Epilepsy Research (2015) 113, 126—131
journal homepage: www.elsevier.com/locate/epilepsyres
Ketogenic diet in patients with epileptic encephalopathy with electrical status epilepticus during slow sleep Gabriela Reyes a, Santiago Flesler a, Marisa Armeno b, Sebastian Fortini a, Agustinho Ariela b, Araceli Cresta b, Graciela Mestre b, Roberto Horacio Caraballo a,∗ a b
Department of Neurology, Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’, Buenos Aires, Argentina Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’, Buenos Aires, Argentina
Received 5 January 2015; received in revised form 10 March 2015; accepted 28 March 2015 Available online 9 April 2015
KEYWORDS Epileptic encephalopathy; Ketogenic diet; ESES syndrome; Refractory epilepsy; Seizures
∗
Summary Epileptic encephalopathy with electrical status epilepticus during slow sleep (ESES) belongs to the group of epileptic encephalopathies that often prove refractory to AED treatment. The ketogenic diet (KD) has been used as an alternative to antiepileptic drugs (AEDs) for patients with refractory epileptic encephalopathies. Purpose: In this retrospective study we assess the efficacy and tolerability of the KD in patients with ESES syndrome. Methods: Between March 1, 1990 and April 1, 2013, 65 patients who met diagnostic criteria of ESES syndrome were seen at our department. Twelve of them were placed on the KD and followed for a minimum of 18 months. Results: The children had previously received a mean of 5.5 different AEDs and were on a mean of 3 AEDs when the diet was started. Eighteen months after initiating the diet, seven of the initial patients (58%) remained on the diet; one patient (8.3%) had become seizure free, one (8.3%) had a 75—99% decrease in seizures, two (16.6%) had a 50—74% decrease in seizures, and the remaining three children (24.9%) had a 50% reduction in seizures (Kossoff et al., 2008; Freeman et al., 2009; Caraballo et al., 2013). Epileptic encephalopathy with electrical status epilepticus during slow sleep (ESES) is now classified among the epileptic encephalopathies (Engel, 2001; Berg et al., 2010) that are generally refractory to AEDs. ESES syndrome is characterized by (Tassinari et al., 2002; Caraballo et al., 2013): (1) Onset with focal or apparently generalized seizures and focal EEG discharges; (2) Further appearance of atypical absences, and myoclonic, atonic (with or without epileptic falls), and/or generalized seizures; (3) Cognitive impairment
127
and/or behavioral disturbances related to the ESES period; (4) ESES occurring in more than 85% of non-REM sleep; however, a lower percentage — between 85% and 30% — may also be included (Tassinari et al., 2002; Caraballo et al., 2013). Cases with ESES syndrome of a genetic or probably genetic, structural, and unknown etiology have been described. The challenge of the management of ESES syndrome lies in its resistance to classic AEDs, steroid dependence, and the fact that little is known about the effectiveness of the KD in ESES. Nevertheless, a few reports suggest to include the diet as an alternative treatment option (Bergqvist et al., 1999; Nikanorova et al., 2009). In this retrospective study, we evaluate the efficacy and tolerability of the KD in patients who met the diagnostic criteria of epileptic encephalopathy with ESES.
Materials and methods Between March 1, 1990 and August 31, 2013, 65 patients who met the diagnostic criteria of epileptic encephalopathy with ESES were seen at our center. Twelve of these 65 patients were placed on the KD using the Hopkins protocol and followed for a minimum period of 18 months. The KD has been proposed to the parents as a treatment option because of drug resistance. Five patients with refractory seizures were not offered the KD as they came from families with a low socioeconomic level who were considered not to be prepared to follow the diet. Frequency of the seizures was registered using daily seizure calendars kept by the parents. Electroencephalograms during wakefulness and sleep were performed at least three months before starting, while on, and after discontinuing the KD. All patients underwent intermittent photic stimulation (IPS). Baseline blood tests and lipid profiles were also obtained. Serum bicarbonate levels were measured in all patients. Efficacy criteria did not only include seizure reduction, but also sleep-EEG and neuropsychological outcome. Children started fasting in the hospital for 36—48 h and were then gradually initiated on the classic KD (Johns Hopkins protocol). Children were begun on a 4:1 ratio (fat: protein plus carbohydrate) and stayed in hospital for another four days for close monitoring. During this period parents were taught about the diet. They were asked to keep the child on the diet for at least two months to regulate the diet for optimal tolerance and seizure control. The ratio of the diet was progressively modified as needed to maintain 80 to 160 mg/dl urinary ketosis and to avoid weight loss. Adverse events and reasons for diet discontinuation were recorded, as were changes in medication.
