55 • VITAMINS, HERBS, AND OTHER ALTERNATIVE THERAPIES 713 psychogenic, nonepileptic seizures (39, 40). Cognitive- behavioral interventions may help epileptic patients with anxiety and depression (35). FEEDBACK THERAPY Andrews-Reiter Method The Andrews-Reiter method, developed by Donna Andrews and Joel Reiter, was a new comprehensive neurobehavioral approach for using biofeedback to treat epilepsy. Their initial positive results from six patients with refractory complex partial seizures (41) were rep- licated at the Victoria Epilepsy Center (MacKinnon J, personal communication, 2002) and others (42, 43). The Andrews-Reiter method was developed to treat patients with refractory epilepsy and antiepileptic drug (AED) side effects who declined surgery or were not good can- didates for it. This approach targets the onset of seizures in developing preventive techniques (44). An essential part of the Andrews-Reiter treatment is to change the patient’s response to preseizure warnings and auras by recognizing them and instituting a new, seizure-preventing response (6). Triggers may be physical (e.g., chemical imbalance, disturbed sleep, and missed medication), external (people, places, or situations that cause pressure or stress), or internal (emotional reactions and stressful states). The Andrews-Reiter treatment pro- gram includes cognitive and behavioral counseling to reduce seizure activity through enhanced awareness of premonitory or aura symptoms, identifying emotional, behavioral, physiologic, or environmental mechanisms that trigger seizure activity, progressive relaxation and reinforcement, deep diaphragmatic breathing, and EEG and electromyographic (EMG) biofeedback (44). Neurofeedback Therapy Operant conditioning of the EEG (i.e., neurofeedback or neurotherapy) is a noninvasive treatment for patients with refractory epilepsy. Neurofeedback may increase the seizure threshold through producing EEG changes. Initially, a quantitative EEG assessment is obtained to iden- tify abnormal regions that can be targeted during treat- ment. Neurofeedback is a learning procedure with the goal of altering recorded EEG patterns. It is based on the law of effect, that is, provide positive reinforcement of EEG pat- terns that approach a normal configuration, and negative reinforcement of abnormal (epileptic) EEG patterns. In practice, a computer processes the EEG signals, identifies the critical components, and then modifies a display on a screen in front of the patient, which provides an inte- grated response dependent upon the EEG pattern. This process can be reduced to a simple game involving the completion of a task followed by the scoring of points. For children, these points can lead to meaningful rewards, such as privileges or money. The ultimate reward is learn- ing to change the underlying circuitry of the brain to raise the seizure threshold. Although a natural consequence of neurofeedback is relaxation, it is not a relaxation tech- nique; on the contrary, neurofeedback is more akin to a “cerebral workout” (6). In animal studies, increasing the sensorimotor rhythm through operant conditioning eliminated or significantly reduced seizures induced by convulsant chemical compounds (45). In other animal experiments, sensorimotor rhythm training increased sleep spindles and improved sleep organization (46). These findings led to a pilot study of neurofeedback for a boy with refrac- tory tonic-clonic seizures; he became seizure free after 3 months (47). The clinical data on neurofeedback is based on uncontrolled, nonblinded studies in which operant con- ditioning reduced seizure frequency by over 50% and also reduced seizure severity (6). There is no relation between AED levels and the outcome of the conditioning (6). Stud- ies using sham feedback, relaxation training, or alternate EEG criteria for reward showed no benefits. Neurofeedback is an expensive and time-consuming process. It can be administered in 1-hour sessions, one to three times per week for periods ranging from 3 months to more than 1 year. It is usually about $100 per session and is often covered by health insurance under the “out- patient mental health” benefit (6). Craniosacral Therapy Craniosacral therapy was created by Dr. William Suther- land in the early 1900s to examine, assess, and correct cranial bone movements (6). Current practice focuses on the cranial and sacral bones and the membrane structures that connect them. This system is hypothesized to have a craniosacral rhythm, created by the flow of cerebrospinal fluid through the membrane complex. A practitioner of craniosacral therapy assesses this rhythm and seeks to treat subtle imbalances in the ner- vous and skeletomuscular systems to restore health. A minimal amount of force (approximately the weight of a nickel) over a long period of time (30 seconds to several minutes) is used during craniosacral therapy. Widespread regions of the body, including many soft tissue structures, are often treated (6). Although craniosacral therapy is used to treat epi- lepsy, there have been no controlled trials. The technique can probably reduce stress and muscular tension, but evidence to support the specific craniosacral rhythm mech- anism of action is lacking. The reliability of palpating a craniosacral rhythm is poor between practitioners (48, 49). This fundamental skill is the basis of therapy. In one V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 714 study (49), two registered osteopaths with postgradu- ate training in craniosacral techniques simultaneously palpated the head and sacrum of 11 normal subjects. Intrarater reliability at