Case Report in Integrative Medicine

CASE REPORT

CASE REPORT IN INTEGRATIVE MEDICINE: A 24-YEAROLD MALE WITH MEDICALLY INTRACTABLE SEIZURES OPHER CASPI, MD, RUSSELL H. GREENFIELD, MD,

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STEVEN GURGEVICH, PhD

Patients with intractable epilepsy continue to suffer medical complications and experience a decline in quality of life despite the advent of new antiepileptic medications. Physicians caring for such patients are often frustrated with the lack of viable options. The case of a 24-year-old male with difficult-to-control seizures who presented to our Integrative Medicine Clinic highlights the integrative approach to patient care and describes additional therapeutic measures that may benefit patients with intractable epilepsy. (Int Med 1998;1:173–176)  1999 Elsevier Science Inc. Key Words: epilepsy; vitamin E; diet; mind-body medicine; integrative medicine.

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24-year-old right handed Hispanic male presented to the Integrative Medicine Clinic at the University of Arizona Health Sciences Center, accompanied by his mother, for the evaluation of a medically intractable seizure disorder present since infancy. At the time of the first visit, he was experiencing a generalized grand mal seizure every week, the duration of which was 2–3 minutes on average. During the previous 2 years, his seizure activity had been stable at 2 episodes per month. His most recent seizure had been 2 weeks prior to his appointment. He noted that seizure activity was related to exertion and fever, but that he had no headache after his seizures nor symptoms of Todd’s paralysis. His seizures were described as beginning with an initial vocalization followed by his eyes “rolling up” and subsequent generalized convulsions. After his postictal period resolved, he experienced significant fatigue of variable duration. Both the patient and his family voiced a desire to decrease his medication requirements. It should be noted that compliance was never in doubt as his anticonvulsant medication levels were consistently within the therapeutic range. He was the product of a full-term pregnancy during which there were no problems except for mild spotting

From the Program in Integrative Medicine, Department of Medicine, College of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona, USA. Address reprint requests to: Opher Caspi, MD, Fellow, Program in Integrative Medicine, Department of Medicine, College of Medicine, University of Arizona—Health Sciences Center, PO Box 245153, Tucson, AZ 85724-5153, USA; Tel: (520) 626-6667; Fax (520) 626-6484; E-Mail: [email protected]

 1999 Elsevier Science Inc. 1096-2190/98/$–see front matter PII S1096-2190(99)00003-7

during the last months of gestation. Labor and delivery were reportedly normal, and he was healthy until he had a generalized seizure in association with a fever at the age of 9 months. The episode continued in a stuttering fashion for 15–30 minutes. The results of an in-depth evaluation at that time were unremarkable. His second seizure occurred 2 weeks later while afebrile. Subsequent seizures were likewise not necessarily associated with febrile episodes. He was treated with phenobarbital thereafter, and 1 year later had diphenylhydantoin added in an attempt to gain enhanced control over the seizure activity. At age 4 months, primidone was inserted in place of phenobarbital. For several years, the patient had a seizure every 2–3 months, with the greatest seizure-free period being 6 months. By age 8, the frequency of seizure activity had increased to 1–2 every 7–14 days. He was on mephobarbital and diphenylhydantoin, and his mother had noted occasional staring spells lasting seconds at a time. An EEG revealed no evidence of petit mal activity, but did show bioccipital slowness, worse on the left, with rare sharp forms, as well as left temporal slowness. At age 12, his daily medication included valproic acid 1,750 mg, carbamazepine 900 mg, and phenobarbital 135 mg. He was noted to be developmentally normal, yet movements were slow and he required special education classes. His baseline seizure activity was now 2–3 episodes per week. An MRI had been performed, the results of which were unremarkable. At the age of 22, he was having a seizure every week, his longest period without a seizure in recent years having been 4–6 weeks. He reported no aura, and EEG, MRI, and neuropsychiatric examinations were noted to be normal. Integrative Medicine Vol. 1, No. 4, pp. 173–176, 1998

