Epilepsy & Behavior. Ketogenic diet treatment in adults with refractory epilepsy

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1 Epilepsy & Behvior 19 (2010) Contents lists vilble t ScienceDirect Epilepsy & Behvior journl homepge: Ketogenic diet tretment in dults with refrctory epilepsy Pvel Klein,, Jromir Jnousek, Arkdy Brber, Rndi Weissberger b Mid-Atlntic Epilepsy nd Sleep Center, Bethesd, MD, USA b Individulized Nutrition Counseling, Bethesd, MD, USA rticle info bstrct Article history: Received 8 July 2010 Revised 6 September 2010 Accepted 8 September 2010 Keywords: Epilepsy Seizures Ketogenic diet Lipids The ketogenic diet (KD) is n effective tretment for refrctory epilepsy in children. It hs been little studied in dults. We evluted the efficcy of, sfety of, nd complince with djunctive KD tretment in dults with refrctory epilepsy in prospective open-lbel pilot study. Seizure frequency ws evluted for 4 bseline months, 4 months of djunctive KD tretment with 3:1 [ft]:[crbohydrte+protein] weight rtio nd 1600 kcl/dy, nd subsequent elective open-ended KD tretment. A 3:1 rtio ws used insted of the 4:1 rtio employed in children becuse of greter pltbility. Averge monthly seizure frequency nd seizurefree months t bseline were compred with KD months 1 4 (phse 1) nd ll KD tretment (phse 2). Diet complince ws evluted with dily urine ketone body nd monthly serum β-hydroxybutyrte levels. Twelve subjects were treted for up to 26 months. Three stopped tretment erly for psychosocil resons (n=2) or lck of efficcy. Seven of the 12 subjects were fully complint, 4 were prtilly complint, nd 1 ws noncomplint. seizure frequency declined by 38.4 nd 44.1% for phses 1 nd 2, respectively (P=0.04). Forty-two percent nd 50% of subjects hd N50% reduction during phses 1 nd 2, respectively. Four of 12 subjects (33%) hd N85% seizure reduction. Twenty percent of subject-months were seizure free t bseline versus 56% during both study phses (P=0.04). Adverse effects were mild: nuse, vomiting, dirrhe, constiption, nd weight loss Elsevier Inc. All rights reserved. 1. Introduction Seizures in pproximtely 35% of ptients with epilepsy fil to respond to ntiepileptic drug (AED) tretment [1 3]. The ketogenic diet (KD) is high-ft, low-protein, low-crbohydrte diet tht is n effective tretment for refrctory epilepsy in children [4,5]. The clssic diet consists of long-chin sturted triglycerides with 3:1 or 4:1 [ft]:[protein+crbohydrte] rtio by weight, with 90% of clories derived from ft. In open-lbel review or prospective studies of the KD in children, 7 15% of children with intrctble epilepsy become seizure free, 25 40% hve 90% seizure reduction, nd 55% hve N50% seizure reduction [6 11]. In study of 145 children rndomized to immedite KD versus KD delyed for 3 months, 38% of ptients in the KD group chieved N50% nd 7% N90% seizure frequency reduction versus 6 nd 0% in the control group [9]. These results compre fvorbly with the efficcy of new AEDs, which led to 1 7% seizure freedom rtes nd 90% seizure frequency reduction in fewer thn 10% ptients with intrctble epilepsy [12,13]. Tretment with the KD is reltively sfe. Potentil side effects in children include constiption or dirrhe, nuse, vomiting, nephrolithisis (3 7%), metbolic cidosis (2 5%), hyperuricemi (2 26%), Corresponding uthor. Mid-Atlntic Epilepsy nd Sleep Center, LLC 6410, Rockledge Drive, Suite 410, Bethesd, MD 20817, USA. Fx: E-mil ddress: kleinp@epilepsydc.com (P. Klein). hypoclcemi (2%), hypomgnesemi (5%), weight loss, hyperlipidemi, bruising, nd osteopeni [4,5,14 17]. Despite its success in children, the KD hs been little studied in dults. Only three studies in dults nd one in dolescents hve been published. In 1930 study 100 dults were treted with KD monotherpy for 1 yer, of whom 12% becme seizure free, 44% improved nd 44% remined unchnged [18]. More recently, there hve been only two smll reports. In one, 11 dults with refrctory epilepsy were treted for 8 