Epilepsy

Epilepsy

1 Overview

Summary and Quick Facts

  • Epilepsy is a neurologic disorder denoted by the periodic occurrence of seizures; numerous types of epilepsy have been described. Approximately 3 million people experience epilepsy in the United States and there are 200,000 cases diagnosed each year.
  • In this protocol, you will learn how irregular electrical activity in the brain causes seizures, and how several variables influence neuronal excitability. You will also read about several novel and underutilized treatment strategies and scientifically studied natural compounds with the potential to modulate the overactive neural network of the epileptic brain.
  • Standard conventional treatments for epilepsy often rely on antiepileptic drugs (AEDs), which may need to be taken for many years. Many natural compounds also affect the brain and may be able to influence epilepsy; natural compounds will likely be most beneficial as adjuvants to conventional therapies.

What is Epilepsy?

Epilepsy is a neurological disorder characterized by the periodic occurrence of seizures—disruptions in electrical signaling in the brain. Disruptions can be due to several factors, including reactive oxygen species generated by the mitochondria.

There are many types of epilepsy, with seizures ranging from mild sensory disruptions to convulsions and unconsciousness. Epilepsy can be acquired from other health problems or can be idiopathic, meaning the cause is unknown.

Natural interventions such as coenzyme Q10 and magnesium may provide benefit for patients with epilepsy.

What are the Risk Factors for Epilepsy and Seizures?

  • Family history
  • Brain tumors
  • Brain trauma
  • Neurological diseases

Note: Seizures can be "triggered" by certain variables. Common triggers include:

  • Electrolyte imbalance/dehydration
  • Caffeine and other stimulants
  • Stress
  • Fatigue and lack of sleep
  • Certain foods
  • Low blood sugar

What are Signs and Symptoms of a Seizure?

  • Repetitive motions
  • Changes in breathing rate
  • Sudden lapse of consciousness
  • Hallucinations
  • Rhythmic twitching of muscles and/or generalized loss of muscle control
  • Some seizures also have a preliminary phase, called an aura. Patients who experience auras may be aware a seizure is imminent and can act to prevent it.

What are Conventional Medical Treatments for Epilepsy?

  • Antiepileptic drugs (AEDs)
    • Sodium channel blockers (eg, carbamazepine)
    • Calcium current inhibitors (eg, valproic acid)
    • Gamma-aminobutyric acid enhancers (eg, vigabatrin)
    • Glutamate blockers (eg, topiramate)
    • Carbonic anhydrase inhibitors (eg, acetazolamide)
    • Others (eg, levetiracetam)
  • Surgery
  • Vagal nerve stimulation
  • Deep brain stimulation
  • Transcranial magnetic stimulation

What are Emerging Therapies for Epilepsy?

  • Novel AEDs
  • Hormone therapy
  • People with epilepsy who do not respond well to AEDs may benefit from a biofeedback technique, where biological monitoring (eg, EEG readings) is used to help identify how their body responds to different situations.

What Dietary and Lifestyle Changes Can Be Beneficial for Epilepsy?

  • The ketogenic diet (or modified versions) can be effective at reducing the number of seizures.
  • Patients who experience auras can practice seizure interruption techniques, such as smelling something pleasant or changing mental imagery.
  • Manage stress effectively; try meditation or relaxation techniques.
  • Get enough good quality sleep.
  • Engage in a regular form of exercise.

What Natural Interventions May Be Beneficial for Epilepsy?

  • Vitamin D and calcium. Patients taking AEDs have lower levels of vitamin D, which is necessary for calcium absorption. Patients on AEDs may therefore be at increased risk of osteoporosis and should consider taking vitamin D and calcium supplements).
  • Magnesium. Magnesium deficiency is associated with seizures, as it acts as a natural calcium channel blocker similar to some AEDs. A form of magnesium, called magnesium-L-threonate, penetrates the brain effectively and may offer more protection for patients with epilepsy.
  • B vitamins. AED use may lower levels of some B vitamins (eg, folate, B6, and B12), raising homocysteine levels. This may place epileptics at a higher risk of heart disease. Certain seizure types are even directly linked to B6 deficiency.
  • Melatonin. Melatonin helps calm neural signaling and has been shown to be beneficial for patients with epilepsy.
  • As mitochondrial dysfunction may contribute to epileptic seizures, protectants such as coenzyme Q10 and pyrroloquinoline quinone (PQQ) may offer benefits.
  • Other natural interventions that may benefit epileptic patients include vitamins E and C, selenium, essential fatty acids, resveratrol, bacopa, and phytocannabinoids (eg, cannabidiol).

2 Introduction

Seizures, which are characterized by transient behavioral changes, are due to abnormal electrical activity within the brain. Epilepsy is a neurological disorder denoted by the periodic occurrence of seizures; numerous types of epilepsy have been described.

Approximately 3 million people experience epilepsy in the United States and there are 200,000 cases diagnosed each year. Epilepsy most commonly begins in children under the age of 2 or adults over the age of 65. Roughly 3% of the general population will experience epilepsy by age 75.1

Conventional treatment for epilepsy is primarily based on anti-epileptic drugs (AEDs), and often, epilepsy patients must endure significant clinical experimentation to find a regimen that works for them. Most importantly, not all patients will respond well to AEDs, either due to a lack of effectiveness or due to side effects.

Research has shed light on aspects of epilepsy that remain underappreciated by the conventional establishment. For example, special dietary regimens, such as the ketogenic diet, have the capacity to provide benefit for epilepsy patients and represent a potential adjuvant to mainstream therapies.

Moreover, magnesium is a well-known anticonvulsive agent, and studies show that magnesium deficiency is associated with epilepsy; intravenous magnesium can effectively control different types of seizures as well.2-4 However, the efficacy of supplemental magnesium has historically been limited in the context of conditions involving the central nervous system due to the inability of most types of magnesium to efficiently cross the blood-brain-barrier. Recently, though, scientists at the Massachusetts Institute of Technology developed a groundbreaking new form of supplemental magnesium, called magnesium-L-threonate, that elevates brain magnesium levels more than conventional types of magnesium.5

Other important contributors to epilepsy include oxidative stress and mitochondrial dysfunction.6 Recent evidence indicates that supplementation with mitochondrial protectants like ubiquinol (CoQ10) and pyrroloquinoline quinone (PQQ) can target these underlying pathological features of epilepsy and may complement the effects of conventional AEDs.7,8

In this protocol, you will learn how irregular electrical activity in the brain causes seizures, and how several variables influence neuronal excitability. You will also read about several novel and underutilized treatment strategies and scientifically-studied natural compounds with the potential to modulate the overactive neural network of the epileptic brain.

3 Background

Epileptic seizures range in severity from mild sensory disruption to a short period of staring or unconsciousness to convulsions. Seizures can manifest in a variety of symptoms, including repetitive motions, changes in breathing rate, flushing, sudden lapses in consciousness, hallucinations, rhythmic twitching of muscles or a generalized loss of muscle control.9

People with epilepsy have a substantially higher mortality rate than the general population. This is attributable to a phenomenon known as sudden unexplained death in epilepsy patients (SUDEP). SUDEP is unexpected and non-traumatic and occurs in approximately 1% of epileptics.10 It has no clear anatomical or toxicological cause, although it may be due to cardiac arrhythmias sometimes triggered by epileptic electrical activity. In the United States, SUDEP may account for 8% to 17% of all deaths in individuals with epilepsy, with greater incidence in younger individuals. Major risk factors for SUDEP include epilepsy occurring earlier in life, lying in bed in a face down position, having poorly controlled epilepsy, and being male. In fact, the male-to-female ratio can be as high as 1.75:1.11 One of the most important things that epileptics can do to lower their risk of SUDEP is to improve the control of their disease, which for many patients can be achieved by changing their diet and taking supplements in addition to taking their AEDs. Sleeping on your back may also lower your risk of SUDEP.12

4 Neurobiology of Epilepsy

The brain contains billions of neurons, which are in constant communication with one another. During nerve cell signaling, or "firing," chemicals called neurotransmitters are released into the space between neurons (synapse) to carry the signal. Neurotransmitters influence the action of neurons, either by triggering (exciting) or discouraging (inhibiting) a neuron's firing. The firing of neurons is mediated by electrical signals; as a result, abnormal electrical activity can cause uncontrolled neuron firing, leading to seizures.

Epileptic seizures are caused by a disruption in electrical activity among neurons in the cerebral cortex, the most highly developed part of the human brain. Comprising about two-thirds of the brain's mass, the cortex is responsible for thinking, perception and the production and understanding of language. The cortex is also responsible for processing and interpreting the five senses.

The nervous system has two major divisions: the central nervous system and the peripheral nervous system. The central nervous system consists of the brain and the spinal cord. The peripheral nervous system also has two parts: the somatic nervous system and the autonomic nervous system (which is further divided into three parts: sympathetic, parasympathetic, and enteric). The autonomic nervous system exercises control over automatic or involuntary functions in the body, such as heart rate and respiration, among others. Although seizures emanate from the brain, there is a complex interaction between the autonomic nervous system and the central nervous system with regard to seizures.

