Brain synapses play a role in epilepsy

Epilepsy

Epilepsy

Last Section Update: 09/2020

Contributor(s): Shayna Sandhaus, PhD

Table of Contents

  1. Overview
  2. Introduction
  3. Background
  4. Neurobiology of Epilepsy
  5. Causes of Epilepsy and Common Seizure Triggers
  6. Diagnosis
  7. Conventional Treatments
  8. Novel and Emerging Strategies
  9. Dietary Management: The Ketogenic Diet and Others
  10. Lifestyle Modifications
  11. Nutrients
  12. Update History
  13. References

1 Overview

Summary and Quick Facts for Epilepsy

  • 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 main dietary strategies used in the context of 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 diet, which was developed in the 1920s, consists of high intake of fats (80%) and low intake of protein and carbohydrates.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 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 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 per kilogram of body weight to ensure adequate protein intake. The ketogenic diet typically begins with a brief fasting period, though this is not necessary and often based on the clinician's preferences.88

How the ketogenic diet prevents seizure is still under investigation. One of the prevailing theories is that the ketones produced by the metabolic state induced by diet are able to enter the brain. From there, ketones 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 shown to be an effective treatment for epilepsy. Reviews have found over 50% of children undergoing treatment with the ketogenic diet have a greater than 50% reduction in 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 randomized control trials, which are the type of studies that generate the most robust evidence of treatment efficacy.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 and low-glycemic index diet, 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 diet allows a higher amount of carbohydrates (40‒60 grams per day) as long as they have a glycemic index of less than 50. Both these modified ketogenic diets have also proven beneficial in the treatment of epilepsy.96

A recent clinical trial randomized 158 children with drug-resistant epilepsy to adhere to the ketogenic, modified Atkins, or low-glycemic index diets. After 24 weeks, the children in the ketogenic group experienced a median 66% reduction in seizure frequency, while those in the modified Atkins and low-glycemic index groups experienced 45% and 54% median reductions, respectively. While the trial was unable to provide evidence that the other diets were equivalent to the ketogenic diet in terms of benefit, the low-glycemic index diet was significantly less likely to cause serious adverse events than the ketogenic diet.182 These results indicate the need for individualized risk-benefit evaluations.

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 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 Nutrients

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.

2020

  • Sep: Updated Dietary Management: The Ketogenic Diet and Others

2012

  • Feb: Comprehensive update & review

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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