months with djunctive 4:1 rtio KD. Three hd N90%, three hd 50 89%, nd one hd b50% seizure reduction; four stopped the diet premturely [19]. Adverse events (AEs) included constiption nd menstrul irregulrities. In nother study, nine dults with refrctory epilepsy were to be treted with the KD for 12 weeks. Only two subjects completed the study, both with N50% seizure frequency reduction; the rest dropped out becuse of side effects (dirrhe, hunger, elevted lipids) nd lck of efficcy [20]. Recently, two studies evluted the modified Atkins diet in dults. This diet hs 0.9: 1 [ft]: [crbohydrte+protein] weight rtio, with 65% of clories derived from ft. In one study of 30 dults, 33% subjects chieved N50% seizure reduction t 6 months; one subject becme seizure free [21], nd 33% stopped tretment before 3 months. In nother study with crbohydrte restriction of 20 g/dy, three of eight ptients continued with the diet for 6 months, with seizure reductions of N50%, N30%, nd b30% [22]. Given the pprent efficcy nd sfety of the KD in children nd the lck of effective tretment in dults with intrctble epilepsy, it is /$ see front mtter 2010 Elsevier Inc. All rights reserved. doi: /j.yebeh

2 576 P. Klein et l. / Epilepsy & Behvior 19 (2010) remrkble tht the KD hs not been evluted more brodly in dults. The min reson ppers to be n untested ssumption tht dults would not comply with the unpltble diet. The gol of the present study ws to obtin pilot dt on complince with nd efficcy nd sfety of djunctive KD tretment in dults with intrctble epilepsy. 2. Methods This prospective open-lbel study ws pproved by the institutionl review bord of Holy Cross Hospitl, Silver Spring, MD, USA. s signed institutionl review bord-pproved consent forms. The study ws performed in ccordnce with the ethicl stndrds of the 1964 Declrtion of Helsinki s Men nd women ged with refrctory primry generlized (PGE) or locliztion-relted (LRE) defined s filed tretment with three or more AEDs nd seizure frequency of 1 every 2 months were recruited. Epilepsy ws clssified using ILAE criteri [23]. Exclusion criteri were renl, liver, crdiovsculr or cerebrovsculr (therosclerotic), mitochondril, or ftty cid metbolism disese, history of renl clculi, hyperuricemi, hyperclcemi, porphyri, nd fmily history of hyperlipidemi Pretretment evlution s were evluted by tem consisting of n epileptologist, nutritionist, nd nurse. They met seprtely with ech tem member once or twice for 1-hour-long eduction visits. They were tught the cloric nd compositionl content of foods nd how to determine it. Bsl cloric intke ws clculted from retrospective recll dt nd prospective (7 dys) food records. A history of food llergies ws obtined. Smple recipes nd menus were creted tht incorported the subject's food preferences. s were given set of these recipes nd dily mel plns for five mels (three set mels nd two sncks) Initition of the ketogenic diet The ketogenic diet ws initited during 4- to 5-dy-long hospitliztion. s fsted for the first hours, followed by dily cloric increse to 33, 66, nd 100% of cloric trget. Urine ketone levels were checked t ech urintion using Ketostix (Byer AG, USA). s were tught to do the mesurements. Fst continued until urine ketones reched 40 mg/dl. Blood glucose ws checked for possible hypoglycemi every 2 hours during the first 48 hours, then every 6 hours. The protocol included glucose rescue pln if blood glucose fell to b50 mg/dl. The diet contined 3:1 [ft]: [protein +crbohydrte] weight rtio with 1600 kcl/dy cloric restriction, supplemented with vitmins, clcium, nd phosphorus to meet the requirements of stndrd U.S. Dietry Reference Intkes. Cloric restriction ws used bsed on trditionl usge of the KD Mintennce of ketogenic diet s were seen by n epileptologist nd nutritionist 1 week, 3 weeks, 5 weeks, nd 2 months fter dischrge, then monthly by the epileptologist nd every 3 months by the nutritionist. If seizures did not improve fter 2 months, the KD rtio ws