Results Sixty-five children with a diagnosis of epileptic encephalopathy with ESES were followed for 2 to 21 years. Of these children, 12 (eight boys and four girls) were placed on the KD as add-on to the use of one to three AEDs. Ages at initiation of the KD were between 7 and 11 years (mean 8.5 years).
128 All patients had more than one type of seizure before starting the diet: Five patients had two types, four had three types, and three had more than three types of seizures. Patients with positive myoclonias and absence seizures had an average of 65 and 66 episodes a month, respectively. Patients with atonic seizures and negative myclonic jerks had an average of 52 episodes, those with focal seizures had an average of 16 episodes, and those with secondary generalized tonic-clonic seizures had an average of five episodes a month. The children had previously received a mean of 5.5 different AEDs and were on a mean of 3 AEDs when the diet was begun. None of the patients responded well to steroids. Seven cases of 12 were of structural etiology. Four of them had unilateral polymicrogyria, two had shunted hydrocephalus, and the remaining patient had perinatal injury. Five cases were cryptogenic. Considering the efficacy of the diet, no differences were found according to etiology. Previous to the ESES period, the neuropsychological evaluation showed a normal IQ and no cognitive and behavioral disturbances in the five cryptogenic cases. Of the seven structural cases, six had moderate mental retardation, associated with hyperactivity disturbances in three, and one had mild mental retardation. Table 1 shows the electroclinical features, treatment, and outcome of the patients before diet initiation and while on the KD.
Duration on the diet One of the seven children stayed on the diet for 18 months, four children remained on the diet for 2 years, one child for 3 years, and one for 3.5 years.
Efficacy of the diet Eighteen months after initiating the diet, seven of the initial patients (58.3%) remained on the diet. One patient (8.3%) became seizure free, one child (8.3%) had a 75-to-99% decrease in seizures, two patients (16.6%) had a 50-to74% decrease in seizures, and the remaining three children (24.9%) had a less than 50% seizure reduction. The patient that became seizure free had a structural epileptic encephalopathy with ESES; in the child with a 75-to-99% decrease in seizures the etiology was unknown; and of the two cases with a 50-to-74% decrease in seizures the etiology was structural in one and unknown in the other. The remaining patients who had less than 50% seizure reduction were structural cases. In our series of patients, the KD was effective in all types of seizure.
Reasons for discontinuing the diet, tolerability, and adverse events Five of the 12 children (41.6%) who initiated the diet discontinued within the first three months. In three, the reason given for discontinuing the diet was lack of effectiveness. Two of these children discontinued between 1 and 2 months and one discontinued 3 months after starting the diet. In two children persistent and severe vomiting was the reason
G. Reyes et al. for discontinuing the diet one month after initiation. Seven patients who remained on the diet for more than one and a half year did not develop severe complications.
Electroencephalographic changes In all patients who followed the KD with good response, EEG recordings of at least 3 months before starting the KD showed very frequent symmetric or asymmetric bilateral spike-and-wave paroxysms during slow sleep. Eighteen months after initiating the diet, the EEG abnormalities had improved in all of them. The EEG recording was normal in one patient who became seizure free. In the patient with a 75-to-99% seizure reduction the EEG during sleep improved significantly (between 40% and 80%). In both patients who achieved a 50-to-74% seizure decrease, EEG abnormalities during sleep improved between 20% and 50%, and in those patients who achieved a less than 50% seizure reduction, the EEG recording showed frequent generalized spikes and waves and multifocal spikes. The changes in the abnormalities were determined according to the quantity of paroxysmal discharges on the sleep EEG recording.
