When medication isn t quite enough. Alternative and complementary treatment strategies in epilepsy Topics to be addressed Hormonal progesterone Diet Atkins, ketogenic Supplements Tina Shih, MD UCSF Epilepsy Center May 22, 09 Omega-3 fatty acids Catamenial epilepsy ovulatory cycles Reproductive hormones have neuroactive properties Progesterone: seizures Estrogen: seizures Neuroactive reproductive hormone levels vary during the menstrual cycle Serum hormone levels E2 10 100 0 P 30 2 1 10 Phase Estradiol pg/ml Progesterone ng/ml C2 F O L C1 M 0 1 3 7 9 11-14 -12-10 -8-6 -4-2 1 3 Day of cycle Herzog AG et al Epilepsia 1997 1
Avg No Seizures / Day 0.6 0. 0.4 0.3 ovulatory cycles Serum hormone levels E2 100 80 60 40 P 2 1 10 anovulatory cycles Phase F O L M Estradiol ug/ml Progesterone ng/ml C3 0.2 Menstrual -3 to +3 8 cycles M vs F, O, L: p <.001 O vs F, L: p <.0 Follicular 4 to 9 Ovulatory 10 to -13 Luteal -12 to -4 Herzog AG et al Ann Neurol 04 0 1 3 7 9 11-14 -12-10 -8-6 -4-2 1 Day of the cycle Herzog AG etal Epilepsia 1997 3 Avg No Seizures / Day 0.8 0.7 0.6 0. 0.4 0.3 anovulatory cycles Menstrual -3 to +3 86 cycles; 123 seizures F vs M, F vs O, F vs L: p <.001 Follicular 4 to 9 Ovulatory 10 to -13 Luteal -12 to -4 Herzog AG et al Epilepsia 1997 Treatment Regimen Number of patients Number improved Seizure frequency Cyclical progestin therapy 1 ρ<0.0 2 ρ<0.01 Progesterone 3 month follow up 100-0 mg tid Progesterone 3-year follow-up 2 1 of original 2 18 (72%) 1 (60% overall) -4% CPS 2-8% GTCs 1-62% CPS 2-74% GTCs 2 Herzog AG et al Neurology 1999 and 199 2
Cyclical progestin treatment: NIH RO1 NS 39466 Initial 3 year pilot: 10 women in 3 centers Catamenial epilepsy (4 women, 137 progesterone, 67 placebo) Regimen: 0 mg tid D14-2, 100 mg tid D26-27, 0 mg tid D8 (Natural progesterone) Prometrium vs compounding pharmacy Other forms of hormonal treatment Treatment Action Side effects Depomedroxyprogesteron e (IM Depoprovera) Progesterone Hot flashes, vaginal bleeding, weight gain Long term: bone density, CV risks Clomiphene (Clomid) Anti-estrogen Liver toxicity, risk of endometrial CA, pregnancy, ovarian cysts GnRH analog Estrogen Worsening of seizures, hot flashes, vaginal dryness, dyspareunia Oral synthetic progestins Progesterone Vaginal bleeding, weight gain Long term: bone density, CV risks Ketogenic diet Long history (modern era since 19s, references in New Testament and medieval writings) Unknown mechanism of action Children with intractable seizures of any type, from almost any cause Ages 1-1 initial screening evaluation Counseling: expectations, psychosocial impacts Nutritional assesment: BMI Laboratory evaluation: screening inborn errors of metabolism, CBC, Chem, fasting lipid profile Ancillary testing (optional): renal u/s, EKG, EEG, MRI, CSF Recommendations of International Ketogenic Diet study group. Epilepsia 08 3
Fasting night before hospital admission and during admission (FSBG q4) until large urine ketones Day 1: 1/3 eventual caloric goal Day 2: 2/3 eventual caloric goal Day 3: 100% caloric goal Discharge from hospital: day 4- (following urine ketones 1 st month) Classic ketogenic diet 4:1 (4g fat, 1g protein and carbohydrate), fluid restricted to 6 ml/kg/day <100 ml/day Sample meal: chocolate milk shake (sugarfree), steamed broccoli w/ butter, julienne chicken in butter Medium-chain triglyceride diet Modified medium-chain triglyceride diet potential long term effects Stunting of growth (23/28) Kidney stones (7/28) Dyslipidemia (0/28) Osteoporosis, skeletal fractures (6/28) Pancreatitis (0/28) Constipation (1/28) Modified Atkins diet Classic ketogenic diet 4:1 ratio Modified Atkins diet 1:1 ratio Standard Diet 0.3:1 ratio Groesbeck DK Dev Med Child Neurol 07 protein carbohydrate fat Kossoff EH Epilepsia 08 4
Modified Atkins diet: Carbohydrates <10g/day 1 st month (<1g/day adults) Urine ketones monitored twice/week Medications: low sugar formulations Carbohydrate counting: education/resources Monitoring of CBC, Chem, fasting lipid panel (baseline, 3 months, 6 months) Clinic visit Modified Atkins diet No improvement 1-0% 1-7% 76-99% Sz-free 1 months 1 (0%) 1(30%) 10(33%) 4(14%) 0(0%) 3 months 14(47%) 2(6%) 7(24%) 6(%) 1(3%) 6 months 1(0%) (17%) 6(%) 3(10%) 1(3%) Kossoff EH et al Epilepsia 08 Omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA(docosahexaenoic acid) Proposed mechanisms of action Increase seizure threshold Anti-inflammatory properties Reduce risk of SUDEP Omega 3 fatty acids Study N Method Dosing Bromfield et al 07 Yuen et al 0 21 Randomized Double-blind Placebocontrolled 6 12 week 1.3 g EPA 0.9 g DHA 1g EPA 0.7g DHA Result >0% reduction in seizures 2/12 treatment 0/9 placebo /29 treatment 0/27 placebo