Epilepsy and Vitamin D

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 ´ 1 Zsofia ´ Clemens,2,3 and Péter Lakatos4 András Hollo, National Institute for Medical Rehabilitation, Budapest, Hungary; 2 National Institute of Neuroscience, Budapest, Hungary; 3 Department of Neurology, University of Pécs, Pécs, Hungary; 4 1st Department of Internal Medicine, Semmelweis University, Budapest, Hungary

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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. KEYWORDS: vitamin D deficiency, antiepileptic drugs, neurosteroids

Introduction

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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, vitamin D is implicated in diverse functions such as cardiovascular health, tumor prevention, immunological functioning, as well as glucose metabolism [1]. It is now assumed that vitamin D status is a major factor influencing life expectancy [2]. As regards the central nervous system vitamin D is involved in both brain development and adult brain function [3,4]. Deficient levels of vitamin D have been associated with several brain disorders including multiple sclerosis [5], Alzheimer [3,6,7] and Parkinson diseases [8], autism [9–11], schizophrenia [12], and cerebrovascular disorders [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 membraneassociated receptors. It is synthesized from 7-dehydrocholesterol 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 ´ Clemens, National Institute of Neuroscience, Correspondence: Zsofia ´ 57, Hungary. Tel: 00 3614679300. H-1145 Budapest, Amerikai ut Fax: 00 3612558869. E-mail: [email protected]

vitamin D3 is the form naturally occurring in mammals. Metabolism of vitamin D3 is highly complex with the major route involving two consecutive hydroxylation steps taking place in the liver and the kidney. The first hydroxylation results in 25(OH)D, the major circulating form of vitamin D also used to measure vitamin D status. The second hydroxylation step is mediated by the 1-alpha-hydroxylase enzyme and results in 1,25(OH)D. This is the active form of vitamin D meaning 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 throughout the body including the brain [10]. Vitamin D receptors as well as the 1-alpha-hydroxylase enzyme activity have been described in virtually all brain structures, neuronal 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 (ecological and epidemiological) evidence together with experimental data as well as two interventional human studies suggest a role of vitamin D in epilepsy. Here we review what is currently known on the 1

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relation between epilepsy, antiepileptic drugs (AEDs), and vitamin D.

ity of interictal EEG abnormalities among Nigerian as compared to British epileptic patients with grand mal seizures [28].

Ecological studies Variations in disease prevalence or severity according to seasons or geographic latitude are generally thought to reflect variations in vitamin D levels as these are the major 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, Procopio et al. [19] found a significant excess of epileptic births in January and a deficit in September as compared to births in the general population. A similar seasonal pattern was found in a Danish sample by the same author [20]. A third study by Procopio et al. [21] investigated patients from Australian hospitals. This study also found a seasonal birth pattern different from that in the general population but unlike the unimodal sinusoid distribution present in the two earlier studies, a bimodal pattern was found with peaks during the winter 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 distribution of the epileptic seizures themselves. The first one assessed seizure events occurring in an epilepsy inpatient ward throughout a year [22] and found a significant 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 investigating 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 find an association of infantile spasm onset with calendar month and length of photoperiod. Electrophysiological abnormalities Strong seasonal variation in photoparoxysmal discharges in epilepsy patients with summer deficits and winter excess have been reported by Danesi [26,27]. Of note, Danesi was the first to explain his findings by seasonal variation in the amount of sunshine. In support of his theory, Danesi also demonstrated a relative rar-

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 first one was carried out almost 40 years ago and was controlled by placebo [29]. Here supplementation of vitamin D2 (4000 IU/day), in the treatment group resulted in an average seizure reduction of 30%, whereas no significant seizure reduction was present in the control group. The seizure reduction was not associated 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 deficient 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 revealed a significant reduction of seizure numbers with a median of 40%. We also found a trend for a larger percentage of seizure reduction in those with larger elevations 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 intrahippocampal 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 administering 1,25(OH)D subcutaneously in mice. In another study by the same group, increased seizure susceptibility was reported in rats with vitamin D receptor knockout genes [33]. In a study by Borowicz et al. [34], administration of vitamin D3 raised the electroconvulsive threshold and also potentiated the anticonvulsant activity of phenytoin and valproate. Putative mechanisms Like other neurosteroids, vitamin D is thought to exert 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 regulating the expression of several proteins expressed in the nervous system including neurotrophins such as neurotrophin-3, neurotrophin-4, and nerve growth factor 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 genomic 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 signaling cascade. Major signal transduction events are regulation of calcium and chloride channels, activation of protein kinase C, and mitogen-activated protein kinase [44]. In addition to specific binding to membrane-associated vitamin D receptors, allosteric modulation of the GABA(A) receptor and thereby finetuning 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. ganaxolone) 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 aspect 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 several 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 demonstrate 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 P450 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 enzyme inducer AED studies such as those with phenobarbital and primidone also indicated a 25(OH)D lowering 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 lowers 25(OH)D. Several cross-sectional studies in epileptic patients taking valproate showed no significant reduction of 25(OH)D levels [59,66,83–87]. At the same time, out of the five longitudinal prospective studies three [69,72,75] demonstrated decreased, whereas two C