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He had sustained multiple injuries in the past related to his seizure activity, including facial lacerations and skull fractures. He was on carbamazepine 900 mg, valproic acid 3,000 mg, and gabapentin 2,700 mg daily. He had been on diphenylhydantoin but developed gingival hyperplasia, and stopped taking phenobarbital due to memory lapses, aggressive behavior, and poor concentration. At this time, he was offered three options: 1) evaluation for surgical intervention, 2) entrance into a drug study protocol, or 3) starting on lamotrigine (though it was stated “it would be remarkable if he would respond to lamictal [lamotrigine] at this time”). A decision was made to undergo video EEG monitoring in preparation for possible surgery, but noninvasive monitoring did not reveal a localized point for surgical intervention. It was felt that invasive monitoring would be required prior to surgery, but the patient declined. Two years later, he presented to the Integrative Medicine Clinic. The only other pertinent medical history was a tonsillectomy. There was no history of meningitis, encephalitis, any other CNS infection, nor head trauma. He denied smoking, alcohol, or drug use. He did partake of caffeinated beverages and chocolate on occasion, and his diet was unrestricted. He had graduated high school and had some friends, but spent most of his days helping his father at work and caring for a horse and dog. He relaxed by listening to music, and stated that his greatest desire was to drive a car. His mood was noted to be generally very good, and he was rarely if ever depressed. His mother related a history of febrile seizures until age 8. Two first cousins on the mother’s side, as well as an aunt and an uncle, reportedly had seizure disorders. Physical examination revealed a well-developed, wellnourished Hispanic male who spoke slowly but clearly. Vital signs were: temperature 36.58C, pulse 68, blood pressure 130/74. Head and neck examination was unremarkable except for slightly visible scars and very mild lateral nystagmus bilaterally. Auscultation of the lungs and heart was unremarkable, and the abdominal examination was normal. The extremities were free of clubbing, cyanosis, or edema. On neurological examination cranial nerves II–XII were intact. Motor function was 5/5 throughout and sensation was intact to light touch and pin prick. There was no dysmetria, and Romberg testing was normal. Subsequent to the patient’s initial visit, he was presented to the Integrative Medicine team at the weekly case conference. Various therapeutic approaches to patient care are represented at the table, and participants include a practitioner of Oriental medicine, a psychologist with expertise in mind- body interventions, a practitioner of homeopathy, an osteopathic physician, a nutritionist, a pharmacist, a spiritual/religious leader, an expert in botanical medicine, and the program in Integrative Medicine personnel. Each expert had the opportunity to address the patient’s presenting issue(s) and was offered the opportunity to contribute to the patient’s care plan. Recommendations were discussed in depth with the patient and his family at the first follow-up visit, and included an emphasis on the use of 174

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vitamin E, a discussion of the ketogenic diet, and a description of mind-body interventions. On follow-up evaluation 4 months later, he had experienced a 6-week seizure-free period until having a seizure the week prior to his appointment. His mother noted that his seizure episodes seemed “lighter,” and that the postictal periods were shorter than usual. His neurologist had tapered him off of neurontin while increasing his valproic acid to 2,000 mg and his carbamazepine to 1,200 mg a day. He had started taking vitamin E 400 IU every day and was avoiding caffeinated products. The family had made a group decision against trying the ketogenic diet due to its rigorous nature. Hypnotherapy was recommended as adjunctive therapy, and he subsequently underwent this mind-body intervention in the Integrative Medicine Clinic. A tape was made for him to utilize at home during his second and last session. During the following months, his frequency of seizure activity remained at one per 4–6 weeks. His neurologist, who was aware of the patient’s additional therapies, weaned him down to 2,500 of valproic acid and 800 mg of carbamazepine a day. The patient again declined surgical intervention, including the use of a vagus nerve stimulator, but stated that he wanted his medical regimen simplified even further. A decision was made to start lamotrigine in the hope of ultimately controlling his seizures with a single agent. Two months later, the patient had experienced one seizure in the previous 6 weeks.

