Vitamin D3 and epilepsy

Kevin Pendo, Christopher M. DeGiorgio.  Vitamin D3 for the Treatment of Epilepsy: Basic Mechanisms, Animal Models, and Clinical Trials.  Front. Neurol., 08 December 2016 | https://doi.org/10.3389/fneur.2016.00218  http://journal.frontiersin.org/article/10.3389/fneur.2016.00218/full?utm_source=newsletter&utm_medium=email&utm_campaign=Neurology-w1-2017

There is increasing evidence supporting dietary and alternative therapies for epilepsy, including the ketogenic diet, modified Atkins diet, and omega-3 fatty acids. Vitamin D3 is actively under investigation as a potential intervention for epilepsy. Vitamin D3 is fat-soluble steroid, which shows promise in animal models of epilepsy. Basic research has shed light on the possible mechanisms by which Vitamin D3 may reduce seizures, and animal data support the efficacy of Vitamin D3 in rat and mouse models of epilepsy. Very little clinical data exist to support the treatment of human epilepsy with Vitamin D3, but positive findings from preliminary clinical trials warrant larger Phase I and II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D3 as a treatment for human epilepsy.

Introduction

Epilepsy affects approximately two million Americans and 65 million people worldwide. Among those with epilepsy, 22–30% have drug-resistant epilepsy (DRE). DRE causes cognitive and mood impairment, injuries, and increased risk of death including sudden death in epilepsy (SUDEP). Antiepileptic drugs (AEDs) are the primary medical treatment for epilepsy. However, even for those whose seizures are well controlled by AEDs, allergies, neurological and systemic toxicity, depression, memory loss, and osteoporosis are common problems. Because of the limitations and potential toxicity of existing AEDs, there is significant clinical interest in finding alternative therapies for epilepsy.

In the search for alternative epilepsy treatments, Vitamin D3 is an intriguing candidate. As early as 1974, Christiansen postulated that supplementation of Vitamin D might improve calcium and magnesium levels and may decrease hyperexcitability in patients with epilepsy. In the four decades since, progress has been made in understanding the biochemical and cellular mechanisms of Vitamin D3’s anticonvulsant properties. Animal data have supported the anticonvulsant effects of Vitamin D3 in mice and rats. Existing evidence for the use of Vitamin D3 in treating human epilepsy is very limited. There is a critical need for larger clinical trials to establish the safety and efficacy of vitamin D3 in epilepsy. In this review, we will critically analyze the animal and human evidence to date supporting the use of Vitamin D3 as a treatment for epilepsy.

Among its variety of health benefits, Vitamin D3 plays an important role in the human brain and nervous system, as indicated by increasing evidence gathered over the past several decades. Researchers have explored the role of Vitamin D3 in Alzheimer’s disease and dementias, Parkinson’s disease , multiple sclerosis, schizophrenia, affective disorders, cognitive decline, and epilepsy. Vitamin D3 is also involved in neuroprotection, brain cell proliferation and differentiation, and brain development. A neurological role of Vitamin D3 is further supported by the presence of Vitamin D3-specific receptors and enzymes in neurons and glial cells throughout the brain, in the spinal cord, and in the peripheral nervous system. The broad role of Vitamin D3 in the nervous system has engendered research into Vitamin D3’s anticonvulsant action in the brain, and the proposed mechanisms of action can generally be categorized as either genomic or non-genomic…

Genomic mechanisms behind Vitamin D3’s anticonvulsant effect are based on Vitamin D3’s ability to regulate the expression of genes, a process that is mediated by a nuclear Vitamin D3 receptor (VDR). VDR is a ligand-specific transcription factor, which is activated by Vitamin D3 and subsequently alters gene expression. Through this mechanism, Vitamin D3 lowers the expression of certain proconvulsant cytokines, such as IL-1β and TNF-α. These cytokines can increase seizure susceptibility in several ways…

Through its nuclear VDR, Vitamin D3 can also increase the expression of anticonvulsant growth factors GDNF and NT3. NT3 leads to an anticonvulsant effect by downregulating TrkA and TrkC receptors, which are receptors that regulate synaptic strength. The mechanism behind GDNF’s anticonvulsant action remains largely unknown, but it is speculated that, similar to that of NT3, it involves some modulation of synaptic transmission. Vitamin D3-activated VDR also promotes expression of the calcium-binding proteins parvalbumin and calbindins, which inhibit epileptic episodes. By binding to Ca2+ in the presynaptic terminal, these calcium-binding proteins prevent excessive Ca2+-induced neurotransmitter release and thus protect against epileptic activity…

However, evidence suggests that Vitamin D3’s anticonvulsant effect is not wholly attributable to its role in altering calcium levels . Rather, it is more likely that Vitamin D3’s rapid, anticonvulsant effect results from its ability to fine-tune Ca2+ and Cl− currents across neuronal membranes. Vitamin D3 initiates non-genomic signal transduction pathways that ultimately alter the conductance of L-type calcium channels and chloride channels, therefore affecting neuronal excitability and seizure susceptibility at the threshold level...

Nearly 40 years after Christiansen et al.’s findings, Holló et al. conducted the most recent clinical study of Vitamin D3 therapy in human epilepsy... Among all subjects, 10/13 experienced fewer seizures after initialization of Vitamin D3 treatment, 2/13 had more seizures, and 1/13 had the same number of seizures. The median reduction in seizure number following treatment onset was 40% and was significant (p = 0.04). In addition, 5/13 patients experienced a ≥50% reduction in number of seizures. The existing clinical evidence suggests a therapeutic effect of Vitamin D3 in human epilepsy, but there is a need for larger Phase I trials and Phase II randomized, placebo-controlled trials to investigate optimal dosing and short-term and long-term efficacy…

The weight of evidence from basic research and animal models over the past several decades supports an anticonvulsant effect of Vitamin D3. Vitamin D3’s anticonvulsant action may be via genomic and non-genomic mechanisms. Epidemiological data as well as a variety of case studies also point to a connection between Vitamin D3 and epilepsy and support the use of Vitamin D3 as a potential therapy for human epilepsy, both in its own right and in conjunction with existing AEDs. However, the clinical data that exist are limited by small sample size and/or lack of randomization and double-blind placebo control. Despite these limitations, existing clinical data have, in the opinion of this review, been positive enough to warrant larger Phase I and Phase II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D3 as a treatment for human epilepsy. Recently, our group has received an IND for a Phase I study of Vitamin D3 in DRE to study the safety, preliminary efficacy, and potential cardiac benefits of Vitamin D3 5,000 IU/day in DRE.