Some seizures have a preliminary phase, known as an aura. An aura is a brief electrical discharge in the brain that can alert a person with epilepsy that a larger seizure is imminent. Epilepsy auras can range from a nonspecific strange or peculiar sensation to feelings of extreme fear or euphoria to the experience of strange lights or strange sounds. (Epilepsy auras are different from migraine headache auras.) The auras are actually small focal seizures that do not affect consciousness. Researchers have also developed techniques that allow them to identify the type of brain activity that occurs in auras in the hopes of learning more about how these focal electrical disturbances contribute to more generalized seizure activity.13

5 Causes of Epilepsy and Common Seizure Triggers

There are multiple different health problems that can cause epilepsy. For example, brain tumors, either benign or malignant, brain trauma, autoimmune irregularities, and neurological diseases such as stroke and Alzheimer's can lead to seizures.14 These represent forms of epilepsy that are acquired and have a distinct cause.

Idiopathic epilepsy describes epilepsies with no identifiable cause. Genetics are thought to play a role in many cases of idiopathic epilepsy, as close relatives of an epileptic are five times as likely to develop epilepsy themselves.15

In susceptible individuals, seizures can be precipitated by the presence of certain factors referred to as triggers, which include low blood sugar (hypoglycemia), dehydration, fatigue, lack of sleep, stress, extreme heat or cold, depression, and flashing or flickering lights. Food and environmental sensitivities may trigger seizures in some people.

Electrolyte Imbalances

Electrolytes are minerals, such as sodium and potassium, which have an electrical charge when dissolved in the body's fluids. The human brain relies on these minerals to generate the electrical currents needed for neurons to function and communicate. Consequently, alterations in the levels of these electrolytes can severely affect the electrical activity in the brain and trigger seizures in epileptics. Diminished sodium levels (hyponatremia) were associated with increased frequency of seizures in a cross-sectional study of 363 patients in a county hospital.16 New onset epileptic seizures in a 54-year-old woman who consumed a large amount of a soft drink were described in a case report; her seizures were attributed to a sudden drop in sodium levels due to excessive fluid consumption.17 Magnesium and calcium deficiencies can also trigger or exacerbate seizures in epileptics.18

Hormone Imbalances

Hormone imbalances may play a role in epilepsy. Female epileptics often have an exacerbation of their condition at specific points during their menstrual cycle, which is sometimes called catamenial epilepsy. Seizures in women often increase during periods of low progesterone.19 Research has found that estrogen increases neuronal excitability and progesterone reduces neuronal activity, which suggests that an imbalance between estrogen and progesterone could increase seizure frequency.20 Lower progesterone levels are also associated with more frequent seizures in women, and elevated estrogen levels during perimenopause also appear to exacerbate epilepsy.21,22

Caffeine and Methylxanthines

Methylxanthines, including caffeine, are a family of natural stimulants that can be found in many foods and beverages, including coffee, tea, and chocolate. Methylxanthines increase activity in the central nervous system and can increase the excitability of neurons. There have been case reports of increasing seizure frequency, even in patients with formerly well-controlled epilepsy, following heavy coffee consumption. In one case, four cups of coffee a day was associated with an increase in seizure frequency from two per month to several per week, and in another, five to six cups daily caused two seizures in a month in a young epileptic with well-controlled epilepsy.23-25 Experimental models indicate that caffeine lowers the seizure threshold, thus making AEDs less effective.26 After thoroughly reviewing the available evidence and conducting some animal model experiments, one group of investigators said that "the existing clinical data confirm the experimental results in that caffeine intake in epileptic patients results in increased seizure frequency. It may be concluded that epileptic patients should limit their daily intake of caffeine."27

Stress

A 2003 study revealed that emotional stress exacerbated seizures in 64% of epileptics.28 Other studies have corroborated these findings.29,30 Similarly, fatigue and a lack of sleep can also trigger seizures.31,32

Reactive Oxygen Species

Free radicals may play a role in epilepsy.33,34 These compounds have the ability to damage proteins, DNA and the membranes of cells, potentially causing neurons to fire erratically leading to a seizure. Many factors can induce production of free radicals, including head trauma and neurodegenerative diseases as well as normal cellular metabolism.35 Mitochondria, the cellular energy cores in which adenosine triphosphate (ATP) production takes place, are the primary source of free radicals within the body. As we age, the efficiency and integrity of these vital organelles begins to falter, leading to increasing oxidative stress and cellular deterioration. With regard to epilepsy, a relevant consequence of age-related mitochondrial dysfunction is cellular membrane damage, which can impair cellular communication, potentially leading to seizures. Indeed, experimental models indicate that animals genetically prone to a poor ability to quench mitochondrial free radicals are more likely to have seizures than normal animals.36 Moreover, in humans, heritable defects in the mitochondrial genome cause a subclass of epilepsy called mitochondrial epilepsy.6

Mitochondrial energy metabolism can be targeted with some natural compounds; in particular, coenzyme Q10 (CoQ10) and pyrroloquinoline quinone (PQQ). Studies indicate that both of these nutrients quell mitochondrial oxidative stress and promote overall mitochondrial vigor; PQQ even stimulates the growth of new mitochondria via a process called mitochondrial biogenesis.8,37 In a well-designed animal model, researchers recently showed that CoQ10 reduced the severity of seizures and quelled the seizure-induced increase in oxidative stress that is responsible for epilepsy-related neuronal damage. Most important, CoQ10 augmented the effects of phenytoin, a conventional AED, and spared cognitive function in rats that had seizures.7 In other words, when seizure-prone animals were given CoQ10 plus phenytoin, their seizures were less severe than in animals receiving the AED alone.

Aspartame

Phenylalanine, a metabolite of aspartame, can be neurotoxic at high concentrations. Therefore, it is plausible that very high doses of aspartame may trigger seizures, though this has not been observed in controlled clinical studies. In a study of people who anecdotally reported that aspartame triggered their seizures, no seizures were produced under controlled conditions of aspartame exposure.38 Another study of children with a particular type of seizure called petit mal seizures, however, did demonstrate changes in brain electrical activity after very high oral doses of aspartame, though none of the subjects had an actual seizure.39 In this study, the dose administered was 40 mg/kg, or about 2,800 mg for a 70 kg (154 lb.) human. For perspective, a can of diet soda typically contains about 180 mg of aspartame; therefore, the dose of aspartame administered to the children in the study was equivalent to over 15 cans of diet soda for an adult. In contrast, an intensive review published in 2002 found that there was no conclusive scientific evidence linking aspartame to epilepsy.40

Similarly, the food additive monosodium glutamate (MSG) has been alleged to cause seizures. However, evidence implicating the amounts of MSG commonly encountered in food in the pathology of seizures is primarily, though not exclusively, anecdotal in nature. Monosodium glutamate can indeed induce seizures in animal models, but the dose required is equivalent to several thousand grams of MSG for a grown human—a dose highly unlikely to be attainable through dietary means alone. Nonetheless, some older reports suggest that MSG might lower seizure threshold in sensitive children.41

Even though peer-reviewed evidence that directly implicates these dietary excitotoxins in necessarily triggering seizures among adult humans is lacking, some innovative doctors have noted substantial, though anecdotal, benefit when their seizure patients have been advised to carefully avoid food containing MSG. Therefore, it may be prudent for seizure patients, especially children, to avoid ingestion of aspartame and MSG.

Environmental Toxins

Many environmental toxins, including some pesticides and heavy metals, are known to trigger seizures. For instance, mercury and lead are associated with seizures.42-44 For more information on the health impact of heavy metals, refer to the "Heavy Metal Detoxification" protocol. Also, insecticides known as organophosphates increase brain activity and can cause seizures.45,46 Additional information is available in the "Metabolic Detoxification" protocol.

6 Diagnosis

Epilepsy is usually diagnosed on the basis of a combination of clinical findings, including patient history, physical examination, and laboratory testing. During an office visit, a patient will typically undergo a standard neurological examination, which includes evaluation of orientation, reflexes, motor control, nerve function, coordination, and sensory perception. It is often helpful for a physician to examine the person as soon after seizure activity as possible.

The most common diagnostic test to detect epilepsy is the electroencephalogram (EEG), which monitors electrical activity in the brain. However, brain activity may be normal between seizures, so a normal EEG does not rule out a diagnosis of epilepsy. Other brain imaging studies, including magnetic resonance imaging (MRI) and computed tomography (CT) scanning, are sometimes used to identify physical causes of seizures, such as tumors or malformations in the brain's vasculature (aneurysms).

7 Conventional Treatments

Anti-Epileptic Drugs (AEDs)

Standard conventional treatments for epilepsy often rely on AEDs, which may need to be taken for many years. AEDs are grouped by their mechanism of action (many of the drugs listed below have multiple mechanisms of action):

  • sodium channel blockers (carbamazepine [Tegretol, Carbatrol]; lamotrigine [Lamictal]; phenytoin [Dilantin]);
  • calcium current inhibitors (valproic acid [Depakene, Depakote]);
  • gamma-aminobutyric acid enhancers (vigabatrin [Sabril]; benzodiazepines, barbituates);
  • glutamate blockers (topiramate [Topamax], also targets sodium channels);
  • carbonic anhydrase inhibitors (acetazolamide [Diamox]); and
  • those with unknown mechanisms (levetiracetam [Keppra])

Drug selection is based on clinical diagnosis as well as characteristics of the AED and its side effects. The choice of drug also depends on the personal preferences and experiences of the treating physician as well as the clinical context (eg, in an emergency room, intravenous administration would be a typical approach). Sometimes the type of epilepsy can also guide the choice of drug. For example, the medication valproic acid is often more effective in treating generalized epilepsy than other AEDs.47 On the other hand, ethosuximide (Zarontin), another AED, is sometimes more effective for absence seizures. In an outpatient setting, many choices are available.

