Chapter 163 Epilepsy
The word epilepsy derives from the Greek word epilepsia, which means “to take hold of” or “to seize.” Epilepsy is not a disease in itself but rather a symptom of disease. The epilepsies are a group of disorders characterized by sudden, recurrent, episodic changes in neurologic function caused by abnormalities in the electrical activity of the brain.1–4 Each episode of neurologic dysfunction is called a seizure. Seizures are termed convulsive when accompanied by motor manifestations or nonconvulsive when accompanied by sensory, cognitive, or emotional events. Epilepsy can occur because of a number of abnormalities, such as neurologic injuries, structural brain lesions, or some systemic diseases. Epilepsy is termed idiopathic when there is neither a history of neurologic insult nor other apparent neurologic dysfunction.3 Whatever the etiology, the common denominator in all these conditions is the epileptic attack or seizure.
The reported incidence and prevalence rates of epilepsy have varied widely because of uncontrolled methodologic factors.5 According to the best available data, the prevalence of chronic recurrent epilepsy is about 10 per 1000, and it has been estimated that 10% of the population will have one or more seizures at some point in life. The cumulative lifetime incidence of epilepsy is approximately 3%.6 An additional 2% to 5% of children experience febrile convulsions during the first several years of life. About 10% of these children, especially those in whom the febrile seizure is prolonged, develop epilepsy later in life.1 Prospective studies show that more than 60% of newly diagnosed patients enter remission with conventional treatment.7
Epilepsy may be idiopathic, cryptogenic, or symptomatic.8 Idiopathic epilepsies are generally genetic in origin and account for 70% to 80% of all cases of epilepsy. The role of genetic factors in the pathogenesis is complex because of diverse conditions leading to the common symptom of seizures. In general, the prevalence of seizures in close relatives is three times that of the overall population.1 William Lennox meticulously studied the relationship of epilepsy to genetics from 1934 through 1958, using twin studies. He concluded that epilepsy was a condition in which genetic and exogenous factors interact in all patients, with variable weighting in each particular case.9
This understanding sparked the concept that many factors play a role in the epileptic condition. Cryptogenic epilepsies are those in which an underlying cause is suspected but the etiology remains undetected. Finally, epilepsies for which there is an underlying structural cause or major metabolic derangement are considered symptomatic, for a probable cause has been identified.4 As shown in Table 163-1, probable causes can be determined by age at onset of seizures. Box 163-1 lists the most common etiologic factors.
|AGE AT ONSET||PRESUMPTIVE CAUSES|
|Birth to 2 years||Birth injury, degenerative brain disease|
|2-19 years||Congenital birth injury, febrile thrombosis, head trauma, infection (meningitis or encephalitis)|
|20-34 years||Head trauma, brain neoplasm|
|35-54 years||Brain neoplasm, head trauma, stroke|
|55 years and older||Stroke, brain neoplasm|
Data from references 3 and 4.
The current classification of epileptic seizures is based on clinical and electroencephalographic criteria proposed by the International League Against Epilepsy. Box 163-2 lists the clinical features.
Modified from Willmore LJ, Ferrendelli JA. Epilepsy. In Dale DC, Federman DD, eds. Scientific American medicine. New York: Scientific American, 1997:11, XII-1-14.
Differentiating between partial or focal seizures and generalized seizures is of great clinical significance. Partial seizures begin focally with a specific sensory, motor, or psychic aberration that reflects the affected part of the cerebral hemisphere.5 These types of seizures may remain localized, whereas generalized seizures appear to generalize from their onset and usually affect both consciousness and motor function.2–5 Differentiation is important because partial seizures are usually indicative of focal brain disorders such as tumors or gliosis, whereas generalized seizures rarely have a definable etiology (although some studies now implicate metabolic disorders).
An eyewitness account of a typical attack can be of great value in classifying the seizure. Past trauma, infections, and the use of drugs and alcohol should be fully explored, as should the family history. A complete neurologic examination should be performed as a preliminary screen for neoplasms. Laboratory work should include the following4:
Examination of the cerebrospinal fluid is indicated if infection or meningeal neoplasm is suspected.1 MRI is considered the gold standard in evaluating epilepsy, as the resolution is superior to that of the CT scan.6 Newer studies also employ EEG recording during functional MRI scanning in order to map normal and pathologic brain function.10 Epilepsy should not be diagnosed on the basis of a solitary seizure. The recurrence rate after a single seizure is approximately only 27% over 3 years.11
The hallmark of the altered physiologic state of epilepsy is a rhythmic, repetitive, synchronous discharge of many neurons in a localized area of the brain.3 This discharge pattern is easily recorded on the EEG during an attack. However, the cause of the abnormal discharges is still not known. Research shows that the synchronous depolarization of masses of neurons is the result of a combination of increased excitatory mechanisms and decreased inhibitory mechanisms.12
Seizures can be induced in experimental models by blocking inhibitory mechanisms. For example, agents that block the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are potent convulsants in humans. Conversely, the antiepileptic drugs phenobarbital and benzodiazepines enhance GABA, thus supporting the inhibitory mechanism. In some forms of chronic focal epilepsy, inhibitory terminals on neurons in areas around cortical gliotic lesions are in fact diminished.
