PEDIATRICS Vol. 108 No. 4 October 2001, pp. 898-905

The Ketogenic Diet: A 3- to 6-Year Follow-Up of 150 Children Enrolled Prospectively

Cheryl Hemingway, MB ChB, John M. Freeman, MD, Diana J. Pillas, BA, and Paula L. Pyzik, BA

From the Johns Hopkins Medical Institutions, Baltimore, Maryland.

	ABSTRACT

Top Abstract Methods Results Discussion Conclusion References

Objective.  To document the long-term outcome of the 83 children with difficult-to-control seizures who were enrolled prospectively in a study of the efficacy of the ketogenic diet and who had remained on the diet for 1 year.

Methods.  A total of 150 consecutive children were entered prospectively into a study of the ketogenic diet's efficacy and tolerability. Three to 6 years after diet initiation, all 150 families were sent a survey inquiring about their child's current health status, seizure frequency, and current anticonvulsant medications. They were asked about their experience with the diet and reasons for discontinuation. Several telephone attempts were made to contact those who did not respond to the written questionnaire. Responses were entered in an Access database and analyzed.

Results.  In 1999, 3 to 6 years after initiating the diet, 107 of 150 families responded to a questionnaire. Thirty-five additional families were interviewed by telephone, 4 were lost to follow-up, and 4 children had died, unrelated to the diet. Of the original 150 patient cohort, 20 (13%) were seizure-free and an additional 21 (14%) had a 90% to 99% decrease in their seizures. Twenty-nine were free of medications, and 28 were on only 1 medication; 15 remained on the diet. There were no known cardiac complications.

Conclusion.  Three to 6 years after initiation, the ketogenic diet had proven to be effective in the control of difficult-to-control seizures in children. The diet often allows decrease or discontinuation of medication. It is more effective than many of the newer anticonvulsants and is well-tolerated when it is effective.  Key words:  seizures, epilepsy, ketogenic diet.

The ketogenic diet is a high-fat, low-carbohydrate, adequate-protein diet that was developed in the 1920s for the management of difficult-to-control seizures.¹ The short-term benefits of the ketogenic diet in improving seizure control in children with difficult-to-control seizures are no longer disputed.^1-3 As an unbiased evaluation for Blue Cross/Blue Shield reported,⁴ "The diet's effectiveness in providing seizure control for children with difficult-to-control seizures has remained as good or better than any of the newer medications." This study was designed to evaluate the long-term effectiveness of the diet.

Between August 1, 1994, and August 31, 1996, we enrolled 150 children with difficult-to-control seizures in a prospective study of the effectiveness of the classical ketogenic diet.² The original study required that the children be between 1 and 16 years of age, have a minimum of 2 seizures per week, and have failed 2 anticonvulsant medications. This cohort had a mean age of 5.3 years, averaged 410 seizures/mo, and had been treated previously with an average of 6.2 medications. They initially were followed for 1 year or until they discontinued the diet, and their outcome has been reported.² One year after diet initiation, 83 (55%) remained on the diet and almost all had a >50% reduction in their seizures. Forty-one (27%) had a >90% seizure reduction. This current report follows these same children 3 to 6 years after their initial enrollment and evaluates their seizure control and the parents' evaluation of the diet experience.

	METHODS

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Our original cohort consisted of 150 consecutive children who were enrolled prospectively, ages 1 to 16 years, and had seizures of multiple types and varied frequencies. Virtually all of these children had >2 seizures per week, despite adequate therapy with at least 2 anticonvulsant medications.² They were treated with the ketogenic diet using the Hopkins protocol³ and followed for a minimum of 1 year. Seizure frequency was tabulated from patients' daily seizure calendars, and seizure reduction was calculated from the average daily frequency recorded in the month before reporting and tabulated as the percentage reduction from the baseline frequency, recorded prospectively. Adverse events and reasons for diet discontinuation were recorded, as were medication changes. Informed consent was obtained from all parents before enrollment.

To determine the long-term outcome of these children, we mailed a follow-up questionnaire to all parents in 1999, 36 to 72 months after diet initiation. Several telephone attempts were made to contact those who did not return the questionnaire. The survey questioned parents regarding their child's current health status and the presence and frequency of seizures as well as the child's current medications. Medications had been reduced in a nonsystematic manner because our primary goal had been seizure control. Parents were asked about their experience with the diet, the diet's efficacy for their child, and their reason(s) for discontinuing the diet. They were asked whether they would recommend the diet to others and whether they would try the diet again. Questions also were asked regarding alternative treatments that were tried subsequently. The results were entered into an Access database and analyzed.