The optimal treatment outcome is complete cessation of seizures with one AED, also known as monotherapy. In general, almost 50% of adult patients and 66% of pediatric patients will become seizure free with the first drug that they try.48,49 If the first AED fails or causes intolerable side effects, another one can be selected; many physicians will opt for an AED with a different mechanism of action. If the first AED fails because of intolerable side effects, a second trial of AEDs will be successful in approximately 50% of patients; however, in patients for whom the first drug was not effective, a second AED will be effective less than 15% of the time.50

When successful seizure control with monotherapy cannot be achieved, other AEDs are added to the treatment regimen. Polypharmacy (the use of multiple AEDs for epilepsy) is based on a combination of the various known mechanisms of action.51 Each medication should be titrated upward in dosage until either seizures are eradicated or side effects become intolerable. Certain individuals with intractable seizures can be treated with as many as four different AEDs concomitantly.

Most AEDs have some side effects that can be intolerable for patients. As a result, although AED therapy is one of the mainstays of epilepsy treatment, other options may provide significant relief with fewer or milder side effects. In most instances, careful blood monitoring must be performed to determine the blood levels of each AED especially when a patient is taking multiple AEDs or other pharmaceuticals that alter metabolism.

Surgical Intervention

Surgery for epilepsy is a very highly specialized operation and is typically reserved for patients who do not respond well to AEDs. It should be performed only by the most experienced teams of neurosurgeons, epileptologists (neurologists specializing in epilepsy), and other physicians in major academic centers. Successful surgery for epilepsy is dependent on finding a "focal lesion," an abnormality that can be seen on a radiological imaging scan. Common examples of focal lesions include masses; less common focal lesions include scars or fibrosis. The best surgical outcomes occur in individuals who have a diagnosis of temporal lobe epilepsy, a well-circumscribed focal lesion, or abnormal EEG data that are focal in nature to match the imaging abnormality.

In these cases, the success rate, defined as patients that become seizure-free, ranges from 80% to 90%. For individuals who do not have matching lesions on EEG and imaging, the success rate falls to about 50% (still considered favorable). Complications are few and insignificant compared to the improved quality of life as a result of seizure reduction.52 However, surgery is not the only procedure that can provide significant relief for epileptics.

Other Neurological Procedures

Vagal nerve stimulation. The vagus nerve, which relays information to and from the brain, has many connections to neurological areas that are instrumental in seizures. Vagal nerve stimulation (VNS) is the only form of electrical treatment for epilepsy approved by the United States Food and Drug Administration (FDA). VNS was approved by the FDA in July 1997 as an adjunctive treatment for partial-type seizures in adults and adolescents older than 12 who did not respond well to AEDs. In VNS, a small electrical device, about the size of a pocket watch, is implanted under the skin along with a connecting wire in the left upper chest area. Small leads are attached to the vagus nerve on the left side of the neck. The implantation takes about two hours. After implantation, the stimulator device is programmed to deliver electrical stimulation automatically 24 hours a day (usually every few minutes).53

Not only can VNS reduce the severity and frequency of seizures, but it can also abort a seizure after it starts. Although the mechanism of VNS therapy is still unclear, researchers think that it is able to increase inhibitory signals in the brain, helping to prevent the electrical activity that leads to seizures. VNS has been found to be safe and effective. Patients that have their seizure frequency reduced by 50% or more are classified as "responders." With long term use, between 50% and 80% of patients who receive VNS treatment will become responders, depending on the seizure type.54-58 Reduction of AED use was reported in 43% of patients following VNS for intractable epilepsy, and subjective improvement in quality of life occurred in 84%.59

Deep brain stimulation. Deep brain stimulation (DBS) is another novel therapy that may provide significant benefits for epileptics. This treatment involves the placement of electrodes in the brain using minimally invasive surgery that can then be used to send mild electrical currents to particular regions of the brain, such as the thalamus, the cerebellum and other deep regions in the brain. This technique was initially developed in the 1980s as a way to reduce tremors in patients with Parkinson's disease and has gained support for treating other movement disorders, such as dyskinesia. Its effects on these other neurological issues have spurred interest using DBS to treat epilepsy.60-62

Early clinical studies on DBS have found that it is generally safe, with the adverse effects being transient and mild. Some patients have experienced side effects such as episodic nystagmus (uncontrollable eye movements), auditory hallucinations, and lethargy.61 However, one of the advantages of DBS is that it can be switched off if side effects appear and the entire procedure is reversible. Early results from multiple clinical trials of DBS have found that it can reduce seizures in a significant portion of patients, depending on its placement.63

Transcranial magnetic stimulation. Transcranial magnetic stimulation is a noninvasive technique that uses electromagnetic currents to alter the electrical activity in the brain. This therapy has shown great promise for reducing seizures in epileptics by reducing neuronal excitability. Some of the earliest studies found that transcranial magnetic stimulation can induce a prolonged period of protection from the types of electrical activity that cause seizures.64 Case studies have found that this technique can reduce seizure frequency by over 60% in patients.65 The most serious side effect associated with transcranial magnetic stimulation is a headache, though there is a small risk of seizure during this treatment.66 However, this risk is low and this technique is considered to be safe; in addition, as transcranial magnetic stimulation technology advances and is combined with EEGs, this therapy can be used in a more targeted and safer way.67

8 Novel and Emerging Strategies

The pharmaceutical industry continues to make new AEDs to provide additional options for controlling epilepsy while also minimizing side effects. One new AED, known as levetiracetam, has recently been approved for monotherapy. Though the specific mechanisms are unclear, levetiracetam works by inhibiting synaptic conductance in ways different than traditional AEDs, so it may be effective for the treatment of epilepsies that have not responded well to other medications.68 Other novel AEDs are only approved for adjunctive treatment, which means they can be added onto already existing drug regimens. Three of the newest AEDs that are approved for adjunctive therapy are eslicarbazepine acetate, lacosamide, and retigabine.

Eslicarbazepine acetate works using a similar mechanism to an already established AED, carbamazepine, but it has less neurotoxicity.69,70 Eslicarbazepine also has fewer reported side effects than a similar AED, oxcarbazepine and can be taken once per day. As a result, eslicarbazepine acetate is being used as an additional AED for patients who do not have adequate control of their epilepsy with other medications.71 Another recently developed AED is lacosamide.49 This drug has been shown to reduce electrical seizure activity in the brain without affecting other aspects of brain function.72 Lacosamide works on a different part of neurons than other AEDs, so its novel mechanism may allow it to be more effective in patients that have not responded well to other AEDs.73,74 Similarly, the new medication retigabine also has a different mechanism than other AEDs and so it can be added onto the treatment regimens of epileptics who are still having frequent seizures with less of a concern of impaired effectiveness.75

Together, these new medications, as well as other new drugs like stiripentol (Diacomit) and rufinamide (Banzel), have the potential to treat previously intractable cases of epilepsy or to reduce side effects. Some researchers have also noted that diuretics, such as furosemide and bumetanide, may also be able to reduce seizures by affecting the levels of water and ions in the brain.76 Although there have not been any recent clinical studies of the effects of diuretics on epilepsy, studies examining the effects of these medications in tissue and animal models of epilepsy have been promising, and one small clinical study published in 1976 found that diuretics were able to significantly reduce seizure frequency in some patients.77

Hormone Restoration Therapy

Progesterone restoration therapy has been studied as a possible treatment of epilepsy and initial results have been promising.78 The effects of hormones on epilepsy still needs to be better elucidated, as some studies have suggested that estrogen can have pro-epileptic and anti-epileptic properties, depending on its levels.79 Women are not the only patients that can have their epilepsy affected by sex hormone levels; testosterone and its metabolites also have anti-seizure effects.80,81 Indeed, in a case report of a man with posttraumatic seizures, testosterone therapy caused his seizures to lessen and nearly disappear.82 These findings suggest maintaining optimal testosterone levels may ameliorate seizure disorders in men. Free testosterone is a good indicator of testosterone activity; optimal levels are 20–25 pg/mL.

For more information about hormone testing and hormone replacement, refer to the "Male Hormone Restoration" and "Female Hormone Restoration" protocols.

9 Dietary Management: The Ketogenic Diet and Others

The idea that diet can affect epilepsy was first postulated by Hippocrates, who noticed that fasting could prevent convulsions.83 Currently there are four different dietary treatments that can be used for epilepsy: the ketogenic, medium chain triglyceride, modified Atkins, and low-glycemic index diets.