incresed to 4: Evlutions Seizure frequency ws evluted prospectively for 4 months t bseline nd 4 26 months fter initition of the KD with dily seizure diry. AEDs were held stble during the bseline observtion nd KD period. At ech visit, seizure frequency, tretment complince, nd AEs were evluted nd physicl exmintion ws performed. Body mss index (BMI) ws clculted. Ptients checked urine for ketones with Ketostix one to three times dily nd documented results in combined ketone/seizure diry which ws reviewed t ech visit. Urine Ketostix mesures urine cetocette with colorcoded scle with ketone body (KB) level brckets of 15, 40, 80, nd 160 mg/dl. Diet complince ws ssessed by mesuring dily urine KBs nd monthly serum β-hydroxybutyrte (BOHB) levels. Urine KB complince ws scored on scle of 0 3, where 0 =no complince (KB detectble on 75% of dys); 1=mild (KB=N15 b40 on 75% of dys); 2=moderte (KB 40 on 75% of dys; 3=complete (KB 40 on 95% of dys). Undocumented dys were counted s 0. Serum BOHB complince ws scored monthly s 1 when BOHB ws elevted bove norml (0 3 mmol/l), 0 when it ws not, nd clculted s the percentge of study months with complince. Urine KB nd serum BOHB complinces were converted to frctions (e.g., urine KB 1=0.33, 2=0.66, 3=1.00), combined, nd verged to yield n overll complince score: b10%=0, b50%=1, b90%=2, 100% =3. Qulity of life ws evluted t ech visit with the Ptient-Weighted Qulity of Life in Epilepsy inventory (QOLIE-31-P). Alertness ws evluted with the Epworth Sleepiness Scle (ESS). Lbortory evlutions included CBC, CMP, BOHB,.m. fsting (10-hour) lipid levels (cholesterol, triglycerides [TGs], high, low nd very low density lipoprotein (HDL, LDL nd VLDL), glucose nd insulin levels, glycosylted hemoglobin (HBA 1c ), leptin levels (becuse of the ssocition of KD with weight loss nd of serum leptin levels with weight loss), serum trough AED levels, nd urine clcium nd cretinine level (for risk of nephrolithisis). These were done 1 month before KD initition, on dy 1 of the fst, nd then monthly. s treted for N3 months who stopped the diet hd lipid levels checked monthly for 3 months fter KD discontinution. The primry efficcy im ws comprison of verge monthly seizure frequency during the 4-month bseline with tht during the 4 months of KD tretment. s who elected to continue KD tretment beyond 4 months were evluted monthly for tretment months 5 12, then every 2 months. The secondry efficcy im ws comprison of verge monthly seizures during bseline with those for the whole tretment durtion. Other outcome mesures included proportion of seizure-free months, rte of KD discontinution, AEs, weight, BMI, QOLIE-31-P scores, nd ESS scores. Dt were nlyzed using Wilcoxon's test for nonprmetric nd Student's t test for normlly distributed continuous vribles (ll two-tiled). Significnce ws set t Pb Results 3.1. Demogrphics/disese chrcteristics Demogrphics, disese chrcteristics, nd bseline tretment re summrized in Tble 1. Twelve subjects were enrolled (eight women, four men, ge rnge 24 65). An dditionl 23 eligible ptients were screened nd declined prticiption becuse of reluctnce to give up their regulr diet (n=17), the complexity of the KD (n=5), nd cost. The screened to enrolled rtio ws 35/12 (2.92) disposition Tretment lsted 4 dys to 26 months (Tble 2). Three subjects discontinued tretment during the first 4 months for psychosocil resons (n=2, t 4 dys nd 1.5 months) nd lck of efficcy (n=1 t 2.5 months). Nine of twelve subjects elected to continue tretment pst the initil 4-month study period, including six subjects treted for