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Table 1. Longitudinal studies (with a follow-up of a minimum of 3 months) on the relationship between AEDs and 25(OH)D

AED

Reference

Number of patients

PHB

Sumi et al., 1978 Menon et al., 2010 Bell et al., 1979 Krishnamoorthy et al., 2010 Menon et al., 2010 Nicolaidou et al., 2006 Kim et al., 2007 Misra et al., 2010 Menon et al., 2010 Verrotti et al., 2000 Verrotti et al., 2002 Cansu et al., 2008 Nicolaidou et al., 2006 Krishnamoorthy et al., 2010 Menon et al., 2010 Verrotti et al., 2010 Kim et al., 2007 Kim et al., 2007 Koo et al., 2012

42 2 5 19 14 24 10 32 7 12 20 34 27 15 3 20 15 8 61

PHT

CBZ

OXC VPA

LTG LEV

Direction of change in 25(OH)D decreased decreased decreased decreased decreased decreased decreased decreased decreased unchanged unchanged decreased decreased decreased decreased unchanged unchanged unchanged unchanged

AED, antiepileptic drug; PHB, phenobarbital; PHT, phenytoin; 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 vitamin D levels [59,81,89]. As compared to the classic AEDs, much less studies 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 levetiracetam [92] as investigated in cross-sectional studies were neither shown to be associated with decreased levels of serum 25(OH)D. A longitudinal study of levetiracetam 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 significantly decreased serum 25(OH)D [53]. On the contrary, another cross-sectional study did not find decreased vitamin D levels in children taking oxcarbazepine [94]. Finally, the only longitudinal study of oxcarbazepine also confirmed its effect of lowering vitamin D [95]. Concerning the remaining new AEDs (e.g. gabapentin, zonisamide, lacosamide), there are insufficient clinical data currently available as regard to their effect on vitamin D metabolism. Some inconsistencies 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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between study populations [53,96]. To overcome some of these methodological confounds, a focus on longitudinal rather than cross-sectional studies may be helpful 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 longitudinal design that is investigating the same set of patients before and after AED administration. In addition, this table is confined 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 influence the relationship of vitamin D and AEDs [97]. From the studies assessed, we can conclude that the enzyme inducer AEDs lower vitamin D. Concerning valproate results are unequivocal. The newer nonenzyme inducer AEDs (lamotrigine, levetiracetam, and topiramate) does not seem to lower vitamin D levels.

Epilepsy comorbidities In epilepsy care, AED-induced osteomalacia is the comorbidity usually considered as being related to vitamin D. Enzyme inducers as compared to newer AEDs have been shown to be associated with more deleterious effects on bone [66,98,99]. Vitamin D supplementation proved to be an effective way to prevent and treat AED-related osteomalacia [79,100]. Of note, AEDs may also exert a detrimental effect on bones through several mechanisms other than lowering vitamin D [48,101–103]. Beyond the osteopenic effects, additional important epilepsy-comorbidities may emerge in the context of vitamin D including polycystic ovary syndrome (PCOS) and associated fertility problems [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 considered in patients with epilepsy [98,108,109]. Autism is another condition frequently associated with epilepsy [110–112] as well as linked to vitamin D deficiency [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 findings point to the importance for screening and supplementing pregnant epileptic mothers and children taking AEDs [9].

Current recommendations According to the Practice Guideline on Vitamin D issued by American Endocrine Society [118], antiepilep-

tic medication should be considered as an indication for measuring vitamin D levels. It is also suggested that patients 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 recommendations 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, especially 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 deficiency and the known relationship of insufficient vitamin D levels with the major disorders of civilization warrant routine screening and supplementation of vitamin D in epilepsy patients. Further 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 conflicts of interest. The authors alone are responsible for the content and writing of this paper.

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