rt Seizures Decrease Rapidly After Fasting Preliminary Studies of the Ketogenic Diet John M. Freeman, MD; Eileen P.G. Vining, MD Objectives: To evaluate the change in atonic or myo- clonic seizures associated with the Lennox-Gastaut syn- ‘drome during the initiation of the ketogenic diet, and to describe the development of a blinded crossover study of the efficacy of the ketogenic diet Design: A before-alter rial Setting: The Johns Hopkins Hospital, Baltimore, Md. Patients: Change in clinical seizure frequency was ex- amined in 17 consecutively treated patients with atonic ‘or myoclonic seizures. In afew patients, a 24-hour am- bulatory electroencephalogram was obtained before and alter diet initiation. We demonstrated the ability to ma- nipulate the ketosis induced by fasting with the addi- tion of glucose (dextrose) in I patient Interventions: Children fasted for 36 hours, and the dict was gradually introduced over 3 days. Parents were instructed to keep a baseline seizure frequency calendar for the month before the initiation ofthe diet. These cal- endars continued to be maintained as the diet was ini ated, Outcome Measure: Seizure decrease from base- Results: The atonic or myoclonic seizures decreased in these children by more than 50% immediately. Using a 24-hour ambulatory electroencephalogram, we docu- ‘mented that the seizures reported by a parent represent only a fraction of the electroclinical events; the tech- nique could be used to measure the profound decrease in electrically documented seizures. Ketosis was elimi- nated with glucose, 60 g/d. Conelustons: It is feasible to evaluate the ketogenie di- ets efficacy in atonic or myoclonic seizures ina blinded, crossover study. The diet can be manipulated on a short” term basis in a blinded manner, and ketosis can be achieved or eliminated. Arch Pediatr Adolesc Med. 19995153:946-949 a double-blind, crossover study. iditor’s Note: In this study, Kool-Aid is a cool aid to designing. Catherine D. DeAngelis, MD. diethas made the design of blinded, cross- over study daunting, and the lack of such trials has caused continued skepticism, The Lennox-Gastaut syndrome (LGS) 4s characterized by multiple seizure types HE °CLASSIC™ high-fat, ad cequate-protei, hydrate ketogenic diet was developed in the 1920s, based on observations of the benefits of fasting on seizure control." The diet was successfully used during the 19208 and a characteristic polyspike and slow- wave electroencephalogram (EEG), and is olten associated with mental retardation. thas many causes, and the cause in aspe- cific childs usually undetermined. Chil- dren affected with LGS often have many “drop” (atonic or myoclonic) day, and these drops, whe! low-carbo- izures per fer mild From the Pedatic Epilepsy Centr, The Johns Hopkins ‘Medical Insitutions, Baltimore, Md Downloaded From: https: and 1930s, but use declined after the dis- covery of phenytoin (Dilantin). Reports’ of ts efficacy and of the elficacy of the me- dium-chain triglyceride diet continued to occasionally appear during the 1970s and 1980s." Although there has been a recent resurgence of interest in the die."” its ef ficacy has never been evaluated ina placebo- controlled, blinded manner. The igor of the “slumping” or more active “crashes” to the floor, are often associated with substan- ial impairment of the child's quality of life Measurement of the change in fr quency of the drops would provide an as- sessment of the efficacy of the diet While evaluating the efficacy of the diet in an unblinded manner, we encoun- tered a 4-year-old with LGS who was (©1909 American Medical Association, All ights reserved. jamanetsrork.com/ on 05/16/2023.PATIENTS AND METHODS Inour standard ketogenic diet treatment protocol,’ bilder swith dilficul-to-control seizures, refractory to atleast 2 an- Uiconvulsent medications are admitted to the hospital, made toast for 36 hous, gradually introduced to their allotted diet, and then discharged from the hospital. During these 4 day ‘of hospitalization, blood sugar levels are monitored, and daly ‘lasses ate conducted to teach the parents how to calculate and prepare the diet and how to avoid carbohydrate ‘containing foods and medications, Parents keep calenders of the seizure frequency fora minimum of 1 month before a mission, during