either the head or the sacrum was fair to good (correlation coefficients, 0.52Ϫ0.73). Inter- examiner reliability was poor to nonexistent (correlation coefficients, Ϫ0.09Ϫ0.31). VITAMINS The use of vitamins, minerals, and other dietary sup- plements in the care of children with epilepsy takes multiple forms, including treatment of seizures in the case of vitamin-deficient or vitamin-dependent seizure disorders involving, for example, pyridoxine, biotin, and folinic acid, the replacement or supplementation of vita- min stores, such as folate and carnitine, depleted by the adverse effects of AEDs, and the use of multivitamins for general health maintenance. Biotin Biotin, a water-soluble B vitamin, was discovered to be an essential nutrient in the 1930s, when animal studies of diets containing large quantities of raw egg whites resulted in toxicity manifested by severe dermatitis, hair loss, and poor motor coordination. Biotin administra- tion reversed the symptoms. Subsequently, avidin, a glycoprotein in egg whites, was found to irreversibly bind biotin, preventing its absorption. Cooking eggs destroys the ability of avidin to bind biotin. Biotin deficiency, which is rare, can result from eat- ing raw eggs, total parenteral nutrition without biotin supplementation, AED use, and prolonged antibiotic use. Antiepileptic medications associated with biotin deficiency include phenytoin, primidone, and carbamazepine; these agents can inhibit transport across the intestinal mucosa and accelerate the metabolism of biotin. Alteration of intestinal flora results in biotin deficiency with antibiotic use. Human biotin deficiency is manifested by seborrheic dermatitis, fungal infections, a perioral, erythematous, macular rash, fine brittle hair, hair loss, depression, men- tal status changes, myalgias, and paresthesias. In addition to biotin therapy to counteract the adverse effects of AEDs, biotin is used to treat seizures secondary to biotinidase deficiency. Biocytin, the product of proteolysis of biotin-containing proteins and peptides, is cleaved by biotinidase into lysine and biotin, which is then free to be absorbed across the intestinal mucosa and used in multiple carboxylation reactions. Mutation of the gene that encodes for biotinidase is localized to chromosome 3p25 and results in seizures, ataxia, neu- ropathy, auditory dysfunction, breathing irregularities, and optic atrophy, as well as skin rashes, hair loss, and chronic candidiasis. Seizures are the presenting symp- tom in 38% of patients with biotinidase deficiency and are found in up to 55% of patients at some time before treatment (50). Generalized seizures (tonic-clonic, clonic, and myoclonic) and infantile spasms can occur (51, 52). Biotinidase deficiency is readily screened for by enzyme assay, and is part of newborn screening in many states and countries around the world. Recommended daily treatment is 5 to10 mg of biotin. Pyridoxine Pyridoxine, or vitamin B 6 , is a cofactor involved in the metabolism of amino acids and multiple neurotransmit- ters, including gamma-aminobutyric acid (GABA). Glu- tamate decarboxylase, the enzyme responsible for the conversion of glutamate to GABA, requires pyridoxine. Insufficient concentrations of pyridoxine or glutamate decarboxylase dysfunction result in diminished pro- duction of GABA and increased concentrations of the excitatory neurotransmitter glutamate, producing cir- cumstances favoring seizure activity. Seizures associated with pyridoxine are classified as pyridoxine deficient, pyridoxine dependent, or pyridoxine responsive. Pyridoxine-deficient seizures were first reported in 1950 when children given a diet lacking in pyridoxine experienced seizures that resolved rapidly with intravenous doses of 50 mg pyridoxine (53). Later case reports were associated with baby formulas containing insufficient levels of pyridoxine. Vitamin B 6 -deficient seizures typically begin in the first 4 months of life. The seizures are refractory to AEDs, and a family history of seizures is unlikely. These seizures typically respond to a single dose of pyridoxine (1–5 mg) and do not recur if dietary intake is adequate. Neonatal seizures refractory to standard AEDs are the characteristic manifestation of pyridoxine-dependent epilepsy, a rare genetic disorder that can present as late as the second year of life. These neonatal seizures may take the form of partial, atonic, or generalized myoclonic episodes, as well as infantile spasms (54). Status epilepti- cus or seizures may occur in utero. EEG findings include focal, multifocal, and generalized epileptiform discharges. If seizures in early life are resistant to standard treat- ment, consider pyridoxine-dependent seizures and give an intravenous dose of 50 to 100 mg of pyridoxine. The response to pyridoxine may be dramatic and rapid; EEG monitoring during administration may reveal an abrupt cessation of seizure activity. Children responding to the intravenous dose of vitamin B 6 should then be maintained on daily supplementation to ensure seizure control and promote normal development. Confirmation of the diag- nosis requires cessation of treatment with recurrence of seizure activity, then restarting vitamin B 6 and regaining a seizure-free state. An atypical form of pyridoxine-dependent seizures characterized by later onset may be manifested by 55 • VITAMINS, HERBS, AND OTHER ALTERNATIVE THERAPIES 715 seizures with febrile illness and episodes of status epilepticus. Intravenous pyridoxal phosphate, the active form of vitamin B 6 , may be more effective than the oral form of pyridoxine in treating pyridoxine-dependent seizures (55). Pyridoxine-responsive seizures were first described in 1968 (56). Pyridoxine is used to treat infantile spasms associated with diminished GABA concentrations in chil- dren and evidence of pyridoxine deficiency. There are no randomized, controlled trials of this use, but two prospective, open-label studies of pyridoxine treatment for infantile spasms revealed response rates of 13% to 29% (57, 58), raising the question of whether response to pyridoxine therapy exceeds the spontaneous remis- sion rate. Data are insufficient to determine whether vitamin B 6 is effective in treating infantile spasms (59). Folate Folate is another vitamin that plays an important role in the health care of individuals with epilepsy, primarily in relation to AED side effects and the care of women of childbearing age, but also in the treatment of seizures in rare metabolic disorders. Folate is essential for DNA synthesis, and inadequate concentrations are associ- ated with an increased risk of fetal neural tube defects. Certain AEDs (phenytoin, carbamazepine, and barbi- turates) can decrease folate absorption. The American College of Obstetricians and Gynecologists in 1996 and the American Academy of Neurology in 1998 published statements recommending folate supplementation in women with a history of a previous pregnancy affected by a neural tube defect and girls and women of childbearing age with epilepsy. Dosage recommendations range from 0.4 to 4 mg daily. Folate deficiency is also associated with elevated homocysteine levels, which increase the risk of cardiovascular disease in both men and women. Seizures are associated with two disorders of folate activity, cerebral folate deficiency, and folinic acid- responsive seizures. Folinic acid-responsive seizures are most often noted in the neonatal period. The medically refractory seizures are at times mistakenly thought to be related to perinatal hypoxic-ischemic injury because of the presence of atrophy and abnormalities of the white matter seen on magnetic resonance imaging (MRI) of the brain. Analysis of cerebrospinal fluid with high-perfor- mance liquid chromatography revealed an as yet uniden- tified compound (60). Seizures responded to treatment within 24 hours of folinic acid administration. AMINO ACIDS AND SUPPLEMENTS Gamma-Aminobutyric Acid The fact that GABA is an inhibitory neurotransmitter has led to both the development of aids that enhance the effect of GABA and attempts to increase its cerebral concentrations via oral supplementation. GABA is not well absorbed across the blood-brain barrier, even when nitric oxide and other free radicals thought to increase the permeability of the blood-brain barrier are used simulta- neously, and increased brain GABA levels are not known to affect seizure activity (61, 62). Carnosine Research into the use of carnosine in the treatment of epilepsy has led to conflicting results. In one study (63), higher levels of homocarnosine were found in children with refractory epilepsy than in those with medically controlled epilepsy. In other studies (64, 65), greater concentrations of homocarnosine were associated with better seizure control. The usefulness of carnosine in the treatment of epilepsy remains uncertain. Taurine Taurine is an amino acid that acts as an inhibitory neu- rotransmitter in multiple metabolic pathways, includ- ing cell membrane stabilization, regulation of cellular calcium levels, and detoxification. Genetic variations of taurine metabolism occur in some epilepsies (66). Although taurine in higher concentrations is associated with lower seizure susceptibility, and in lower concentra- tions with increased seizure activity, there is no conclusive evidence that taurine supplementation improves seizure control (67). One unblinded study of 25 children with intractable epilepsy treated with taurine reported com- plete seizure control in only 1 patient, a greater than 50% decrease of seizure frequency in another, and a less than 50% decrease of seizures in 4 patients, but no effect in 18 patients (68). No more than transient effects were noted in another unblinded study of 9 patients with intractable seizures. Five patients were seizure free for about 2 weeks, seizure frequency was temporarily reduced by 25% in 1 patient, and no effect was noted in the remaining 3 patients (69). Carnitine Treatment of mice with carnitine before exposure to a pro- convulsant agent had a protective effect on the brain, with reduced seizure frequency noted, but no human research has shown similar results (70). Carnitine- deficient states can be associated with the use of valproate. Clinically significant carnitine deficiency is not common, but may be associated with fatigue, weakness, cardiomyopathy, hypotonia, poor growth, and hyperammonemia. Carni- tine supplementation is recommended for patients with deficiency syndromes, but the use of carnitine prophy- lactically is not advised (71). V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 716 Glycine Glycine, another inhibitory neurotransmitter, may reduce seizure frequency at a dose of 200 mg a day (72), and one study showed a reduction of seizures provoked by strychnine in animals (73). However, most reports show no significant anticonvulsant effect of glycine (74, 75). HERBS The use of herbal therapy has dramatically increased during the last decade. Despite their common use, lit- tle is known about the efficacy or side effects of these compounds. This is due not only to the paucity of con- trolled trials and rigorous research, but also to the lack of an oversight agency. Moreover, side effects tend to go unreported, or