	RESULTS

Top Abstract Methods Results Discussion Conclusion References

The demographics of the original 150 children were contained in the original report.² Eighty-five were boys, and 65 were girls. They were a heterogeneous group with seizures of varied causes, some idiopathic or cryptogenic, some due to underlying structural lesions of varied types. Children whose seizures were due to known metabolic causes were excluded; otherwise, there was no consistent, identified selection bias. The median age at the time of initiation of the diet was 5.3 years (range: 4 months-16 years). They averaged 410 seizures per month of multiple types and had previously tried an average of 6.2 seizure medications. They were on a mean of 1.8 medications at the diet's initiation.

We were able to obtain follow-up information on all of the 150 children who had initiated the diet. A total of 107 of the 150 who started the diet responded to the questionnaire. Another 35 were interviewed by telephone. By the time of the follow-up, 4 children had died (see below) and 4 were lost to follow-up. One of those lost had moved out of the country during the first year and 1 during the second year. The outcomes of these 8 children are reported as of the time of their last contact.

Duration on the Diet

Eighty-three of the 150 original children (55%) remained on the diet for 12 months. Their seizure status at that time is shown in Table 1. Fifty-eight of the 150 (39%) remained on the diet for 2 years, 30 were on it for 3 years, 19 remained on for 4 years, and 15 remain on the diet >4 years after initiation. One child has been on the diet for 6.5 years.

Diet Efficacy in Controlling Seizures

The efficacy of the diet 12 months after initiation is shown in Table 1. Seven percent of the original 150 children were seizure-free, an additional 20% had a 90% to 99% decrease in their seizure frequency, and 22% had a 50% to 90% decrease from their initial seizure frequency. Thus, 12 months after starting the ketogenic diet, a total of 27% of the original children had a >90% decrease in their seizures and half had a >50% reduction in seizure frequency. These 83 continued on the diet for a mean of 2.3 years. The time that they ultimately discontinued the diet is shown in Table 1. Most of those with a <50% seizure reduction had discontinued the diet during the first year.

Outcome of Those Who Remained on the Diet at 1 Year

The 3- to 6-year outcomes of the 83 children who had remained on the diet at 1 year are shown in Table 2. Of the 11 who were seizure-free at 1 year, all ultimately discontinued the diet a mean of 2.5 years after starting. Eight remained free of seizures, and 3 others had had a recurrence of seizures, although 2 of these were having >90% fewer seizures than at diet initiation and 1 was 50% to 90% improved. Nine of the 11 were free of all medication. One was taking 1 medication, and the other were taking 2. 

Of the 30 who had had a >90% to 99% decrease in seizures at the 1-year mark, 10 of 30 (33%) had become seizure-free by the time of follow-up and 13 others (43%) had remained with only occasional seizures. Four of the 30 (13%) had a 50% to 90% decrease in their seizures, and 3 (10%) had a <50% seizure reduction. Seven of the 30 (23%) continue on the diet. Nine of the original 30 children were off all medications, and only 4 were taking >1 medication. Those who discontinued the diet did so after a mean of 2.4 years. Of the 33 children who had a 50% to 90% decrease at 1 year, only 2 have become seizure-free. Six of the 33 (18%) now have a 90% to 99% reduction in seizures, 15 (45%) have a 50% to 90% decrease, and 10 (30%) have had a < 50% decrease in their seizures. Only 7 have remained on the diet. Eleven children are off all medications, 8 are taking only 1 medicine, 11 are taking 2 medications, and 3 are taking 3 medications. Those who discontinued did so after a mean of 2.3 years. Eight of the 9 children (89%) who had a <50% decrease in seizures at 1 year subsequently discontinued the diet after a mean of 2.4 years. All have continued to have seizures, although 4 of 9 have had a 50% to 90% decrease over their baseline frequency and 5 of 9 have had a <50% decrease from the time of diet initiation. All but 1 remain on medications.

In summary, 1 year after initiating the diet, 27% of the 150 children had a >90% decrease in their seizures and 7% were seizure-free (Table 1). More than 3 years after starting, the same percentage (27%) have a >90% decrease in their seizures (Table 1), 13% of whom are seizure-free. It should be noted that these are not necessarily the same children. In addition, it should be noted that 30 of the 83 (36%) are free of medication, and an additional 28 (34%) are taking only 1 medication. (Table 2).

Reasons for Discontinuation of the Diet

Sixty-seven of the 150 children (45%) who initiated the diet discontinued within the first year. Their reasons for diet discontinuation are shown in Table 3. By 12 months, 33 of the 67 families had discontinued because they believed it to be ineffective. One third of these discontinued within the first 3 months, one third discontinued between 3 and 6 months, and one third discontinued between 6 and 12 months. Twenty of the 67 families found the diet to be too restrictive, with a similar distribution. Most of those who found the diet to be too restrictive did not have good seizure control at the time of discontinuation. Similarly, those who found it to be ineffective also found the diet to be too restrictive or too difficult to be worthwhile. Twelve children discontinued the diet during the first year because of intercurrent illness, unrelated to the diet. Most of those had not found the diet to be effective. Two children who discontinued the diet in the first year were lost to follow-up.