3 P. Klein et l. / Epilepsy & Behvior 19 (2010) Tble 1 Ptient demogrphics nd epilepsy/seizure nd clinicl chrcteristics. Sex Age Epilepsy type Age t epilepsy onset Seizure type of pst AEDs Current AEDs (mg/dy) Comorbidity 1 F 24 PGE 7 GTC, Abs, Myo 8 TPM 1000 Obesity, depression, T 4 VNS (inctive) 2 F 40 PGE 3 GTC, Abs, Myo 7 TPM 350 Obesity, OSA, hypertension, peptic ulcertive disese, T 4 3 M 34 PGE 23 GTC 3 LEV 3000, TPM 50 Obesity, OSA 4 F 46 PGE/JME 10 GTC, Abs, Myo 8 LEV 5000, LTG 600 Obesity, OSA, depression 5 F 65 PGE 27 GTC, Myo 2 LEV 2000 Obesity, OSA, depression, non-insulin-dependent dibetes mellitus 6 F 44 LRE 10 CPS 7 LEV 3000, TPM 400, LTG 300, CBZ 600 Obesity, OSA, perimenopuse 7 F 53 LRE 2 CPS 8 TPM 200, OXC 2100 Obesity, perimenopuse 8 F 33 LRE 13 CPS 8 OXC 1800, LTG 425, TGB 10 None 9 M 37 LRE 31 SPS/CPS 6 LEV 4500, PGB 800, VPA 2000, CBZ 1200 Neurocytom, obesity, 10 F 40 LRE 12 CPS 5 LEV 3000, CBZ 1400, VNS Obesity 11 M 35 LRE 25 SPS/CPS 6 LEV 3000, OXC 600, PGB 800 Anxiety 12 M 24 LRE 10 CPS/GTC 2 OXC 600 Autism, pervsive developmentl disorder PGE, primry generlized epilepsy; LRE, locliztion-relted epilepsy; Ab, bsence seizures; Myo, myoclonic seizures; GTC, generlized tonic clonic; CPS, complex prtil seizures; SPS, simple prtil seizures; CBZ, crbmzepine; LEV, levetircetm; LTG, lmotrigine; OXC, oxcrbzepine; PGB, pregblin; TGB, tigbine; TPM, topirmte; VPA, vlprote; T 4, hypothyroidism; OSA, obstructive sleep pne; VNS, vgus nerve stimultion. N8 months nd four subjects treted for 20 months. Four subjects stopped the KD fter 7, 8, 24, nd 25 months becuse of n unplnned pregnncy (n=1) nd desire for regulr food (n=3). Five subjects re still in tretment (durtion: 6 20 months) Tretment complince Seven of twelve subjects were fully complint (three on the scle of 0 3), including the subject who stopped the KD for lck of efficcy. Two of twelve subjects were modertely (2) nd mildly (1) complint. One subject ws noncomplint (0) nd stopped tretment fter 4 dys (Tble 2) Seizure control Tbles 2 nd 3 summrize dt on generlized tonic clonic seizures (GTC) in subjects with PGE nd complex prtil seizures (CPS) in subjects with LRE. Becuse of the lesser relibility of bsence, myoclonic, nd simple prtil seizure counts, dt nlysis below is confined to GTC seizures/cps. Dt on bsence, myoclonic, nd simple prtil motor seizures re summrized in Supplementl Tble 2 (see Appendix A). Ten of twelve subjects improved, one did not chnge, nd one worsened. Averge monthly seizure frequency for the 11 subjects treted for N1 week declined by 38.4% for KD months 1 4 (P=0.05) nd by 44.1% for the whole tretment durtion (P=0.04). Four of twelve (33%) subjects hd N75% seizure reduction, including one subject who stopped tretment fter 1.5 months; excluding her, 3 of 12 (25%) subjects did. Five of twelve (42%) subjects hd N50% seizure reduction during KD months 1 4, nd 6 of 12 (50%) during the whole tretment; n dditionl 4 of 12 subjects experienced 20 50% seizure reductions during both study phses. During bseline, 20% of subject-months were seizure-free compred with 56% during both study phses (P=0.04). Response to tretment ws fst. In ll subjects with N75% seizure reduction, the full effect occurred during the first month of tretment. In four subjects with dily bsence/myoclonic seizures, response reched its full extent within 4 dys of KD initition. Three subjects with N75% seizure reduction (two with PGE, one with LRE) stopped the diet, fter 1.5, 8, nd 18 months. In ll three, seizures returned to pretretment frequency fter 1 7 months. One successfully restrted the KD. Two subjects with no improvement on the 3:1 diet (both fully complint) incresed the [ft]:[crbohydrte/protein] rtio to 4:1 Tble 2 Monthly frequency of only generlized tonic clonic nd complex prtil seizures for 4-month bseline, KD tretment months 1 4, nd whole tretment durtion. Tretment durtion (months) Seizure frequency/month % Chnge AED chnge on KD Complince Bseline KD months 1 4 Whole tretment KD months 1 4 Whole tretment dc 2/ dc 1/4, dose 2/ b 0.13 n n n n n n 0 b c 2.07 (2.36) 0.99 c (1.56) Complince grding: 0=none; 1=mild, 2=moderte, 3=complete. dropped out fter 4 dys nd is not included in dt nlysis. P=0.05. d P = d (1.58)