their incidence can be increased by the lack of knowledge on proper dosing and administration, misidentification of a particular herb, or poor manufac- turing and quality control. New studies are in progress, but long-term effects will not be known for many years. The lack of information on these supplements makes it even more difficult for the practitioner to advise patients appropriately. Nevertheless, from increasing experience, knowledge about these substances continues to expand. Most of the available information must be adapted from the adult population, keeping in mind the unique dif- ferences in the physiology and underlying conditions of the pediatric population. Extreme caution must be taken when these substances are a component of treatment, because they can have profound side effects, negatively affect other conventional medications, or worsen preex- isting conditions. All herbs have potential risks and side effects during pregnancy and, in particular, can negatively affect the unborn fetus; therefore their use during preg- nancy and lactation is contraindicated (76). Many popular herbs have been used in patients with epilepsy, but the mechanisms of their antiseizure activity are often unknown. Some herbs in toxic doses may actu- ally provoke seizures. Comorbid conditions should be taken into account, because many of these supplements may interact with other medications or may be contra- indicated in certain individuals. Of note, blue cohosh (Caulophyllum thalictroides) is an herb that has some properties similar to those of nicotine and is primarily used to induce labor. Its seeds are bright blue and eye- catching to children, who are at particular risk for poison- ing if they ingest larger than recommended quantities (76). It is beyond the scope of this chapter to describe each individual herb in detail. Table 55-2 provides information about some of the more popular herbs. Kava (Piper methysticum) is used for the allevia- tion of anxiety. It can also be used as an antiepileptic supplement. It potentially exhibits various mechanisms of action, including the inhibition of L-type calcium channels and sodium channels, increase of K ϩ outward current, and enhancement of GABAergic inhibitory neu- rotransmission in animal studies (77). Although many studies have evaluated its efficacy in anxiety, there are few large studies involving patients with epilepsy. Kava’s toxicity is increased when it is combined with alcohol, benzodiazepines, and barbiturates (78). Cases of hepa- totoxicity have been reported. Its use is contraindicated in children less than 12 years of age. Gotu kola (Centella asiatica) has a variety of uses. Animal studies suggest that it is protective against sei- zures via action at D2 receptors and possible cholinergic mechanisms, and it delays penetylenetetrazol-induced seizures. Some reports suggest that this herb may also improve children’s cognitive status, but the sample sizes were small (76). More than 30 herbs have been found to block sei- zures in animal experiments (79). Mistletoe (Viscum), for example, is protective against pentylenetetrazol- and bicuculline-induced seizures in animal models (80), but has no significant effect in the N-methyl-D-aspartic acid (NMDA) tonic seizure model. Data from human stud- ies, however, are insufficient to recommend its use. It is an extremely toxic substance that may cause cardiac, neurologic, and gastrointestinal side effects. Some herbs should not be used despite their popu- larity. Ginkgo biloba has been grown in China for more than 200 years. Typically, it is used in the treatment of cognitive deficits such as in Alzheimer’s and multi-infarct dementia. It is believed to act as a free-radical scavenger. It reportedly can reduce the seizure threshold, induce seizures, or both (81). Ginkgo biloba should be avoided in patients with epilepsy because it can decrease the effec- tiveness of certain AEDs, including carbamazepine, phe- nytoin, and phenobarbital (81). The herb should not be used in individuals taking tricyclic antidepressants, which can also lower the seizure threshold (81). Ginkgo biloba must be used with caution in patients taking anticoagu- lants because of possible bleeding (82, 83). Valerian (Valeriana officinalis) is commonly used as an anxiolytic and sleep aid. It is thought to inhibit the deg- radation and reuptake of GABA. Studies on its efficacy, safety, and potential drug interactions are sparse. Because valerian binds to the same receptors as benzodiazepines and may cause sedation, it should not be combined with benzodiazepines or sedatives such as barbiturates. Tremor, headache, cardiac disturbances, and gastrointes- tinal upset have been reported in patients using valerian in high doses or for a prolonged period of time (84). Primrose oil and borage, both used for various con- ditions, are known to lower the seizure threshold (81). Another widely used herb, St. John’s wort, which is used to treat depression, is believed to inhibit GABA and other neurotransmitters. Theoretically, this mechanism 55 • VITAMINS, HERBS, AND OTHER ALTERNATIVE THERAPIES 717 TABLE 55-2 Common Herbs Used as Adjunctive Treatment in Epilepsy HERB LATIN NAME COMMON USES PLACE OF ORIGIN CHEMISTRY SYSTEMIC EFFECTS CNS EFFECTS PREGNANCY ISSUES American Veratum viride Antiemetic, United Similar to Blood pressure Paresthesias, Teratogenic hellebore neuralgia, States steroids alteration, weakness, pneumonia gastrointestinal and paralysis, respiratory problems, seizure salivation; high risk of side effects, narrow therapeutic index Behen Moringa Antimicrobial, India Contains Gastrointestinal