Epilepsy is a neurological and a systemic disorder.

The basic pathophysiology of epilepsy is still not fully understood. Epidemiological evidence for epilepsy seems to suggest that it may not only be the propensity for seizures to occur. The high prevalence of comorbidity and the finding that premature mortality is still increased in those who are in long-term remission, suggest that there is a systemic component to the condition. This systemic component is an additional shared risk factor that can explain an important proportion of the comorbidities of epilepsy as well as how an individual with inactive epilepsy remains at an elevated risk of premature mortality. This systemic component can be viewed from the perspective of a number of fundamental pathophysiological processes: inflammation, oxidative stress, glycation, and methylation capacity. These processes are associated with all-cause mortality and there is also a growing understanding of their impact on seizure processes. We propose that epilepsy be considered as the sum of seizures and comorbidities caused by systemic dysfunction, and that the comprehensive management of epilepsy should also include the management of the systemic dysfunction.

Can natural ways to stimulate the vagus nerve improve seizure control?

The vagus nerve (VN) is the longest cranial nerve, innervating the neck, thorax and abdomen, with afferent fibers transmitting a range of interoceptive stimuli and efferent fibres to somatic structures and autonomic preganglions. Over the last few decades, electrical stimulation of the VN using implanted devices (VNS) has been developed leading to its approval for the treatment of epilepsy and depression. More recently, non-invasive devices to stimulation the VN have been developed. The VN has many functions and the activity that is most amenable to assessment is its effect in controlling the cardiac rhythm. This can be easily assessed by measuring heart rate variability (HRV). Decreased HRV is a result of poorer vagal parasympathetic tone and is associated with a wide range of ill health conditions including a higher risk of early mortality. People with epilepsy, particularly those with poorly controlled seizures, have been shown to have impaired parasympathetic tone. So, might natural ways to stimulate the VN, shown to improve parasympathetic tone as indicated by increased HRV, improve seizure control? There are numerous natural ways that have been shown to stimulate the VN, improving HRV and hence parasympathetic tone. These natural ways fall mainly into 3 categories - stress reduction, exercise, and nutrition. Though the natural ways to stimulate the VN have been shown to increase HRV, they have not been shown to reduce seizures. The exception is listening to Mozart's music, which has been shown to increase parasympathetic tone and decrease seizures. Clearly much more work is required to examine the effect of the various ways to increase HRV on seizure occurrence.

An acidosis-sparing ketogenic (ASK) diet to improve efficacy and reduce adverse effects in the treatment of refractory epilepsy.

Diets that increase production of ketone bodies to provide alternative fuel for the brain are evolving from the classic ketogenic diet for epilepsy devised nearly a century ago. The classic ketogenic diet and its more recent variants all appear to have similar efficacy with approximately 50% of users showing a greater than 50% seizure reduction. They all require significant medical and dietetic support, and there are tolerability issues. A review suggests that low-grade chronic metabolic acidosis associated with ketosis is likely to be an important contributor to the short term and long term adverse effects of ketogenic diets. Recent studies, particularly with the characterization of the acid sensing ion channels, suggest that chronic metabolic acidosis may increase the propensity for seizures. It is also known that low-grade chronic metabolic acidosis has a broad range of negative health effects and an increased risk of early mortality in the general population. The modified ketogenic dietary treatment we propose is formulated to limit acidosis by measures that include monitoring protein intake and maximizing consumption of alkaline mineral-rich, low carbohydrate green vegetables. We hypothesize that this acidosis-sparing ketogenic diet is expected to be associated with less adverse effects and improved efficacy. A case history of life-long intractable epilepsy shows this diet to be a successful long-term strategy but, clearly, clinical studies are needed.

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.

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.

Can slow breathing exercises improve seizure control in people with refractory epilepsy? A hypothesis.

Studies on various medical conditions have shown that poor health is associated with lower parasympathetic tone. People with epilepsy appear to have decreased parasympathetic tone, with a greater decrease in those with intractable seizures than in those with well-controlled epilepsy. Slow breathing exercises have been shown to increase parasympathetic tone in healthy volunteers. Slow breathing exercises have been shown to improve a number of medical conditions including asthma, hypertension, anxiety states, and posttraumatic stress disorder. We hypothesize that slow breathing exercises in people with epilepsy can lead to an increase in parasympathetic tone and an accompanying reduction in seizure frequency. The slow breathing exercises, probably through baroreceptors, chemoreceptors, and pulmonary stretch receptors, affect cortical activity and hence seizure thresholds. It is also possible that slow breathing exercises might reduce seizure frequency by reducing anxiety. The hypothesis can be tested by employing devices and protocols that have been used to reduce breathing rates and have been shown to improve health outcomes in other medical conditions.

