Increased cardiovascular risk in epilepsy.

Epilepsy is associated with increased mortality. Cardiovascular disease confers a significant portion of this increased risk. Recently there is increased interest in the burden of cardiovascular mortality in people with epilepsy. This review discusses the most common cardiovascular risk factors and their association with epilepsy including obesity, diabetes mellitus, and hyperlipidemia. Hyperlipidemia related to the use of enzyme inducing anti-seizure medications is also discussed as a topic that is of particular importance to prescribers that have patients with comorbid cardiovascular risk and epilepsy. Heart rate variability (HRV) and its association with SUDEP is discussed as well as a contributor to vascular risk. Finally, the authors discuss a potential role for neurologists who treat epilepsy to engage closer with their patient's cardiovascular risk factors using available tools such as a the ASCVD score calculator to determine the overall risk of mortality, as well as acting upon this information to guide treatment approaches integrating the information provided in this review.

Prospective, Randomized Trial Comparing Simulator-based versus Traditional Teaching of Direct Ophthalmoscopy for Medical Students.

OBJECTIVE: To compare results of simulator-based vs traditional training of medical students in direct ophthalmoscopy. DESIGN: Randomized controlled trial. METHODS: First-year medical student volunteers completed 1 hour of didactic instruction regarding direct ophthalmoscopes, fundus anatomy, and signs of disease. Students were randomized to an additional hour of training on a direct ophthalmoscope simulator (n = 17) or supervised practice examining classmates (traditional method, n = 16). After 1 week of independent student practice using assigned training methods, masked ophthalmologist observers assessed student ophthalmoscopy skills (technique, efficiency, and global performance) during examination of 5 patient volunteers, using 5-point Likert scales. Students recorded findings and lesion location for each patient. Two masked ophthalmologists graded answer sheets independently using 3-point scales. Students completed surveys before randomization and after assessments. Training groups were compared for grades, observer- and patient-assigned scores, and survey responses. RESULTS: The simulator group reported longer practice times than the traditional group (P = .002). Observers assigned higher technique scores to the simulator group after adjustment for practice time (P = .034). Combined grades (maximum points = 20) were higher for the simulator group (median: 5.0, range: 0.0-11.0) than for the traditional group (median: 4.0, range: 0.0-9.0), although the difference was not significant. The simulator group was less likely to mistake the location of a macular scar in 1 patient (odds ratio: 0.28, 95% confidence interval: 0.056-1.35, P = .013). CONCLUSIONS: Direct ophthalmoscopy is difficult, regardless of training technique, but simulator-based training has apparent advantages, including improved technique, the ability to localize fundus lesions, and a fostering of interest in learning ophthalmoscopy, reflected by increased practice time.

Changes in epilepsy causes of death: A US population study.

OBJECTIVES: Since 2000, medical treatment for epilepsy and cardiovascular risk-reduction strategies have advanced significantly in the United States (US). However, seizure-free rates remain unchanged, and people with epilepsy are at higher risk than the general population for heart disease and stroke. The purpose of this study is to determine how cardiovascular, epilepsy-related, and other causes of death are changing in epilepsy in comparison with the US population. MATERIALS & METHODS: Changes in the 15 underlying causes of death in epilepsy (ICD-10 G40-G40.9) and the US population were analyzed and compared from 2000 to 2018. The CDC multiple cause-of-death database was utilized as the primary data source. Changes in the relative proportions for each cause-of-death over were evaluated using logistic regression. RESULTS: The proportions of deaths in epilepsy due to heart disease declined 34.4% (p < .001), a rate similar to the general population (39.9%). Epilepsy-related deaths declined 25% as a percentage of all epilepsy deaths (p < .001). The proportions of deaths due to stroke and neoplasms increased significantly in epilepsy versus the US population (p < .001 linear trend). CONCLUSIONS: The reduction in ischemic heart disease in epilepsy is a novel and highly significant finding, which reflects widespread implementation of cardiovascular risk-factor reduction and treatment in the United States. Reductions in epilepsy-related deaths are an exciting development which requires further investigation into causality. The increase in deaths due to neoplasms and stroke relative to the US population is concerning, warranting vigilance and increased efforts at recognition, prevention, and treatment.

Why are epilepsy mortality rates rising in the United States? A population-based multiple cause-of-death study.

