ARTICLE IN PRESS+ModelEPIRES-5246; No. of Pages 5

Epilepsy Research (2014) xxx, xxx—xxx

jo ur nal ho me p ag e: www.elsev ier .com/ locate /ep i lepsyres

Ketogenic diet in pediatric patients withrefractory focal status epilepticus

Roberto Horacio Caraballoa,∗, Santiago Fleslera,Marisa Armenoc, Sebastian Fortini a, Ariela Agustinhoc,Graciela Mestreb, Araceli Crestab, María Celeste Buompadrea,Nidia Escobalc

a Department of Neurology, Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’, Buenos Aires, Argentinab Department of Food Services, Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’, Buenos Aires, Argentinac Department of Clinical Nutrition, Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’,Buenos Aires, Argentina

Received 12 August 2014; received in revised form 20 September 2014; accepted 29 September 2014

KEYWORDSFocal;Status epilepticus;Ketogenic diet;Super-refractory;Seizures

Summary The ketogenic diet (KD) has been used as an alternative treatment for patientswith refractory status epilepticus (SE).Purpose: In this retrospective study we assess the efficacy and tolerability of the KD in patientswith refractory SE.Methods: Between March 1, 2010 and January 1, 2014, 10 patients who met the diagnosticcriteria of refractory SE seen at our department were placed on the KD and followed for aminimum of 6 months.Results: Ketonuria was reached within 2—4 days (mean 3 days) for all patients.

Seizures stopped in two patients and five patients had a 50—75% seizure reduction within2—5 days (mean 2.5 days) following the onset of ketonuria and within 5—7 days (mean 5 days)

following the onset of the diet. Three patients had a <50% seizure reduction and all of them hadsevere adverse events so the diet was discontinued. Seven patients remained on the diet for 6months to 3 years (mean 1.5 years). In all seven patients within 4 months the seizures recurred,but their quality of life did not worsen. The frequency of the seizures consisted of weeklyseizures in two, monthly seizures in two, occasional seizures in two, and isolated seizures in

Please cite this article in press as: Caraballo, R.H., et al., Ketogenic diet in pediatric patients with refractory focal statusepilepticus. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j.eplepsyres.2014.09.033

one. All of them kept a good tolerability of the diet.

∗ Corresponding author at: Neurología, Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’, Combate de los Pozos 1881, CP 1245 BuenosAires, Argentina. Tel.: +54 11 4943 6116; fax: +54 11 4943 6116.

E-mail address: rhcaraballo@arnet.com.ar (R.H. Caraballo).

http://dx.doi.org/10.1016/j.eplepsyres.2014.09.0330920-1211/© 2014 Published by Elsevier B.V.

ARTICLE IN+ModelEPIRES-5246; No. of Pages 5

2

Conclusion: The KD is an effectivtory SE. In patients with focal SE

the KD should be considered earli© 2014 Published by Elsevier B.V.

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he ketogenic diet (KD) is a high-fat, low-carbohydrate, anddequate-protein diet (Stafstrom and Rho, 2004; Freemant al., 2006; Kossoff et al., 2008; Caraballo and Vining,013). The ketogenic diet is now considered a safe andffective optional therapy not only for children but also fordults with intractable epilepsy (Stafstrom and Rho, 2004;reeman et al., 2006, 2009; Kossoff et al., 2008; Caraballond Vining, 2013; Neal et al., 2008, 2009; Caraballo et al.,011). Interest in the diet has been increasing includingor the emergency treatment of status epilepticus (SE)Freeman et al., 2009; Neal et al., 2008, 2009; Caraballot al., 2011; Bodenant et al., 2008; Wusthoff et al.,010; Nabbout et al., 2010; Nam et al., 2011; Cervenkat al., 2011; Vaccarezza et al., 2012; Strzelczyk et al.,013).

It has been suggested that the KD may be beneficialor seizure control in specific epileptic syndromes (Kossofft al., 2008; Caraballo and Vining, 2013; Nangia et al.,012). Over the last years, there has been a remark-ble appearance in the concept of using dietary therapyor emergency management of pharmacoresistant seizuresBodenant et al., 2008; Wusthoff et al., 2010; Nabbout et al.,010; Nam et al., 2011; Cervenka et al., 2011; Vaccarezzat al., 2012; Strzelczyk et al., 2013; Nangia et al., 2012;ossoff and Nabbout, 2013; Sort et al., 2013; Thakur et al.,014).