The most widely used dietary treatment for epilepsy is the ketogenic diet. The ketogenic consists of high intake of fats (80%) and low intake of protein and carbohydrates; it was developed in the 1920s.84,85 The ketogenic diet requires patients to be very careful about what they eat for it to be effective.86,87

The ketogenic diet is carefully designed so that fats, primarily in the form of long-chain fatty acids, provide the main source of calories in the diet. Patients typically need to consume three to four times as much fat by weight compared to carbohydrates and proteins; this means that with this diet, over 90% of the calories come from fat. This high fat diet changes the body's metabolism, causing it to generate chemicals known as ketones, which can then be burned for energy. This diet is also designed to provide approximately 1 gram of protein for every kg of body weight to ensure adequate protein intake. The ketogenic diet typically begins with a brief fasting period, though this is not necessary and is often based on the clinician's preferences.88

The way that the ketogenic diet prevents seizure is still under investigation. One of the prevailing theories is that the ketones produced by the diet are able to enter into the brain. From there, the ketones are able to increase the levels of chemicals that decrease neuron activity, reduce levels of reactive oxygen species and make the brain use energy more efficiently, resulting in fewer seizures.88,89

The ketogenic diet has consistently been proven to be an effective treatment for epilepsy. Reviews have found that over 50% of children undergoing the ketogenic diet have a greater than 50% reduction in their seizure frequency, with over 30% experiencing a decrease in seizure frequency of over 90% and more than 15% becoming completely seizure free.90 These numbers are even greater for children that maintain the ketogenic diet for three months: over half of the children have their seizures reduced by 90% or more and over 30% become completely seizure free.91 The benefits of the ketogenic diet have also been confirmed by the randomized control trial, which is the most rigorous of clinical trials.92

Although the ketogenic diet has traditionally been recommended for children, it may also be used with great success in adolescents and adults. Clinical studies examining the effects of the ketogenic diet on older patients have shown that the diet can produce a significant reduction in seizure frequency in this population as well.93-95 One of the main obstacles for adolescents and adults trying the ketogenic diet is patient compliance, because the diet can be so restrictive. As a result, multiple similar diets have also been designed to try to take advantage of the concept behind the ketogenic diet without significantly reducing its effectiveness. The medium chain triglyceride diet is based on the idea that shorter fat molecules, such as medium-chain triglycerides, produce more ketones and thus allow for more protein and carbohydrate in the diet. Other diet plans, including the modified Atkins Diet and the low-glycemic index treatment, have also been developed to allow more flexibility. The Modified Atkins Diet allows for 10‒30 grams of carbohydrates each day and has no restrictions on protein or caloric intake. The Low-Glycemic Index Treatment allows a higher amount of carbohydrates (40‒60 grams per day) as long as they have a glycemic index of less than 50. Both of these modified ketogenic diets have also proven beneficial in the treatment of epilepsy.96

The ketogenic diet and related metabolic treatments for epilepsy can cause some side effects and nutritional deficiencies. The most common side effects are gastrointestinal issues, such as diarrhea, constipation, nausea, vomiting and increases acid reflux.

This diet can also raise the levels of cholesterol and other lipids in the blood. Patients undergoing the ketogenic diet may also have an increased risk of a vitamin D deficiency, leading to reduced bone strength, as well as kidney stones, selenium deficiency and increased bruising. As a result, vitamin supplementation and careful monitoring may be needed during the ketogenic diet.97-101

10 Lifestyle Modifications

Seizure Interruptions

Although auras do not occur in all individuals with seizure disorders, some people are aware of a change in their sensory perception (whether auditory, olfactory, sensory, visual, or gustatory, sometimes involving malaise, vertigo, or the sense of deja vu) that signals the onset of a seizure. Anecdotal reports indicate that some people have learned to interrupt their seizure process by replacing the aura-induced perception with another. In these individuals, the aura is a known signal of seizure onset. For example, if the aura is a smell or unpleasant odor, these individuals can often interrupt the seizure by immediately smelling something else (in general, something with a more pleasing smell than the aura).

Some people are able to take the interruption technique a step further. By simply relying on mental imagery (eg, remembering a pleasant, positive smell), they can arrest a seizure. Some find that anger can effectively interrupt a seizure; they are able to arrest their seizures by yelling at them. Other individuals who have seizures with an observable onset pattern enlist a support person to shout at them or give them a quick shake when the pattern commences. The techniques that successfully "interrupt" an aura vary from patient to patient and must be performed at a specific time to stop the seizure.102 However, the use of aura interruption may be able to help reduce or eliminate seizures.103

Stress Reduction

Getting a good night's sleep on a regular basis is a very important component of seizure prevention. Some scientists hypothesize that one major function of REM sleep is to reduce the brain's susceptibility to epileptogenic influences.104 Stress reduction and relaxation techniques such as meditation may also aid in reducing seizures.105

Physical exercise can also be an important way to relieve stress that may be particularly beneficial for epileptics. Not only can exercise reduce stress, improve social integration and improve quality of life, regular physical exercise may directly help reduce seizure frequency.106 Physical exercise may "desensitize" neurons to emotional stress, helping avert seizures brought on by other triggers.107

Biofeedback

Biofeedback, another relaxation technique, can also be helpful. When the autonomic nervous system (or the involuntary nervous system) is in a state of overarousal, the likelihood of seizure activity can increase. Biofeedback is a technique that uses displays of some form of biological monitoring, such as an EEG, to help patients identify how their body responds to certain situations. By observing changes in EEG readings, patients are able to learn how to partially control the electrical activity in their brains and can develop the ability to reduce their risk of having seizures. Although most clinical trials involving biofeedback have been small,108-110 a comprehensive review of many studies found that biofeedback can provide significant relief for epileptics, particularly those that have not had success with AEDs.111 On average, almost 75% of people who try EEG biofeedback for epilepsy will experience fewer seizures. Biofeedback using other biologic responses, such as slow cortical potential feedback and galvanic skin response has also been promising.112

Other behavioral interventions may reduce seizure frequency as well. Yoga can improve quality of life and result in fewer seizures.113,114 Acupuncturemay also be helpful in seizure prevention. A thorough review of published trials found that acupuncture may be beneficial, but that more and better designed studies need to be done.115 Studies of the benefits of other relaxation techniques and cognitive behavioral therapy have also found a possible benefit.116

11 Natural and Complementary Therapies

Many natural compounds also affect the brain and may be able to influence epilepsy; natural compounds will likely be most beneficial as adjuvants to conventional therapies.

Vitamins and Minerals

Epilepsy patients should also be aware that long-term use of AEDs can negatively affect their vitamin and mineral status. For instance, patients taking AEDs have significantly lower levels of vitamin D in their blood.117-121 This is because many AEDs increase the activity of a liver enzyme known as cytochrome P450, which also breaks down vitamin D. Vitamin D is essential for the absorption of calcium; consequently, patients taking AEDS absorb less calcium in their diet, which increases their risk of developing osteoporosis. Patients who are taking AEDs may need to take vitamin D and calcium supplements.122

AEDs have also been shown to reduce levels of several B vitamins, including folate and vitamins B6 and B12.123,124 These vitamins are critical for controlling metabolism in the body; low levels of these vitamins can also lead to low red blood cell levels, causing fatigue and pallor. One of the most serious consequences of the low folate levels caused by AEDs is high levels of the compound homocysteine, a risk factor for heart disease.123,125,126 Elevated levels of homocysteine have been implicated in the increased risk of heart disease seen in epileptics. Moreover, some studies have indicated that elevated homocysteine may contribute to AED resistance or increase seizures in epileptics.127 Based on these findings, some researchers call for routine supplementation with the B vitamins, especially the metabolically active form of folic acid, L-methylfolate, to reduce homocysteine levels.128 Folate deficiencies can also lead to seizures, particularly in infants. Impaired folate transport in the body can be a cause of seizures that do not respond well to typical treatments.129 In addition, epileptics often have reduced folic acid levels, possibly due to the use of AEDs.130 Doctors of epileptics should routinely monitor folic acid, vitamin B12 and homocysteine levels in patients to help prevent an increased risk of cardiovascular disease that could otherwise be treated.

Some forms of epilepsy are directly linked to vitamin B6 deficiencies; these convulsions, known as pyridoxine-dependent seizures, can only be treated with high doses of vitamin B6.131 Low vitamin B6 levels are also associated with general epilepsy. Even in patients without pyridoxine-dependent seizures, low levels of pyridoxine might increase seizure sensitivity, although more research needs to be done to determine if pyridoxine can treat seizures.132 Some types of seizures cannot be treated with pyridoxine, but they can be effectively managed with pyridoxal-5-phosphate, the biologically active form of vitamin B6.133-135

Antioxidants, such as vitamin E, vitamin C and selenium are able to mitigate mitochondrial oxidative stress in the brain and other tissues, lowering seizure frequency in various types of epilepsy.136-142 Animal models have shown that alpha-tocopherol alone is able to prevent several types of seizures.143,144 Epileptics are also more likely to have low vitamin E levels, though this may be a result of taking AEDs.145

Magnesium helps maintain connections between neurons. It has been shown to suppress EEG activity and limit seizure severity in animal models, and magnesium deficiency is associated with seizures in humans.146-148 Within the body, ionic magnesium acts as a natural calcium channel blocker, offsetting the excitatory influence of ionic calcium in a manner similar to the calcium channel blocker class of conventional AEDs.149 Moreover, magnesium levels decline sharply following seizures in patients with idiopathic epilepsy.150 In fact, intravenous or intramuscular magnesium is often administered to women to safely prevent eclampsia, a pregnancy-associated disorder characterized by seizures.151