INTRODUCTION: Epilepsy mortality rates are rising. It is unknown whether rates are rising due to an increase in epilepsy prevalence, changes in epilepsy causes of death, increase in the lethality or epilepsy or failures of treatment. To address these questions, we compare epilepsy mortality rates in the USA with all-cause and all-neurological mortality for the years 1999 to 2017. OBJECTIVES: To determine changes in US epilepsy mortality rates versus all-cause mortality, and to evaluate changes in the leading causes of death in people with epilepsy. DESIGN: Retrospective population-based multiple cause-of-death study. PRIMARY OUTCOME: Change in age-adjusted epilepsy mortality rates compared with mortality rates for all-cause and all-neurological mortality. SECONDARY OUTCOME: Changes in the leading causes of death in epilepsy. RESULTS: From 1999 to 2017, epilepsy mortality rates in the USA increased 98.8%, from 5.83 per million in 1999 to 11.59 per million (95% CI 88.2%-110.0%), while all-cause mortality declined 16.4% from 8756.34 per million to 7319.17 per million (95% CI 16.3% to 16.6%). For the same period, all-neurological mortality increased 80.8% from 309.21 to 558.97 per million (95% CI 79.4%-82.1%). The proportion of people with epilepsy who died due to neoplasms, vascular dementia and Alzheimer's increased by 52.3%, 210.1% and 216.8%, respectively. During the same period, the proportion who died due to epilepsy declined 27.1%, while ischaemic heart disease as a cause of death fell 42.6% (p<0.001). CONCLUSIONS: Epilepsy mortality rates in the USA increased significantly from 1999 to 2017. Likely causes include increases in all-neurological mortality, increased epilepsy prevalence and changes in the underlying causes of death in epilepsy, led by increases in vascular dementia and Alzheimer's. An important finding is that ischaemic heart disease and epilepsy itself are declining as underlying causes of death in people with epilepsy.

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.

MELAS: Monitoring treatment with magnetic resonance spectroscopy.

BACKGROUND: To assess the utility of Magnetic Resonance Spectroscopy (MRS) as a biomarker of response to L-arginine in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). AIMS: To describe a case of MELAS treated with L-arginine that showed improvement clinically and on serial MRS METHODS: MRS was performed on a 1.5-Tesla scanner to evaluate a MELAS patient before, during, and after intravenous (IV) L-arginine therapy for the treatment of stroke-like episodes. L-arginine was infused at a dose of 500 mg/kg daily for 7 days followed by oral arginine therapy. RESULTS: The patient had clinical improvement after treatment with IV L-arginine. MRS performed before, during, and after treatment with IV L-arginine showed significant improvement in brain lactate and increase in the N-acetylaspartate/Choline (NAA/Cho) ratio compared to pre-treatment baseline. CONCLUSION: Serial MRS imaging showed significant improvement in lactate peaks and NAA/Cho ratios that corresponded with clinical improvement after L-arginine therapy. Given this correlation between radiologic and clinical improvement, MRS may be a useful biomarker assessing response to treatment in MELAS.

Sudden unexpected death in epilepsy: Risk factors, biomarkers, and prevention.

Sudden unexpected death in epilepsy (SUDEP) is one of the most important direct epilepsy-related causes of death, with an incidence in adults of 1.2 per 1000 person-years. Generalized tonic-clonic seizures have consistently emerged as the leading risk factor for SUDEP, particularly when such seizures are uncontrolled. High seizure burden, lack of antiepileptic drug (AED) treatment, polytherapy, intellectual disability, and prone position at the time of death are other key risk factors. Unfortunately, despite advances in treatment, overall mortality rates in epilepsy are rising. It is imperative that we learn more about SUDEP so that effective prevention strategies can be implemented. To help identify persons at greater risk of SUDEP and in need of closer monitoring, biomarkers are needed. Candidate biomarkers include electrocardiographic, electroencephalographic, and imaging abnormalities observed more frequently in those who have died suddenly and unexpectedly. As our knowledge of the pathophysiologic mechanisms behind SUDEP has increased, various preventative measures have been proposed. These include lattice pillows, postictal oxygen therapy, selective serotonin reuptake inhibitors, and inhibitors of opiate and adenosine receptors. Unfortunately, no randomized clinical trials are available to definitively conclude these measures are effective. Rather, gaining the best control of seizures possible (with AEDs, devices, and resective surgery) still remains the intervention with the best evidence to reduce the risk of SUDEP. In this evidence-based review, we explore the incidence of SUDEP and review the risk factors, biomarkers, and latest prevention strategies.