Several publications have considered the benefits of theD for SE (Bodenant et al., 2008; Wusthoff et al., 2010;abbout et al., 2010; Nam et al., 2011; Cervenka et al.,011; Vaccarezza et al., 2012; Strzelczyk et al., 2013; Nan-ia et al., 2012; Kossoff and Nabbout, 2013; Sort et al.,013; Thakur et al., 2014). The first report was of an adultatient with refractory focal SE, who responded well tohe KD within seven days (Bodenant et al., 2008). Subse-uently, more than 30 pediatric and adult patients withE receiving diet therapy have been published (Bodenantt al., 2008; Wusthoff et al., 2010; Nabbout et al., 2010;am et al., 2011; Cervenka et al., 2011; Vaccarezza et al.,012; Strzelczyk et al., 2013; Nangia et al., 2012; Kossoffnd Nabbout, 2013; Sort et al., 2013; Thakur et al., 2014;’Connor et al., 2014). They were treated with the KD,he modified Atkins diet, and the low glycemic index diet,nd SE was secondary to different etiologies (Kossoff andabbout, 2013). Many of these patients had autoimmuner inflammatory diseases causing SE. Most of the patientsere treated with the traditional KD using a ketogenic

ormula via nasogastric tube. When the diet was success-ul, it worked within 7—10 days (Kossoff and Nabbout,

Please cite this article in press as: Caraballo, R.H., et al., Ketogepilepticus. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j

013).In this study we evaluate the efficacy and tolerability

f the KD in patients who met the diagnostic criteria ofefractory SE.

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PRESSR.H. Caraballo et al.

e and well-tolerated treatment option for patients with refrac-secondary to inflammatory or probably inflammatory diseases,er in the course of the treatment.

aterials and methods

etween March 1, 2010 and January 1, 2014, 10 patients whoet the diagnostic criteria of refractory SE were seen at ourepartment. They were placed on the KD and followed for

minimum of 6 months.The age of the patients ranged from 2 to 9 years (mean

years). The patients had no significant personal or familyistory, except two patients who had a nonspecific febrilellness that preceded the first seizures by 2—7 days and oneho had a relative with epilepsy. The patients were followedver a period of 5 years. The electroclinical features of theatients are described in Table 1.

The patients mainly had repetitive and nearly continu-us focal status epilepticus refractory to the conventionalrotocol treatment of SE, including intravenous benzodi-zepines, phenytoin, sodium thiopental, corticosteroids,nd gamma globulins. Cerebrospinal fluid (CSF) was normaln all patients. Extensive virologic investigations in blood,SF, and urine were negative in all cases. In two patients,nti-NMDAR antibodies were searched for. The test was pos-tive in one. Plasma lactate and pyruvate levels as well aslasma amino acid and urine organic acid chromatographiesere normal. Magnetic resonance imaging (MRI) showedo white-matter hypersignal, but three cases had diffuserain atrophy and one had an asymmetric hypersignal ofhe mesial temporal gray matter on both sides. One patientvidenced features compatible with hemimegalencephaly,wo patients had focal cortical dysplasia, and in the threeemaining patients the MRI was normal.

All patients received a 4:1 KD and glucose administrationas removed, including from intravenous infusion. After 24 hf fasting, the patients were fed with a commercial prepa-ation (KetoCal [KetoCal, SHS]). The diet was administeredia a gastric tube. Urine ketosis was monitored daily withabstix. No attempt was made to measure ketone bodies inlasma.

esults

en children (six boys and four girls) with a diagnosis of SEere placed on the KD as add-on to the use of more than oneED. Three patients received the diet during 1 week by naso-astric tube, but it was discontinued due to severe adverseffects. Of the remaining seven patients, who received theD by nasogastric tube for 1—3 months, four continued toeceive the same formula by oral administration and thether three were switched to the oral classic diet.

reatment of the SE

enic diet in pediatric patients with refractory focal status.eplepsyres.2014.09.033

etonuria was reached within 2—4 days (mean 3 days) in allatients.

