Alternative therapies in treating epilepsy
Doctor of Pharmacy Candidate
Wingate University School of Pharmacy
Michelle Welborn, PharmD
Intractable Childhood Epilepsy Alliance
Many people in the United States experiment with complementary and alternative medicines (CAM) on regular basis. The objective of this article is to provide a synopsis of available literature regarding use of alternative therapies in the treatment of epilepsy. Evidence based data on efficacy of CAM therapies in epilepsy and safety concerns on the use of alternative therapies are discussed. The CAM therapies described in this article are EEG biofeedback, acupuncture, yoga & meditation, Reiki, fish-oil supplementation, homeopathy and traditional herbal medicines.
Alternative therapies in treating epilepsy
Despite the advent of antiepileptic drugs (AEDs) and surgical management of epilepsy, 30 – 40 % of patients do not become seizure free, develop resistance to their AEDs, or experience major AED-related adverse events (Nagai et al., 2004). Patients with epilepsy often choose complementary and alternative medicine (CAM) alone or adjacent to AEDs because they believe that natural remedies are better and safer than prescribed AEDs to treat their chronic condition or they or hopeful alternative therapy will help drug resistant epilepsy. Some people around the world do not have access to modern drug regimens; which is why patients choose CAM, as they are easily accessible. Per the National Center of Complementary and Alternative Medicine (NCCAM) CAM is defined as “a group of diverse medical and health care systems, practices, and products that are not generally considered part of conventional medicine” and is not generally taught at the western medical colleges (e.g. American) . This article will highlight the findings of CAM therapies such as biofeedback, acupuncture, yoga and meditation, reiki, fish oil supplementation, homeopathy, traditional Chinese medications and explores what is known about the utilities of CAM in treating patients with epilepsy based on recent publications.
Epilepsy is a chronic disorder of central nervous system manifested by an abnormal and excessive discharge of a set of neurons of the brain, including cortical cells. It is classified as recurrent unprovoked seizures that affect children’s and adults of all races, ethnic backgrounds, religions and social classes (McElroy, 2009). Per the Centers for Disease Control and Prevention, approximately 200,000 new cases are diagnosed with epilepsy every year and it is estimated that one in ten people will have a seizure at some point in their lives in the United States (CDC, 2010). About 3 million Americans have epilepsy and its prevalence increases with age (CDC, 2010). Although epilepsy can occur at any age, it is most commonly diagnosed either in childhood or after the age of 65 (CDC, 2010). Cheuk et al., suggest that 70% people with epilepsy will find seizure relief on one or more anti-epileptic drugs or go into remission. The remaining patients will continue to have seizures despite treatment with adequate doses of AEDs and are considered drug resistant. (Cheuk et al., 2009). This has lead to constant search for newer drugs and alternative therapies to treat epilepsy.
An literature search of pubmed, Cochrane library, and epilepsy lit between years 2000 and 2010(present) using the words “alternative therapies in epilepsy”, “mind-body therapies for epilepsy”, “EEG biofeedback”, “acupuncture”, “fish-oil for epilepsy”, “epilepsy disorder”, “herbal medicines”, and “Chinese medicines treating epilepsy”. Out of the 80 articles, 24 of them (including review articles, clinical trials, case series or reports) were analyzed to be used for this paper.
EEG Biofeedback or neurofeedback as described by McElroy-Cox (2009) is “a specific index of an automatic body function where in brain waves, heart rate, or skin resistance is monitored and transmitted directly to the patient, thereby enabling the patient to become aware of normally unconscious body processes and to learn to gain control over them”. In epileptic patients, biofeedback is considered similar to the mental relaxation technique that is conducted on observations by modifying EEG components and training them to increase the mu or sensorimotor rhythm or low-frequency components (such as DC-shift or slow cortical potentials) (Kotchoubey, 2002 & Uhlmann, 2001). However, its mechanism of action in helping seizures is not known.
Galvanic skin resistance (GSR) is a type of biofeedback training that acts as an indicator of peripheral autonomic change, with increased in skin conductance associated with an enhanced arousal level(Nagai et al., 2004). The authors conducted a single blind, randomized controlled study on 18 patients with drug-refractory epilepsy for a total of 12 sessions during the 1 month treatment period, to measure the efficacy of GSR (Nagai et al., 2004). Patients were randomly assigned either to an active GSR biofeedback group (n=10) or to a sham (placebo) control biofeedback group (n=8). Two patients were on no medications by choice and rests of them were mainly on combination of AEDs (carbamazepine and sodium valproate). The post treatment period, patients in the biofeedback group (6 out of 10) experienced greater than 50% reduction in seizure frequency compare to no significant change in the control group. Following is the table derived directly from Nagai et al., 2004 of the number of seizures before and after the GSR treatment:
The author concludes, “GSR biofeedback has potential as a potent adjunctive nonpharmacological means of reducing seizure frequency in drug-resistant epilepsy” (Nagai et al., 2004).