4 578 P. Klein et l. / Epilepsy & Behvior 19 (2010) Tble 3 Seizure-free months for 4-month bseline, KD months 1 4, nd whole tretment durtion. fter 2 months. One did not improve nd stopped the diet. Another subject improved nd hs continued with the diet (17 months to dte). Antiepileptic drugs were held constnt in 9 of 11 subjects treted for N1 week. Two subjects reduced AEDs: one subject decresed from four to three AEDs t 6 months, nd nother subject self-discontinued two of two AEDs fter 1 month nd hs continued on the KD lone (20 months to dte) Sfety nd tolerbility No subjects discontinued tretment becuse of AEs. AEs were mild nd included trnsient nuse (n=1), dirrhe (n=2), nd constiption (n=1) during KD initition, nd nuse (n=2), isolted vomiting (n=2), bdominl crmps (n=1), nd mild intermittent constiption (n=4) during KD mintennce. Three subjects (25%) hd mild intermittent hunger, rted 2 3 on scle of Weight Tretment durtion (months) Cloric intke ws reduced from bseline verge of 2412 kcl/ person/dy (rnge= , medin=2400) to 1600 kcl/dy. All 11 subjects treted for N1 week lost weight (Tble 4). Their men weight declined by 38.7 lb from lb t bseline to (rnge=4 80 lb, Pb0.001). BMI ws reduced by 18.3%, from 33.8 to 27.5 kg/m 2 (rnge = %, P b0.001). Eight of nine overweight or obese subjects (BMI= nd 30 kg/m 2, respectively [24]) hd 10% BMI reduction, seven of nine 15%, nd four of nine 20%. The only obese subject who lost b10% of BMI stopped tretment fter 1.5 months. One overweight nd two obese subjects normlized their BMI, nd third obese ptient nernormlized it (BMI=25.8). The weight loss ws ssocited with reduction of men serum leptin levels in 10 of 10 subjects in whom leptin ws mesured, from men bseline 26.6 ng/ml to 12.9 ng/dl (P=0.001) Lipids, glucose, nd other lbs Seizure-free months Bseline KD months Whole 1 4 tretment / / / / / / / / /2.5 0/ / / / c 0.13 N/A N/A N 0 Totl 9/ / /140 % seizure free d 56.1 d Complince b N/A, not pplicble. Tretment months 1 4 re 4 months except for subjects who discontinued tretment erly, for whom number of seizure-free months/number of months on tretment is given. b Complince grding: 0=none; 1=mild, 2=moderte, 3=complete. c dropped out fter 4 dys nd is not included in dt nlysis. d P =0.04. serum cholesterol levels incresed from to mg/dl (P=0.04). TG, HDL, LDL, nd VLDL levels did not chnge significntly Tble 4 Effect of KD on BMI, weight, nd blood leptin levels. (Tble 5). Five of six subjects who stopped the KD fter N1 month hd n increse in serum lipids on the KD. Lipid levels returned to bseline within 3 months of stopping KD, including 3 subjects treted with sttins, in whom sttins were stopped fter the KD ws discontinued. fsting glucose levels were higher t bseline compred with KD mintennce (87.7 mg/dl vs 78.7 mg/dl, P=0.04). glucose levels declined during KD initition, from mg/dl on dys 1 2 to mg/dl on dys 3 5 (p=0.008). There ws no significnt chnge in men pek plsm uric cid levels: 5.6 mg/dl t bseline versus 6.06 mg/dl on the KD Qulity of life QOLIE-31-P globl scores rose nonsignificntly from 5.25 t bseline to 7. ESS scores did not chnge significntly (7.9/24 t bseline vs 7.4/24 t lst KD visit). 4. Discussion BMI (kg/m 2 ) Weight (lb) Leptin (ng/ml) Bseline KD % Chnge Bseline KD Bseline KD n n (6.83) b (5.87) (42.37) b (32.9) (17.23) 12.9 c (17.43) Lowest BMI/weight/leptin level during tretment. BMI nd leptin levels re rounded to the nerest deciml point, weight to the nerest pound. b P b c pb This open-lbel study of djunctive KD tretment in dults with refrctory epilepsy resulted in overll seizure improvement, including N75% seizure frequency reduction in 25% of subjects treted for N4 months. The tretment ws well tolerted nd hd good complince. The study shows tht KD tretment in dults is fesible. The study differs from the two previous completed studies of KD tretment in dults with epilepsy in tht the tretment durtion ws long nd there ws follow-up of subjects fter tretment discontinution to evlute possible disese-modifying properties of the KD in dults. It