Chapter 15 Epilepsy
With contribution from Dr Lily Tomas
Introduction
Epilepsy is a chronic neurological disorder that is characterised by recurrent and unprovoked seizures. The lifetime risk of developing epilepsy is 3.2% with more than of 90% of these cases having partial or localisation-related epilepsy. Despite the introduction of newer anti-epileptic drugs (AEDs), nearly 50% of patients with partial epilepsy will not attain a seizure remission with the use of medication.1, 2, 3 In fact, a recent UK study indicated that although 30 000 people develop epilepsy annually, only 6000 have medically refractory seizures.1 Adverse effects of antiepileptic drugs are a further major impediment to optimal dosing for seizure control.4 In the North American continent more than 3 million people have epilepsy.5
It is therefore easy to understand why at least 25–50% individuals with epilepsy have trialled some form of complementary and alternative medicine (CAM) therapy. Commonly used therapies include mind–body, dietary modification, nutritional and/or herbal supplementation, massage, homeopathy and acupuncture.6–9 It is important to note that many patients use CAM therapies without notifying their physician. Thus, it becomes the responsibility of the physician to actively inquire and then monitor therapies to ensure safety and effectiveness of combined CAM and traditional treatment.6, 10
In many instances, CAM therapies are not substitutes for traditional medications, however, depending on the effectiveness of the intervention(s), dosage reductions or cessation of medications under professional supervision may be possible.11
Lifestyle — general
Weight gain or loss is not an integral part of epilepsy although a sedentary lifestyle can contribute to weight gain. This is an important consideration because pharmacological treatment for epilepsy may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen.12
Sleep
The close relationship between the physiological state of sleep and the pathological process underlying epileptic seizures has been known for centuries, however, it is still not well understood secondary to its complexity.13 Individuals with epilepsy demonstrate multiple sleep abnormalities including increased sleep latency, fragmented sleep, increased awakenings and stage shifts and an increase in stages 1 and 2 of non-REM sleep.14
Indeed, sleep is one of the best documented factors influencing the expression of seizures and interictal discharges. Many seizures are potently activated by sleep or arousal from sleep.14, 15 In fact, seizures occur during sleep in nearly one-third of patients. It has also been demonstrated that non-REM sleep components generally promote, and REM sleep components generally suppress, seizure discharge propagation.16, 17 Sleep deprivation can also increase the frequency of epileptiform discharges and seizures.18, 19, 20 The effective treatment of sleep disorders can improve seizure control. Indeed, AEDs, use of ketogenic dietary principles and vagus nerve stimulation can all improve sleep quality, daytime alertness and neurocognitive function.18
Poor sleep can also be an adverse effect of some AEDs. This should be identified and rectified where possible as sleep disturbance exerts greater effect than short-term seizure control on quality of life scores of patients with epilepsy.4, 21
Mind–body medicine
The historical relationship between the study of epilepsy and religious experience suggests particular potential associations between CAM therapies (especially spiritual healing and care for those with epilepsy).22 Traditional healers still use spiritual healing, often in combination with special magical concoctions, in order to exorcise evil spirits in their treatment of epilepsy.23, 24
Meditation practices
A recent systematic review of various meditative practices (meditation, meditative prayer, yoga, relaxation) has demonstrated strong evidence for the efficacy of meditation in the treatment of epilepsy.25 Clinical studies have shown that transcendental meditation (TM), derived from ancient yogic teachings, may be a potential anti-epileptic treatment. However, TM may possibly also be a double-edged sword as many of the EEG recordings during TM (increased alpha, theta, gamma frequencies with increased coherence and synchrony) are similar to seizure activity, with neuronal hypersynchrony being a cardinal feature of epilepsy. More rigorous trials are needed to determine this.26
Cognitive behaviour therapy
Overall, the current evidence for cognitive behavioural therapy remains contentious as reported by a recent Cochrane review.27 The review reports that 2 trials found CBT to be effective in reducing depression, among people with epilepsy with a depressed affect, whilst another did not. Two trials of CBT found improvement in quality of life scores. One trial of group cognitive therapy found no significant effect on seizure frequency while another trial found statistically significant reduction in seizure frequency as well as in seizure index (product of seizure frequency and seizure duration in seconds) among participants treated with CBT.27
Relaxation therapy and biofeedback
Two trials of combined relaxation and behaviour therapy and 1 of EEG biofeedback and 4 of educational interventions did not provide sufficient information to assess their effect on seizure frequency.27 One small study of galvanic skin response biofeedback reported significant reduction in seizure frequency. Combined use of relaxation and behaviour modification was found beneficial for anxiety and adjustment in 1 study. In 1 study EEG biofeedback was found to improve the cognitive and motor functions in individuals with greatest seizure reduction.27