A meta-analysis performed by Tan et al., (2009) on 10 studies involving 87 patients whose seizures were not controlled by drug therapy. Nine studies reinforced sensorimotor rhythms (SRM) and one study trained patient through slow cortical potentials (SCP). Grouped data of all the studies were presented in this meta-analysis. With contingent EEG biofeedback all the studies showed fewer weekly seizures and a significant reduction (P < 0.05) in seizure frequency. Thus the authors concluded that neurofeedback training is a possible treatment in patient whose seizures do not respond to medical therapies.
Acupuncture is a traditional Chinese therapy with a growing presence in the United States and Europe. Jindal et al., (2008) stated that four percent of the US population used acupuncture at any time in their life span. Acupuncture is a process in which meridian points are pierced with fine needles in the specific areas of the body to achieve therapeutic response. Meridians in Chinese medicine is defined as the pathways of the positive and negative energy power, which carries on some of the communication between the various parts of human beings (Jindal et al., 2008). The safety of acupuncture has made it acceptable among the Chinese origin population. The proposed mechanism of acupuncture is still not clear. Per Moffet (2006) “acupuncture results in stimulation and release of neurochemicals, such as beta endorphins, enkephalins, and serotonin”. Acupuncture enhances the blood flow in the body by strengthening the energy flow (qi) of the kidney, spleen and also regulating the brain (Jindal et al, 2008).
A Cochrane review of acupuncture in epilepsy by Cheuk et al., (2009) included eleven randomized controlled trials. The trials had small sample sizes and some were not powered to show a statistical significance. Some trials in this review also compared acupuncture with AEDs without any sham or placebo control group. Each trial had small sample size with a large percentage of adult patients and, the authors could not prove whether acupuncture has any beneficiary effects to AEDs or on different age groups. The authors suggested that studies using a larger sample size with appropriate standardized control groups are necessary to assess the efficacy of acupuncture in treating epilepsy.
Yoga & Meditation:
Yoga and meditation are widely practiced as a stress-relieving mental exercise to improve physical and behavioral factors. There are no proposed mechanisms or studies claiming that meditation can control or reduce the frequency, duration and intensity of seizuresSathyaprabha et al (2008) conducted a study that investigated “yoga’s effect on the autonomic functions of patients with refractory epilepsy”. Per the author Refractory epilepsy was defined “as seizure frequency greater than two seizures per month for at least 2 years, despite the use of two or more first-line AEDs at their maximum tolerated doses” (Sathyaprabha et al., 2008). This study was conducted with the basis of knowledge that considering autonomic dysfunction may play an important role in the underlying mechanism of sudden unexplained death in epilepsy (SUDEP) (Sathyaprabha et al., 2008). In the study, 18 members performed yoga (breathing exercise, meditation & yoga postures) and 16 members performed non-yoga exercise (quiet sitting & simple physical exercise) for one hour daily for 10 weeks. The autonomic parameters measure included heart rate parameters—(1) deep breathing ratio (beats/minute), (2) Valsalva ratio, and (3) min: max ratio and blood pressure measures—(4) standing ΔSBP (mm Hg) and (5) isometric ΔDBP (mm Hg). The results were measured by baseline autonomic function parameters and by comparing each group with 142 healthy volunteers. The author determined that the yoga group showed significant reduction in seizures (P<0.05) with improved parasympathetic parameters compared to no changes in the non-yoga exercise group. Thus it was concluded that yoga might be used as an adjuvant therapy in management of autonomic dysfunction in patients with refractory epilepsy.
According to McElroy-Cox (2009), “Reiki is a healing practice that originated in Japan in which the practitioner places his or her hands on or just above the patient to facilitate the healing response”. Reiki-like healing practices involving transfer of life force or low level of electro magnetic force (EMF) from the healer to the patient have been in use in patients with seizure disorders (Kumar et al, 2003)
Kumar et al (2003) investigated the effects of Reiki on fifteen patients with refractory epilepsy (patients with persistent seizures, on 3 or more antiepileptic drugs in full dosage, and total compliance over a period of 3 years) that underwent 3 months of treatment with Reiki-like healing practices. All patients and controls were on the same dietary regimen, which gave adequate amounts of trace elements, especially magnesium throughout the course of the study. The Reiki-like treatment practices, if effective, are hypothesized to act via quantal perception since the EMF is too weak to be transferred by normal sensory perceptive mechanisms (Kumar et al, 2003). The present study was conducted to assess the efficacy of such treatment protocols in epileptic patients. The results showed decrease in seizure frequency but further investigation was needed as the study was of poor methodology with no control groups.