Other research demonstrates the instability of the nerve cell membranes in epileptics. During seizure activity, intracellular Ca2+ stored in the cell organelles is released and moves toward the inner cell membranes, where it binds to specific Ca2+-receptive proteins, causing conformational changes in the protein’s structure. These changes cause the transmembranal Ca2+, K+, and Na+ channels to pathologically remain open, potentiating the excitatory state and hence the convulsive activity.1,2
The earliest symptomatology, or aura, that is generated by a focal discharge provides the best clue to the localization and occasionally to the characterization of the responsible lesion. For example, a generalized seizure following an aura of a peculiar abdominal sensation or ill-defined odor indicates a lesion in the temporal lobe. A Jacksonian seizure beginning in the fingers and spreading up the arm before becoming generalized and producing a coma indicates a focal lesion in the convexity of the opposite motor cortex.1
Heavy metals such as lead, mercury, cadmium, and aluminum can induce seizures by disrupting neural function.13 Heavy metal toxicity should be ruled out as a possible cause in all seizures. A hair mineral analysis provides the most cost-effective screening method for the detection of heavy metals. Urine analysis remains the best method for estimating the levels of stored heavy metals after the administration of a chelating agent such as calcium disodium ethylenediaminetetraacetic acid or dimercaptosuccinic acid (see Chapter 53).
Many neuron-, axon-, and myelintoxic chemicals have now been released into the environment. These chemicals are finding their way into human tissues, contributing to neurologic dysfunction. Minimizing exposure and improving the body’s ability to eliminate neurotoxic agents become important aspects of the therapeutics approach. Chapters 35 and 53 discuss the impact of these neurotoxins.
Focal neurologic deficits associated with hypoglycemia have been well described in adults with diabetes,14 and some researchers believe that hypoglycemia is the most important metabolic cause of seizures.13 Researchers have found the following13,15–18:
Although the correlation of blood sugar abnormalities and epilepsy seems well documented, the mechanism of action is unknown. It has been suggested that low blood sugar could impair adenosine triphosphate (ATP) production in nerve cells, reducing the efficacy of the sodium ATPase pump. A defective sodium pump allows for increased intracellular sodium concentrations, which depolarize the cell membrane and thus lowers the firing threshold.
More recent observational studies have pointed to leptin as a factor that may help in regulating the occurrence of seizures. Animal studies have confirmed that injecting leptin reduces the occurrence and severity of seizures. It is well established that low blood sugar results in low circulating leptins levels, leading to another possible mechanism of action.19
The diet is composed of more than 90% fat by weight, low in carbohydrates, and adequate in proteins, vitamins, and minerals. The low carbohydrate intake inhibits fat metabolism, resulting in the production of excessive levels of ketone bodies (acetone, acetoacetic acid, and beta-hydroxybutyric acid), the intermediary oxidation products. Presumably the beneficial effects of such a diet are due to its induction of metabolic acidosis, which corrects an underlying tendency of epileptics toward the spontaneous development of alkalosis.20–22 This acidification is thought to normalize nerve conductivity, irritability, and membrane permeability.