Decreasing and discontinuing medications Medications were decreased non-systematically with the aim of the patient becoming medication free. The patient who became seizure free had a cryptogenic or unknown etiology, is receiving only one AED on the KD instead of three previously, and has a normal IQ. The patient with a 75-to-99% seizure reduction is on one AED instead of three. The neuropsychological profile returned to baseline both in the patient who became seizure free and in the one with a 75-to-99% seizure reduction; however, in the patients with a 50-to-74% seizure reduction the neuropsychological profile improved, but did not return to baseline.
Discussion Our experience with the KD in 12 children with epileptic encephalopathy with ESES shows an overall good response in terms of seizure frequency and tolerability, not only in the unknown but also in the structural group. Interictal epileptiform abnormalities improved in most of our patients who had a seizure reduction of more than 75%. Similar findings have been reported in the literature (Kessler et al., 2011). The KD has been successfully used in children with a variety of seizure types and epileptic syndromes, especially epileptic encephalopathies (Caraballo, 2011; Veggiotti et al., 2011; Nangia et al., 2012; Lemmon et al., 2012). In the literature, patients with epileptic encephalopathy with ESES, including Landau-Kleffner syndrome, who responded well to KD have been published (Bergqvist et al., 1999; Nikanorova et al., 2009) and the KD has been considered in the treatment scheme of cases with ESES syndrome (Lagae, 2009). Nevertheless, ESES cases treated with the KD are few and effective treatments in this epileptic syndrome are limited. As in our studies on the treatment of patients with Dravet syndrome (DS) (Caraballo et al., 2005, 2013, 2015)
The electroclinical features, treatment, and outcome of the patients before starting the KD, while on the KD and at the last follow-up. Seizure frequency Before KD
Seizure frequency on the KD
ESES (%)
EEG at the last follow-up
AEDs before KD
AEDs on KD
Duration of KD
Results
9
Daily
Daily
>85
ESES
No response
7
Daily
Daily
85 >85
ESES Normal
VPA-CLBETM VPA-CLBSTM CLB-LVT VPA
1 month
3.
2 months 18 months
Discont. Adv. effects No response Seizure free
5 Structural
4
7
Daily
Sporadic
85
journal homepage: www.elsevier.com/locate/epilepsyres
Ketogenic diet in patients with epileptic encephalopathy with electrical status epilepticus during slow sleep Gabriela Reyes a, Santiago Flesler a, Marisa Armeno b, Sebastian Fortini a, Agustinho Ariela b, Araceli Cresta b, Graciela Mestre b, Roberto Horacio Caraballo a,∗ a b
Department of Neurology, Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’, Buenos Aires, Argentina Hospital de Pediatría ‘‘Prof Dr Juan P Garrahan’’, Buenos Aires, Argentina
Received 5 January 2015; received in revised form 10 March 2015; accepted 28 March 2015 Available online 9 April 2015
KEYWORDS Epileptic encephalopathy; Ketogenic diet; ESES syndrome; Refractory epilepsy; Seizures
∗
Summary Epileptic encephalopathy with electrical status epilepticus during slow sleep (ESES) belongs to the group of epileptic encephalopathies that often prove refractory to AED treatment. The ketogenic diet (KD) has been used as an alternative to antiepileptic drugs (AEDs) for patients with refractory epileptic encephalopathies. Purpose: In this retrospective study we assess the efficacy and tolerability of the KD in patients with ESES syndrome. Methods: Between March 1, 1990 and April 1, 2013, 65 patients who met diagnostic criteria of ESES syndrome were seen at our department. Twelve of them were placed on the KD and followed for a minimum of 18 months. Results: The children had previously received a mean of 5.5 different AEDs and were on a mean of 3 AEDs when the diet was started. Eighteen months after initiating the diet, seven of the initial patients (58%) remained on the diet; one patient (8.3%) had become seizure free, one (8.3%) had a 75—99% decrease in seizures, two (16.6%) had a 50—74% decrease in seizures, and the remaining three children (24.9%) had a 50% reduction in seizures (Kossoff et al., 2008; Freeman et al., 2009; Caraballo et al., 2013). Epileptic encephalopathy with electrical status epilepticus during slow sleep (ESES) is now classified among the epileptic encephalopathies (Engel, 2001; Berg et al., 2010) that are generally refractory to AEDs. ESES syndrome is characterized by (Tassinari et al., 2002; Caraballo et al., 2013): (1) Onset with focal or apparently generalized seizures and focal EEG discharges; (2) Further appearance of atypical absences, and myoclonic, atonic (with or without epileptic falls), and/or generalized seizures; (3) Cognitive impairment
127
and/or behavioral disturbances related to the ESES period; (4) ESES occurring in more than 85% of non-REM sleep; however, a lower percentage — between 85% and 30% — may also be included (Tassinari et al., 2002; Caraballo et al., 2013). Cases with ESES syndrome of a genetic or probably genetic, structural, and unknown etiology have been described. The challenge of the management of ESES syndrome lies in its resistance to classic AEDs, steroid dependence, and the fact that little is known about the effectiveness of the KD in ESES. Nevertheless, a few reports suggest to include the diet as an alternative treatment option (Bergqvist et al., 1999; Nikanorova et al., 2009). In this retrospective study, we evaluate the efficacy and tolerability of the KD in patients who met the diagnostic criteria of epileptic encephalopathy with ESES.