Dizziness Possible abortive oleifera gastrointestinal glucosinolates, problems effect ailments fatty acids Betony Stachys Respiratory and Europe, Part of mint Hypotension, — Uterine officinalis gastrointestinal North Africa, family, related gastrointestinal contractions ailments, Siberia to tannins problems, hepatic dysfunction Black cohosh Cimicifuga Menstrual pain North America Estrogen effect Hypotension, Sedation, Increased risk of racemosa gastrointestinal headache spontaneous problems; not for abortion long-term use Blue cohosh Caulophyllum Induce labor Midwest and Similar to Hypertension, Seizures Uterine thalictroides Eastern United nicotine gastrointestinal contractions, States, Canada problems, increases teratogenic glucose; poisonous to children, cardiotoxic to neonates Calotropis Calotropis Antineoplastic Asia, India, Related to Gastrointestinal Seizures — procera Africa, Pakistan, steroids steroids Sunda Islands bradycardia; highly toxic European Paeonia Pain, headache Southern Europe, Contains tannins, Hypotension No Uterine peony officinalis Asia flavonoids anticonvulsant contractions effect in studies Ginkgo Ginkgo biloba Cognitive China Platelet-activating Bleeding Seizures — impairment factor antagonist V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 718 Goto kola Centella asiatica Antimicrobial, South East Asia, Consists of Contact dermatitis, — Should not be antineoplastic, India, Sri Lanka, triterpene acids infertility, used in pregnancy CNS depressant, China, and sugar hyperglycemia, wound healing Madagascar, residues, affects hyperlipidemia South Africa, D2 receptors Southeastern and cholinergic United States, system Mexico, parts of South America Groundsel Senecio vulgaris Worm infestation Europe, Asia, Contains Hepatic dysfunction, — — Africa, Australia, alkaloids, carcinogenic; Americas flavonoids should not be taken internally Kava Piper Anxiety South Pacific Inhibits L-type Hypertension, Acute Loss of uterine methysticum Ca 2ϩ and Na ϩ gastrointestinal and dystonic tone channels, respiratory problems, reaction increases K ϩ hepatic dysfunction, outward current, leucopenia, enhances GABA thrombocytopenia, transmission; dermatitis; should member of black not be used in pepper family children Ͻ12 years Lily of the valley Convallaria Arrhythmia, — Related to Gastrointestinal Headache, — majalis cardiac steroids problems, cardiac stupor, changes insufficiency arrhythmia; many in color drug interactions, perception highly toxic, not recommended for use Melatonin* — Sleep disorders, — Derivative of — Drowsiness Should not be jet lag serotonin used in pregnancy TABLE 55-2 (Continued) HERB LATIN NAME COMMON USES PLACE OF ORIGIN CHEMISTRY SYSTEMIC EFFECTS CNS EFFECTS PREGNANCY ISSUES 55 • VITAMINS, HERBS, AND OTHER ALTERNATIVE THERAPIES 719 Mistletoe Viscum album Cancer, England, Contains choline, Blood pressure Coma, seizures, Uterine seizures, Europe, histamine, alteration, sedation, contractions heart disease, Asia tyramine gastrointestinal psychosis headache problems, bradycardia, cardiac arrest; highly toxic Mugwort Artemisia Change of Northern Europe, Part of daisy Dermatitis, allergy; — Uterine vulgaris fetal position Asia, family not recommended contractions, in utero (breech), North America for use increased risk menstrual of abortion problems, depression Pipsissewa Chimaphilia Seizures, Europe, Asia, — Gastrointestinal — Should not be umbellale antispasmodic, North America problems, rash; used in diuretic problems, rash; pregnancy not recommended for use Skullcap Scutellaria Cancer, North America Contains Hepatic dysfunction, Confusion, Should not be laterifolia sedative flavonoids cardiac arrhythmia seizures used in pregnancy Valerian Valeriana Anxiety, sleep Europe, Mexico, Inhibits Gastrointestinal Sedation, Uterine officinalis India, Japan degradation and problems, hepatic tremor, contractions reuptake of GABA dysfunction; many headache; drug interactions should not be used in children Ͻ14 years Yew Taxus baccata Antimicrobial Europe Contains Cardiotoxic, — Causes taxines, arrhythmia, spontaneous flavonoids severely toxic abortion CNS, Central nervous system; GABA, gamma-aminobutyric acid. *not an herb V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 720 can make seizures worse (84). Herbs containing thu- jone, such as wormwood and sage, which are used to treat gastrointestinal disorders, may have proconvul- sant effects. Table 55-3 lists some herbs that may cause seizures. Some herbs can interfere with the hepatic P450 system (Table 55-4) and, when used together with antiepileptic medications, produce toxic side effects or decrease their effectiveness. Other herbs can lower anticonvulsant levels or otherwise interact with AEDs (Table 55-5). MELATONIN Melatonin is an indolamine that is synthesized from tryptophan in the pineal gland. It is released in a cir- cadian pattern, with peak levels in the early morning hours (85). Its apparent main function is to signal the brain to induce sleep. Melatonin is used for a variety of conditions, including sleep disorders, jet lag, and autism. By regulating sleep patterns it appears to be helpful in attaining better seizure control, and from animal models, melatonin is helpful in preventing seizure-related brain damage. A variety of proposed mechanisms are thought to account for melatonin’s antiepileptic effect. It appears to increase GABA’s concentration in the brain and pro- tects against seizure-induced brain damage by inhibiting calcium influx into neurons and by free-radical scaveng- ing properties (86–89). When given orally, its blood concentration peaks within 