Table 2. vitamin D levels in patients on antiepileptic therapy and starting
supplementation in those with low levels.
Table 2
Serum 25(OH)D levels at baseline and at the 3-month control; number of seizures
during the 90-day period before and after treatment onset. Acknowledgment
Patient 25(OH)D (ng/ml) Seizure number
The authors are grateful to Adrien Szomora and Edit Mt for
Before After Before After
their assistance and to Dr. Rita Jakus and Dr. Anna Kelemen for
1 13.4 43.6 59 12 their cooperation.
2 23.9 43 28 47
3 27.5 41.2 80 99
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