A recently developed form of magnesium, known as magnesium-L-threonate, may be particularly effective in epilepsy and other neurological disorders. This form of magnesium appears to be better at penetrating the blood-brain barrier and thus is more efficiently delivered to brain cells.152,153 In fact, in an animal model, magnesium-L-threonate boosted magnesium levels in spinal fluid by an impressive 15% compared to virtually no increase with conventional magnesium. Moreover, oral magnesium-L-threonate was able to modulate learning and memory, indicating that it does indeed impact the central nervous system.153

Thiamine, manganese, and biotin are often low in epileptics as well.132

Melatonin

Melatonin plays an important role in the brain, particularly in regulating the brain's sleep-wake cycle. It also exerts a calming effect at the neuronal level by reducing glutaminergic (excitatory) signaling and augmenting GABAergic (inhibitory) signaling.154 Melatonin is widely used as a sleep aid and to treat jet lag; the side effects of taking melatonin are mild and it is one of the most commonly used supplements in the United States. Animal models have shown that melatonin can be effective in reducing epileptic seizures.155,156 Melatonin has also been beneficial in humans with epilepsy and is particularly effective in the treatment of cases of juvenile epilepsy that do not respond well to AEDs.154 Due to its widespread use and minimal side effects, melatonin has potential to improve control of epilepsy.157

Polyunsaturated Fatty Acids

Polyunsaturated fatty acids (PUFAs), such as omega-3 fatty acids, are a type of essential fat that play an important role in maintaining central nervous system health. Animal studies have suggested that PUFAs, including omega-3 and some omega-6 fatty acids, may be able to modulate neuronal excitability.158,159 This is further supported by the fact that children on the ketogenic diet often have higher levels of PUFAs in their cerebrospinal fluid, which suggests that increased PUFA levels is one of the ways that the ketogenic diet prevents seizures.160,161 Clinical trials in adults have yielded mixed results. In one such study, 57 epileptic patients were given 1 gram of eicosapentaenoic acid (EPA) and 0.7 grams of docosahexaenoic acid (DHA) daily. Seizure activity was reduced over the first six weeks, although the effect was temporary. The researchers called for more in-depth studies, with larger doses and larger observational groups.162 However, a randomized controlled trial did not find that fish oil reduced seizure frequency; although, the study did find, that PUFAs reduced seizures when administered in an open-label format, meaning when subjects knew that they were not receiving a placebo.163 An ongoing National Institutes of Health-sponsored trial is examining the effects of fish oil on cardiac health in epileptics.164

Life Extension suggests that the omega-6 to omega-3 ratio should be kept below 4 to 1 for optimal health. More information on testing and optimizing your omega-6 to omega-3 ratio can be found in the Life Extension Magazine article entitled "Optimize Your Omega-3 Status."

Resveratrol and Bacopa Monnieri

Resveratrol, derived from red grapes and Japanese knotweed (Polygonum cuspidatum), and the plant Bacopa monnieri both appear to be promising in the management of seizure-related neurotoxicity. Resveratrol and bacopa-derived compounds have been extensively studied in experimental settings and consistently shown to guard against neuronal damage.165-168 In the context of epilepsy, numerous mechanisms by which resveratrol might prevent seizures have been proposed,169 and, indeed, in an animal model resveratrol prevented chemical-induced seizures170; though studies on epileptic humans have yet to be performed. Likewise, bacopa has been the subject of several animal model experiments, many of which have revealed a clear benefit relating to seizure frequency and post-seizure brain cell damage.171-173 Nonetheless, bacopa also has yet to be studied in a controlled manner in a population of epileptic humans.

Phytocannabinoids

Phytocannabinoids, which are compounds found in marijuana that closely resemble chemicals the body produces naturally called endocannabinoids, have shown great potential in the treatment of epilepsy. Phytocannabinoids can affect both the central and peripheral nervous system because neurons have receptors that respond directly to binding by cannabinoids. One of the major effects of phytocannabinoids is to reduce neuronal excitability by modulating electrical activity around synapses; as a result, these chemicals are sometimes referred to as potential "circuit breakers" for neurological disorders, including epilepsy.174,175 Therefore, researchers have been studying the effects of tetrahydrocannabinol (THC) and other phytocannabinoids on the brain to try to develop new mechanisms for treating epilepsy.176,177 One small clinical trial found that the phytocannabinoid, cannabidiol, did reduce seizures in epileptics who were already taking AEDs.178 Another study that was largely based on epidemiology found an association between marijuana use and decreased risk of seizure.179 Moreover, it has been reported that patients treated for epilepsy subjectively feel that marijuana use helps ease their epilepsy.180 More research is needed to determine the efficacy and safety of natural and synthetic cannabinoids for the treatment of seizures. A comprehensive review of studies examining the effects of cannabinoids on seizure frequency in humans is currently being carried out by the Cochrane Epilepsy Group.181 Marijuana is illegal except as a prescribed treatment for medical problems in certain states; Life Extension does not recommend consuming illegal drugs as a treatment for epilepsy. However, the benefits of these phytocannabinoids do suggest that marijuana-derived compounds may soon become an accepted form of therapy for epilepsy and other neurological disorders.

