Alan W.C. Yuen

Psychiatric adverse events during levetiracetam therapy

The prevalence and psychopathologic features of psychiatric adverse events (PAE) in 517 patients taking levetiracetam (LEV) were investigated. Fifty-three (10.1%) patients developed PAE. A significant association was found with previous psychiatric history, history of febrile convulsions, and history of status epilepticus, whereas lamotrigine co-therapy had a protective effect. PAE were not related to the titration schedule of LEV, and certain patients seem to be biologically more vulnerable.

Omega-3 fatty acid supplementation in patients with chronic epilepsy: A randomized trial

Animal studies and a preliminary clinical observation suggest that nutritional supplementation with long chain omega-3 fatty acids (omega-3 FAs) may be useful in the nonpharmacological treatment of patients with epilepsy. Omega-3 FAs increase seizure thresholds, and lower inflammatory mediators, which are increased in patients with epilepsy. In this first randomized, placebo-controlled parallel group trial of omega-3 FA supplementation with 1 g eicosapentaenoic acid (EPA) and 0.7 g docosahexaenoic acid (DHA) daily, 57 patients completed a 12-week double-blind phase. Seizure frequency was reduced over the first 6 weeks of treatment in the supplement group, but this effect was not sustained. The supplementation produced a significant increase in EPA and DHA concentrations and a reciprocal fall in arachidonic and linoleic acid concentrations. No change in serum AED concentrations was detected. Further studies are required to examine different omega-3 FA preparations, different doses, longer treatment duration, and larger sample sizes.

Vitamin D: In the evolution of human skin colour

The natural selection hypothesis suggests that lighter skin colour evolved to optimise vitamin D production. Some authors question if vitamin D deficiency leads to sufficient health problems to act as a selection pressure. This paper reviews the numerous effects of vitamin D deficiency on human health and argues that vitamin D deficiency is sufficient to pose as a potent selection pressure for lighter skin colour. Vitamin D deficiency manifesting as rickets and osteomalacia are sufficient to impair reproductive success, but additionally, animal studies and some clinical observations suggest that vitamin D may have more direct impact on human fertility. Vitamin D deficiency may lead to a whole host of clinical conditions which impair health and increase mortality rates: increase susceptibility to bacterial and viral infections; rickets, osteomalacia and osteoporosis, with increased risk of falls and fractures; increased risk of cancers; hypertension and cardiovascular disease; maturity onset diabetes; autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and Type 1 diabetes; and gum disease. We submit that at higher latitudes, lighter skin colour evolved to facilitate vitamin D production under conditions of low ultra-violet B radiation in order to avoid a plethora of ill health, reproductive difficulties and early mortality.

Is omega-3 fatty acid deficiency a factor contributing to refractory seizures and SUDEP?: A hypothesis

Epilepsy, the commonest serious neurological condition, is associated with an increased risk in premature deaths, including an estimated 500 sudden unexpected deaths (SUDEP) per year in the UK. In some patients seizures are associated with cardiac arrhythmias, which are thought to be a major factor in SUDEP. Omega-3 fatty acids have been shown to reduce cardiac arrhythmias in animal studies and to reduce sudden cardiac deaths, thought to be due to cardiac arrhythmias, in both healthy subjects and in those who have had one myocardial infarction. Additionally, omega-3 fatty acids in animal studies and in a small clinical observation study have shown anti-seizure effects. Omega-3 fatty acid supplementation in patients with refractory seizures may reduce seizures and seizure associated cardiac arrhythmias and hence SUDEP.

Mortality and morbidity rates are increased in people with epilepsy: is stress part of the equation?

People with epilepsy (PWE), particularly those with more severe seizures, are at risk of premature death. The contribution of deaths unrelated to epilepsy to this risk is likely to be significant. Recent studies indicate that comorbid conditions are similarly increased in PWE. The reason for these increases in unrelated deaths and comorbid conditions is unclear. In this article, we argue that having seizures is psychologically stressful, and that this stress can lead to a whole range of pathophysiological changes that may trigger various physical illnesses. Hence, psychological stress may be a significant factor contributing to the increase in mortality and comorbidity rates in PWE. This speculation is unlikely to be proven at this stage because of the complexity of the trials required. In PWE who continue to have seizures, more needs to be done to help them cope with the stress. Additionally, attention needs to be paid to improve nutritional status and physical fitness. These steps are likely to enhance the overall health of PWE and may reduce premature mortality and comorbidity rates.