Fish oil is mainly composed of omega-3 fatty acids (FAs), eicosapentaonoic acid (EPA) and docosahexaenoic acid (DHA). Pischon et al. (2003) showed that increasing the dietary intake of omega-3 FAs can reduce the plasma inflammatory markers and Schlanger (2002) demonstrated that EPA could reduce seizures by decreasing these markers. Inflammation may be necessary in the development of atherosclerosis, and inflammatory markers such as interleukin (IL)-6, C-reactive protein (CRP) and tumor necrosis factor (TNF) alpha are autonomous risk factors for cardiovascular disease (Pischon et al., 2003). n-3 fatty acids have anti-inflammatory properties that are clinically used to treat symptoms of inflammatory diseases (Pischon et al., 2003). Pischon et al., 2003 also said that “both n-3 and n-6 fatty acids are substrates for human eicosanoid production and they share the same enzymes for the synthesis of prostaglandins and leukotrienes”. Eicosanoids (derived from n-3 fatty acids) has less inflammatory properties compared to n-6 fatty acids and so that author suggested that the ratio of n-3 to n-6 fatty acid intake may be crucial to inflammatory processes (Pischon et al., 2003). These relations were dependent on the intake of n-6 fatty acids suggesting that at low levels of n-3 fatty acid intake, n-6 fatty acids are linked with high levels of inflammatory markers, yet at high levels of n-3 fatty acid intake, the combination of both types of fatty acids is related to the lowest levels of inflammation (Pischon et al., 2003). Also evidence from previous studies and clinical trials has indicated that omega-3 FAs reduce the risk of developing cardiovascular diseases.
Sudden unexpected death in epilepsy (SUDEP) is one of the causes of death in epilepsy (Tomson et al, 2005). Epileptic patients with cardiovascular abnormalities during and between the seizures may possibly be at higher risk of dying from SUDEP (Stollberger, 2004). In 2008, Ferrari et al. determined that “chronic treatment with omega-3 fatty acids promotes neuroprotection and increases parvalbumin-positive neurons in the hippocampal formation of rats with epilepsy, suggesting that intake of omega-3 fatty acids may lead to positive plastic changes (lifelong ability of the brain to reorganize neural pathways based on new experiences) of the hippocampal formation of rats with epilepsy”. Parvalbumin is a member of a family of low-molecular weight, calcium-binding protein, that has been localized immunohistochemically in certain distinct subpopulations of neurons in the central nervous system and in non-neural tissue (skeletal muscles) (Shen W et al). It function is to acts as an intracellular buffer of calcium that is uniquely important in conferring protection to certain neurons in the hippocampus during epileptic seizure (Shen W et al).
A 12-week double blind, placebo-controlled, parallel group trial of 1.7g of omega-3 FAs supplementation was conducted in a residential facility on 68 patients with refractory epilepsy (four epileptic seizures per month) (Yuen et al., 2005). This trial concluded that there was a 50% percent of reduction in complex partial seizures during the first 6 weeks of treatment in both the supplement group (weeks 1-6) and the placebo group during the maintenance phase (Weeks 13-18). But the results were not consistent during the following 6-week periods. Adverse affects such as diarrhea, depression, paranoia, fatigue, breathlessness and sleepiness reported were less in the supplemental group compared to the placebo group. Due to the formulations used in this trial, EPA and DHA were raised while there was significant reduction in omega-6 FA arachidonic acid (AA) in RBCs and plasma; which could be the reason why there was no change in seizure activity during the rest of the 6-week period. In this trial, Fatty acid concentrations were measured by collecting 20 ml of venous blood in test tubes with EDTA and centrifuging the blood to separate erythrocytes (RBCs) from plasma. AED concentrations were measured using fluorescence polarization immunoassay and high-performance liquid chromatographic techniques (Yuen et al., 2005). In general, patients with neurologic disorder have shown much better efficacy with omega-3 FA supplementations when pure EPA was given. Thus, further investigation is needed to determine different doses of omega-3 FAs and its preparations in trials with large sample size and with longer duration of treatment (Yuen et al., 2005).
Homeopathy medicine is an alternative medical system that was developed by Samuel Hahnemann in late 1700s in Germany. He proposed a simple principle that “like should be cured with like” and that’s how homeopathic medicines are prepared today. The treatment is mainly individualized on the basis of patient’s physical & emotional state and is given in very small doses of remedies that in larger quantities would produce similar symptoms of illness.