  1. Epilepsy Foundation. Incidence and Prevalence 2010. Available at: http://www.epilepsyfoundation.org/aboutepilepsy/whatisepilepsy/statistics.cfm. Accessed January 22, 2012
  2. Oladipo OO, Ajala MO, Okubadejo N, et al. Plasma magnesium in adult Nigerian patients with epilepsy. Niger Postgrad Med J. 2003;10(4):234-7.
  3. Sinert R et al. Serum ionized magnesium and calcium levels in adult patients with seizures. Scand J Clin Lab Invest. 2007;67(3):317-26.
  4. Oliveira Ld et al. The role of magnesium sulfate in prevention of seizures induced by pentylenetetrazole in rats. Arq Neuropsiquiatr. 2011;69(2B):349-55.
  5. Slutsky I, Abumaria N et al. Enhancement of Learning and Memory by Elevating Brain Magnesium. Neuron 2010; 65(2): 165-177
  6. Rahman S. Mitochondrial disease and epilepsy. Dev Med Child Neurol. 2012 Jan 28. doi: 10.1111/j.1469-8749.2011.04214.x. [Epub ahead of print]
  7. Tawfik MK. Coenzyme Q10 enhances the anticonvulsant effect of phenytoin in pilocarpine-induced seizures in rats and ameliorates phenytoin-induced cognitive impairment and oxidative stress. Epilepsy Behav. 2011 Dec;22(4):671-7. Epub 2011 Oct 26.
  8. Stites T et al. Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. J Nutr. 2006 Feb;136(2):390-6.
  9. NINDS National Institute of Neurological Disorders and Stroke 2012. Available at: http://www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm. Accessed April 20, 2012.
  10. Jehi L and Najm IM. Sudden Death in Epilepsy: Impact, Mechanisms and Prevention. Cleveland Clinic Journal of Medicine 2008 March; 75(2) S66-70
  11. Nouri, S, Devinsky O, et al. Sudden Unexpected Death in Epilepsy 2004. Available at: http://www.emedicine.com/NEURO/topic659.htm. Accessed April 20, 2006.
  12. Nashef L, Hindocha N et al. Risk Factors in Sudden Death in Epilepsy (SUDEP): The Quest for Mechanisms. Epilepsia 2007; 48(5) 859-71
  13. Fukao K, Inoue Y et al. Magnetoencephalographic correlates of different types of aura in temporal lobe epilepsy. Epilepsia. 2010; 51(9): 1846-51
  14. Vincent A, Irani S et al. Potentially Pathogenic Autoantibodies Associated with Epilepsy and Encephalitis in Children and Adults. Epilepsia 2011; 52(Supp 8):8-11
  15. Bhalla D, Godet B et al. Etiologies of Epilepsy: A Comprehensive Review. Expert Reviews in Neurotherapeutics 2011. 11(6): 861-876.
  16. Halawa I, Andersson t et al. Hyponatremia and Risk of Seizures: A Retrospective Cross-Sectional Survey.Epilepsia 2011; 52(2):410-413
  17. Mortelmans LJ, Loo MV et al. Seizures and Hyponatremia After Excessive Intake of Diet Coke. European Journal of Emergency Medicine 2008; 51(15): 51
  18. Castilla-Guerrera L, Fernandez-Moreno MC et al. Electrolytes Disturbances and Seizures. Epilepsia 2006; 47(12):1990-1998
  19. El-Khayat HA, Soliman NA. Reproductive Hormonal Changes and Catamenial Pattern in Adolescent Females with Epilepsy. Epilepsia 2008; 49(9):1619-1626
  20. Finocchi C and Ferrari M. Female Reproductive Steroids and Neuronal Excitability. Neurological Science 2011; 32:S31-S35
  21. Murialdo G, Magri F et al. Seizure Frequency and Sex Steroids in Women With Partial Epilepsy on Antiepileptic Therapy. Epilepsia 2009; 50(8):1920-1926.
  22. Erel T and Guralp O. Epilepsy and Menopause. Archives of Gynecology and Obstetrics 2011; 284:749-755
  23. Blaszczyk B. Influence of Coffee Drinking on Epilepsy Control. Journal of Clinical and Pre-Clinical Research 2007; 1(1): 098-099
  24. Kaufman KR, Sachdeo RC. Caffeinated beverages and decreased seizure control. Seizure. 2003 Oct;12(7):519–21.
  25. Bonilha L, Li LM. Heavy coffee drinking and epilepsy. Seizure. 2004;13(4):284-5.
  26. Chrościńska-Krawczyk M, Jargietto-Baszak M et al. Caffeine and the Anticonvulsant Potency of Antiepileptic Drugs: Experimental and Clinical Data. Pharmacological Reports 2011. 63:12-18
  27. Jankiewicz K, Chrościńska-Krawczyk M, Blaszczyk B, et al. [Caffeine and antiepileptic drugs: experimental and clinical data]. [Article in Polish]. Przegl Lek. 2007;64(11):965-7.
  28. Haut SR, Vouyiouklis M et al. Stress and Epilepsy: A Patient Perception Survery. Epilepsy and Behavior 2003; 4: 511-514
  29. Gilboa T. Emotional Stress-Induced Seizures: Another Reflex Epilepsy? Epilepsia 2011; 1-4
  30. Maggio N and Segal M. Stress and Corticosteroid Modulation of Seizures and Synaptic Inhibition in the Hippocampus. Experimental Neurology 2012.
  31. Frucht MM, Quigg M, et al. Distribution of seizure precipitants among epilepsy syndromes. Epilepsia. 2000 Dec;41(12):1534–9.
  32. Nakken KO, Solaas MH et al. Which Seizure-Precipitating Factors Do Patients With Epilepsy Most Frequently Report? Epilepsy and Behavior 2005; 6:85-89
  33. Waldbum S and Patel M. Mitochondrial Oxidative Stress in Temporal Epilepsy. Epilepsy Research 2010 Jan; 88(1) 23-45
  34. Pieczenik SR and Neustadt J. Mitochondrial Dysfunction and Molecular Pathways of Disease. Experimental and Molecular Pathology 2007; 83:84-92
  35. Halliwell B. Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant treatment. Drugs Aging. 2001;18(19):685–716.
  36. Liang LP et al. Mitochondrial oxidative stress and increased seizure susceptibility in Sod2(-/+) mice. Free Radic Biol Med. 2004 Mar 1;36(5):542-54.
  37. Sourris KC et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic Biol Med. 2012 Feb 1;52(3):716-23. Epub 2011 Nov 21.
  38. Rowan AJ, Shaywitz BA, et al. Aspartame and seizure susceptibility: Results of a clinical study in reportedly sensitive individuals. Epilepsia. 1995 Mar;36(3):270–5.
  39. Camfield PR, Camfield CS, et al. Aspartame exacerbates EEG spike-wave discharge in children with generalized absence epilepsy: A double-blind controlled study. Neurology. 1992 May;42(5):1000–3.
  40. Butchko HH, Stargel WW et al. Aspartame: Review of Safety. Regulatory Toxicology and Pharmacology 2002; 35: S1-S93
  41. Shovic A et al. 'We think your son has Lennox-Gastaut syndrome'--a case study of monosodium glutamate's possible effect on a child. J Am Diet Assoc. 1997 Jul;97(7):793-4.
  42. Landrigan PJ. Health Effects of Environmental Toxins in Deficient Housing. Bulletins of the New York Academy of Medicine 1990; 66(5): 491-499
  43. Brenner PJ and Snyder RD. Late EEG Findings and Clinical Status After Organic Mercury Poisoning. Archives of Neurology 1980; 37(5): 282-284.
  44. Istoc-Bobis M and Gabor S. Psychological Dysfunction in Lead- and Mercury-Occupational Exposure. Revue Romaine de Sciences Sociales 1987; 31(2): 183-191
  45. Sanborn MD, Cole D et al. Identifying and Managing Adverse Environmental Health Effects: 4. Pesticides. Canadian Medical Association Journal 2002; 166(11): 1431-1436.
  46. Simpson WM and Schuman SH. Recognition and Management of Acute Pesticide Poisoning. American Family Physician 2002; 65(8):1599-1605
  47. Marson AG, Appleton R et al. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial. Health Technology Assessment 2007; 11(37).
  48. Kwan P and Brodie MJ. Effectiveness of First Epileptic Drug. Epilepsia 2001; 42(10):1255-1260.
  49. Prunetti P and Perucca E. New and Forthcoming Anti-Epileptic Drugs. Current Opinion in Neurology 2011; 24(2):159-164.
  50. Kwan P and Brodie MJ: Early Identification of Refractory Epilepsy. New England Journal of Medicine 2000; 342(5):314-319
  51. Ochoa JG, Riche W, et al. Antiepileptic Drugs: An Overview 2005. Available at: http://www.emedicine.com/neuro/topic692.htm. Accessed April 20, 2006.
  52. Alarcon G, Valentin A, et al. Is it worth pursuing surgery for epilepsy in patients with normal neuroimaging? J Neurol Neurosurg Psychiatry. 2006 Apr;77(4):474-80.
  53. Karceski S. Vagus Nerve Stimulation Therapy. UpToDate 2011.
  54. Qiabi M, Bouthiller A et al. Vagus Nerve Stimulation for Epilepsy:The Notre-Dame Hospital Experience. Canadian Journal of Neurological Science 2011; 38:902-908
  55. De Herdt V, Poon P et al. Vagus Nerve Stimulation For Refractory Status Epilepticus. European Journal of Pediatric Neurology 2007:261-269
  56. Shawhan A, Bailey C, et al. Vagus Nerve Stimulation for Refractory Epilepsy in Children: More to VNS Than Seizure Frequency Reduction. Epilepsia. 2009; 50(5):1220-1228.
  57. Milby AH, Halpern CH et al. Vagus Nerve Stimulation for Epilepsy and Depression. Neurotherapeutics 2008; 5:75-85
  58. Elliott RE, Carlson C et al. Refractory epilepsy in tuberous sclerosis: Vagus nerve stimulation with or without subsequent resective surgery. Epilepsy Behav. 2009 Nov;16(3):454-60.
  59. McLachlan RS, Sadler M, et al. Quality of life after vagus nerve stimulation for intractable epilepsy: is seizure control the only contributing factor? Eur Neurol. 2003;50(1):16-9.
  60. Pereira EA, Green AL et al. Refractory Epilepsy and Deep Brain Stimulation. Journal of Clinical Neuroscience 2012; 19: 27-33
  61. Lega BC, Halpern CH et al. Deep brain stimulation in the treatment of refractory epilepsy: Update on current data and future directions. Neurobiology of Disease 38 (2010) 354–360
