Ketogenic Diet as a Therapeutic Option in Super-refractory Status Epilepticus

Abstract

Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 hours or more after the onset of anesthetic therapy and constitutes up to 15% of all SE admissions. One underpowered randomized controlled study has compared barbiturate treatment and propofol treatment for SRSE.1Shorvon S. Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.Brain. 2011; 134: 2802-2818Crossref PubMed Scopus (439) Google Scholar Limited additional information on potential treatments for SRSE comes from single case reports and small case series.1Shorvon S. Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.Brain. 2011; 134: 2802-2818Crossref PubMed Scopus (439) Google Scholar, 2Rossetti A.O. Milligan T.A. Vulliémoz S. Michaelides C. Bertschi M. Lee J.W. A randomized trial for the treatment of refractory status epilepticus.Neurocrit Care. 2011; 14: 4-10Crossref PubMed Scopus (161) Google Scholar A ketogenic diet (KD) has an antiepileptic effect and is suggested as a treatment option for refractory epilepsy in children and young adults.3The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE guidelines [CG137]. Available at: http://www.nice.org.uk/guidance/cg137/. Accessed August 1, 2014.Google Scholar KD is generally well tolerated and side effects are relatively mild.4Kossoff E.H. Zupec-Kania B.A. Amark P.E. Ballaban-Gil K.R. Christina Bergqvist A.G. Blackford R. et al.Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group.Epilepsia. 2009; 50: 304-317Crossref PubMed Scopus (402) Google Scholar However, the lack of robust data, together with limited clinical experience, has limited the use of KD in SRSE. In addition, SRSE is a heterogeneous group of conditions with variable etiology, course, and prognosis. It is recognized that conducting adequate trials to support the efficacy of KD in SRSE will be difficult.2Rossetti A.O. Milligan T.A. Vulliémoz S. Michaelides C. Bertschi M. Lee J.W. A randomized trial for the treatment of refractory status epilepticus.Neurocrit Care. 2011; 14: 4-10Crossref PubMed Scopus (161) Google Scholar Shorvon and Ferlisi1Shorvon S. Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.Brain. 2011; 134: 2802-2818Crossref PubMed Scopus (439) Google Scholar reviewed available therapies for SRSE and suggested that KD should probably be tried in all severe cases. Successful implementation of KD requires the collaboration and communication between neurologists, intensivists, dietitians, and nursing staff. Health care professionals using KD need to know the principles and potential uses of the diet and the importance of meticulously calculating the carbohydrate load of infusions. Here we report the clinical characteristics, treatment, and outcome of four patients with SRSE treated with KD in our intensive care unit (ICU) from January 2011 to August 2014 (Table 1). However, possible efficacy of KD was observed in only one patient (Patient 4), whose seizures were fully controlled after achieving ketosis for 3 days. At that stage we could successfully wean the patient off the anesthetic agents. One patient failed to achieve ketosis while the other two patients had ongoing seizures despite ketosis. Our review of these patients identified some practical points regarding the use of KD in an ICU setting.(1)Optimal timing to start KDTable 1Use of Ketogenic Diet (KD) in four patients admitted to the Pediatric Intensive Care Unit, Prince of Wales Hospital, Hong Kong with super-refractory status epilepticus from January 2011 to August 2014.Patient 1Patient 2Patient 3Patient 4Demographic & medical backgroundAge (y)161668SexFemaleMaleMaleFemalePre-existing epilepsyNilNilNilNilNeurodevelopmentNormalNormalNormalNormalFeverYesYesYesYesMRI brainNormalBasal ganglia T2 hyperintensitiesNormalLimbic encephalitisCSF StudiesNormalNormalNormalNormalImmunologicalNegativeAnti-Caspr2 Antibody positiveNot doneAnti-GAD antibody low positivePresumptive diagnosisNORSEVGKC antibody associated encephalitisFIRESEncephalitis of possible autoimmune originTreatment historyThiopentone useYesYesYesYesMidazolam useYesYesYesYesPropofol useYesYesNoNoNumber of anticonvulsants tried before KD3445Duration of status epilepticus before KD use (d)18171221KD usageRegimeFat to protein/ carbohydrate ratio 3:1 on Day 1 & then step up to 4:1 in next 2 daysFat to protein/ carbohydrate ratio 4:1 with 1/3 of total calories on Day 1 & then step up to full calories in next 2 daysFat to protein/ carbohydrate ratio 4:1 with 1/3 of total calories on Day 1 & then step up to full calories in next 2 daysFat to protein/ carbohydrate ratio 4:1 with 1/3 of total calories on Day 1 & then step up to full calories in next 2 daysFormula usedKetocal - Nutricia Advanced Medical NutritionTotal duration of KD use (d)1091011Ketosis achievedNoYesYesYesConcomitant treatment adjustmentPlasmapharesisPlasmapharesisphenyotinB6/folinic acid/midazolam infusionClobazam & midazolam infusionPerceived