admission, and afterdischarge. These data are prospectively collected and recorded in our database. This protocol has been approved by the appropriate institutional review board, and informed consent was obtained from the parent or legal guardian and/or the child, if appropriate Seventeen consecutively admitted children with atonic cor myoclonic seizures their primary seizure type were ex amined for change in seizure frequency according parental report. Theseizure frequency t the initiation ofthe diet (day ‘} was compared with he frequency onsubsequent days (1-5). Since it was cleat thatthe diet appeared to have ad ‘matic and immediate effect on seizure fequency in thes dren, a method for objective confirmation ofthe parental: ure reports wassought, Duringa 24-hour ambulatory El {he clinical (push-button) events indicated by the parents wer then coreelated withthe electrical pattern seen st that time Atypical burst that correlated witha clinical event is shown in Figure ¥, Having leaned to recognize the electrical a= pects fa clinical seisure from the parents, we could then mes- Sire the number of “sisure bursts” during sustained riod, even when the patient was not being observed. The seizure bursts were reviewed and counted by an electroen- cephalographer (EP.G.V.). The 24-hour EEG was obiained, before diet onset and atthe end of the hospital stay (day 5). “Another reqitementfordesigning short-term, binded. placcbo-controlled crossover study wouldbe the ability torap- {dy negate the ketosis (and presumably the efficacy of ted). Suidies by Gamble” and Htenlocher suggested that the ef {ectsof the ketogeni dct could be eliminated by administer- ing 4010 60gof glucose (dextrose). This was done in I child RC f FAN FRG ut . rR att 4.3 eS Fr le = try rhe cory cor ass Figure 1, Abus of se ard spare acti a vas recoded ona 24tour anu ecromoepalgram anda cored with detected pus ator lnc azure he paren. Tas prope was sed fo exabish hereon for dtemanig addon eececicl vets i adn terest fe ty. (©1909 American Medical Association, All ights reserved. ‘Downloaded From: https:/jamanetwork.com/ on 05/16/2023having more than 60 drop seizures per day. The child's parents had kept meticulous computerized records of the number of drop seizures, and as the diet was initiated the records documented a dramatic decline in seizures, These ‘observations piqued our interest in the possibility of us- ing this type of seizure disorder in studying the efficacy ‘of the diet ina short-term crossover study. Wea Same po Oay arate 1 E Figure 2. The change nsw equency ding the § days afer taton ofthe leiogente etn § cen whose predominant sazure ype was onc ormyeclont Ina chien, ere asa get han 5D derease Selures Each bar epresents an indidul patent Sere equency was ecard byte parents before esting anon day ae ating and det intatn. ES} The atonie or myoclonic seizure frequency of 17 pa jents was known at baseline and was assessed by par- ents during the initial 5 days of the diet, In all of these children, a greater than 50% decrease in seiztires was re- ported by the fifth day. The rapidity of this decrease is shown in Figure 2 for the 5 children with the greatest frequency of seizures at on: ‘With this clinical confirmation, we then obtained a 24-hour ambulatory EEG in several patients, A discrete change in the EEG was associated with the clinical se ures noted by parents, and this was used to measure ele twoclinical seizures. The impact of initiation ofthe diet on this phenomenon is shown in Figure 3. In the predict study, the number of bursts (seizures) per hour was quite variable, but clearly increased markedly during sleep. The family report ical seizures in the 24 hours sev- eral days after diet initiation, the BEG documented sev- eral electrical events, again usually while the children were asleep. Finally, negation of the urinary ketosis was con- firmed ina pilot patient. This child fasted and received the ketogente diet and was assigned, in a blinded man- ner, to a daily “Kool-Aid-like” drink containing glu- cose, 60 g/d, with saccharin (negating ketosis) oran iden- ical Kool-Aid-like drink that only contained saccharin (preserving ketosis). When this child initially lasted, she os «. eoteeanaiae ee a. gure 3. An ambuton elecronceptalogram (6) a te electron events, busts