PEDIATRICS Vol. 109 No. 5 May 2002, pp. 780-783
Efficacy of the Ketogenic Diet for Infantile Spasms
From the Departments of Neurology and Pediatrics, Pediatric Epilepsy Center, Johns Hopkins Medical Institutions, Baltimore, Maryland
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective. The objective of this study was to determine whether the ketogenic diet is safe, well-tolerated, and efficacious in the treatment of infantile spasms.
Methods. During a 4-year period, 23 children with infantile spasms, aged 5 months to 2 years, were started on the ketogenic diet; 9 (39%) had symptomatic infantile spasms, and 16 (70%) had hypsarrhythmia. Children had an average prediet exposure to 3.3 anticonvulsants. Two children were enrolled before any medication had been tried. Seizure reduction was analyzed retrospectively, using parent reports and electroencephalograms (EEGs) when available.
Results. At 3, 6, 9, and 12 months, 38%, 39%, 53%, and 46%, respectively, of all patients currently on the diet were >90% improved (3 were seizure-free at 12 months); 67%, 72%, 93%, and 100% were >50% improved. Fifty-six percent remained on the diet at 12 months, 46% of whom were >90% improved and 100% were >50%. Fifty percent of those with hypsarrhythmia and follow-up EEGs had EEG improvement. Fifty-seven percent had their medications reduced or discontinued by 12 months. Fifty-seven percent had improvement in development, which was correlated with seizure control. Independent factors that predicted improvement included age younger than 1 year and previous exposure to 3 or fewer anticonvulsants. No child has died, and 7 children had diet-related adverse reactions (nephrolithiasis, gastroesophageal reflux).
Discussion. The ketogenic diet is a safe, well-tolerated, and possibly effective potential alternative to other therapies for infantile spasms.
Key Words: infantile spasms • ketogenic diet • seizures
Abbreviations: ACTH, adrenocorticotropic hormone • EEG, electroencephalogram
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Infantile spasms are a generalized seizure disorder characterized by clusters of sudden flexor or extensor jerks in infants who are younger than 1 year.1,2 It is associated with both an arrest in psychomotor development and the electroencephalographic pattern of hypsarrhythmia or one of its variants. Prognosis is usually unfavorable.
Treatment for infantile spasms has traditionally included adrenocorticotropic hormone (ACTH) and prednisone. Side effects from these medications include irritability, hypertension, susceptibility to infection, gastrointestinal hemorrhage, and weight gain.3 Also, these medications can be used only for a limited period should spasms recur. Sodium valproate and clonazepam have had only limited success in abolition of seizures. Recently, vigabatrin has received much attention for its efficacy in infantile spasms.3–6 The potential side effects of visual field constriction, loss of acuity, and color vision may be irreversible.7 Newer drugs, such as topiramate, lamotrigine, zonisamide, and ganaxolone, have been tested for infantile spasms but have limited efficacy with their own side effects.8–11 With significant morbidity in regard to epilepsy and development, the need for additional therapies for infantile spasms is important.
The ketogenic diet has been used in children with recalcitrant seizures for >80 years.12,13 This high-fat, adequate-protein, low-carbohydrate diet has been shown to reduce seizures.14–17 As a subset of a large retrospective study of the ketogenic diet done previously at our institution, 39% of children with infantile spasms had >90% seizure reduction.15 On the basis of this information, we expanded our investigation to include cases of infantile spasms for 4 years. The objective of this study was to determine whether the ketogenic diet is safe, well-tolerated, and efficacious in the treatment of infantile spasms.
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METHODS |
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During a 4.5-year period, from February 14, 1996, to September 12, 2000, 23 children with infantile spasms were started on the ketogenic diet as part of an ongoing protocol for assessing the efficacy of the ketogenic diet in epilepsy. All information was obtained retrospectively. The Johns Hopkins Committee on Clinical Investigation approved the protocol, and informed consent was obtained. Infantile spasms were defined as clusters of flexor or extensor jerks in association with classic hypsarrhythmia (disorganized, high-voltage rhythm without normal background patterns) or one of its variants on electroencephalogram (EEG). All children were younger than 1 year when spasms began, had solely infantile spasms as their predominant seizure type at the initiation of the ketogenic diet, and had developmental arrest at the onset of seizures. Thirty percent had other seizure types (myoclonic, generalized tonic-clonic) at the time of ketogenic diet initiation, but infantile spasms were clearly predominant (at least 80% of total seizures).