Ranking the Leading Risk Factors for Sudden Unexpected Death in Epilepsy.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is rare in well-controlled epilepsy. However, SUDEP is a common cause of death in drug-resistant epilepsy. Over the last 30 years, multiple cohort and population studies have identified clinical risk factors associated with an increased risk for SUDEP. OBJECTIVE: To identify and rank the leading SUDEP risk factors from major cohort and population-based studies. The incidence of SUDEP is also evaluated in special clinical situations, including antiepileptic drug treatment, epilepsy surgery, devices, and assignment to placebo in clinical trials. METHODS: A PubMed search for English language human cohort studies for the terms Sudden, Death, and Epilepsy was performed for the years 1987-2017. Risk factors for SUDEP were identified and ranked by the weighted log adjusted odds ratio (OR)/relative risk ratio (RR). FINDINGS: The top 10 leading risk factors ranked from highest to lowest log adjusted OR/RR are the following: ≥3 GTC seizures per year; ≥13 seizures in the last year; No Antiepileptic Drug (AED) treatment; ≥3 AEDs; ≥3 GTCs in the past year; 11-20 GTC seizures in the last 3 months; age of onset 0-15 years old; IQ < 70; 3-5 AED changes in the last year; ≥3 AEDs. Two risk factors from separate sources (≥3 GTC seizures and ≥3 AEDs) occur twice in the top 10 risk factors. CONCLUSION: The top 10 risk factors for SUDEP are identified and ranked. A ranking of the top risk factors could help clinicians identify patients at highest risk for SUDEP.

Vitamin D3 for the Treatment of Epilepsy: Basic Mechanisms, Animal Models, and Clinical Trials.

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.

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.

Risk Assessment for Sudden Death in Epilepsy: The SUDEP-7 Inventory.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in those with drug-resistant epilepsy (DRE). There is a need for inventories and biomarkers associated with the risk for SUDEP. OBJECTIVE: To explore the revised SUDEP Risk Inventory (SUDEP-7) in a cohort with DRE and determine the association with Heart Rate and other covariates. METHODS: Twenty-five subjects with severe DRE were enrolled in a clinical trial for epilepsy. Baseline demographics, duration of epilepsy, seizure types, seizure frequency, seizure severity, AEDs, and vital signs were collected. Heart rate variability (HRV) was calculated from 1-h recordings of ECG. A SUDEP Risk Inventory (SUDEP-7) was administered, which included seven validated and weighted risk factors initially identified by Walczak et al. as factors associated with SUDEP risk. RESULTS: The total score on the revised SUDEP-7 ranged from 1 to 7, mean = 3.4 (SD 1.8). The SUDEP Risk Inventory score was inversely correlated with RMSSD (Pearson r = -0.45, p = 0.027). The following variables were significantly associated with RMSSD: epilepsy duration (p = 0.02), age (p = 0.03), and developmental intellectual disability (p < 0.001). The correlation between RMSSD and SUDEP-7 tended to persist also after the adjustment for patient age (r = -0.40, p = 0.05). Two subjects died of SUDEP: their SUDEP-7 scores were above average and in the upper twenty-fifth and fiftieth percentiles, respectively (6 and 4, mean = 3.4). CONCLUSION: RMSSD, a measure of low frequency HRV, was significantly associated with SUDEP Risk Inventory (SUDEP-7) scores. Using a multivariate model, the covariates of developmental intellectual disability, age, and duration of epilepsy were also significantly associated with decreased HRV. The correlation between decreased HRV and a higher SUDEP-7 score remained unchanged even after the adjustment for patient age. The results suggest that older age, greater duration of epilepsy, and the presence of developmental intellectual disability may increase the risk of SUDEP through their direct influence on decreasing the vagus nerve-mediated HRV. Further validation of the SUDEP-7 inventory is indicated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00871377.

The SUDEP Risk Inventory: Association with postictal generalized EEG suppression.