1 hour, and usually returns to baseline within 4 to 8 hours (90). Melatonin’s effectiveness has been shown in ani- mal models. It inhibits kainic acid-induced seizures in rats. It also inhibits lipid peroxidation, is a potent free-radical scavenger, and reduces seizure-induced brain damage (91). Melatonin also blocks potassium cyanide-induced seizures in mice (92). Melatonin stimu- lates brain glutathione peroxidase activity, which is an antioxidative enzyme that metabolizes the precursor of the hydroxyl and peroxyl radicals to water. It also raises the electroconvulsive threshold in animal models and potentiates the anticonvulsive activity of carbam- azepine and phenobarbital (93). In addition, melato- nin significantly reduces neurobehavioral changes in mice, as well as morphologic changes in association with seizures, mostly in the CA3 region of the rat hip- pocampus (94). Most clinical studies have looked at the use of mela- tonin in a limited number of subjects. Its effectiveness and safety profile in epilepsy patients was supported by several open-label trials. Peled et al (95) found that five of six children with intractable epilepsy had significant improvement not only in seizure control but also in their cognitive function. Bazil et al (96) showed that patients with epilepsy had a peak level of melatonin that was 50% of controls’ peak level and that the peak occurred 3 hours before that of controls. Some studies have shown a lack of melatonin’s efficacy, which may be related to inadequate dosing or other factors (97, 98). TABLE 55-3 Herbs That May Cause Seizures Bearberry (Arcostaphylos uva-ursi) Borage (Borago officinalis) Ephedra (Ephedra sinica) Gingko (Gingko biloba) Ginseng (Panax ginseng) Ma Huang (Herba ephedra) Monkshood (Aconitum sp.) Primrose (Oenothera biennis) Yohimbe (Pausinystalia yohimbe) TABLE 55-4 Herbs That Inhibit the P450 System American hellebore Chamomile Echinacea Garlic Licorice Milk thistle Mugwort Pipsissewa Pycnogel St. John’s wort* Trifolium pratense (red clover) *Effect on the P450 system is controversial. TABLE 55-5 Herbs and Their Effects on Antiepileptic Drugs HERB DRUG EFFECT Septilin Carbamazepine Decreases drug level Sho-seiryu-to Carbamazepine Delays drug absorption Paeoniae radix Phenytoin Delays drug absorption Thujone Phenobarbital Reduces drug (wormwood, sage) efficacy Ginkgo Phenytoin, Reduces phenobarbital, drug efficacy carbamazepine 55 • VITAMINS, HERBS, AND OTHER ALTERNATIVE THERAPIES 721 PHYTOTHERAPY Practitioners of phytotherapy believe that there is an imbalance in the body and that specific herbs may restore this balance. Many plants are known for their anticon- vulsant properties. Approximately 150 preparations of plants have been investigated. Individual plants are usu- ally used but can be combined if necessary. In most cases, the active compound has not yet been identified. Studies have shown that some natural plant coumarins and tri- terpenoids exhibit anticonvulsant properties (99, 100). Several show promise against seizures (see Table 55-6), but further study is needed before their routine use. Albizia lebbek increases levels of GABA in the brain. Piper nigrum may have antagonistic actions at NMDA receptors. The efficacy of Casimiroa edulis has been shown in animal studies to be similar to that of phenytoin and phenobarbital. Ipomoea stans is similar in effectiveness to valproic acid. The action of Piper guineese and Psidium guyanensis is similar to that of phenobarbital (101). The toxicity or side effects of these plants are largely unknown. Some plants may interact with antiepileptic medications; Ruta chalepensis, for example, may increase the hypnotic effects of pheno- barbital. More work on the use of phytotherapy in epilepsy is needed. ASIAN MEDICINE Traditional Chinese medicine has been used for thousands of years and has been gaining interest in the Western world for quite some time. It is partly based on the view that the body is closely related to its surrounding outside world. The organs inside of the body are themselves con- sidered to be interconnected via an interlacing network of channels and collaterals (102). Most therapies are com- posed of several herbs. The use of combination therapy is thought to improve the effectiveness and lessen any pos- sible side effects. From the Chinese perspective, certain types of seizures are considered to be due to an exogenous or endogenous “wind.” In children, the pathogenesis is attributed to the insufficiency of the spleen, stagnation of phlegm, and reversed flow of qi (known as the vital forces of the body), and stirring up of the endogenous wind (103). Some open-label studies of traditional Chinese herbal mixtures have shown a reduction in seizures and fewer side effects compared with standard AEDs, but well-controlled double-blind studies are lacking. Numer- ous combinations of Chinese herbs are used to combat seizures; only a few will be discussed. Tianma gouteng yin is composed of amino acids, alkaloids, and fatty acids in addition to other compounds. Interestingly, it has been found to act as an NMDA-receptor antagonist. Not only does it have direct influences at the receptor, but it also helps to prevent neuronal injury and death (102). When quingyangsen (root) was given as an adjunct to standard AED treatment, almost 30% of patients had seizure control ranging from 2 to 9 months after initiating therapy (104). This compound has also been shown to block seizures in animal models (105). Zhenxianling contains different flowers, animal parts, and human placenta in addition to other substances. A study using Zhenxianling in 239 