Sunshine
The long-term treatment with various anticonvulsants may result in hypocalcaemia, osteomalacia and osteopaenia independent from Vitamin D metabolism. Regional variances in the incidences of drug-induced bone disease has been attributed to differences in sunlight exposure, with most reports from areas of little sunshine or from institutionalised patients.28, 29
Environment
Toxins
Toxic causes of seizures are numerous and include alcohol and other substances of abuse, drugs, and industrial and household products. Epileptic seizures have been induced by occupational nickel and other heavy metal exposure.30 There is also a reduction in the threshold for seizures in animals whose blood contents of lead are similar to those of humans from some urban areas with high levels of air pollution.31
Diurnal and seasonal variations
Research on hospital admissions with status epilepticus reveals an important association with several environmental protective and precipitating factors. There is a significant diurnal pattern, with most admissions between 4–5 p.m. and least admissions in early morning hours. Admissions also vary significantly across the lunar cycle, peaking at day 3 after the new moon and being minimal 3 days before new moon. Admissions are greatest on bright, sunny days whereas dark days, high humidity and high temperature appear to be significantly protective factors.32
Physical activity
Exercise
Many people with epilepsy, especially those with uncontrolled seizures, live a sedentary life and have poor physical fitness.33 Despite a shift in medical recommendations towards encouraging rather than restricting exercise, epileptics often fear they may suffer with exercise-induced seizures.34 Although there are rare cases of exercise induced seizures, clinical and experimental data has shown that physical activity can decrease seizure frequency, as well as lead to improved cardiovascular and psychological health in patients with epilepsy.35, 36, 37 Indeed, regular physical exercise may have a moderate seizure-preventative effect in 30–40% of this population.33
Animal studies are currently investigating whether physical activity is beneficial for preventing or treating chronic temporal lobe epilepsy.38
The majority of sports, including contact sports, are safe to participate in. Water sports and swimming are also considered to be safe if seizures are well controlled and supervision is present. Sports such as hang-gliding and scuba diving are not recommended given the risk of severe injury or death if a seizure was to occur.36
However, as this patient group is highly heterogeneous, counselling regarding exercise should be individualised and take into account both seizure type and frequency.33
Yoga
Recent studies have shown that yoga can significantly reduce seizure index and increase quality of life in people with epilepsy.39 Yoga also significantly improves parasympathetic parameters, indicating that yoga may have a role as an adjuvant therapy in the treatment of autonomic dysfunction in patients with refractory epilepsy.40
Nutritional influences
Diets
Potentially beneficial dietary interventions should always include the identification and treatment of blood glucose dysregulation, the identification and elimination of allergenic foods and the avoidance of suspected triggers such as alcohol, artificial sweeteners, diet soft-drinks, energy drinks and MSG.11, 41, 42
Growth retardation is common amongst children with epilepsy and this appears to be primarily due to poor dietary intake. Approximately 30% of children with intractable epilepsy have been noted to have intakes below the recommended daily allowance (RDA) for Vitamins D, E and K, folate, calcium, linoleic acid and alpha-linolenic acid. It is the physician’s responsibility to be aware of this pattern of low nutrient intake and to educate families to provide an adequate diet or consider vitamin and mineral supplementation.43
Dietary treatments for epilepsy (ketogenic, modified Atkins, low glycaemic index diets) have been in continuous use since 1921. These dietary interventions have been well studied, with approximately 50% children having a 50% reduction in seizures after 6 months. Approximately one-third will attain >90% reduction in their seizures. It is important to note that the diet maintains its efficacy when provided continuously for several years. Furthermore, long-term benefits may be seen even when the diet is ceased after only a few months, indicating neuroprotective effects.44
Ketogenic diet (KD)
The KD is a high-fat, low-carbohydrate, high-protein diet used to treat medically refractory epilepsy.45 A recent RCT in children with refractory epilepsies showed that the KD was superior to continuation of medical treatment in reducing seizure frequency in this population. The KD has also been used successfully in a variety of epilepsy syndromes, such as Lennox-Gastaut syndrome.46 Despite nearly a century of use, however, the mechanisms underlying its clinical efficacy remain unknown.47 As the KD is effective in syndromes of various aetiologies, this suggests there are multiple mechanisms of action.45,46–53 It is beyond the scope of this chapter to discuss these in detail, however, 4 such hypotheses include the pH, metabolic, amino acid and the ketone hypotheses.54 The KD is principally high in fat, has adequate protein and is low in carbohydrates (no more than 4:1 ratio weight of fat: combined protein/carbohydrate).
