Safety and tolerability of Vitamin D3 5000 IU/day in epilepsy.

PURPOSE: Preclinical and early clinical research indicates that Vitamin D3 may reduce seizures in both animal models and open-label clinical trials. METHODS: This is an initial report of an ongoing pilot study of oral Vitamin D3 5000 IU/day in subjects with drug-resistant epilepsy. After Institutional Review Board (IRB) approval and informed consent, subjects with ;less than one focal onset or generalized tonic-clonic seizure per month were enrolled. Subjects entered a 4-week baseline, followed by a 12-week treatment period. Serum 25, OH Vitamin D3, Blood Urea Nitrogen (BUN), creatinine, and calcium levels were monitored at baseline and at 6 and 12 weeks. RESULTS: High-dose Vitamin D3 5000 IU/day was well tolerated. Serum 25, OH Vitamin D3 levels increased significantly at six and twelve weeks. Vitamin D insufficiency, defined as a 25, OH Vitamin D3 level of <20 ng/ml normalized in all subjects with insufficient vitamin D levels. Median seizure frequency declined from 5.18 seizures per month to 3.64 seizures per month at 6 weeks and to 4.2 seizures per month at 12 weeks. The median percent change in seizure frequency was -26.9% at six weeks, and -10.7% at 12 weeks (not significant, Wilcoxon Signed Rank Test, P > 0.34). CONCLUSIONS: High-dose oral Vitamin D3, 5000 IU/day was safe and well tolerated in subjects with epilepsy. Vitamin D levels increased significantly at 6 and 12 weeks but never exceeded potentially toxic levels, defined as >100 ng/ml. To reduce variability, we will now recruit subjects who only have three or more seizures per month.

Omega-3 fatty acids (ῳ-3 fatty acids) in epilepsy: animal models and human clinical trials.

INTRODUCTION: There is growing interest in alternative and nutritional therapies for drug resistant epilepsy. ῳ-3 fatty acids such as fish or krill oil are widely available supplements used to lower triglycerides and enhance cardiovascular health. ῳ-3 fatty acids have been studied extensively in animal models of epilepsy. Yet, evidence from randomized controlled clinical trials in epilepsy is at an early stage. AREAS COVERED: This report focuses on the key ῳ-3 fatty acids DHA and EPA, their incorporation into the lipid bilayer, modulation of ion channels, and mechanisms of action in reducing excitability within the central nervous system. This paper presents pre-clinical evidence from mouse, rat, and canine models, and reports the efficacy of n-3 fatty acids in randomized controlled clinical trials. An English language search of PubMed and Google scholar for the years 1981-2016 was performed for animal studies and human randomized controlled clinical trials. Expert commentary: Basic science and animal models provide a cogent rationale and substantial evidence for a role of ῳ-3 fatty acids in reducing seizures. Results in humans are limited. Recent Phase II RCT evidence suggests that low to moderate dose of ῳ-3 fatty acids reduce seizures; however, larger multicenter randomized trials are needed to confirm or refute the evidence. The safety, health effects, low cost and ease of use make ῳ-3 fatty acids an intriguing alternative therapy for drug resistant epilepsy. Though safety of profile is excellent, the human data is not yet sufficient to support efficacy in drug resistant epilepsy at this time.

Fish oil (n-3 fatty acids) in drug resistant epilepsy: a randomised placebo-controlled crossover study.

BACKGROUND: n-3 fatty acids inhibit neuronal excitability and reduce seizures in animal models. High-dose fish oil has been explored in two randomised trials in drug resistant epilepsy with negative results. We performed a phase II randomised controlled crossover trial of low-dose and high-dose fish oil in participants with drug resistant epilepsy to explore whether low-dose or high-dose fish oil reduces seizures or improves cardiovascular health. METHODS: Randomised placebo-controlled trial of low-dose and high-dose fish oil versus placebo (corn oil, linoleic acid) in 24 participants with drug resistant epilepsy. A three-period crossover design was utilised lasting 42 weeks, with three 10-week treatment periods and two 6-week washout periods. All participants were randomised in double-blind fashion to receive placebo, high dose or low dose in different sequences. The primary outcome was per cent change in total seizure frequency. FINDINGS: Low-dose fish oil (3 capsules/day, 1080 mg eicosapentaenoic acid+docosahexaenoic acid) was associated with a 33.6% reduction in seizure frequency compared with placebo. Low-dose fish oil was also associated with a mild but significant reduction in blood pressure. High-dose fish oil was no different than placebo in reducing seizures or improving cardiac risk factors. INTERPRETATION: In this phase II randomised crossover trial, low-dose fish oil was effective in reducing seizures compared with placebo. The magnitude of improvement is similar to that of recent antiepileptic drug trials in drug resistant epilepsy (DRE). The results indicate that low-dose fish oil may reduce seizures and improve the health of people with epilepsy. These findings justify a large multicentre randomised trial of low-dose fish oil (n-3 fatty acids <1080 mg/day) in drug resistant epilepsy. TRIAL REGISTRATION NUMBER: NCT00871377.