Seventeen children were boys, and 6 were girls. The average age at enrollment was 1.1 years (range: 5 months–2 years). The average duration of infantile spasms before the ketogenic diet was 8.0 months (range: 0.5–24 months). All children had neuroimaging performed during their evaluation for cause. Nine (39%) children had symptomatic infantile spasms (2 with tuberous sclerosis; 2 twins with a presumed mitochondrial disorder; and 1 each with Down syndrome, 22 translocation, right frontal dysgenesis, dysmyelination, and bilateral cortical dysgenesis). The remaining 14 had cryptogenic infantile spasms. Sixteen had classic hypsarrhythmia. The children averaged 541 spasm clusters per month (range: 60–3000) and had been previously exposed to an average of 3.3 antiepileptic medications (range: 0–7). Two children started the ketogenic diet before any medications. Medications that were attempted without success in these patients included topiramate, phenytoin, primidone, nitrazepam, diazepam, valproic acid, felbamate, carbamazepine, ACTH, phenobarbital, clonazepam, and vigabatrin. Seventeen (74%) had previously failed or relapsed after ACTH or steroids. The children were required to be off ACTH or steroids at least 1 month, secondary to the confounding management issues of the ketogenic diet with serum glucose, calorie intake, and weight gain.
Children were fasted and started on the ketogenic diet per the Hopkins protocol.13,14 The diet was started at the classic 4:1 ratio (ratio of grams of fat to protein and carbohydrate) in 9 children, 3.5:1 in 1 child, and 3:1 in 13. Younger children were started at the lower ratio to allow more protein. Calories were calculated on the basis of basal metabolic needs plus activity. Children were followed by telephone contact and seen in the clinic frequently after discharge to help titrate calories and maintain ketosis. Medications were often reduced shortly after initiation of the diet when seizures were controlled. Several children were cared for elsewhere after starting on the diet at Johns Hopkins.
Efficacy of the diet was assessed through patient visits, surveys, and telephone contact with parents. All 23 children are currently alive, and only 1 child’s parent was unavailable for information (seizure frequency assessed via contact with the pediatrician). Parents were asked to keep records of their child’s seizure frequency on a monthly calendar, which was also used to document urine ketones. All children had routine (30-minute) EEGs before beginning the diet, but not all had follow-up studies within the 12-month period. Improvement in the number of spasm clusters was classified into 4 categories: seizure-free, >90% reduction in seizures, 50% to 90% reduction, and <50% improvement. Assessment of development was based on both parental reports and office clinical examination. Categorical data were analyzed using Pearson’s 
2 for independence of rows and columns. Multivariate analysis of data was analyzed using logistic regression. The significance level for all tests was P = .05.
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RESULTS |
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Twenty-three patients were enrolled in the ketogenic diet during the period stated. The average time on the diet was 1.6 years. The shortest time on the diet was 5 weeks (stopped secondary to illness), and the longest duration is 5.5 years (child is still on the diet to date). Twenty-one (91%) of 23 patients were on the diet at 3 months, 18 (78%) at 6 months, 15 (65%) at 9 months, and 13 (56%) at 12 months. As of this writing, 4 children remain on the ketogenic diet.
Improvement in seizure frequency for those children who remained on the ketogenic diet is shown in Table 1. Overall, >50% improvement was seen in 67% of the children at 3 months, 72% at 6 months, 93% at 9 months, and 100% at 12 months. When analyzing seizure reduction regardless of diet duration (intention-to-treat), 46% were >90% improved at 12 months, and 86% were >50% improved. Of the 3 children who became seizure-free by 3 months, additional investigation revealed the time to response was actually quicker (1 week in 2 patients, 1 month in the third).
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Several factors were analyzed for potential value in predicting response to the ketogenic diet (Table 2). The 10 children with >90% improvement at 12 months (analyzed as intention-to-treat) were specifically investigated for these indicators. There was a clear relationship between age at diet initiation and seizure reduction (P = .02). Seven (70%) of the children who were younger than 1 year stopped the diet within 12 months (mean: 6 months; range: 2.4–11 months). Of these 7 young children with short-term diet exposure, 4 (57%) were >90% improved and 6 (86%) were >50% improved when assessed at the 12-month period despite being off the diet. One child was seizure-free at 12 months and remains seizure-free to date.