Chronic ketosis is thought to modify the TCA cycle to increase GABA synthesis in the brain, limit ROS generation and boost energy production in brain tissue.47, 55 Acetone is the principal ketone body elevated in the KD with demonstrated robust anticonvulsant properties. Recent research has shown that acetone enhances the anticonvulsant effects of valproate, carbamazepine, lamotrigine and phenobarbital without affecting their pharmokinetic or side-effect profiles.56 Indeed, therapeutic indices in animal models are comparable to or better than those of valproate, a standard broad-spectrum anticonvulsant.57
At least 15–20% patients using the KD experience a >50% reduction in seizure frequency. For this reason, the KD should be considered as an early treatment for drug-resistant epilepsy, not only as a ‘last resort’.58, 59, 60 Unfortunately, 10–40% discontinue this strict diet secondary to a lack of response or adverse side-effects. Available data indicates that genetic factors are likely to affect the efficacy of this diet.61
A recent blinded cross-over trial involved children with Lennox-Gastaut syndrome placed on the KD with an addition of 60g glucose daily to negate the ketosis. This additional glucose did not significantly alter the frequency of EEG-assessed seizures, however, it did decrease the frequency of parent-reported ‘drop’ seizures during the follow-up period of 12 months. Fasting had significant effects on both seizures and EEG-assessed events.62
The efficacy of the KD develops over 1–3 weeks, suggesting that adaptive changes in gene expression are involved in its anticonvulsant effects.63 It has proven to be a valuable therapeutic option for children with drug-resistant focal epilepsy, particularly those with a recent deterioration of seizure control. Because of its rapid effects, the KD may also be a useful support to IV emergency drugs in such a situation.64
Modified Atkins diet
The modified Atkins diet is a less restrictive ketogenic diet which does not involve fasting and has no restrictions on calories, fluids or protein. The consumption of 10g/day of carbohydrates in children and 15g/day carbohydrates in adults is allowed whilst high fat foods are encouraged. Approximately 45% patients have 50–90% seizure reduction with 28% having >90% seizure reduction, results that are very similar to those produced by the KD.65 The KD appears to exert its seizure-reducing effects quicker than the modified Atkins diet, however, by 6 months the difference is no longer considered significant.59
Low glycaemic index diet (LGIT)
Children on the KD may exhibit poor weight gain and have lower blood glucose levels compared with children on standard balanced diets. One recent study reported on the efficacy, safety and tolerability of the LGIT in paediatric intractable epilepsy. Greater than 50% reduction from baseline seizure frequency was seen respectively in 42%, 50%, 54%, 64% and 66% of children at 1, 3, 6, 9 and 12 months. No significant changes were seen in BMI. Of the participants, 24% discontinued the LGIT secondary to its restrictiveness.66
Nutritional supplementation
Vitamins and minerals
Antioxidants
Neuronal hyperexcitability and excessive production of free radicals have been strongly implicated in the pathogenesis of idiopathic epilepsy. As such, there is a possible role of antioxidants as an adjunct to AEDs for better seizure control.67, 68, 69
The pro-oxidant/antioxidant balance is modulated by both seizure activity and by AEDs.67 Gingival hyperplasia is a side-effect of some of these drugs and appears secondary to increased oxidative stress. Studies reveal reduced levels of superoxide dismutase, glutathione peroxidase, glutathione reductase, ascorbic acid and alpha-tocopherol with elevated lipid peroxides in these patients.70 Oxidative stress after long-term treatment with valproate has only been found to occur in overweight children. This is important as it may contribute to endothelial dysfunction and atherosclerosis that is of increased incidence in the adult life of many people with epilepsy.71 Antioxidant markers are again increased when valproate is ceased.72, 73
Plasma and RBC levels of the antioxidants Vitamins A, C and E, superoxide dismutase, glutathione reductase and selenium are markedly lower in epileptic patients compared with controls. These levels improve with supplementation.74, 75
Anti-epileptic medications may also deplete total body selenium stores and failure to give appropriate Se supplementation, especially to pregnant women taking valproate, may increase the risk of neural tube defects or other free radical mediated damage.76
Alpha-tocopherol is the antioxidant most studied with respect to reducing frequency of epileptic activity in both animal models and humans. Results have thus far been mixed and more studies are required before definitive recommendations can be made.77–86
Selenium deficiency has also been implicated in the pathogenesis of epilepsy.87 Recent studies have shown that topiramate and Vitamin E have protective effects on pentylenetetrazol-induced (PTZ-induced) nephrotoxicity by inhibition of free radicals and support of the antioxidant redox system.88 Similarly, topiramate and selenium exert protective effects on PTZ-induced brain injury and blood toxicity by inhibiting free radical production, regulating calcium-dependent processes and supporting the antioxidant redox system.89, 87