Cuprum, hyosciamus, agaricus muscaricus, stramonium, silicea, causticum, aethusa cynapium, artemesia absinthium and cicuta virosa are the most frequently used homeopathic remedies in epilepsy (Ricotti et al., 2006). A case series conducted by Varshney (2007) on a homeopathic preparation of “Belladonna” in an uncontrolled study showed reduction in tonic-clonic seizures in 10 of 10 dogs with idiopathic epilepsy. “Belladonna is associated with violence of attack and suddenness of onset of convulsive movements” as said in the trial (Varshney, 2007). Unfortunately, studies on humans have not been conducted to prove the efficacy of homeopathic treatments.
Traditional Chinese medicine (TCM):
Since ancient times, herbal remedies have been utilized in TCM for the treatment of epilepsy. In the US, herbal medicines are regulated by the 1994 Dietary Supplement and Health Education Act. Kaufman et al (2002) stated that “nearly one in six adults in the United States taking prescription drugs are also taking at least one herbal remedy”. Herbal medicines are used by one-third of the patients with epilepsy to supplement their medical regimen with AEDs (Deckers et al., 2003). Physicians may be unaware of patient’s using herbal remedies with their prescription drugs; which may potentially lead to herb-drug interaction, toxicity or may cause death in some cases. Patients already on AEDs can increase their risk of toxicity by consuming herbal medicine that also contains AEDs in it.
A study conducted in Boston with 70 herbal medicines found that 20 % of these products contain potentially harmful levels of neurotoxic materials such as lead, mercury or arsenic that may cause seizures (Saper et al., 2004). Gingko biloba, ephedra, eucalyptus, pennyroyal, shankhapusphi, star fruit, star anise & sage are some of the herbal medicines containing neurotoxic components which can induce seizures (Samuels et al., 2008). Also herbs such as Saint John’s wort, ginkgo biloba, shankhapusphi, sho-seiryu-to/sho saiko –to and grapefruit can significantly alter the response to AED treatment, even with accepted therapeutic doses (Samuels et al., 2008). Predicting herb-drug interaction is extremely difficult as the herbal formulas contain several herbs and it is generally harder to know which herbs are present and at what concentrations. Following is the table derived from Samuel et al., 2008, which shows the mechanism of action and interactions of the herbal products discussed in this trial:
In United States, NCCAM recommended that anyone who wants to use an herbal supplement should consult a properly qualified medical professional in herbal medicine. As of now, there are no such guidelines out on herbal remedies for the treatment of epilepsy. Li Q et al (2009) conducted a Cochrane review that evaluated data from 1125 patients from five studies in which participants were randomized to either AEDs or traditional Chinese medicine (TCM). The herbal medicines compared in these 5 studies with AEDs are as follows :1) Xiaxingci granule versus Phenytoin, 2) Dianxianning pill versus valproate, 3) Tianmadingxian capsule versus Phenytoin, 4) Zhixian I versus Phenytoin & 5) ‘Antiepilepsy capsule’ versus Phenobarbital. The outcomes reported in these studies included improvement in EEG and adverse effects, seizure freedom or having a 50% or less reduction in seizure frequency. Although the studies found some benefits, they were not conducted using proper methods (such as randomization, blinding, or allocation concealment) and also provided limited explanations of baseline and follow up data. There were no adverse effects reported other than a slight gastrointestinal discomfort in two of this studies. Thus the authors concluded that the data available is not reliable to support TCM as a treatment for epilepsy and suggested that high quality randomized clinical trials with larger sample size are needed to evaluate the effectiveness and safety of herbal medicines for epilepsy (Li Q et al., 2009).
CAM therapies are heterogeneous and have become increasingly popular in the past two decades. Clinical studies have markedly shown that a significant number of people with epileptic disorders use these treatments. As shown in this article, most studies lacked a well-designed, large sample size, and randomized setting to determine if the respective therapies are reliable for the treatment of epilepsy. Though, there is couple of therapies where the evidence for the CAM showed some benefits, but the studies were not reliable to claim of their use for the treatment of epilepsy. Physicians should regularly ask their patients about the use of CAM therapies, due to the potential risk of herb-drug interactions. As most of the studies could not prove to determine if CAM therapies are used for the treatment of epilepsy, additional research is still warrantedto see if they actually improve quality of life for the patients with epilepsy. Additional studies on herb-drug interaction with AEDs based on pharmacokinetics and pharmcodynamics are needed.
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