Another possible benefit of the KD may be in augmenting ATP production by utilizing ketone bodies in place of glucose. It has been documented that many epileptics are hypoglycemic, thus compromising mitochondrial ATP production. The KD may provide an alternative route for balancing this deficit.24
The two main types of KDs are (1) the classic diet and (2) the medium-chain triglyceride diet. The classic KD produces ketosis by limiting intake of carbohydrates and protein to less than 10% of energy combined. The medium-chain triglyceride diet uses medium-chain triglyceride fat to produce ketosis. This allows for a larger intake of carbohydrates and protein.20
Research continues to document the efficacy of these types of dietary therapy. For example, one study of 27 children from 1 to 16 years of age using the classic diet found that 40% experienced a reduction of seizures of more than 50%, with 25% becoming seizure-free.25 However, 35% discontinued the diet owing to difficulty in following the rigorous guidelines. A review from 1996 concluded that the KD had efficacy in one third to one half of childhood epilepsy cases and was partially effective in another one-third of cases.26 A review article from 1997 states that the KD’s success rate “greatly exceeds that of the medications” and that its side effects are fewer and the therapy cheaper.27
One prospective nonrandomized study measured the nutrient intakes, growth, and biochemical indexes of 30 children from 1 to 16 years of age who had intractable epilepsy before and after a 4-month protocol using a KD. Fourteen children on the classic diet and 11 on the medium-chain triglyceride diet completed the study, for an 83% completion. The results indicated that linear growth was maintained in patients from baseline to 4 months on both therapies. However, body weight decreased for children on both diets, which could be a result of inadequate energy intake. Protein intake met recommendations for both diets. In the medium-chain triglyceride group, there was a 0.7 decrease in the ratio of total cholesterol to high-density lipoprotein ratios at 4 months. All biochemical indices including albumin levels remained within normal limits.20 However, this was only a 4-month study. Longer-term evaluations may show eventual unwanted changes in these parameters. The authors concluded that the medium-chain triglyceride diet may be more nutritionally adequate and thus confer an advantage over the classic KD.
Although the previously mentioned study demonstrated a relatively short use of 4 months, the KD is not without side effects. The long-term risks of a high-fat diet are well known, and a KD may prove unhealthy for a growing child. One retrospective investigation found that the linear growth of some children might be retarded.28 When treating children on a KD, clinicians should recommend adequate intake of energy and protein, a higher proportion of unsaturated to saturated dietary fats, and also consider vitamin and mineral supplements.20 Also, children should not be allowed to eat large meals, because these may predispose them to seizures. Small, frequent meals may be appropriate and may decrease hypoglycemic episodes.
In a study appearing in Seizure, researchers evaluated the long-term efficacy and tolerability of the KD in pediatric drug-resistant epileptic patients. The authors concluded that despite the retrospective nature of the study and the inhomogeneous patient sample, their results pointed to good long-term effects of the KD on seizure frequency, EEG readings, and neurologic development.29
The Atkins diet, which has gained great popularity in past years as a weight-loss tool, theoretically may be useful to treat epilepsy.30 Like the KD, it too produces a ketotic state but creates this effect with less restriction on protein intake. In one pilot study, 6 patients ranging from 7 to 52 years of age were prescribed the Atkins diet for intractable focal and multifocal epilepsy. Five of the patients maintained moderate to large ketosis for periods of 6 weeks to 24 months and 3 experienced seizure reduction. As a result, they were able to reduce their antiepileptic medications.31 Larger trials are necessary to explore whether the Atkins diet may be useful to treat patients with epilepsy.
Leptin is a protein hormone that plays a key role in regulating appetite and metabolism. Acting on the receptors of the hypothalamus, it inhibits hunger by counteracting the affects of neuropeptide Y and anandamide, two powerful feeding stimulants. Now research is demonstrating the ability of leptins to act on receptors that activate signaling proteins, which, in turn, trigger changes that reduce brain excitability and thus seizures frequency and intensity.19,32
The anticonvulsant action of leptin was tested in animal seizure models by either injecting leptin directly into the cortex or administering it intranasally. Focal seizures in these animals were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. Results showed that seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures.33
The theorized mechanism of action may involve leptin’s effect in activating two signaling proteins known as JAK2 (Janus kinase) and PI3K (phosphotidylinositol 3-kinase). These proteins blocked nerve impulses triggered by the neurotransmitter glutamate, thus reducing the severity and frequency of seizures. PI3K is also involved in regulating GLUT4, a cytoplasmic protein essential for sugar regulation. This may be another important mechanism of action of elevated leptins.33,34
Although these preliminary studies show that leptin can reduce seizures in acute settings, leptin’s usefulness in chronic cases is yet to be determined. One challenge would be the fact that leptin has a relatively short half-life (15-30 minutes), leading to dosing problems. However, creating a physiologic environment that improves blood leptin levels through dietary and supplemental intervention could prove therapeutic.
There appears to be a link to the KD, since this diet increases the amount of circulating leptins—perhaps another plausible mechanism of action of KD. Future research may involve testing foods that have a propensity to increase circulating leptins and examining their effect on seizure frequency and intensity.34
Another link to the anticonvulsant action of leptin is hypoglycemia. It has been established that low blood sugar is associated with an increase in seizure formation, and hypoglycemic individuals also have low leptin levels. This may explain in part why hypoglycemia is associated with the occurrence of seizures.