  62. Wakerley B, Schweder Pet al. Possible seizure suppression via deep brain stimulation of the thalamic ventralis oralis posterior nucleus Case Reports / Journal of Clinical Neuroscience 18 (2011) 972–973.
  63. Janszky J et al. [Role of deep brain stimulation in epilepsy]. Ideggyogy Sz. 2011 Sep 30;64(9-10):317-20.
  64. Chen R, Classen J et al. Depression of Motor Cortex Excitability by Low-Frequency Transcranial Magnetic Stimulation. Neurology 1997; 48(5): 1398-1403.
  65. Sun W, Fu W et al. Low-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Refractory Partial Epilepsy. Clinical EEG Neuroscience 2011. 42(1) 40-44
  66. Bae EH, Schrader LM et al. Safety and Tolerability of Repetitive Transcranial Magnetic Stimulation in Patients with Epilepsy: A Review of the Literature. Epilepsy and Behavior 2007; 10(4) 521-528.
  67. Rotenberg A. Prospects for Clinical Applications of Transcranial Magnetic Stimulation and Real-Time EEG in Epilepsy. Brain Topography 2010; 22(4): 257-266.
  68. Lysing-Williamson KA: Spotlight on Levetiracetam in Epilepsy. CNS Drugs 2011; 25 (10): 901-905
  69. Benes J, Parada A, Figueiredo AA, et al. Anticonvulsant and sodium channel-blocking properties of novel 10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide derivatives. J Med Chem. 1999 Jul;42(14):2582-7.
  70. Ambrósio AF, Silva AP, Araújo I, et al. Neurotoxic/neuroprotective profile of carbamazepine, oxcarbazepine and two new putative antiepileptic drugs, BIA 2-093 and BIA 2-024. Eur J Pharmacol. 2000 Oct;406(2):191-201.
  71. Fattore C, Perucca E. Novel medications for epilepsy. Drugs. 2011 Nov;71(16):2151-78.
  72. Duncan GE, Kohn H. The novel antiepileptic drug lacosamide blocks behavioral and brain metabolic manifestations of seizure activity in the 6 Hz psychomotor seizure model. Epilepsy Res. 2005 Oct-Nov;67(1-2):81–7.
  73. Errington AC, Stohr T, Heers C, et al. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008; 73: 157-69
  74. Curia G, Biagini G, Perucca E, et al. Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. CNS Drugs 2009; 23: 555-68
  75. Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII). Epilepsy Res. 2007;73(1):1-52.
  76. Maa EH, Kahle KT, Walcott BP, et al. Diuretics and epilepsy: will the past and present meet? Epilepsia. 2011 Sep;52(9):1559-69.
  77. Ahmad S, Clarke L, Hewett AJ, Richens A. (1976) Controlled trial of furosemide as an antiepileptic drug in focal epilepsy. Br J Clin Pharmacol 3:621–625.
  78. Stevens SJ and Harden CL. Hormonal Therapy for Epilepsy. Current Neurological and Neuroscience Reports 2011; 11:435-442
  79. Veliskova J, Jesus GD et al. Females, Their Estrogens and Seizures. Epilepsia 2010; 51(3):141-144
  80. Frye CA, Ryan A et al. Antiseizure effects of 3a-androstanediol and/or 17b-estradiol may involve actionsat estrogen receptor b. Epilepsy and Behavior 2009; 16:418-422
  81. Reddy DS and Jian K. The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors. The Journal of Pharmacology and Experimental Therapeutics. 2010 Sep;334:1031–1041
  82. Tan M, Tan U. Effects of testosterone and clomiphene on spectral EEG and visual evoked response in a young man with posttraumatic epilepsy. Int J Neurosci. 2001 Jan;106(1-2):87-94.
  83. Kelley SA and Hartman AL.Metabolic Treatments for Intractable Epilepsy. Seminars in Pediatric Neurology 2011; 18:179-185
  84. Francois LL, Manel V, et al. [Ketogenic regime as anti-epileptic treatment: Its use in 29 epileptic children]. Arch Pediatr. 2003 Apr;10(4):300–6. French.
  85. Stafstrom CE, Bough KJ. The ketogenic diet for the treatment of epilepsy: a challenge for nutritional neuroscientists. Nutr Neurosci. 2003 Apr;6(2):67-79.
  86. Sheth RD, Stafstrom CE. Intractable pediatric epilepsy: vagal nerve stimulation and the ketogenic diet. Neurol Clin. 2002 Nov;20(4):1183-94.
  87. Mady MA, Kossoff EH, McGregor AL, et al. The ketogenic diet: adolescents can do it, too. Epilepsia. 2003 Jun;44(6):847-51.
  88. Kosoff EH, Zupec-Kania BA et al. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. Epilepsia, 50(2):304–317, 2009
  89. Bough KJ and Rho JM. Anticonvulsant Mechanisms of the Ketogenic Diet. Epilepsia 2007; 48(1):43-58
  90. Lefevre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics. 2000 Apr;105(4):E46.
  91. Henderson CB, Filloux FM et al. Efficacy of the Ketogenic Diet as a Treatment Option for Epilepsy: A Meta-Analysis. Journal of Child Neurology 2006;21:193
  92. Neal EG, Chaffe H et al. The Ketogenic Diet for the Control of Childhood Epilepsy: A Randomised Control Trial.Lancet Neurology 2008;7:500-506
  93. Mady MA, Kossoff EH, et al. The ketogenic diet: adolescents can do it, too. Epilepsia. 2003 Jun;44(6):847-51.
  94. Mosek A, Natour H et al. Ketogenic Diet in Adults with Refractory Epilepsy: A Prospective Pilot Study. Seizure 2009; 18:30-33
  95. Klein P, Janousek J et al. Ketogenic Diet Treatment in Adults with Refractory Epilepsy. Epilepsy and Behavior 2010; 19:575-579
  96. Payne NE, Cross JH et al. The Ketogenic Diet and Related Diets in Adolescents and Adults---A Review. Epilepsia 2011; 52(11):1941-1948.
  97. Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia. 2004;45(9):1116.
  98. Groesbeck DK, Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol. 2006 Dec;48(12):978-81.
  99. Bergqvist AG, Schall JI, Stallings VA. Vitamin D status in children with intractable epilepsy, and impact of the ketogenic diet. Epilepsia. 2007;48(1):66.
  100. McNally MA, Pyzik PL, Rubenstein JE, Hamdy RF, Kossoff EH. Empiric use of potassium citrate reduces kidney-stone incidence with the ketogenic diet. Pediatrics. 2009;124(2):e300.
  101. Bank IM, Shemie SD, Rosenblatt B, Bernard C, Mackie AS. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol. 2008;39(6):429.
  102. Wolf, P. Epileptic Seizures and Syndromes: With Some of their Theoretical Inplications. John Libbey Eurotext 1994.
  103. Elsas SM, Gregory WL et al. Aura interruption: The Andrews/Reiter behavioral intervention may reduce seizures and improve quality of life — A pilot trial. Epilepsy and Behavior 2011; 22:765-772.
  104. Jaseja H. Purpose of REM sleep: Endogenous anti-epileptogenesis in man—a hypothesis. Med Hypotheses. 2004;62(4):546–8.
  105. Swinehart R. Two cases support the benefits of transcendental meditation in epilepsy. Med Hypotheses. 2008;70(5):1070. Epub 2008 Jan 14.
  106. rida RM, Scorza FA et al. The Potential Role of Physical Exercise in the Treatment of Epilepsy. Epile[psy and Behavior 2010; 17:432-435
  107. Arida RM, Scorza FA et al. Physical Exercise in Epilepsy: What Kind of Stressor Is It? Epilepsy and behavior 2009. 16:381-387
  108. Tozzo CA, Elfner LF, et al. EEG biofeedback and relaxation training in the control of epileptic seizures. Int J Psychophysiol. 1988 Aug;6(3):185-94.
  109. Andrews DJ, Schonfeld WH. Predictive factors for controlling seizures using a behavioural approach. Seizure. 1992 Jun;1(2):111-6.
  110. Ramaratnam S, Baker GA, Goldstein L. Psychological treatments for epilepsy. Cochrane Database Syst Rev. 2001;(4):CD002029.
  111. Tan G, Thornby J et al. Meta-Analysis of EEG Biofeedback in Treating Epilepsy. Clinical EEG and Neuroscience 2009; 40(3)
  112. Nagai Y. Biofeedback For Epilepsy. Current Neurological and Neuroscience Reports 2011. 11:443-450.
  113. Lundgren T, Dahl J, Yardi N, et al. Acceptance and Commitment Therapy and yoga for drug-refractory epilepsy: a randomized controlled trial. Epilepsy Bahav. 2008 Jul;13(1):102-8.
  114. Khan N, Ahmad N et al. Epilepsy Control by Prayer Type Yoga Exercise. Computer Research and Development 2010: 391-395
  115. Cheuk DK and Wong V. Acupuncture for Epilepsy. CochraneDatabase of Systematic Reviews 2008, Issue 4.
  116. Ramaratnam S, Baker GA, Goldstein LH. Psychological treatments for epilepsy. Cochrane Database Syst Rev. 2008 Jul;(3):CD002029. Update of Cochrane Database Syst Rev. 2004;(4):CD002029.
  117. Menon B and Harinarayan CV. The effect of anti epileptic drug therapy on serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism—A longitudinal study. Seizure 2010;19:153-158
  118. Shellhaas RA and Joshi SM. Vitamin D and Bone Health Among Children with Epilepsy. Pediatric Neurology 2010; 42:385-393.
  119. Pack AM and Morell MJ. Epilepsy and Bone Health in Adults. Epilepsy and Behavior 2004; 5:S024-S029.
  120. Valsamis HA, Arora SK et al. Antiepileptic Drugs and Bone Metabolism. Nutrition and Metabolism 2006;3(36)
  121. Mintzer S, Boppana P, et al. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia. 2006 Mar;47(3):510–5.
  122. Fong CY, Mallick AA, Burren CP, et al. Evaluation and management of bone health in children with epilepsy on long-term antiepileptic drugs: United Kingdom survey of paediatric neurologists. European Journal of Pediatric Neurology 2011; 15(5):417-423
  123. Sener U, Zorlu Y et al. Effects of common anti-epileptic drugmonotherapy on serum levels of homocysteine, Vitamin B12, folic acid and Vitamin B6. Seizure 2006;15:79-85