DISCUSSION Most patients with medically intractable seizures suffer from idiopathic epilepsy or have some underlying pathology which may or may not be readily identifiable [1]. Despite the plethora of new antiepileptic medications, difficult-tocontrol seizures continue to affect an estimated 25% of adults with epilepsy and an even higher proportion of epileptic children. The inverse relationship between efficacy and tolerability often associated with these newer agents makes medical intervention increasingly complicated [2,3]. Side effects or lack of therapeutic efficacy often result in noncompliance or discontinuation of the medication, leaving the physician with the difficult challenge of finding “effective alternatives.” In this setting, healing rather than curing is a reasonable goal for many such patients. In addressing the patient with epilepsy, or any other medical condition for that matter, Integrative Medicine offers a unique approach that is holistic, highly individualized and healing oriented [4]. As the case of this young man demonstrates, patients with a long history of epilepsy, and especially those with intractable seizures, often have significant psychosocial issues surrounding their chronic malady and its consequent limitations. An approach that takes into consideration all aspects of patient well-being and health (and not merely the patient’s physical medical problem) improves the chances that therapeutic interven-

tion will impact the patient’s illness and quality of life in a positive fashion. Integrative Medicine emphasizes the importance of a patient-doctor relationship founded upon mutual respect and trust, but also utilizes, when appropriate, therapeutic options not commonly employed in conventional medicine. The purpose of this report is to shed light on three complementary approaches that can be offered to patients with difficult-to-control epilepsy, with emphasis on their integration into a comprehensive treatment plan. Vitamin E and Epilepsy Vitamin E (a-tocopherol acetate) has been suggested as a useful adjunctive therapy in epilepsy. Vitamin E appears to act as a membrane stabilizer and an enzyme repressor, and may also enhance the activity of Vitamin A [5]. The rationale for vitamin E supplementation for patients with epilepsy is based upon the observation that patients receiving antiepileptic medication have decreased serum a-tocopherol levels as compared with both normal controls and epileptic patients not on medication [6]. It is hypothesized that patients taking antiepileptic medications have enhanced lipid peroxidation resulting in increased mobilization of the vitamin and the subsequent reduction of serum levels [7]. The results of clinical trials assessing the role of vitamin E in epileptic patients are contradictory. In a randomized, double-blind, placebo-controlled, cross-over trial of D-a-tocopherol as add-on therapy for 3 months in uncontrolled epilepsy, Raju et al. [8] were unable to show a statistically significant change in seizure frequency in the vitamin E group compared to the placebo group regardless of seizure type. Interestingly, seizure frequency was significantly reduced in both groups when compared with baseline. In contrast, Ogunmekan and Hwang [9] studied the therapeutic effect of vitamin E in epileptic children and found a statistically significant reduction in seizure frequency in the vitamin E group compared with placebo. Despite the suggestion that it may be an effective anticonvulsant [10], the present role of vitamin E in the treatment of seizures is as an adjunct and not as solo anticonvulsant therapy. It is always difficult to extrapolate data from a study group to an individual patient, especially when that data is conflicting. Considering our patient’s presentation, we recommended he take vitamin E. Ketogenic Diet and Epilepsy The ketogenic diet was developed in the 1920s in an attempt to control epileptic activity in individuals with difficult-to-control seizures [11]. The diet is utilized to create an environment that mimics the biochemical changes associated with starvation, based on the observation that this metabolic state is associated with a reduced incidence of seizures. More than 70 years after the first report of this association, the mechanism through which the ketogenic diet affects seizure activity remains unknown [12]. To achieve