Materials and methods Between March 1, 1990 and August 31, 2013, 65 patients who met the diagnostic criteria of epileptic encephalopathy with ESES were seen at our center. Twelve of these 65 patients were placed on the KD using the Hopkins protocol and followed for a minimum period of 18 months. The KD has been proposed to the parents as a treatment option because of drug resistance. Five patients with refractory seizures were not offered the KD as they came from families with a low socioeconomic level who were considered not to be prepared to follow the diet. Frequency of the seizures was registered using daily seizure calendars kept by the parents. Electroencephalograms during wakefulness and sleep were performed at least three months before starting, while on, and after discontinuing the KD. All patients underwent intermittent photic stimulation (IPS). Baseline blood tests and lipid profiles were also obtained. Serum bicarbonate levels were measured in all patients. Efficacy criteria did not only include seizure reduction, but also sleep-EEG and neuropsychological outcome. Children started fasting in the hospital for 36—48 h and were then gradually initiated on the classic KD (Johns Hopkins protocol). Children were begun on a 4:1 ratio (fat: protein plus carbohydrate) and stayed in hospital for another four days for close monitoring. During this period parents were taught about the diet. They were asked to keep the child on the diet for at least two months to regulate the diet for optimal tolerance and seizure control. The ratio of the diet was progressively modified as needed to maintain 80 to 160 mg/dl urinary ketosis and to avoid weight loss. Adverse events and reasons for diet discontinuation were recorded, as were changes in medication.
Results Sixty-five children with a diagnosis of epileptic encephalopathy with ESES were followed for 2 to 21 years. Of these children, 12 (eight boys and four girls) were placed on the KD as add-on to the use of one to three AEDs. Ages at initiation of the KD were between 7 and 11 years (mean 8.5 years).
128 All patients had more than one type of seizure before starting the diet: Five patients had two types, four had three types, and three had more than three types of seizures. Patients with positive myoclonias and absence seizures had an average of 65 and 66 episodes a month, respectively. Patients with atonic seizures and negative myclonic jerks had an average of 52 episodes, those with focal seizures had an average of 16 episodes, and those with secondary generalized tonic-clonic seizures had an average of five episodes a month. The children had previously received a mean of 5.5 different AEDs and were on a mean of 3 AEDs when the diet was begun. None of the patients responded well to steroids. Seven cases of 12 were of structural etiology. Four of them had unilateral polymicrogyria, two had shunted hydrocephalus, and the remaining patient had perinatal injury. Five cases were cryptogenic. Considering the efficacy of the diet, no differences were found according to etiology. Previous to the ESES period, the neuropsychological evaluation showed a normal IQ and no cognitive and behavioral disturbances in the five cryptogenic cases. Of the seven structural cases, six had moderate mental retardation, associated with hyperactivity disturbances in three, and one had mild mental retardation. Table 1 shows the electroclinical features, treatment, and outcome of the patients before diet initiation and while on the KD.
Duration on the diet One of the seven children stayed on the diet for 18 months, four children remained on the diet for 2 years, one child for 3 years, and one for 3.5 years.