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.

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.

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.

Impaired mitochondrial energy production: the basis of pharmacoresistance in epilepsy.

Twenty to thirty percent of people who develop epilepsy continue to have seizures despite antiepileptic drug (AED) treatment. The introduction of many new AEDs in the last two decades does not appear to have reduced substantially the proportion of people who are pharmacoresistant and continue to have seizures. Currently there are two main mechanisms suggested for pharmacoresistance in people with epilepsy: the transporter and target hypothesis. There are inadequacies in both these hypotheses and alternatives should be considered. There is accumulating evidence from animal studies, human physiological measurements and imaging studies that there is impaired mitochondrial energy production in the epileptogenic zone. Impaired mitochondrial function and lower bioenergetic state is associated with higher extracellular glutamate and increased neuronal hyperexcitability. Conversely, the ketogenic diet effective in reducing seizures, has been shown in animal studies to be associated with up-regulation of mitochondrial genes and increased mitochondrial biogenesis. A human imaging study has also shown improved cerebral energy metabolism in people on a ketogenic diet. Hence, the hypothesis is that the likelihood of seizures occurring results mainly from the interplay of three factors: the seizuregenic potential of the epileptic focus, the efficacy of AEDs and the efficiency of mitochondrial function. This hypothesis can be tested by comparing mitochondrial function in people with epilepsy who are pharmacoresistant with those who have become seizure free. The implication of the hypothesis is that the management of epilepsy should take account of the many drugs, toxins, nutrition and lifestyle factors that are known to affect mitochondrial function.

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.

Effects of AEDs on biomarkers in people with epilepsy: CRP, HbA1c and eGFR.

The standardised mortality ratio in people with epilepsy is raised to between 2 and 3 compared with the general population. Some biomarker levels, including higher C-reactive protein (CRP), higher glycosylated haemoglobin (HbA1c) and lower estimated glomerular filtration rate (eGFR), are associated with an increase risk of premature mortality. These biomarkers were measured in 125 people with refractory epilepsy to estimate the potential effect of antiepileptic drug (AED) use on these markers. Multiple regression analysis showed that valproate (N=50) use was associated with 55% lower mean CRP concentrations and higher mean eGFR values; and phenytoin (N=32) use with 4% lower mean HbA1c values. These potentially represent health markers improved by AEDs. On the other hand, lamotrigine use (N=48) was associated with 13% lower mean eGFR and this may represent a negative effect on a health marker. These preliminary observations clearly require further controlled studies ideally in people on AED monotherapy.

The long-term retention of pregabalin in a large cohort of patients with epilepsy at a tertiary referral centre.

Pregabalin (PGB) is a new antiepileptic drug (AED) which is a structural, non-functional analogue of gamma-aminobutyric acid. It acts at presynaptic calcium channels to modulate neurotransmitter release in the CNS. While the efficacy and tolerability of PGB have been demonstrated in several randomised controlled trials, few studies have addressed long-term outcome in large groups of patients. A cohort of patients attending a tertiary referral centre for epilepsy was identified as having started taking PGB. Patients' data were obtained through medical records. Of 402 patients included, 42% of patients were still taking PGB at last follow-up. The estimated 2.5-year retention rate was 32%. Males appeared more likely to continue on PGB therapy than females. The common adverse experiences (AEs) leading to withdrawal were CNS-related, psychiatric AEs and weight gain. Published retention rates for levetiracetam appear to be higher, and those for gabapentin lower, than the rates estimated for PGB.

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.

Low-grade chronic metabolic acidosis is a contributory mechanism in the development of chronic epilepsy.

In most people with epilepsy, the condition is readily controlled, but 20-30% develop chronic epilepsy. An estimated 80,000 patients with epilepsy require ongoing specialist care in the United Kingdom. Nutrition may be a factor in the development of chronic epilepsy. Modern Western diets are thought to produce a low-grade chronic metabolic acidosis. The hydrogen ion, H+, is a potent modulator of NMDA-activated currents, and in cultured neurons, increased external [H+] strongly suppresses these currents. The effect of chronic metabolic acidosis in vivo has not been fully studied. It is possible that low-grade chronic metabolic acidosis chronically inhibits the NMDA-activated currents, and this may lead to upregulation of the NMDA receptor. This would result in a greater hyperexcitable state and may contribute to the development of chronic epilepsy.

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.