Epilepsy and Vitamin D

Abstract

Summary Several disorders, both systemic and those of the nervous system, have been linked with vitamin D deficiency. Neurological disorders with a vitamin D link include but are not limited to multiple sclerosis, Alzheimer and Parkinson disease as well as cerebrovascular disorders. Epilepsy which is the second leading neurological disorder received much less attention. We review evidence supporting a link between vitamin D and epilepsy including those coming from ecological as well as interventional and animal studies. We also assess the literature on the interaction between antiepileptic drugs and vitamin D. Converging evidence indicates a role for vitamin D deficiency in the pathophysiology of epilepsy.

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International Journal of Neuroscience, 2013; 00(00): 1–7
Copyright ©2013 Informa Healthcare USA, Inc.
ISSN: 0020-7454 print / 1543-5245 online
DOI: 10.3109/00207454.2013.847836
ORIGINAL ARTICLE
Epilepsy and Vitamin D
Andr´
as Holl´
o,1Zs´
oa Clemens,2,3and P´
eter Lakatos4
1National Institute for Medical Rehabilitation, Budapest, Hungary; 2National Institute of Neuroscience, Budapest,
Hungary; 3Department of Neurology, University of P´
ecs, P´
ecs, Hungary; 41st Department of Internal Medicine,
Semmelweis University, Budapest, Hungary
Several disorders, both systemic and those of the nervous system, have been linked with vitamin D deciency.
Neurological disorders with a vitamin D link include but are not limited to multiple sclerosis, Alzheimer and
Parkinson disease, as well as cerebrovascular disorders. Epilepsy which is the second leading neurological
disorder received much less attention. We review evidence supporting a link between vitamin D and epilepsy
including those coming from ecological as well as interventional and animal studies. We also assess the literature
on the interaction between antiepileptic drugs and vitamin D. Converging evidence indicates a role for vitamin
D deciency in the pathophysiology of epilepsy.
KEYWORDS: vitamin D deficiency, antiepileptic drugs, neurosteroids
Introduction
Understanding the role of vitamin D in various health
functions has increased exponentially in the past few
years. Beyond its well-known role in bone health, vi-
tamin D is implicated in diverse functions such as
cardiovascular health, tumor prevention, immunologi-
cal functioning, as well as glucose metabolism [1]. It
is now assumed that vitamin D status is a major factor
inuencing life expectancy [2]. As regards the central
nervous system vitamin D is involved in both brain
development and adult brain function [3,4]. Decient
levels of vitamin D have been associated with sev-
eral brain disorders including multiple sclerosis [5],
Alzheimer [3,6,7] and Parkinson diseases [8], autism
[9–11], schizophrenia [12], and cerebrovascular disor-
ders [13]. Yet as compared, much less attention has
been paid to epilepsy, the second major neurological
disorder.
Vitamin D is a member of a large family of
steroid hormones signaling via nuclear and membrane-
associated receptors. It is synthesized from 7-dehydro-
cholesterol in the skin through exposure to ultraviolet
B radiation. A number of vitamin D forms exist but
Received 19 August 2013; revised 18 September 2013; accepted 18 September
2013
Correspondence: Zs ´
oa Clemens, National Institute of Neuroscience,
H-1145 Budapest, Amerikai ´
ut 57, Hungary. Tel: 00 3614679300.
Fax: 00 3612558869. E-mail: clemenszsoa@gmail.com
vitamin D3 is the form naturally occurring in mam-
mals. Metabolism of vitamin D3 is highly complex with
the major route involving two consecutive hydroxyla-
tion steps taking place in the liver and the kidney.
The rst hydroxylation results in 25(OH)D, the ma-
jor circulating form of vitamin D also used to measure
vitamin D status. The second hydroxylation step is me-
diated by the 1-alpha-hydroxylase enzyme and results in
1,25(OH)D. This is the active form of vitamin D mean-
ing that this metabolite binds to the nuclear vitamin
D receptor and mediates genomic responses. In fact,
the 1-alpha-hydroxylase enzyme activity is not limited
to the kidney but is present in various tissues through-
out the body including the brain [10]. Vitamin D recep-
tors as well as the 1-alpha-hydroxylase enzyme activity
have been described in virtually all brain structures, neu-
ronal and glial cell types [14]. The catabolizing enzyme
of 1,25(OH)D which is upregulated at high levels of
1,25(OH)D is also present in the brain [15]. Based on its
molecular structure, bioactivation in the nervous system
and mechanism of action of vitamin D is considered as
a neurosteroid [16,17]. Neurosteroids are increasingly
recognized as modulators of neuronal excitability and
seizure susceptibility (for a review see [18]).