ketonemia, the biochemical hallmark of starvation, the diet promotes the intake of high-fat, low-protein, low-carbohydrate foods. Therefore, the diet is individually calculated and rigidly controlled. According to the Johns Hopkins protocol [13], following an initial fasting period of 36–48 hours, dietary guidelines recommend a 4:1 ratio of grams of fat to grams of protein plus carbohydrate. Although the diet is generally considered safe, it is important to note that the diet should only be followed under careful medical supervision because there is the potential for short-term complications including hypoglycemia, severe metabolic acidosis, and dehydration. Long-term adverse sequelae are rare and include the development of kidney stones, poor feeding, status epilepticus, and ataxia. Ordinarily, one should wait at least 2 weeks for the diet to be well-established before any change in antiepileptic regimen is made. Numerous uncontrolled, retrospective studies performed over the course of several decades have reported that 60– 75% of children with difficult-to-control seizures experienced a .50% decrease in seizure frequency [14]. Despite these remarkable results, as new anticonvulsant medications became widely available the diet was employed less frequently. Lack of experience with the diet ultimately led to the opinion that the diet was ineffective and difficult to tolerate [15]. However, two recently published clinical trials of the ketogenic diet in children with difficult-tocontrol epilepsy [16,17] challenge this perception and provide results that are very encouraging regardless of seizure type, both with respect to tolerability and efficacy. In the ketogenic diet multi-center diet group study [16], 88% of all children initiating the diet remained on it at 3 months, 69% at 6 months, and 47% at 1 year. Over the duration of the study, frequency of seizures had decreased by more than 50% in 40–54% of the children. A full 10% of children were seizure-free 1 year after entering the study. Age, sex, principal seizure type, and EEG pattern were not statistically related to the outcome. Freeman et al. [17], who studied the diet in 150 children with epilepsy, reported similar improvements in 34% of the children, achieving a .90% decrease in seizure frequency while following the diet. There were no statistically significant differences with respect to seizure control based on age, sex, seizure frequency, or seizure type. In both studies, as is commonly the case in clinical practice, most of those patients who discontinued the diet did so because the regimen was either ineffective or too restrictive, with the perception of restriction being inversely correlated to the degree of effectiveness. Based on the above data, and considering that most of the available research focuses on the pediatric population, we offered this option to the patient and his family. They declined participation in the diet plan due to concerns about its rigorous nature. As noted by Nordli and deVivo [12] “the question is not “does the ketogenic diet have a role in the treatment of epilepsy?” but rather, “how can we maximize using the ketogenic diet and learn from it to benefit all children with epilepsy?” Others [17,18] have likewise concluded that the Int Med 1998; 1(4)

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ketogenic diet should be offered to patients with intractable seizures when several medications have already proven ineffective, rather than exhausting every medication available. We agree. Mind-Body Medicine and Epilepsy People with epilepsy are at increased risk of developing symptoms of anxiety and depression and experiencing low self esteem, often due to the stigma attached to having epilepsy [19]. In addition, psychological factors have become increasingly recognized as playing a part in the occurrence of seizures. The current dynamic view of epilepsy as being an interaction between the functioning brain and seizure discharges leads to the hypothesis that many seizures may not arise at random. There is now abundant evidence supporting the close interrelation between seizure activity and behavior (for example, evidence from animal literature and uncontrolled patient observations has demonstrated that seizures can even be learned). Consequently, psychological methods for the treatment of epilepsy have been developed and include reward management, self-control techniques, and psychophysiological treatments which make use of various forms of mind-body medicine [20]. The term “mind-body medicine” is inclusive of a number of treatments modalities, ranging from meditation and relaxation training to social support groups. These therapeutic interventions are designed to enlist the mind in improving emotional well-being and physical health, mainly by reducing the effects of stress. A growing body of research now supports the use of these techniques, which are essentially risk-free, inexpensive, and can easily be applied in the context of allopathic medicine [21]. Since seizure control, whether the etiology be organic or hysterical, can be enhanced to some degree using hypnosis as a complementary therapy, we recommended the patient experience hypnotherapy. Hypnosis is known to induce relaxation and to enhance control of seizures in the setting of epilepsy [22,23]. The patient had several hypnotherapy sessions that went extremely well and in which he was taught simple techniques of self-hypnosis. The hypnotic trance is a naturally-occurring state characterized by aroused, attentive, focused concentration accompanied by relative constriction of peripheral awareness. Both we and the patient relate much of his symptomatic improvement to this powerful form of intervention. SUMMARY The strategy underlying the treatment plan for this man with medically intractable seizures was to take a multidisciplinary approach while at the same time trying to actively involve him in his journey towards health and well-being.

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We believe that this Integrative approach may have enhanced the patient’s own innate healing capability, and together with his conventional medical regimen, resulted in his symptomatic improvement. It is our hope and expectation that continued healing will take place in the future, and that he may achieve greater control over his seizures with the aid of fewer medications.

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