Efficacy of the diet Eighteen months after initiating the diet, seven of the initial patients (58.3%) remained on the diet. One patient (8.3%) became seizure free, one child (8.3%) had a 75-to-99% decrease in seizures, two patients (16.6%) had a 50-to74% decrease in seizures, and the remaining three children (24.9%) had a less than 50% seizure reduction. The patient that became seizure free had a structural epileptic encephalopathy with ESES; in the child with a 75-to-99% decrease in seizures the etiology was unknown; and of the two cases with a 50-to-74% decrease in seizures the etiology was structural in one and unknown in the other. The remaining patients who had less than 50% seizure reduction were structural cases. In our series of patients, the KD was effective in all types of seizure.
Reasons for discontinuing the diet, tolerability, and adverse events Five of the 12 children (41.6%) who initiated the diet discontinued within the first three months. In three, the reason given for discontinuing the diet was lack of effectiveness. Two of these children discontinued between 1 and 2 months and one discontinued 3 months after starting the diet. In two children persistent and severe vomiting was the reason
G. Reyes et al. for discontinuing the diet one month after initiation. Seven patients who remained on the diet for more than one and a half year did not develop severe complications.
Electroencephalographic changes In all patients who followed the KD with good response, EEG recordings of at least 3 months before starting the KD showed very frequent symmetric or asymmetric bilateral spike-and-wave paroxysms during slow sleep. Eighteen months after initiating the diet, the EEG abnormalities had improved in all of them. The EEG recording was normal in one patient who became seizure free. In the patient with a 75-to-99% seizure reduction the EEG during sleep improved significantly (between 40% and 80%). In both patients who achieved a 50-to-74% seizure decrease, EEG abnormalities during sleep improved between 20% and 50%, and in those patients who achieved a less than 50% seizure reduction, the EEG recording showed frequent generalized spikes and waves and multifocal spikes. The changes in the abnormalities were determined according to the quantity of paroxysmal discharges on the sleep EEG recording.
Decreasing and discontinuing medications Medications were decreased non-systematically with the aim of the patient becoming medication free. The patient who became seizure free had a cryptogenic or unknown etiology, is receiving only one AED on the KD instead of three previously, and has a normal IQ. The patient with a 75-to-99% seizure reduction is on one AED instead of three. The neuropsychological profile returned to baseline both in the patient who became seizure free and in the one with a 75-to-99% seizure reduction; however, in the patients with a 50-to-74% seizure reduction the neuropsychological profile improved, but did not return to baseline.
Discussion Our experience with the KD in 12 children with epileptic encephalopathy with ESES shows an overall good response in terms of seizure frequency and tolerability, not only in the unknown but also in the structural group. Interictal epileptiform abnormalities improved in most of our patients who had a seizure reduction of more than 75%. Similar findings have been reported in the literature (Kessler et al., 2011). The KD has been successfully used in children with a variety of seizure types and epileptic syndromes, especially epileptic encephalopathies (Caraballo, 2011; Veggiotti et al., 2011; Nangia et al., 2012; Lemmon et al., 2012). In the literature, patients with epileptic encephalopathy with ESES, including Landau-Kleffner syndrome, who responded well to KD have been published (Bergqvist et al., 1999; Nikanorova et al., 2009) and the KD has been considered in the treatment scheme of cases with ESES syndrome (Lagae, 2009). Nevertheless, ESES cases treated with the KD are few and effective treatments in this epileptic syndrome are limited. As in our studies on the treatment of patients with Dravet syndrome (DS) (Caraballo et al., 2005, 2013, 2015)
The electroclinical features, treatment, and outcome of the patients before starting the KD, while on the KD and at the last follow-up. Seizure frequency Before KD
Seizure frequency on the KD
ESES (%)
EEG at the last follow-up
AEDs before KD
AEDs on KD
Duration of KD
Results
9
Daily
Daily
>85
ESES
No response
7
Daily
Daily
85 >85
ESES Normal
VPA-CLBETM VPA-CLBSTM CLB-LVT VPA
1 month
3.
2 months 18 months
Discont. Adv. effects No response Seizure free
5 Structural
4
7
Daily
Sporadic
85