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The 15 children who had been exposed to 3 or fewer anticonvulsants tended to do better than the 8 children who had been exposed to 4 or more. Multivariate analysis revealed that age and exposure to 3 or fewer anticonvulsants were independent predictors (P = .012 for age, P = .009 for anticonvulsants). The 2 children without any drug exposure before the diet were quite different in their response: 1 child was >90% improved and the other was <50% at 12 months. Children who had previously been unsuccessfully treated with ACTH or steroids specifically also had improvement: 15 (88%) of 17 demonstrated >50% improvement at 12 months.
Patients with classic hypsarrhythmic patterns on EEG were less likely to have a good response, but this only neared significance (P = .07). Of the 16 children with documented hypsarrhythmia before diet initiation, 10 (62%) had follow-up routine EEGs during the 12-month period. Five (50%) were believed by the interpreter to be improved over the previous pattern (2 completely normal). The remaining 5 children had EEG patterns of spike wave discharges (2), continued hypsarrhythmia (2), and Lennox Gastaut syndrome (1).
No relationship was seen between improvement in seizure control and presence of underlying cause, gender, previous seizure frequency, and the ketogenic fat to carbohydrate and protein ratio.
Medications were reduced or discontinued in 13 (57%) of 23 during the 12-month period. These were decreased in a nonsystematic manner on an individual basis. Seizures would frequently flurry at the time of a medication decrease, but the tapering would continue unless seizures persisted longer than 1 week.
No child has died during the treatment with the ketogenic diet or since discontinuation. Adverse reactions that potentially were associated with the diet during the 12-month period occurred in 7 children. These included severe gastroesophageal reflux (3), renal stones (2), calcifications in the urine associated with viral cystitis (1), and hip dislocation (1). The 2 children with renal stones were managed medically with hydration and remained on the ketogenic diet with no additional stones. Growth was adequate in our patients, with an average weight gain of 1.5 kg and 7.5 cm height increase in a 6-month period.
Twenty-one of 23 families provided information regarding developmental milestones during the 12-month study period. Twelve (57%) were believed to be making developmental progress. Improvement in development was related to seizure control, with only 1 (11%) of the 9 children without gains in development having >90% seizure improvement compared with 7 (58%) of 12 with developmental improvement (P = .03).
No child with <50% improvement at 1 year continued on the diet beyond that point. Reasons for discontinuation included perceived ineffectiveness (9), seizure-free (4), intercurrent viral illness (3), and feelings of restrictiveness (2). Of note, 8 of 9 children with perceived ineffectiveness were 50% to 90% improved, according to their parents at the time of discontinuation. Longitudinal observation showed that 9 (64%) of the 14 children who had >50% improvement at 3 months remained on the diet at least 12 months.
Of the 13 patients who were on the diet for at least 1 year, 4 patients are still on the diet, 5 discontinued the diet after 1.65 to 2.35 years because of perceived ineffectiveness, and 4 children were purposefully discontinued after 2.1 to 4 years on the diet after becoming seizure-free. No child had the diet discontinued after 1 year because of reasons of restrictiveness or intercurrent illness.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The ketogenic diet is a reasonable alternative to other standard therapies for infantile spasms, even those that have been resistant to other anticonvulsants. Studies of the effectiveness of vigabatrin and ACTH by Cossette et al18 revealed 76% of patients with >50% reduction for vigabatrin and 86% for ACTH at 15 days, although 31% of the vigabatrin-treated infants and 40% of the ACTH-treated patients had recurrent seizures by 12 months. These numbers are comparable to ours at 3 months and less efficacious in preventing recurrence by 12 months. Other studies of vigabatrin have shown slightly less efficacy, with 48% to 76% of patients showing reduction in spasms with vigabatrin at 2 weeks to 6 months.3,4,6 Of note, these studies all were done on patients with newly diagnosed and previously untreated infantile spasms. Our patients were significantly more recalcitrant, as failure occurred with an average of 3 previous anticonvulsants, including ACTH and vigabatrin. Other therapeutic options for infantile spasms, such as valproate, benzodiazepines, and newer anticonvulsants, do not have significantly higher proven efficacy.
The safety and efficacy in our study parallels a recent report from Nordli et al16 in which 12 of 17 children (70%) with infantile spasms had >50% improvement on the ketogenic diet. It is interesting that all patients in this study who became seizure-free had the diagnosis of infantile spasms. The 67% of patients with improvement at 3 months on the diet is similar to our study, but their data beyond this time period in terms of EEG and clinical response are lacking.
In our study, the significant reduction in spasms noted in 6 of 7 children who were younger than 1 year and had only a few months of ketogenic diet exposure was surprising. This might indicate the presence of a critical period of neurologic susceptibility in patients with infantile spasms. In a similar manner to short-term ACTH therapy, perhaps only weeks of the ketogenic diet may be necessary to eradicate spasms.