The long-term retention of zonisamide in a large cohort of people with epilepsy at a tertiary referral centre

Zonisamide (ZNS) is an antiepileptic drug (AED) with multiple putative mechanisms of action. It is chemically unrelated to other AEDs. It has been available in Japan since 1989 but was only licensed in Europe in 2005. Its efficacy and tolerability have been shown in several randomised controlled trials, but large studies on long-term performance in Western clinical practice are scarce. We assessed a large cohort of consecutive people who started ZNS at a tertiary epilepsy referral centre, from June 2005 to July 2009. Forty-six percent of the 417 people included were still taking ZNS at last follow-up, with an estimated retention rate at three years of 30%. Almost one third of the population reported a period of improvement in terms of seizure reduction of at least six months duration whilst on ZNS. Sixteen people became seizure free for at least six months and seven of these were seizure free for one year or more. Adverse events occurred in 58%, frequently CNS-related. People on three or more AEDs and people starting zonisamide at 25mg daily rather than 50mg or more, were more likely to discontinue ZNS. Retention rates for ZNS were similar to those previously reported, and comparable to lamotrigine, topiramate, pregabalin, higher than gabapentin, and lower than levetiracetam.

Rationale for using intermittent calorie restriction as a dietary treatment for drug resistant epilepsy.

There has been resurgence in the use of dietary treatment, principally the classical ketogenic diet and its variants, for people with epilepsy. These diets generally require significant medical and dietician support. An effective but less restrictive dietary regimen is likely to be more acceptable and more widely used. Calorie-restricted diets appear to produce a range of biochemical and metabolic changes including reduced glucose levels, reduced inflammatory markers, increased sirtuins, increased AMPK signaling, inhibition of mTOR signaling, and increase in autophagy. There are studies in animal seizure models that suggest that these biochemical and metabolic changes may decrease ictogenesis and epileptogenesis. A calorie-restricted diet might be effective in reducing seizures in people with epilepsy. Hence, there is a sufficient rationale to undertake clinical trials to assess the efficacy and safety of calorie-restricted diets in people with epilepsy.

Erythrocyte and plasma fatty acid profiles in patients with epilepsy: Does carbamazepine affect omega-3 fatty acid concentrations?

Fatty acids (FAs) determine membrane properties and may affect cardiac and neuronal function. In this study, FA profiles were determined in 56 patients with epilepsy who participated in a 12-week double-blind randomized trial of omega-3 FA supplementation (1 g eicosapentaenoic acid and 0.7 g docosahexaenoic acid daily). At baseline, subjects on carbamazepine (CBZ) had lower docosahexaenoic acid levels, lower levels of long-chain omega-3 FAs, and a lower Omega-3 Index (a risk factor for coronary heart disease mortality), whereas those on oxcarbazepine had higher total polyunsaturated FAs and a higher Omega-3 Index. Following omega-3 FA supplementation, the Omega-3 Index, eicosapentaenoic acid, and docosahexaenoic acid concentrations significantly increased. Patients on CBZ exhibited a less favorable FA profile, associated with a greater risk of coronary heart disease mortality. As arrhythmias are thought to be an important mechanism in coronary heart disease mortality and sudden unexplained death in epilepsy (SUDEP), the effect of CBZ effect in reducing omega-3 FAs might potentially explain some cases of SUDEP among patients prescribed CBZ.

Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis

Magnesium is required for over 300 enzyme systems and is critical for many cellular functions including oxidative phosphorylation, glycolysis, DNA transcription and protein synthesis. Studies suggest that the modern Western diet and lifestyle may lead to magnesium deficiency, and this appears to be associated with a wide range of medical conditions. Magnesium deficiency decreases seizure thresholds in animal models of epilepsy and indeed low magnesium concentration in the perfusate is a common method of generating spontaneous epileptiform discharges from rat hippocampal slices. Magnesium is a potential modulator of seizure activity because of its ability to antagonize excitation through the N-methyl-d-aspartate receptor. Some studies have shown that people with epilepsy have lower magnesium levels than people without epilepsy. There are case reports of seizures being controlled with magnesium supplementation in people with specific conditions, and recently in an open randomized trial, children with infantile spasms responded better to adrenocorticotropic hormone (ACTH) plus magnesium than to ACTH alone. We hypothesise that magnesium supplementation can reduce seizures in people with epilepsy. This hypothesis can be tested in a controlled randomised supplementation trial. If proven, magnesium supplementation needs to be considered in the overall management of people with refractory epilepsy.

Non-randomized open trial of eicosapentaenoic acid (EPA), an omega-3 fatty acid, in ten people with chronic epilepsy

This is a non-randomized open assessment of eicosapentaenoic acid (EPA) supplementation in ten people (five males) with refractory focal seizures. Each received 1000 mg of EPA daily for 3 months. Six people had fewer seizures during the supplementation period compared with baseline (range 12 to 59% reduction) and one other person had markedly reduced seizure severity. The mean reduction in seizure frequency was 16% (95% CI - 10% to 35%, p=0.26). With the small number of participants and open nature of the study, interpretation of the results is difficult, but a possible weak effect of EPA on seizures cannot be discounted. Further examination of EPA supplementation should be undertaken with larger numbers of people in controlled trials. Higher doses and longer duration of treatment should be considered.