ARTICLE IN PRESS+ModelEPIRES-5246; No. of Pages 5

Ketogenic diet and status epilepticus 3

Table 1 The electroclinical features, treatment, and evolution of 10 patients with SE on the KD.

Patients Age at KDinitiation (years)

Type of FSE Ictal focal EEGabnormalities

Side effects Durationof the KD

Results

1 8 Simple andcomplex

Ryhthmic delta-thetaslow-wave discharges

— 6 months 75—99%

2 9 Simple Rhythmic fastdischarges

Severevomiting andhypoglycemia

3 months <50%

3 0.5 Complex Rhythmicspike-and-wave andslow-wave discharges

— 2 months 50—74%

4 7 Simple andcomplex

Slow waves withinterposed spikes

— 3 years 50—74%

5 16 Complex withsecondarygeneralization

Rhythmic thetaslow-wave dischargesfollowed bygeneralized spikesand waves

Pancreatitis 7 days <50%

6 4 Simple Slow-wave dischargesfollowed by rhythmicfast paroxysms

— 1 year 50—74%

7 11 Simple withsecondarygeneralization

Focal spike-and-wavedischargespropagated to thecontralateralhemisphere

— 1 year 50—74%

8 5 Simple andcomplex

Rhythmic theta slowwaves followed byspikes

Pancreatitis 8 days <50%

9 8 Complex Rhythmic slow-wavedischarges

— 1.5 years 75—99%

10 10 Simple andcomplex

Rhythmic fastparoxysms followedby rhythmic slowwaves

2.5 years 50—74%

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Abbreviation: FSE: focal status epilepticus.

Two patients had a 75—99% seizure reduction and fivepatients had a 50—75% seizure reduction within 2—5 days(mean 2.5 days) following the onset of ketonuria and 5—7days (mean 5 days) following the initiation of the diet. Threepatients had a <50% seizure reduction; all three had severeadverse events so the diet was discontinued.

Patients with a good response recovered consciousnesswithin 48 h following seizure cessation or reduction andmotor function improved in the following weeks.

Reasons for discontinuing the diet, tolerability, andadverse events

Three children (25%) discontinued the diet within the first 7days. The reason for discontinuing the diet was pancreatitisin two, secondary to valproic acid in one of them. In theremaining patient, the reason for discontinuation was per-

Please cite this article in press as: Caraballo, R.H., et al., Ketogepilepticus. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j

sistent and severe vomiting and hypoglycemia. The otherseven patients on the KD did not develop severe complica-tions, such as high levels of uric acid, kidney stones, severeacidosis, lethargy, or hypoglycemia.

S(4t

lectroencephalographic changes

he EEG recordings performed before starting the diethowed rhythmic focal abnormalities compatible with focalE. After initiating the diet, in all patients the EEG abnor-alities improved, even in those with severe complications.The improvement of the EEG abnormalities remained

nchanged in the patients in whom the diet was maintained.

ecreasing and discontinuing medications

edications were decreased and discontinued non-ystematically with the aim of achieving a rationalolitherapy.

ong-term evolution

enic diet in pediatric patients with refractory focal status.eplepsyres.2014.09.033

even patients remained on the diet for 6 months to 3 yearsmean 1.5 years). In six of them the seizures recurred within

months, however, their quality of life did not worsen andhey continued on the diet and some modifications were

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ARTICLEPIRES-5246; No. of Pages 5

ade in the AED scheme. The frequency of the seizuresas weekly in two and monthly in two. Occasional seizuresccurred in two and isolated seizures in the remaining case.olerability of the diet was good in all of them. As in theseeven patients in whom the seizures recurred seizure fre-uency was not high, quality of life of life did not worsen.

iscussion

n our experience with the KD in 10 children with refrac-ory SE, seven had a good response in terms of reduction ofeizure frequency and tolerability.