Recent information has proposed a connection between corticotropin-releasing hormone and the mechanism of infantile spasms pathogenesis via neuronal injury.19 Decreased insulin levels (as are seen in the fasting state) have been shown to reduce norepinephrine and increase dopamine neurotransmission, the combination of which can reduce seizure sensitivity.20 As the ketogenic diet has been shown to decrease serum insulin levels and increase cortisol levels, its potential effect on neurotransmitters and therefore neuronal excitability warrants investigation.20 However, the indirect effect of the ketogenic diet on corticotropin-releasing hormone specifically, although logical, remains to be proved.21
Slightly more than half of the children had medications reduced, which may be critical to quality of life and development. Growth was not adversely affected by the ketogenic diet; an appropriate average increase in height was seen in even the youngest of patients. In addition, even at this young age, lack of growth was not a limiting factor in discontinuation of the diet, similar to what has been found in other studies.16
Development also seems to be progressing in children who were treated with the ketogenic diet with improvement in their seizure frequency. This was significantly correlated with elimination of hypsarrhythmia, as seen in other reports.22 Controversy exists regarding whether early treatment improves developmental outcome.23,24 At least in this study, even patients with significant delay in adequate treatment of their spasms (before being started on the ketogenic diet) still had developmental progress.
The children in our study had a relatively high percentage (61%) of cryptogenic cases. Recent reports have indicated a decreasing number of cryptogenic cases to approximately 25%.22 It has been noted that a cryptogenic cause predicts a smaller incidence of other forms of seizures and neurologic deficits than symptomatic cases. In our patients, although the correlation of cause with seizure reduction was not quite significant, it was perhaps attributable only to the few numbers of symptomatic cases. Clarification, in a larger cohort, of specific causes of infantile spasms that may be more sensitive to the ketogenic diet is indicated to help identify appropriate candidates.
Established side effects of the ketogenic diet include constipation, hyperlipidemia, and potential dehydration.13,25 One needs to be concerned about renal calculi in patients who are on the ketogenic diet as well.26 All patients with infantile spasms should be screened for potential metabolic disorders. This is especially true before the ketogenic diet, as diseases that could potentially worsen with the ketogenic diet include pyruvate carboxylase deficiency, porphyria, carnitine deficiency, mitochondrial disorders, and fatty acid oxidation defects.25 Despite the potential side effects of the ketogenic diet, those caused by the multiple antiepileptics often used for patients with infantile spasms are potentially more severe. The absence of mortality and serious morbidity in these children, although limited in number, speaks to this point.
It is possible that some of the improvement seen in our patients may have been secondary to spontaneous remission, which can be as high as 25% by 12 months.27 We believe, however, that it is unlikely on the basis of the 8-month average duration of previous spasms in our patients, despite multiple anticonvulsants. In addition, the literature suggests that a majority of children will have cessation of spasms before age 1, with a smaller number improving after that age.23,24
This study has several limitations. It is retrospective, and parental reports are unquestionably less accurate than EEG or video monitoring. Considering the high frequency of parent telephone calls and clinic visits, we believe that the reliability of reports was generally good. In addition, many reports indicate that development may be a more important outcome measure than seizure frequency. Fifty-seven percent of our patients had improvement in development, a number similar to the 46% with >90% improvement at 12 months. Our patient population was also recalcitrant to multiple anticonvulsants, which also may have altered brain chemistry and the natural history of their infantile spasms. A prospective trial of the ketogenic diet, with objective outcome measures, in previously untreated infantile spasms is necessary to reduce this confounding issue.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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We suggest consideration of the ketogenic diet as an early treatment in children with infantile spasms, even in those in which other anticonvulsants have failed. Its relative lack of side effects when compared with the current anticonvulsants effective for infantile spasms makes the risk-benefit ratio for the diet favorable. Additional prospective study of the ketogenic diet as initial therapy for infantile spasms is indicated before considering this therapy as first line. Other anticonvulsants that were successful as add-on therapy were less promising later as initial treatment.8–10
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ACKNOWLEDGMENTS |
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This work was partially supported by the Charlie Foundation, Santa Monica, CA.
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FOOTNOTES |
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Received for publication Oct 11, 2001; Accepted Jan 8, 2002.
Reprint requests to (E.H.K.) Meyer 2-147, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail: ekossoff{at}jhmi.edu
Dr Kossoff is the recipient of the Roxanne Fellowship for 2001.
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