Direct evidence for a role of vitamin D in epilepsy
is limited. However, several lines of indirect (eco-
logical and epidemiological) evidence together with
experimental data as well as two interventional hu-
man studies suggest a role of vitamin D in epilepsy.
Here we review what is currently known on the
1

2A. Holl ´
oetal.
relation between epilepsy, antiepileptic drugs (AEDs),
and vitamin D.
Ecological studies
Variations in disease prevalence or severity according to
seasons or geographic latitude are generally thought to
reect variations in vitamin D levels as these are the ma-
jor factors determining vitamin D status.
Epileptic births
Three epidemiological studies investigated the seasonal
variation of births of epileptic patients. Assessing a large
epileptic sample from England and Wales hospitals, Pro-
copio et al. [19] found a signicant excess of epileptic
births in January and a decit in September as com-
pared to births in the general population. A similar sea-
sonal pattern was found in a Danish sample by the same
author [20]. A third study by Procopio et al. [21] in-
vestigated patients from Australian hospitals. This study
also found a seasonal birth pattern different from that
in the general population but unlike the unimodal si-
nusoid distribution present in the two earlier studies, a
bimodal pattern was found with peaks during the win-
ter and summer. The second peak during the Australian
summer was supposed to be due to the fact that about
20% of the total population was born outside Australia.
Collectively, these studies indicate a rather consistent
seasonal pattern with a winter excess in epileptic births
Epileptic seizures
There are two studies assessing the seasonal distribu-
tion of the epileptic seizures themselves. The rst one
assessed seizure events occurring in an epilepsy inpa-
tient ward throughout a year [22] and found a signicant
seasonal variation with the least seizures during summer
and most during winter. Recently, we have carried out
a study in which we analyzed individual seizure diaries
and found decreasing seizure frequencies from January
to August and increasing seizure frequencies throughout
the rest of the year [23]. There are two studies investi-
gating the seasonal onset of infantile spasms. The study
by Cortez et al. [24] found greatest frequency of onset
in December and January and lowest incidence during
April and May. Another study [25] on the contrary did
not nd an association of infantile spasm onset with cal-
endar month and length of photoperiod.
Electrophysiological abnormalities
Strong seasonal variation in photoparoxysmal dis-
charges in epilepsy patients with summer decits and
winter excess have been reported by Danesi [26,27]. Of
note, Danesi was the rst to explain his ndings by sea-
sonal variation in the amount of sunshine. In support
of his theory, Danesi also demonstrated a relative rar-
ity of interictal EEG abnormalities among Nigerian as
compared to British epileptic patients with grand mal
seizures [28].
Vitamin D and antiepileptic action
Clinical studies of vitamin D administration
There are two studies where the effect of vitamin D
supplementation on seizure control was investigated.
The rst one was carried out almost 40 years ago
and was controlled by placebo [29]. Here supplemen-
tation of vitamin D2 (4000 IU/day), in the treatment
group resulted in an average seizure reduction of 30%,
whereas no signicant seizure reduction was present in
the control group. The seizure reduction was not as-
sociated with a change in the serum levels of calcium
and magnesium. In 2011, we have carried out a study
in which we measured and corrected decient levels of
serum 25(OH)D levels by supplementing vitamin D3
in 13 therapy-resistant epilepsy patients [30]. Assessing
seizure numbers before and after treatment onset re-
vealed a signicant reduction of seizure numbers with
amedianof40%.Wealsofoundatrendforalarger
percentage of seizure reduction in those with larger ele-
vations in serum 25(OH)D levels. Although this was an
uncontrolled study, the effect size of 40% is greater than
could be expected for a placebo response.
Animal models
In an early study by Siegel et al. [31] both in-
trahippocampal and intravenous administration of
1,25(OH)D resulted in elevation of seizure treshold in
rats. More recently, Kalueff et al. [32] found reduced
severity of chemically induced seizures when adminis-
tering 1,25(OH)D subcutaneously in mice. In another
study by the same group, increased seizure susceptibil-
ity was reported in rats with vitamin D receptor knock-
out genes [33]. In a study by Borowicz et al. [34], ad-
ministration of vitamin D3 raised the electroconvulsive
threshold and also potentiated the anticonvulsant activ-
ity of phenytoin and valproate.
Putative mechanisms
Like other neurosteroids, vitamin D is thought to ex-
ert its actions by multiple ways. Most studied are
its genomic actions [35]. These involve binding of
1,25(OH)D to the nuclear vitamin D receptor and reg-
ulating the expression of several proteins expressed in
the nervous system including neurotrophins such as
neurotrophin-3, neurotrophin-4, and nerve growth fac-
tor and glial cell-derived neurotrophic factor as well as
parvalbumin a calcium-binding protein [36–39], and
inhibiting the synthesis of the nitric oxid synthetase
[40]. Parvalbumin is known for its antiepileptic effects
[41], while inhibiting nitric oxid synthetase is thought to
International Journal of Neuroscience

Epilepsy and vitamin D 3
convey general neuroprotective effects [42]. These ge-
nomic actions occur with a time lag of hours or days.