The KD has been recommended by several authors foratients with refractory SE, not only adults but childrens well, regardless of their etiology (Bodenant et al.,008; Wusthoff et al., 2010; Nabbout et al., 2010; Namt al., 2011; Cervenka et al., 2011; Vaccarezza et al.,012; Strzelczyk et al., 2013; Nangia et al., 2012; Kossoffnd Nabbout, 2013; Sort et al., 2013; Thakur et al., 2014;’Connor et al., 2014; Kumada et al., 2010). Nevertheless,atients with a febrile-illness-related epilepsy syndromeeem to be particularly good candidates, and should thus betrongly considered for treatment with the diet (Nabboutt al., 2010; Kossoff and Nabbout, 2013; Caraballo et al.,013). Four of our 10 patients had refractory focal seizuresssociated with febrile illness. Nine patients with this con-ition were reported by Nabbout et al. (2010). They hadefractory SE and the KD was introduced via nasogastric tubechieving seizure control within 4—6 days in seven patients.

Interestingly, our patients with Dravet syndrome (DS)Caraballo et al., 2011) who had episodes of febrile SE alsoesponded well to the KD. In one of them the KD was startedt 2 years of age, the patient did not repeat episodes ofebrile SE, and the quality of life of this patient and his fam-ly significantly improved. These findings also support theypothesis that the KD is beneficial in the management ofatients with febrile illness and seizures (Nabbout et al.,010; Kossoff and Nabbout, 2013).

The use of the KD for the treatment of SE is rapidlyncreasing throughout the world (Nam et al., 2011; Cervenkat al., 2011; Vaccarezza et al., 2012; Strzelczyk et al.,013; Nangia et al., 2012; Kossoff and Nabbout, 2013; Sortt al., 2013; Thakur et al., 2014; O’Connor et al., 2014;umada et al., 2010); however, to implement the diet inhe treatment of these critical patients that often recovern the intensive care unit, a ketogenic-diet team, includ-ng a trained neurologist and dietitian, is necessary. Such aeam will also provide the possibility to continue the dietnd install a longer-term treatment when it is successfulKossoff et al., 2008; Kossoff and Nabbout, 2013; Caraballond Vining, 2013). It is important to emphasize that thentensive care unit physicians and nurses should accompanyhe diet process accordingly, avoiding any AED changes dur-ng 10 days to allow the diet to work well (Kossoff andabbout, 2013). In the team decisions on each individualatient should be made based on electroclinical aspectsKossoff and Nabbout, 2013).

Please cite this article in press as: Caraballo, R.H., et al., Ketogepilepticus. Epilepsy Res. (2014), http://dx.doi.org/10.1016/j

It is well known that the KD may be specially benefi-ial in specific epileptic syndromes (Kossoff et al., 2008;araballo, 2011; Caraballo and Vining, 2013; Nangia et al.,012). Therefore, when evaluating treatment with the

C

PRESSR.H. Caraballo et al.

raditional KD in patients with refractory SE, the epilepticyndrome, etiology, and seizure type should be considered.his may provide an opportunity to start the KD early in theanagement of patients with refractory SE.In line with this concept, the fact that experimental

tudies have shown that conditions with inflammatory ornfectious mechanisms respond especially well to the treat-ent may point to an anti-inflammatory action of the diet

Ruskin et al., 2009; Gasior et al., 2006).The results of this study support the findings of other

uthors showing that the diet is useful in the manage-ent of patients with refractory focal SE (Bodenant et al.,

008; Wusthoff et al., 2010; Nabbout et al., 2010; Namt al., 2011; Cervenka et al., 2011; Vaccarezza et al.,012; Strzelczyk et al., 2013; Nangia et al., 2012; Kossoffnd Nabbout, 2013; Sort et al., 2013; Thakur et al., 2014;’Connor et al., 2014). Additionally, it has also been sug-ested that the KD should be considered in the treatment ofther types of SE. Prospective studies in patients with dif-erent types of refractory SE, not only children but adults asell, should be conducted in order to define the role of theiet in the treatment of these patients.

onclusion

he KD is a promising therapy for focal SE, with over half ofhe children showing an important reduction in seizures. Ithould be considered as an alternative option in the man-gement of SE.

In patients with focal SE secondary to inflammatory orrobably inflammatory diseases, the KD should be consid-red earlier in the course of the treatment of SE. Whenood seizure control is achieved, the use of the diet mayvoid cognitive deterioration and behavioral disturbances.

onflict of interest

e do not have any financial and personal relationships withther people or organizations to disclose that could inappro-riately influence this work.

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