patients with refractory epilepsy, of whom 147 were aged 1.5 to 20 years, showed that 66% had a greater than 75% seizure reduction and an additional 30% had a greater than 50% reduction of their seizures (106). These effects were seen 1 to 5 days after treatment. In 15 patients with absence seizures, 11 had their seizure frequency reduced by 50% to 75%. A few studies have been performed using longdanxiegan tang, or a modified version, in absence epilepsy. Approxi- mately 90% of patients taking this herb showed signifi- cant clinical or EEG improvement (107, 108). In a study using capsules composed of a variety of Chinese supplements, a significant improvement was found among children with different types of epi- lepsy (103). More than 900 children were treated with these capsules, and their response was compared with that of only 160 patients treated with phenobarbital. In children taking the capsules, 57% had their seizures reduced by more than 75%. An additional 26% had a seizure reduction of 50% to 75%. The duration of indi- vidual seizures was also significantly diminished. In the control group, 40% of patients achieved a 75% seizure decrease and 12% had a 50% reduction in seizures. Approximately 1% had worsening seizure control. Fifty percent of children with absence and benign rolandic seizures had a 75% decrease in seizures. Two cases of infantile spasms were included in this study. One patient had a 75% reduction of seizures and the other a 50% to 75% decrease. Of those in the treatment group who previously had abnormal EEGs, 54% had normal EEGs at the end of the study period. In Japan, kampo medicines are herbal remedies used to combat various medical conditions, including epilepsy. Most of these therapies are mixtures of different herbs, TABLE 55-6 Some Homeopathic Remedies Used for Seizues FEBRILE SEIZURES NONFEBRILE SEIZURES Aconitum napellus Atropa belladonna Aethusa cynapium Chamomilla vulgaris Cuprum metallica Glonoinum Ignatia amara Zincum metallicum V • ANTIEPILEPTIC DRUGS AND KETOGENIC DIET 722 some of which are similar to those used in traditional Chinese medicine. Sho-saiko-to is an herbal formula commonly used to treat liver disorders; it also is recom- mended as a possible treatment for intractable epilepsy. Another formula similar to this compound, the Chinese bupleurum–cinnamon combination (chai-hu-keui-chi- tang), has shown some preliminary benefit in epilepsy. These formulas contain the same nine herbs with minor variations in their relative amounts. They appear to have equivalent effects (109). Sho-saiko-to has been adminis- tered to adults and children. The pediatric dose depends on the child’s weight (110). There are no well-designed clinical studies on the benefit of this formula in epilepsy. In one study (111), it was given to 24 patients who were taking multiple drugs for uncontrolled epilepsy. Six of the 24 patients had no seizures within 10 months of the herbal therapy. An additional 13 patients were improved, three had no change, and two did not complete the study. Improvements were seen as soon as 1 month. Tonic-clonic seizures seemed to have the best response rate. Another study (112) revealed possible cognitive improvements with the use of this supplement, but the study was flawed and not optimally designed. Animal studies (113) have shown that it can inhibit pentylenetetrazol-induced sei- zures as well as cobalt-induced seizures and neuronal damage. Other studies (114, 115) revealed that there were no changes in barbiturate potentiation. Adverse effects have rarely been reported. The for- mula has caused pneumonitis or hepatitis, or both, in a number of patients with liver disease, and has caused fatalities. Patients using this supplement must be advised to report coughs and fevers to their health care providers; prompt and careful follow-up is necessary (116, 117). Occasionally, gastrointestinal upset or mild transient symptoms are present. In addition to side effects, some of these supplements have been known to contain toxic ingredients that are not named on the label. These herbal remedies have been found to contain such elements as lead, arsenic, and mercury, which, if consumed in greater than safe amounts, can lead to serious consequences (118, 119). Although some report significant success with the use of these products, extreme caution should be main- tained. ACUPUNCTURE Acupuncture has been practiced in Asia for more than two thousand years. In the United States, where it has increased in popularity over the past 30 to 40 years, it is used by approximately one million individuals. This ancient therapy is used mostly for pain management, but also for a number of different conditions, includ- ing epilepsy. Up to 70% of people who undergo acu- puncture treatments do not inform their health care providers (120). Acupuncture involves the use of fine needles (now made of stainless steel) that are inserted into the skin at defined points of the body. For epilepsy, points along the scalp are key, as acupuncturists consider the scalp a direct projection of the cerebral cortex. Differ- ent points are selected depending on the different types and symptoms of seizures (121). Acupuncture is presumed to restore balance to the disruption of the natural flow of energy that the body requires to function normally. Acupuncture releases endor- phins, adrenocorticotropic hormone (ACTH), and other neurochemicals, such as GABA (122). Some studies show that afterward there is an increase of the serotonin level, which may lead to improved cognitive function (123). Specific sites are used to combat different conditions. The