However, more rapid vitamin D actions have also been
described suggesting the co-existence of nongenomic
pathways [43,44]. In fact, studies of epileptic animals
reported a rapid anticonvulsive effect following vitamin
D administration [31,32,34]. Nongenomic actions of
vitamin D include binding to a membrane-associated
vitamin D receptor thereby activating intracellular sig-
naling cascade. Major signal transduction events are
regulation of calcium and chloride channels, activa-
tion of protein kinase C, and mitogen-activated pro-
tein kinase [44]. In addition to specic binding to
membrane-associated vitamin D receptors, allosteric
modulation of the GABA(A) receptor and thereby ne-
tuning neuronal excitability has also been suggested
[45]. The GABA(A) receptor is well-known as a target
of other classical neurosteroids such as progesterone as
well as its natural and synthetic analogues (e.g. ganax-
olone) that are also known to convey antiepileptic effects
[18,46,47].
Antiepileptic medication and vitamin D
The impact of antiepileptic medication on vitamin D
levels and bone metabolism is the most studied as-
pect of epilepsy and vitamin D (for a review see [48]).
Early reports from the 1960s have already shown that
the use of antiepileptic medication is associated with
impaired bone quality and increased risk for fractures
[49,50]. This observation led to an extensive research
on the interaction of AEDs and vitamin D metabolism.
Currently, a large body of evidence indicates that sev-
eral AEDs lower 25(OH)D levels and are associated
with adverse effects on bones and muscles [48,51,52].
Among all AEDs, carbamazepine and phenytoin are
most studied in this regard. Cross-sectional [53–66]
as well as longitudinal [CBZ: 67–73; PHT: 72,74,75]
studies of these two drugs rather consistently demon-
strate their 25(OH)D lowering effect. This effect is
thought to be due to the enzyme inducing properties
of these antiepileptics. Induction of the cytochrome P-
450 system is known to increase catabolism of vitamin
D by upregulating enzymes converting 25(OH)D into
inactive metabolites [76,77]. The majority of other en-
zyme inducer AED studies such as those with phenobar-
bital and primidone also indicated a 25(OH)D lower-
ing effect [56,59,78–82]. Although valproate is regarded
as a cytochrome P-450 noninducer, currently available
data are unequivocal as to whether this drug also low-
ers 25(OH)D. Several cross-sectional studies in epilep-
tic patients taking valproate showed no signicant re-
duction of 25(OH)D levels [59,66,83–87]. At the same
time, out of the ve longitudinal prospective studies
three [69,72,75] demonstrated decreased, whereas two
Table 1. Longitudinal studies (with a follow-up of a minimum
of 3 months) on the relationship between AEDs and 25(OH)D
Direction of
Number of change in
AED Reference patients 25(OH)D
PHB Sumi et al., 1978 42 decreased
Menon et al., 2010 2 decreased
PHT Bell et al., 1979 5 decreased
Krishnamoorthy et al., 2010 19 decreased
Menon et al., 2010 14 decreased
CBZ Nicolaidou et al., 2006 24 decreased
Kim et al., 2007 10 decreased
Misra et al., 2010 32 decreased
Menon et al., 2010 7 decreased
Verrotti et al., 2000 12 unchanged
Verrotti et al., 2002 20 unchanged
OXC Cansu et al., 2008 34 decreased
VPA Nicolaidou et al., 2006 27 decreased
Krishnamoorthy et al., 2010 15 decreased
Menon et al., 2010 3 decreased
Verrotti et al., 2010 20 unchanged
Kim et al., 2007 15 unchanged
LTG Kim et al., 2007 8 unchanged
LEV Koo et al., 2012 61 unchanged
AED, antiepileptic drug; PHB, phenobarbital; PHT, pheny-
toin; CBZ, carbamazepine; OXC, oxcarbazepine; VPA, valproate;
LTG, lamotrigine; LEV: levetiracetam
[70,88] indicated unchanged 25(OH)D levels (Table 1).
Polytherapy as compared to monotherapy of traditional
AEDs was also associated with larger decrease in vita-
min D levels [59,81,89].
As compared to the classic AEDs, much less stud-
ies are available regarding the new antiepileptics.