Refractory status epilepticus treated with trigeminal nerve stimulation.

Refractory status epilepticus (RSE) is a neurologic emergency associated with significant morbidity and mortality. Alternative therapies are needed for patients who do not respond to more traditional therapies for RSE. We report on a patient with RSE treated with external trigeminal nerve stimulation (eTNS). On admission, the patient was experiencing consecutive focal dyscognitive seizures with secondary generalization without recovery in between. His seizures remained refractory to multiple therapies, including IV lorazepam, valproic acid, levetiracetam, phenobarbital, and midazolam. Although a burst suppression pattern was achieved with a continuous pentobarbital infusion, seizures returned following attempts to taper it. Given his beneficial response to eTNS during a previous clinical trial, eTNS was initiated. Four days after starting eTNS, the pentobarbital infusion was finally weaned, and his EEG revealed no further seizures. The patient's mental status improved and he was ultimately discharged with only moderately severe disability. Our case demonstrates that eTNS may have antiseizure effects in RSE. Given our patient's quick response, such benefit may have arisen from EEG-desynchronization. If confirmed in larger studies, eTNS could one day be considered along with other adjuvant treatments for RSE.

Neurostimulation for drug-resistant epilepsy.

PURPOSE OF REVIEW: The purpose of this review is to provide an evidence-based update on the neurostimulation options available for patients with drug-resistant epilepsy in the United States and in European countries. RECENT FINDINGS: The field of neurostimulation for epilepsy has grown dramatically since 1997, when vagus nerve stimulation became the first device to be approved for epilepsy by the US Food and Drug Administration (FDA). New data from recently completed randomized controlled trials are available for deep brain stimulation of the anterior thalamus, responsive neurostimulation, and trigeminal nerve stimulation. Although vagus nerve stimulation is the only device currently approved in the United States, deep brain stimulation and responsive neurostimulation devices are awaiting FDA approval. Deep brain stimulation, trigeminal nerve stimulation, and transcutaneous vagus nerve stimulation are now approved for epilepsy in the European Union. In this article, the mechanisms of action, safety, and efficacy of new neurostimulation devices are reviewed, and the key advantages and disadvantages of each are discussed. SUMMARY: The exponential growth of the field of neuromodulation for epilepsy is an exciting development; these new devices provide physicians with new options for patients with drug-resistant epilepsy.

Trigeminal nerve stimulation in major depressive disorder: acute outcomes in an open pilot study.

Most patients with major depressive disorder (MDD) do not recover with initial pharmacotherapy, and many pursue combination treatments. Combining a medication with neuromodulation offers an alternative to purely pharmacologic strategies. In prior open and double-blind controlled trials for drug-resistant epilepsy, adjunctive external trigeminal nerve stimulation (eTNS) was found to be safe and well tolerated, to significantly reduce seizures, and to be associated with an improvement in depressive symptoms. Here, we present a comprehensive description of the first open pilot investigation in MDD. In this 8-week trial, eleven adults with unipolar MDD received nightly stimulation (V(1) branch). All entered with moderate to severe symptom levels despite at least two antidepressant medication trials in this episode. All the eleven adults completed the acute trial, without serious adverse events. Symptoms of depression improved significantly, whether assessed with clinician- or self-rated scales (all p < 0.01; effect sizes d 1.0-1.8), as did quality of life (p < 0.02). Four of the 11 achieved remission. These improvements from nightly adjunctive eTNS in treatment-resistant depression merit replication under double-blind conditions.

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy.

OBJECTIVE: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. METHODS: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. RESULTS: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). CONCLUSIONS: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. CLASSIFICATION OF EVIDENCE: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy.

Trigeminal nerve stimulation (TNS) is a novel therapy for drug-resistant epilepsy. We report in detail the safety of external TNS (eTNS), focusing on acute and long-term heart rate and systolic and diastolic blood pressure in response to TNS from the pilot feasibility study. The data indicate that eTNS of the infraorbital and supraorbital branches of the trigeminal nerve is safe and well tolerated.

Trigeminal nerve stimulation: seminal animal and human studies for epilepsy and depression.

The unique ability to stimulate bilaterally, extracranially, and non-invasively may represent a significant advantage to invasive neuromodulation therapies. In humans thus far the technique has been applied noninvasively, and is termed external trigeminal nerve stimulation (eTNSTM).

Trigeminal nerve stimulation in major depressive disorder: first proof of concept in an open pilot trial.

Modulation of brain activity via trigeminal nerve stimulation is an emerging therapy in drug-resistant epilepsy. This cranial nerve also projects to structures implicated in depression (such as the nucleus tractus solitarius and locus coeruleus). We examined the effects of external trigeminal nerve stimulation in major depressive disorder as an adjunct to pharmacotherapy. Five adults (mean age 49.6, SD 10.9, three females and two males) participated in an 8-week open-label outpatient trial; all had persistent symptoms despite adequate pharmacotherapy, with a mean score on the 28-item Hamilton Depression Rating Scale of 25.4 (SD=3.9) at entry. Nightly stimulation over the V(1) branch was well tolerated. Both the clinician-rated 28-item Hamilton Depression Rating Scale (P=0.006) and the self-rated Beck Depression Inventory (P=0.0004) detected significant symptomatic improvement. This novel neuromodulation approach may have use as an adjunct to pharmacotherapy in major depressive disorder. Additional larger trials are needed to delineate efficacy and tolerability with greater reliability.