point naokong (GB19) is located near the occipital pro- tuberance. It is selected for acupuncture in a variety of medical conditions in addition to epilepsy, and has been used in children. It is said to have tranquilizing effects, regulate blood flow, and calm “endopathic wind.” In terms of efficacy, there is a paucity of well- performed and well-controlled clinical trials for evalu- ating the usefulness of acupuncture in epilepsy, as well as other medical conditions. This is due in part to the individualization of therapy. Acupuncture differs between individuals, making standardization difficult. Even sham acupuncture is difficult to assess, because nonspecific needling can lead to the stimulation of neurohormonal responses (124). Kloster et al (125) compared the effects of sham acupuncture and actual acupuncture in patients with intractable epilepsy. There was a small but statistically nonsignificant reduction in seizure frequency in both groups, perhaps due to the small sample size. No signifi- cant EEG changes were appreciated. Stavem et al (126) also failed to show that acupuncture significantly reduced seizures or had any effect on the patients’ quality of life. Adverse effects are rare, the most common being infection and trauma. Other rare complications such as pneumo- thorax, cardiac tamponade, hepatitis, and spinal cord injuries have also been reported. The transmission of human immunodeficiency virus (HIV) has rarely been reported. The importance of sterilization and universal precautions cannot be emphasized enough (120). In a child who had almost continuous simple par- tial seizures, acupuncture improved the seizures after seven sessions, and almost completely eliminated them by 30 sessions (127). Six months later, the patient was reported to be seizure free. In another study (121) involv- ing almost 100 children and adults, 66% had a greater than 75% reduction in seizures, and an additional 24% had a 50% to 75% reduction. Yang (128) reported the use of acupuncture in eight children with status epilepti- cus. Different acupoints were used depending on the case. Seizures ceased within 10 minutes in all cases. No [...]... Kenkyu 199 3; X:240–241 [As cited in reference (53)] ZONISAMIDE 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 737 Hosoda N, Miura H, Takanashi S, et al Clinical effects and blood concentration of zonisamide in epileptic children with partial seizures treated with a once-daily dose of zonisamide monotherapy Jpn J Ther Drug Monit 199 4; O-18:68 [As... nonepileptic seizures Epilepsy Behav 2004; 5:587– 592 Reiter JM, Lambert RD, Andrews DJ, et al Complex-partial epilepsy: a therapeutic model of behavioral management and EEG biofeedback Self-Control Epilepsy 199 0; 1:27–38 Andrews DJ, Schonfeld WH Predictive factors for controlling seizures using a behavioral approach Seizure 199 2; 1:111–116 Meencke HJ, Schmid-Schonbein C, Heinen G Methods and results of a... neuronal protector: experimental and clinical evidence Neurology 199 8:13:501–5 19 Ross C, Whitehouse W Melatonin treatment for sleep disorders in children with neurodevelopmental disorders: an observational study Dev Med Child Neurol 2002; 44:3 39 344 55 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 1 09 • VITAMINS, HERBS, AND OTHER ALTERNATIVE THERAPIES Mohanan PV, Yamamoto HA Preventative... perception survey Epilepsy Behav 2003; 4:511–514 Spatt J, Langbauer G, Mamoli B Subjective perception of seizure precipitants: results of a questionnaire study Seizure 199 8; 7: 391 – 395 Spector S, Cull C, Goldstein LH Seizure precipitants and perceived self-control of seizures in adults with poorly-controlled epilepsy Epilepsy Res 2000; 38:207–216 Lai C-W, Trimble MR Stress and epilepsy J Epilepsy 199 7; 10:177–186... infection and with sustained liver disease Am J Chin Med 199 1; 19: 121–1 29 111 Narita Y, Satowa H, Kokubu T, Sugaya E Treatment of epileptic patients with the Chinese herbal medicine “saiko-keshi-to.” IRCS Med Sci 198 2; 10:88– 89 112 Nagakubo S, Niwa S, Kumagai N, Fukuda M, et al Effects of TJ -9 6 0 on Sternberg’s paradigm results in epileptic patients Jpn J Psychiatry Neurol 199 3; 47:6 09 6 19 113 Sugimoto... co-treatment with qingyangshen and diphenylhydantoin sodium on rat hippocampal c-fos expression during seizures J Tradit Chin Med 199 6; 16:48–50 Tiancai W Effects of Chinese medicine Zhenxianling in 2 39 cases of epilepsy J Tradit Chin Med 199 6; 16 :94 97 Li X The herbal treatment of petit mal epilepsy based on traditional Chinese medicine liver and spleen therapies Liaoning J Tradit Chinese Med 199 8;... doses (and with placebo) and during the fixed-dose phase of the trial Additional pivotal studies with ZNS utilizing a randomized, placebo-controlled, add-on design have been performed in adult patients with refractory, partial-onset epilepsy (57– 59) Representative results of these four studies are shown in Table 5 6-1 Continued observation of these refractory partialepilepsy patients with open-label... 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Jpn J Psychiatry Neurol 199 3; 47:6 09 6 19. 113. Sugimoto A, Ishige A, Sudo K, et al. Protective effect of “Sho-siko-to-go-keishi-ka- shaduyaku-to” (TJ -9 6 0) against cerebral ischemia. In:. precipitants and perceived self-control of seizures in adults with poorly-controlled epilepsy. Epilepsy Res 2000; 38:207–216. 17. Lai C-W, Trimble MR. Stress and epilepsy. J Epilepsy 199 7; 10:177–186. . Effect of Sho-saiko-to (xiao-chai-hu-tang) on HBeAg clearance in children with chronic hepatitis B virus infection and with sustained liver disease. Am J Chin Med 199 1; 19: 121–1 29. 111. Narita