efficacy of KDNoNoNoYesSeizures stopped 5 days after ketosis establishedDifficulties/ problems encounteredFalling plasma proteinVomiting, suspected sepsisIncrease breakthrough seizuresRefuse KD upon recoveryReasons for stopping KDNot usefulNot usefulNot usefulCompliance problemsFinal OutcomeICU stay3 months6 months4 weeks32 daysOutcomeRefractory epilepsyMild cognitive impairmentCritical illness polyneuropathiesRefractory dystoniaSevere physical handicapRefractory epilepsyBehavior problemsSeizure freeReturn to “baseline” without significant deficitCSF = cerebral spinal fluid; FIRES = fever induced refractory epileptic encephalopathy in school-age children; GAD: glutamic acid decarboxylase; ICU = intensive care unit; KD = ketogenic diet; MRI = magnetic resonance imaging; NORSE = new onset refractory status epilepticus syndrome; VGKC = voltage gated potassium channel. Open table in a new tab CSF = cerebral spinal fluid; FIRES = fever induced refractory epileptic encephalopathy in school-age children; GAD: glutamic acid decarboxylase; ICU = intensive care unit; KD = ketogenic diet; MRI = magnetic resonance imaging; NORSE = new onset refractory status epilepticus syndrome; VGKC = voltage gated potassium channel. Nam et al5Nam S.H. Lee B.L. Lee C.G. Yu H.J. Joo E.Y. Lee J. et al.The role of ketogenic diet in the treatment of refractory status epilepticus.Epilepsia. 2011; 52: e181-e184Crossref PubMed Scopus (66) Google Scholar suggest starting KD when the patients have active bowel movements and in the absence of infection, sepsis, or disseminated intravascular coagulation. Other reports indicate that the interval between the onset of SE and the use KD have ranged from 2 days to 14 months. We started KD at a median time of 17.5 days after the development of SE (range, 12–21 days).(2)Optimal mode and rate of initiation Ready-made enteral formula was used in most reported series. O'Connor et al6O'Connor S.E. Richardson C. Trescher W.H. Byler D.L. Sather J.D. Michael E.H. et al.The ketogenic diet for the treatment of pediatric status epilepticus.Pediatr Neurol. 2014; 50: 101-103Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar suggested that continuous feeding could improve tolerability. Gradually stepping up the formula as tolerated may be a good option since gastroesophageal reflux is commonly encountered in these patients. However, this carries a disadvantage since it may take longer to achieve ketosis.(3)Expected course of treatment Other reports note that apparent clinical response to KD occurs after a mean/median of 3 days5Nam S.H. Lee B.L. Lee C.G. Yu H.J. Joo E.Y. Lee J. et al.The role of ketogenic diet in the treatment of refractory status epilepticus.Epilepsia. 2011; 52: e181-e184Crossref PubMed Scopus (66) Google Scholar to 10 days.7Sort R. Born A.P. Pedersen K.N. Fonsmark L. Uldall P. Ketogenic diet in 3 cases of childhood refractory status epilepticus.Eur J Paediatr Neurol. 2013; 17: 531-536Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In our series, we continued KD for at least 5 days after achieving ketosis before concluding that there was a lack of response. O'Connor et al6O'Connor S.E. Richardson C. Trescher W.H. Byler D.L. Sather J.D. Michael E.H. et al.The ketogenic diet for the treatment of pediatric status epilepticus.Pediatr Neurol. 2014; 50: 101-103Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar has suggested that KD should be continued for at least 2 weeks to observe any effect.(4)Monitoring treatment response Since patients with SRSE are usually critically ill, it may take several days for ketosis to be established. In addition it is often necessary to add other treatments while stepping up KD, making it difficult to be certain whether patients who stop seizing do so because of KD or because of concomitant treatment changes or a combination of both treatments. These difficulties emphasize the importance of careful qualitative documentation of the use of KD and other concomitant treatments for SRSE.(5)Duration of treatment after seizure control In the literature, many SRSE patients showing an apparent response to KD will continue this diet, or change to a modified Atkin's diet, for weeks to months. The optimal duration of continuing KD is uncertain. We found some difficulties in keeping patients on KD once full oral feeding was resumed. Patients and their families need to be fully counseled about the practical issues of KD to help them accept the limitations and difficulties of taking KD, especially when there is clinical improvement. In summary our experience suggests that KD is a safe and feasible option in an ICU setting and can be considered as a treatment option for SRSE. Standardized guidelines for the implementation and monitoring of KD in ICU settings for SRSE may help to improve our understanding of its role and efficacy in status epilepticus. The authors declare that there is no conflict of interest with reference to the search or publication of this article.