To help identify patients at greatest risk for sudden unexpected death in epilepsy (SUDEP), screening inventories like the SUDEP-7 Inventory can be useful. In this study, we examined the strength of association between this inventory's risk factors and postictal generalized EEG suppression (PGES), a biomarker of SUDEP risk. We reanalyzed data from an epilepsy monitoring unit study of 37 children. We performed a 2 by 2 contingency table analysis to determine the association between "yes" responses on the inventory questions and PGES following >=1 seizure. Having a history of >3 generalized tonic-clonic seizures (GTCS) in the past year had the strongest association with PGES (Pearson chi-square p<0.001, Cramer's V=0.75). Having >=1 GTCS in the past year was also strongly associated with PGES (Pearson chi-square p<0.001, Cramer's V=0.636). Histories of >50 seizures of any type/month (Pearson chi-square p=0.14, Cramer's V=0.241) and intellectual disability (Pearson chi-square p=0.04, Cramer's V=0.337) were not as robustly associated with PGES. Current use of >=3 AEDs had the weakest association with PGES (Pearson chi-square p=0.66, Cramer's V=0.072). Given that all study patients had >=1 seizure per year and epilepsy durations <30 years, the strength of association with these questions and PGES could not be analyzed.

Neuromodulation in the Treatment of Epilepsy.

OPINION STATEMENT: Neuromodulation devices are used in the treatment of medically refractory epilepsy. This has been defined as epilepsy with persistent seizures despite adequate trials of at least two anti-epileptic drugs (AEDs). In most cases of medically refractory partial epilepsy, the first choice of treatment is resective surgery if the seizure focus can be definitively localized and if surgery can be safely performed without causing intolerable neurologic deficits. Patients with medically refractory epilepsy who are not candidates for potentially curative surgery may benefit from the implantation of a neuromodulation device. While most of these devices require surgical implantation, they provide a significant added seizure reduction without typical medication side effects. Furthermore, the efficacy of these devices continues to improve over years. There are currently no head-to-head trials comparing the different neuromodulation devices but efficacy appears to be roughly similar. The choice of device therefore depends on the type of epilepsy, whether the seizure focus can be identified, and other clinical factors. Vagal Nerve Stimulation (VNS) does not require identification of the seizure focus and also carries an FDA indication for depression. While in the United States VNS is only approved for use in partial epilepsy, it is commonly used off-label to treat generalized seizures as well. VNS delivers stimulation on a scheduled basis, in response to patient activation, or in response to heart rate increases serving as a proxy for seizures. Responsive Neurostimulation (RNS) requires the identification of up to two seizure foci and delivers stimulation only in response to the detection of epileptiform activity. While it requires intracranial placement of electrodes, it allows for long-term monitoring of electrographic seizures and may be effective where VNS has not produced an optimal response. Deep brain stimulation of the anterior nucleus of the thalamus is not FDA approved at this time but is available in Europe and many other parts of the world. While it also carries an indication only for partial epilepsy, it does not require identification of the seizure focus and may be particularly helpful for temporal lobe epilepsy. It also appears effective in cases where VNS has not been sufficiently helpful. The Trigeminal Nerve Stimulation (TNS) system is another treatment modality which is not yet FDA approved but is available in Europe and other countries. Its mechanism of action is similar to the VNS system and it also appears to have anti-depression effects in addition to anti-epileptic benefits. However, the most compelling feature of TNS is that it is not implanted but rather applied to the skin with transdermal electrodes, typically at night.

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.

A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy.

BACKGROUND: External trigeminal nerve stimulation (eTNS) is an emerging noninvasive therapy for drug-resistant epilepsy (DRE). We report the long-term safety and efficacy of eTNS after completion of a phase II randomized controlled clinical trial for drug-resistant epilepsy. METHODS: This was a prospective open-label long-term study. Subjects who completed the phase II randomized controlled trial of eTNS for DRE were offered long-term follow-up for 1year. Subjects who were originally randomized to control settings were crossed over to effective device parameters (30s on, 30s off, pulse duration of 250s, frequency of 120Hz). Efficacy was assessed using last observation carried forward or parametric imputation methods for missing data points. Outcomes included change in median seizure frequency, RRATIO, and 50% responder rate. RESULTS: Thirty-five of 50 subjects from the acute double-blind randomized controlled study continued in the long-term study. External trigeminal nerve stimulation was well tolerated. No serious device-related adverse events occurred through 12months of long-term treatment. At six and twelve months, the median seizure frequency for the original treatment group decreased by -2.39 seizures per month at 6 months (-27.4%) and -3.03 seizures per month at 12 months (-34.8%), respectively, from the initial baseline (p<0.05, signed-rank test). The 50% responder rates at three, six, and twelve months were 36.8% for the treatment group and 30.6% for all subjects. CONCLUSION: The results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug-resistant epilepsy.