Lamotrigine—as investigated in both cross-sectional
[54,55] and longitudinal studies [70]—does not seem
to lower vitamin D levels. Topiramate [90,91] and leve-
tiracetam [92] as investigated in cross-sectional studies
were neither shown to be associated with decreased lev-
els of serum 25(OH)D. A longitudinal study of levetirac-
etam involving 61 patients did neither show vitamin D to
be decreased [93]. As regards, oxcarbazepine—a study
comparing this drug with carbamazepine—revealed that
the former, in spite of being regarded as a limited
inducer, also signicantly decreased serum 25(OH)D
[53]. On the contrary, another cross-sectional study did
not nd decreased vitamin D levels in children taking
oxcarbazepine [94]. Finally, the only longitudinal study
of oxcarbazepine also conrmed its effect of lowering
vitamin D [95]. Concerning the remaining new AEDs
(e.g. gabapentin, zonisamide, lacosamide), there are in-
sufcient clinical data currently available as regard to
their effect on vitamin D metabolism. Some inconsisten-
cies regarding the vitamin D lowering effect of the same
AEDs in different studies may be due to differences in
the study design, geographic location, or dietary habits
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4A. Holl ´
oetal.
between study populations [53,96]. To overcome some
of these methodological confounds, a focus on longitu-
dinal rather than cross-sectional studies may be help-
ful in determining whether a given AED actually lowers
serum 25(OH)D level or not. For this reason in Table
1, we only highlight those studies that have a longitudi-
nal design that is investigating the same set of patients
before and after AED administration. In addition, this
table is conned to those studies that have a minimum
follow-up of 3 months to enable comparison. It should
also be mentioned that some genetic factors may also
inuence the relationship of vitamin D and AEDs [97].
From the studies assessed, we can conclude that the en-
zyme inducer AEDs lower vitamin D. Concerning val-
proate results are unequivocal. The newer nonenzyme
inducer AEDs (lamotrigine, levetiracetam, and topira-
mate) does not seem to lower vitamin D levels.
Epilepsy comorbidities
In epilepsy care, AED-induced osteomalacia is the co-
morbidity usually considered as being related to vita-
min D. Enzyme inducers as compared to newer AEDs
have been shown to be associated with more dele-
terious effects on bone [66,98,99]. Vitamin D sup-
plementation proved to be an effective way to pre-
vent and treat AED-related osteomalacia [79,100]. Of
note, AEDs may also exert a detrimental effect on
bones through several mechanisms other than lower-
ing vitamin D [48,101–103]. Beyond the osteopenic ef-
fects, additional important epilepsy-comorbidities may
emerge in the context of vitamin D including polycystic
ovary syndrome (PCOS) and associated fertility prob-
lems [104,105]. The PCOS has a higher prevalence
(10%–25%) among epileptic women as compared with
the normal female population [106,107]. Since both
PCOS and fertility problems are more frequent in those
with low levels of vitamin D, a possible association with
AED-induced hypovitaminosis D should also be con-
sidered in patients with epilepsy [98,108,109]. Autism
is another condition frequently associated with epilepsy
[110–112] as well as linked to vitamin D deciency
[9,113]. The estimated prevalence of autism spectrum
disorder (ASD) among epilepsy patients ranges between
15% and 32% [114,115]. In addition, Bromley et al.
found ASD to be more common among offsprings of
epileptic mothers taking AED, than in a control group
[116,117]. These ndings point to the importance for
screening and supplementing pregnant epileptic moth-
ers and children taking AEDs [9].
Current recommendations
According to the Practice Guideline on Vitamin D is-
sued by American Endocrine Society [118], antiepilep-
tic medication should be considered as an indication for
measuring vitamin D levels. It is also suggested that pa-
tients on antiepileptic medications should be given even
two to three times more vitamin D for their age group
to satisfy their body’s vitamin D requirement. Within
the epilepsy literature, too, several experts recommend
screening vitamin D [102,119–121]. These recommen-
dations concentrate on preventing detrimental effects of
antiepileptics on bones.
Conclusions
The anticonvulsive effect of vitamin D is now supported
by evidence coming from different sources including
ecological and clinical interventional studies as well as
animal experiments. Several antiepileptic drugs, espe-
cially those with enzyme inducer properties,decrease
vitamin D level which paradoxically may predispose to
more seizures. These facts together with the worldwide
problem of vitamin D deciency and the known rela-
tionship of insufcient vitamin D levels with the major
disorders of civilization warrant routine screening and
supplementation of vitamin D in epilepsy patients. Fur-
ther studies are needed to more closely determine the
optimal level of vitamin D from the epilepsy point of
view.
Declaration of Interest
The authors report no conicts of interest. The authors
alone are responsible for the content and writing of this
paper.
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