of spor psp, and sow waves was permed inmedately batoefstng an ater days recente eager et. The Bars sha the umber felectrcincal events er hou Duin he 24 hors before de, the patent ha 856 eetocna events andthe parents reported 6 cna sours. Ae S days of recehing to dt, the gretsepoted ao seures an ie ambulatory EES recorded 30 ecto events, most of sate duration tan onthe preceding recording. Many bust of acti occured when the patent tna asep and no cna seure was wines (©1909 American Med Association, All rights reserved.a faa Das Ge it Pte w cy aah w 1234 86 7 @ 8 om on as at Figure 4. The protocol developed ora bnded crossover study of te efeaty ote ktogeni det nce wis atone ar acon sezures. A ‘2¢-hou abut eetoencphaogram (EE) il be permed before te onset of asin anda the end ofeach arm of he tay. The Ketogente eis nto doy Sard apa se ae aig ay 8 Dung one arm. chi tec 2 Kool Ad-e" Had conaeng 209 ‘of case and saccharin to mask the ast 3 ies each day. Dug he ‘te arm, the i cana saccharin burke glucose. The end pint of thet isthe number of sives on he ambulatory EEG athe Gnelson ofeach sty arm became ketotic, but when the glucose-containig fluid was introduced, the ketosis rapidly disappeared. The child was fasted again and received the same ketogenic diet with fluid containing saccharin (placebo). Alter this change, she developed ketosis again, which was then main- tained. Based on the data of the 17 patients who dramati- «ally responded to ketosis, our demonstratedability © mea- sure seizures in a blinded manner (24-hour ambulatory EEG) and our ability to manipulate ketosis rapidly and in blinded manner, a protocol that would permit blinded, placcho-controlled, crossover evaluation of the diets effi ‘cacy, was designed. The schematic protocol for sucha study is shown in Figure 4. The primary end point ofthe trial would be the number of EEG-documented electroclinical ‘events on the last day of each treatment period. Lees Since efficacy and tolerability are closely linked, in an- ticonvulsant tials!” and with the diet,’ the rigidity and difficulty of the ketogente diet has made long-term, pla- cebo-controlled study difficult for the child and family to tolerate. The preliminary evidence of the rapid elfect of the diet on the drop seizures of LGS, and the rapid abil- lay to negate the ketosis with the administration of glu- cose, make it feasible to assess, ina randomized, blinded, crossover, placebo-controlled manner, the short-term ef- ficacy of the ketogenic diet in reducing the number of atonic or myoclonic seizures in children with LGS. The protocol developed has been funded by the National In- stitutes of Health, Bethesda, Md, and the study has been Initiated. Ifthe efficacy ofthe diet is documented in such a study, itis likely to lead to more acceptable, wide- spread use of the diet in appropriate populations, Accepted for publication January 12, 1999, This study was supported in part by the Charlie Foun- dation, Los Angeles, Calif and the Pediatric Clinical Re- search Center, The Johns Hopkins Medical Institutions, Bal- timore, Mal Reprints not available from the authors. EES] 1. SwnkTD, Voing PFJ. The kop 17. Aa a 187 ear a8 2 ir AM Th ts ot tana onthe course of pee. Myo Cin Bul yor230, 8. Goan Fang aa mstod or weting plea. Ma ae. 180180:087. ‘cd, 4 Ptman MG. The ktogeni et int trary rian = port Aube Tanta 288 5 Rie PR Wow A Sore M Mum hinsrsils satrap, formal chleod ope Neuro. 197.21 108-103. 6 ing EPG, Freman AM Blan Ka a Amer td ofthe arf atts hoon dat Ac euro! 100838 US. TsT 7 aman i Ving Plas Fy PL, Casey JC. Ky MT. The ateacy ‘tha age et 1008 prospcive oun of tarventon 150 ch ten, Pena, 1998102138183, 8 Far Symptaratcgeealzed pgs and Lemna Sstut yo Wl ed The Traunen Epes: Prince and Proce Banas, Mi Wi & Wikis 9955304, 0 rsa Kl MT Freeman. Te Ely Ds Tatmen A ara: too ete Maogn it New York, WY: roy 109488100 nl Physical iformation aed rom ties onthe rr aon. In The Hana Lectures, Sore 42 Lanes, Pe: The Sone Pree Pieg (toner ott HutelcherPR.Ktonani and ewes: mato and anton atts ‘ftvoletogon ats cichood. Pea Fas 1875: 1028550, Hatson Caner I Cains tal Comparson al cbanazepine, p= aarti panna mio paral an sect genera lone scares Ment Jed 1065315105151 (©1909 American Med jamanetsrork.com/ on 05/16/2023. Association, All rights reserved.