RMSSD, a measure of vagus-mediated heart rate variability, is associated with risk factors for SUDEP: the SUDEP-7 Inventory.

OBJECTIVE: The goal of this study was to determine if specific measures of heart rate variability (HRV) are associated with the total score on a new seven-item inventory for sudden unexplained death in epilepsy (SUDEP). METHODS: Nineteen subjects with intractable partial seizures, at least three per month, were enrolled in a randomized clinical trial of omega-3 fatty acids in epilepsy. At study entry, subjects underwent a 1-hour ECG recording for the determination of HRV. To estimate the risk of SUDEP, we assembled a seven-item inventory (the SUDEP-7 Inventory) from risk factors prospectively validated by T.S. Walczak, I.E. Leppik, M. D'Amelio M, et al. (Neurology 2001;56:519-25). The SUDEP-7 score was then correlated with measures of HRV using the Pearson correlation and other parametric and nonparametric methods. RESULTS: Subjects had highly drug-resistant seizures, with a mean seizure frequency of 22.8 seizures per month. Scores on the SUDEP-7 inventory ranged from 1 to 7 of a maximum possible score of 12. RMSSD, a measure of high-frequency HRV, was inversely correlated with the SUDEP-7 score, r=-0.64, P=0.004. Subjects with higher SUDEP-7 scores had reduced levels of HRV (RMSSD). Other time-dependent measures of HRV (SDNN, SDANN) were not significantly correlated with SUDEP risk scores. CONCLUSIONS: RMSSD, a measure of HRV, which reflects the integrity of vagus nerve-mediated autonomic control of the heart, is highly associated with the total score on a new seven-item SUDEP risk inventory. Lower RMSSD values were associated with higher risk scores on the new SUDEP risk inventory. This provides new evidence that HRV (specifically RMSSD) is a marker of SUDEP risk.

n-3 fatty acids (fish oil) for epilepsy, cardiac risk factors, and risk of SUDEP: clues from a pilot, double-blind, exploratory study.

OBJECTIVE: The goal of the work described here was to determine the effect of high-dose n-3 fatty acids (eicosapentanoic acid+docosahexanoic acid, fish oil) on several outcomes in subjects with refractory epilepsy, including seizure severity, seizure frequency, cardiac risk factors, and heart rate variability, in a pilot, exploratory planning trial. METHODS: Pilot, randomized, double-blind two-period crossover clinical trial of high-dose fish oil (9600 mg of fish oil/day, 2880 mg of n-3 fatty acids) in 11 subjects with refractory seizures. Outcomes included seizure frequency, seizure severity, lipid panel, and heart rate variability as measured by SDNN and SDANN (defined as the standard deviation of all normal R-R intervals for 1h, and the standard deviation of all R-R intervals in each successive 5-min epoch, respectively). RESULTS: Preliminary data identified trends towards lower seizure severity, lower triglycerides, higher HDL, and increased SDNN/SDANN in those with low SDNN/SDANN at baseline (Spearman's correlation=-0.65, P=0.03). No positive effect on seizure frequency was identified. CONCLUSIONS: Further study of the effect of n-3 fatty acids is indicated in people with epilepsy, as favorable trends were identified on cardiac risk factors (triglycerides) and in a subgroup with low heart rate variability (low SDNN/SDANN), a marker of sudden death risk. To our knowledge, this is the first trial to explore the beneficial effects of n-3 fatty acids on cardiac risk factors and heart rate variability in people with epilepsy.

Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial.

The safety and preliminary efficacy of trigeminal nerve stimulation (TNS) for epilepsy was evaluated in a pilot feasibility study of transcutaneous stimulation of the infraorbital and supraorbital branches of the trigeminal nerve. TNS was well tolerated. Four (57%) of seven subjects who completed >or=3 months experienced a >or=50% reduction in seizure frequency. The results of this pilot study support further investigation into the safety and efficacy of TNS for epilepsy.

Vagus nerve stimulation therapy, epilepsy, and device parameters: scientific basis and recommendations for use.

Our understanding of a precise dose-response relationship for vagus nerve stimulation (VNS) therapy in the treatment of seizures is still evolving. Because several parameters are involved in VNS therapy, the individual contribution of each is not well understood. This review discusses the efficacy of stimulation parameters used in the VNS clinical trials. The background, influence on safety and efficacy, and role in helping to achieve seizure control are discussed for each VNS device parameter: output current, pulse duration, frequency, and duty cycle. Finally, we provide an algorithm for the adjustment of VNS device settings (see Appendices).