Better regulation of the lipid peroxidation and antioxidants and fewer disturbances in mineral metabolism have been observed with patients on monotherapy vs polytherapy and with carbemazepine vs valproate therapy.90
Zinc
Zinc is a fundamental trace element present in high levels in many structures of the limbic circuitry. Altered zinc homeostasis appears to be associated with epilepsy, however, the definitive role of zinc as a neuromodulator in synapses is still uncertain.91–96 Intracellular zinc homeostasis is sensitive to pathophysiological environmental changes such as acidosis, inflammation and oxidative stress.97 Zinc itself can also induce oxidative stress by promoting mitochondrial and extra-mitochondrial production of reactive oxygen species.98 Studies have revealed that zinc chelation decreases the duration of behavioural seizures and electrical after-discharges and the duration of EEG spikes frequency.99
Animal studies reveal that zinc deficiency is associated with an increase in epileptic seizures and hippocampal cell death. This appears to happen through abnormal calcium metabolism.100, 101, 102
Other vitamins and minerals
Most AEDs reduce folic acid levels, thereby raising homocysteine (Hcy) levels. Hcy, however, is a convulsing agent resulting in heightened seizure recurrence and intractability to AEDs. Furthermore, AEDs can disturb lipid metabolism with subsequent hypercholesterolaemia and dyslipidaemia, with additional altered uric acid metabolism. As such, routine supplementation with folic acid, Vitamin B12, B6, C, E and beta-carotene for all those on AEDs becomes increasingly important.103
A recent Cochrane review has found that thiamine improves neuropsychological and cognitive functions in patients with epilepsy. In the same review, Vitamin D was found to improve bone mineral density in those taking AEDs. However, more trials are obviously needed.11, 77
A recent systematic review has demonstrated that manganese deficiency can also be accompanied by seizures in both animals and humans. As yet, it is unclear as to whether this is a cause or effect of the convulsions, justifying the need for more intensive research.104
Individuals with seizures may also have lower levels of vitamin A, B1, B12, C, folate, magnesium, selenium, zinc, carnitine, carnosine, choline and possibly serine. Furthermore, disorders of metabolism involving vitamin B6, D, calcium and tryptophan may play important roles.105 Seizure type and number of stimuli seem to be the determinant factors for changes in zinc, copper and magnesium levels.106, 107, 108 There has also been found a statistically significant increase in serum copper levels in patients with epilepsy compared with controls.109
Other supplements
Polyunsaturated fatty acids (PUFAs)
A higher dietary intake of PUFAs may be partially responsible for the potent anticonvulsant effects of the KD as concentrations of both ketone bodies and PUFAs have been found to be increased in the CSF and plasma of patients.2, 110 Animal studies have shown that increased intake of PUFAs may reduce the risk of epileptic seizures through various biochemical mechanisms, including PUFA-induced openings of voltage-gated potassium channels.2, 110 Omega-3 supplementation has also been shown to prevent status epilepticus-associated neuropathological changes in the hippocampus in animals.111
Some AEDs, such as carbemazepine, are known to decrease levels of long-chain omega-3 PUFAs, particularly DHA, and thereby increase the risk of cardiovascular events (arrhythmias, sudden unexplained death in epilepsy) in this population. Following 3 months of omega-3 supplementation (1g EPA/0.7g DHA daily), plasma and RBC levels increased significantly and patients taking carbemazepine (or not) exhibited a more favourable cardiovascular profile.112, 113, 114 Furthermore, omega-3 supplementation may be associated with reduced membrane phospholipid breakdown in the brain with an improvement in brain energy metabolism.115
Recent animal studies with Evening Primrose Oil (EPO) have conflicted previous thoughts that EPO could potentiate seizures. Rather, prolonged supplementation of linoleic acid and gamma-linolenic acid appears to exert anticonvulsant activity through various biochemical pathways.116 Nevertheless, more research is warranted to ensure the safety of EPO in epileptic patients.
Although PUFAs reduce seizures in several animal models, available data regarding the effects of supplementation with PUFAs (1–3g EPA/DHA daily) in epileptic patients reveal mixed results with respect to seizure frequency.114, 117, 118, 119, 120 Therefore, more research is required before PUFAs can be presented as a treatment option for epilepsy.2
Amino acids
Because of the high proportion of patients with drug-resistant epilepsy, new hypotheses about the mechanisms of pharmacoresistance are actively being researched. In particular, the role of brain serotonin in epilepsy has been turned upside down in recent years with current thoughts being that serotonin has an anti-epileptic effect. Serotonin receptors are expressed in almost all networks involved in epilepsies. Some SSRIs, such as Fluoxetine, have indeed improved seizure control and some AEDs have recently been found to increase endogenous serotonin levels.121, 122, 123