is the first study of KD tretment, to our knowledge, to incorporte quntittive mesurement of complince. Limittions of the study include its smll size, uncontrolled selection of subjects, nd the open-lbel, nonrndomized design. Despite its success in the tretment of children with refrctory epilepsy, the KD hs been little evluted in dults with refrctory epilepsy, with only 20 subjects in two studies reported since 1930, nd only 13 of these subjects treted for 12 weeks or longer [19,20]. The ssumption hs been tht dults my not comply with the unpltble nd complicted diet. The present study suggests tht this my not be true. The modified Atkins diet hs been tried in dults insted of the KD in the belief tht complince would be better [21,22]. The Atkins diet shres with the KD crbohydrte restriction. However, it differs significntly from the clssic ketogenic diet: only 60 65% of clories re ft-derived, nd protein content is higher. It hs been less studied in children thn the KD. We therefore chose to study the "clssic" KD.

5 P. Klein et l. / Epilepsy & Behvior 19 (2010) Tble 5 Fsting serum lipid levels t bseline nd on KD, mesured t the end of KD tretment (the lst vlue for subjects still on tretment) or before initition of tretment with lipidlowering gents (sttins, n=3). Bseline KD Sttin Chol TG HDL VLDL LDL Chol TG HDL VLDL LDL trement Yes Yes Yes n P = (38.38) (81.47) 59.6 (20.4) 22.1 (16.3) (40.52) (107.3) 60.4 (15.82) 25.5 (16,16) (81.27) We used the 3:1 rtio becuse it my be more pltble thn the 4:1 rtio often used in children. Seventy-five percent of our subjects completed the plnned 4 months of the study nd elected to continue KD tretment beyond the initil 4 months. This rte of subject retention is similr to retention rtes in investigtionl AED phse 3 studies nd their open-lbel extensions [12]. However, two thirds of potentilly eligible subjects declined to prticipte becuse of the restrictive nd complex nture of the diet. This mde recruitment into the study chllenging, nd could be limiting fctor in lrger KD studies. The efficcy dt in this study re similr to those from peditric studies, nd suggest tht the KD my be very effective in proportion of dults. Twenty-five percent of our subjects treted long term hd N75% seizure frequency reduction nd 42% hd N50% reduction. This is in line with recent rndomized peditric study in which 38% of subjects hd N50% nd 7% hd N90% seizure frequency reduction [9], nd is similr to the only other completed modern dult KD study in which 3 of 11 subjects hd N90% seizure reduction nd 55% hd 50% seizure decrese [20]. Tht study diet used 4:1 [ft]: [crbohydrte/protein] rtio. Our dt suggest tht the 3:1 rtio my be similrly effective. In peditric studies, the ntiepileptic effect my persist fter KD discontinution [11]. Adult studies hve not previously evluted the effect of KD on epilepsy fter tretment discontinution. In our study, seizure improvement did not outlst KD tretment. This indictes possible difference between dult nd peditric responses to the KD. Tretment noncomplince is common trigger of seizures [25]. It cn be expected to be worse with the KD becuse of the diet's restrictive nd complicted nture, mking monitoring importnt. We used combined quntittive self-reported dily urine nd serum ketone body level mesurements, llowing comprison of subjectbsed nd subject-independent complince evlution tht could be used in future studies. Monitoring diet complince with urinry ketosis hs limittions becuse urinry ketosis my be reduced by fctors other thn complince, such s use of crbohydrte-contining medictions, liver dysfunction, or overhydrtion; however, t present, it is the only method vilble short of direct food intke observnce. Appendix A. Supplementl dt Supplementry dt ssocited with this rticle cn be found, in the online version, t doi: /j.yebeh References [1] Kwn P, Brodie MJ. Erly identifiction of refrctory epilepsy. 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