There has been little research into the correlation between food allergy and epilepsy, with only anecdotal case histories,35,36 single-case double-blind placebo-controlled studies,37,38 and uncontrolled studies being reported. It is postulated that epileptic patients may have allergic reactions in the brain that are similar to the swelling, anoxia, and inflammatory chemical reactions seen at other sites of local allergic reactions.35
One uncontrolled study evaluated oligoantigenic diets in 63 children with epilepsy. Of 45 children with recurrent headaches, hyperkinetic behavior, or abdominal symptoms, 25 ceased to have seizures and 11 had fewer seizures during diet therapy. Headaches, abdominal pain, and hyperkinetic behavior ceased in all patients whose seizures ceased and in some of those whose seizures did not cease. Reintroduction of foods reproduced symptoms. Of 24 children with generalized epilepsy, 18 recovered or improved, as did 18 of 21 children with partial epilepsy. In double-blind provocation, 15 of 16 children experienced recurrence of symptoms, including seizures in 8, whereas none improved in the placebo group. Another group of 18 children who had epilepsy alone had no improvement with dietary change.39 This study suggests that food allergy should be suspected in epileptic patients who suffer from multiple other symptoms of food allergy (see Chapter 15).
Another study evaluated two females, 5 and 23 years of age, who had focal occipital epilepsy with cerebral calcifications and were not responding well to antiepileptic therapy. Both had celiac disease as well as documented folic acid deficiency (a common side effect of most antiepileptic drugs). A gluten-free diet combined with supplementation with folic acid (dosage not reported) led to complete normalization of the EEG in the 5-year-old and cessation of seizures. The 23-year-old experienced significant improvement in her EEG and enhanced seizure control. Folic acid returned to the normal range within several months.40
A larger study looked more closely at the association between celiac disease and epilepsy. A total of 43 patients (15 male) between 4 and 31 years of age were evaluated for the association between celiac disease, epilepsy, and cerebral calcifications. Intestinal biopsy on the 31 patients with cerebral calcifications of unexplained origin and epilepsy found a flat intestinal mucosa in 24, suggesting celiac disease. CT scans showed cerebral calcifications in 5 of the 12 patients with celiac disease and epilepsy. Antibodies to gluten and folic acid serum concentrations were measured, and histocompatibility leukocyte antigen typing was done in most patients. Only 2 patients with cerebral calcifications and epilepsy had gastrointestinal symptoms at the time of biopsy. A gluten-free diet in epilepsy was found to be inversely related to the duration of epilepsy before the diet and to the patient’s age at the beginning of the diet.
The authors strongly recommend that celiac disease be considered in all cases of epilepsy and cerebral calcifications of unexplained origin, especially when the epilepsy is characterized by occipital seizures and the calcification is located bilaterally in the posterior regions.41 One work involving 72 epileptic children and 202 controls revealed significantly higher rates of eczema in the mothers and rhinitis in the siblings of the epileptic patients as well as a generally higher incidence of allergic pathologies in both of these groups compared with the controls. Additionally, a significantly higher incidence of allergy to cow’s milk as well as asthma was documented in the epileptic children with respect to the control group. Prick tests gave a significantly higher rate of positive results for cow’s milk proteins in the epileptic patients versus controls.42
Direct research into the possible benefits, with regard to seizure formation, of optimizing mitochondrial ATP production is minimal. However, there is peripheral evidence supporting this idea. For example, it is well accepted that individuals with mitochondrial diseases compromising ATP production have an increase in seizure frequency. This may be related to ATP production and the importance of this respiratory chain substrate in controlling the stability of cell membranes.43
In one observational study, 37 family members with a genetic mitochondrial disease (a mild defect in the NADH-ubiquinone oxidoreductase step) showed a significant increase in seizures (22% of the group developed epilepsy).44
Studies of subjects with mitochondrial encephalopathies have consistently shown epileptic seizures as a main recognized symptom. Partial seizures, chiefly with elementary motor symptoms, and focal or multifocal EEG epileptiform activity characterized the epileptic presentation in 71% of these patients.45
Supplementation with ubiquinone has shown positive effects in improving symptomatology produced by mitochondrial encephalopathies. In a study of patients with mitochondrial encephalopathies (which can lead to seizures) showed a significant improvement in fatigability and muscle endurance after the administration of supplemental ubiquinone.
Ubiquinone has been shown to have significant benefits in several neurologic disorders (e.g., Parkinson’s disease, Huntington’s chorea). Thus, using this agent as part of the anticonvulsant protocol may have some merit.46–48
Even the positive effects of the ketogenic diet (KD) may have some relationship to mitochondrial functionality. A recent study showed that animals placed on a KD had a 46% increase in the density of mitochondria in neuronal tissues. KD has been hypothesized to work on several levels; it is plausible to assume that increasing mitochondrial density and thus ATP production could be one of them.49,50