  124. Linnebank M, Moskau S et al. ;Antiepileptic Drugs Interfere with Folate and Vitamin B12 Serum Levels. Annals of Neurology 2011; 69:352-359
  125. Kurul S, Unalp A et al. Homocysteine Levels in Epileptic Children Receiving Antiepileptic Drugs. Journal of Child Neurology 2007; 22(12): 1389-1392.
  126. Apeland T, Mansoor MA et al. Antiepileptic Drugs as Independent Predictors of Plasma Total Homocysteine Levels. Epilepsy Research 2001; 47:27-36
  127. Diaz-Arrastia R. Homocysteine and Neurologic Disease. Archives of Neurology 2000;57:1422-1427
  128. Morrell MJ. Folic Acid and Epilepsy. Epilepsy Curr. 2002 Mar;2(2):31-34.
  129. Djukic A. Folate-Responsive Neurologic Diseases. Pediatric Neurology 2007; 37:387-397
  130. Asadi-Pooya AA. Risk Factors for Carbemazepine-Induced Leukopenia in Children and Adolescents. Journal of Pediatric Neurology 2005. 3:233-235.
  131. Asadi-Pooya AA, Minzer S, Sperling M. Nutritional supplements, foods, and epilepsy: Is there a relationship? Epilepsia. 2008;49(11):1819-27.
  132. Gaby AR. Natural Approaches to Epilepsy. Alternative Medicine Review. 2007; 12(1):9-24.
  133. Tamura T, Aiso K, Johnston KE, et al. Homocysteine,folate, vitamin B-12 and vitamin B-6 in patientsreceiving antiepileptic drug monotherapy. Epilepsy Res 2000;40:7-15.
  134. Jiao FY, Gao DY, Takuma Y, et al. Randomized, controlled trial of high-dose intravenous pyridoxine in the treatment of recurrent seizures in children. Pediatr Neurol 1997;17:54-57.
  135. Wang HS, Kuo MF, Chou ML, et al. Pyridoxalphosphate is better than pyridoxine for controlling idiopathic intractable epilepsy. Arch Dis Child 2005;90:512-515.
  136. Tamai H, Wakamiya E, Mino M, Iwakoshi M. Alphatocopherol and fatty acid levels in red blood cells in patients treated with antiepileptic drugs. J Nutr Sci Vitaminol (Tokyo) 1988;34:627-631.
  137. Zaidi SM, Banu N. Antioxidant potential of vitamins A, E and C in modulating oxidative stress in rat brain. Clin Chim Acta. 2004 Feb;340(1-2):229–33.
  138. Savaskan NE, Brauer AU, et al. Selenium deficiency increases susceptibility to glutamate-induced excitotoxicity. FASEB J. 2003 Jan;17(1):112–4.
  139. Yamamoto N, Kabuto H, et al. Alpha-tocopheryl-L-ascorbate-2-O-phosphate diester, a hydroxyl radical scavenger, prevents the occurrence of epileptic foci in a rat model of post-traumatic epilepsy. Pathophysiology. 2002 Jun;8(3):205–14.
  140. Ogunmekan AO. Vitamin E deficiency and seizures in animals and man. Can J Neurol Sci 1979;6:43-45.
  141. Ogunmekan AO, Hwang PA. A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children. Epilepsia. 1989 Jan;30(1):84–9.
  142. Ogunmekan AO. Plasma vitamin E (alpha tocopherol) levels in normal children and in epileptic children with and without anticonvulsant drug therapy. Trop Georgr Med. 1985;37(2):175-7.
  143. Levy SL, Burnham WM et al. An Evaluation of the Anticonvulsant Effects of Vitamin E. Epilepsy Research 1990; 6:12-17.
  144. Levy SL et al. The anticonvulsant effects of vitamin E: a further evaluation. Can J Neurol Sci. 1992 May;19(2):201-3.
  145. Higashi A, Tamari H et al. Serum Vitamin E Concentration in Patients With Severe Multiple Handicaps Treated with Anticonvulsants. Pediatric Pharmacology 1980; 1:129-134.
  146. Oladipo OO et al. Plasma magnesium and calcium levels in children with epilepsy in lagos. Niger Postgrad Med J. 2007 Mar;14(1):26-9.
  147. Nuytten D, Van Hees J, Meulemans A, Carton H. Magnesium deficiency as a cause of acute intractable seizures. J Neurol 1991;238:262-264.
  148. Borges LF, Gucer G. Effect of magnesium on epileptic foci. Epilepsia 1978;19:81-91.
  149. Touyz RM. Magnesium supplementation as an adjuvant to synthetic calcium channel antagonists in the treatment of hypertension. Med Hypotheses. 1991 Oct;36(2):140-1.
  150. Gupta SK et al. Serum magnesium levels in idiopathic epilepsy. J Assoc Physicians India. 1994 Jun;42(6):456-7.
  151. Bhattacharjee N et al. A randomised comparative study between low-dose intravenous magnesium sulphate and standard intramuscular regimen for treatment of eclampsia. J Obstet Gynaecol. 2011 May;31(4):298-303.
  152. Slutsky I, Abumaria N, Wu J, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan;65(2):165-77.
  153. Abumaria N, Yin B et al. Effects of Elevation of Brain Magnesium on Fear Conditioning, Fear Extinction, and Synaptic Plasticity in the Infralimbic Prefrontal Cortex and Lateral Amygdala. Journal of Neuroscience 2011; 31(42): 14871-14881.
  154. Banach M, Gurdziel E et al. Melatonin in Experimental Seizures and Epilepsy. Pharmacological Reports 2011; 63:1-11
  155. Lima E, Cabral FR et al.Melatonin Administration After Pilocarpine-Induced Status Epilepticus: A New Way to Prevent or Attenuate Post-Lesion Epilepsy? Epilepsy and Behavior 2011; 20:607-612
  156. Costa-Latufo LV, Fonteles MM et al. Attenuating Effects of Melatonin on Pilocarpine-Induced Seizures in Rats. Comparative Biochemistry and Physiology 2002; 131:521-529
  157. Fauteck JD, Schmidt H et al. Melatonin In Epilepsy: First Results of Replacement Therapy and First Clinical Results. Biological Signals Receptors 1999; 8:105-110
  158. Blondeau N, Widmann C, et al. Polyunsaturated fatty acids induce ischemic and epileptic tolerance. Neuroscience. 2002;109(2):231–41.
  159. Taha AY, Burnham WM et al. Polyunsaturated Fatty Acids and Epilepsy. Epilepsia 2010; 51(8):1348-1358
  160. Xu X, Erichsen D et al. Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanism of antiseizure action. Epilepsy Research 2008;80(1):57-66.
  161. Auvin S. Fatty Acid Oxidation and Epilepsy. Epilepsy Research 2011
  162. Yuen AW, Sander JW, et al. Omega-3 fatty acid supplementation in patients with chronic epilepsy: A randomized trial. Epilepsy Behav. 2005 Sep;7(2):253–8.
  163. Bromfeld E, Dworetzky et al. A Randomized Control Trial of Polyunsaturated Fatty Acids For Refractory Epilepsy. Epilepsy and Behavior 2008; 12:187-190
  164. ClinicalTrials.gov. Double Blind Crossover Study of Fish Oil [EPA and DHA] for Intractable Partial Seizures. Available at: http://clinicaltrials.gov/ct2/show/NCT00871377. Accessed January 22, 2012.
  165. Jyoti A, Sethi P, Sharma D. Bacopa monniera prevents from aluminum neurotoxicity in the cerebral cortex of rat brain. J Ethnopharmacol. 2007 Apr;111(1):56-62.
  166. Hosamani R et al. Neuroprotective efficacy of Bacopa monnieri against rotenone induced oxidative stress and neurotoxicity in Drosophila melanogaster. Neurotoxicology. 2009 Nov;30(6):977-85. Epub 2009 Sep 8.
  167. Kanthasamy K et al. Neuroprotective effect of resveratrol against methamphetamine-induced dopaminergic apoptotic cell death in a cell culture model of neurotoxicity. Curr Neuropharmacol. 2011 Mar;9(1):49-53.
  168. Chung IM et al. Neuroprotective effects of resveratrol derivatives from the roots of Vitis thunbergii var. sinuate against glutamate-induced neurotoxicity in primary cultured rat cortical cells. Hum Exp Toxicol. 2011 Sep;30(9):1404-8. Epub 2010 Nov 17.
  169. Shetty AK. Promise of resveratrol for easing status epilepticus and epilepsy. Pharmacol Ther. 2011 Sep;131(3):269-86. Epub 2011 Apr 28. Review.
  170. Wu Z et al. Protective effect of resveratrol against kainate-induced temporal lobe epilepsy in rats. Neurochem Res. 2009 Aug;34(8):1393-400. Epub 2009 Feb 14.
  171. Pandey R et al. Baccoside A suppresses epileptic-like seizure/convulsion in Caenorhabditis elegans. Seizure. 2010 Sep;19(7):439-42. Epub 2010 Jul 3.
  172. Mathew J et al. Behavioral deficit and decreased GABA receptor functional regulation in the cerebellum of epileptic rats: effect of Bacopa monnieri and bacoside A. Epilepsy Behav. 2010 Apr;17(4):441-7. Epub 2010 Feb 11.
  173. Krishnakumar A et al. Upregulation of 5-HT2C receptors in hippocampus of pilocarpine-induced epileptic rats: antagonism by Bacopa monnieri. Epilepsy Behav. 2009 Oct;16(2):225-30. Epub 2009 Aug 22.
  174. Wallace MJ, Blair RE, et al. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther. 2003 Oct;307(1):129-37.
  175. Katona I and Freund TF. Endocannabinoid Signaling as a Synaptic Circuit Breaker in Neurological Disease. Nature Medicine 2008; 14(9).
  176. Hoffman ME and Frazier CJ. Marijuana, Endocannabinoids, and Epilepsy: Potential and Challenges for Improved Therapeutic Intervention. Experimental Neurology 2011
  177. Hill AJ, Williams CM et al. Phytocannabinoids as Novel Therapeuric Agents in CNS Disorders. Pharmacology and Therapeutics 2012; 133:79-97.
  178. Cunha JM, Carlini EA et al. Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients. Pharmacology 1980; 21(3):175-185.
  179. Ng SK, Brust JC et al. Illicit Drug Use and the Risk of New-Onset Seizures. American Journal of Epidemiology 1990; 132(1):47-57.
  180. Gross DW, Hamm J, et al. Marijuana use and epilepsy: Prevalence in patients of a tertiary care epilepsy center. Neurology. 2004 Jun 8;62(11):2095–7.
  181. Gloss D, Vickrey B. Cannabinoids for epilepsy (Protocol). Cochrane Database of Systematic Reviews 2011, Issue 8.