Of the 83 who remained on the diet at 12 months, 25 discontinued during the second year (Table 3). Six of the 25 (24%) stopped the diet because they had become seizure-free or markedly improved, 7 found the diet to be insufficiently effective, 5 found the diet to be too restrictive, 6 discontinued because of illness, and 1 moved out of the country. Two of the 83 continue on the diet but are followed elsewhere; 1 is 90% to 99% improved, and the other is 50% to 90% improved.

Fifty-eight children remained on the diet >24 months. Between 2 and 3 years, 28 of these discontinued the diet: 11 because they had become seizure-free or had markedly (90%-99%) improved, 7 because they found the diet to be insufficiently effective, 1 found it to be too restrictive, and 8 discontinued because of illness. One moved out of the country and was lost to follow-up, and 1, who was <50% controlled, discontinued because of fear of potential long-term illness. Three of the 58 remain on the diet but are now being followed elsewhere; 2 of the 3 are 50% to 90% improved, and 1 continues to be 90% to 99% improved.

Thirty children remained on the diet for >3 years. Between 36 and 48 months, 11 children discontinued the diet: 9 because they were either seizure-free or markedly improved (90%-99%), 1 found the diet to be ineffective, and 1 found it to be too restrictive. Three of these 30 remain on the diet but are followed elsewhere; 1 is 90% to 99% improved, 1 is 50% to 90% improved, and 1 is <50% improved from baseline. Nineteen have remained on the diet until 48 months. Fifteen of these remained on the diet for >4 years; 1 is seizure-free, 8 have 90% to 99% improvement, 4 have 50% to 90% improvement, and 2 have <50% improvement from baseline but have been able to discontinue some medications. Often these children have profound developmental delays and/or are tube-fed, and the diet is not a problem for the child or for the family. Four of the 19 subsequently have discontinued the diet: 1 because of substantial seizure improvement, 1 found it to be ineffective, and 2 because of illness. In the last 3 cases, the diet was not sufficiently effective. Three of the 19 who continue on the diet are followed elsewhere; 2 of them are 90% to 99% improved, and 1 is <50% improved (Table 3).

Medications

The 83 children who remained on the diet for 1 year had a decrease not only in the number of seizures but also in the number of medications taken. As shown in Table 4, at the time they initiated the diet, 49 of the 83 patients (59%) were taking 2 or more medications and 22 (27%) were taking 3 or more medications. The mean number of medications taken per child was 1.97. Twelve months after initiating the diet, 45 children (54%) were medication-free, 25 (30%) were taking 1 medication, and 13 (16%) were still taking 2 or more medications. The mean number of medications taken at 12 months was 0.65. At follow-up 3 to 6 years after starting the diet, 28 of the 83 (34%) who completed 1 year on the diet were medication-free, 31 (37%) were taking 1 medication, and only 24 of 83 (30%) were taking 2 or more medications. The mean was 1.0 medication taken.

As might be expected, those who had the best seizure control on the diet at 1 year were most likely to reduce substantially or eliminate their medications. As shown in Table 2, 9 of the 11 (82%) who were seizure-free at 1 year were medication-free at follow-up. Nine of the 30 (30%) who had had a 90% to 99% decrease in seizures at 1 year also were medication-free at follow-up. A total of 36 of the 41 children (87%) who had had a >90% to 99% decrease in seizures at 1 year were taking no medication or only 1 medication at follow-up. Those who had <90% control at 1 year went from a mean of 1.8 medications to a mean of 1.3 medications. The correlation of seizure control at diet initiation at 12 months and at the 3- to 6-year follow-up with the number of medications at each time is shown in Table 5.

Illness

The majority of children remained well on the diet; only 11% of parents reported major illness. Thirty-three percent had an episode of status epilepticus during their time on the diet; most other severe illnesses were flu-like and resolved.

Deaths

Four of the 150 children who had initiated the diet have died, none while on the diet, and none attributable to the diet. (Two additional deaths occurred within days of being scheduled to initiate the diet, indicating the fragility of some of these children.) The course of each child who died is presented below. Cardiomyopathy and prolonged QT intervals have been reported as complications of the ketogenic diet.^5,6 Although cardiac evaluation with electrocardiography and echocardiography were not part of the routine evaluations, none of our children are known to have developed clinical or laboratory evidence of cardiomyopathy.

A. A. developed infantile spasms at 5 weeks of age. The metabolic workup was negative, and magnetic resonance imaging scans showed only hypomyelination. The spasms did not respond to steroids or multiple drugs. At 16 months, in association with croup, he developed bradycardia to 20 beats per minute, requiring 3 hours of resuscitation. He was found to have multifocal ectopic cardiac beats that required ablation of 1 focus and a pacemaker. Two months later, the ketogenic diet was initiated for his continued spasms. Although there was a decrease in his seizures and anticonvulsant medications and, according to his mother, an improvement in his quality of life, he had profound disabilities. After 2 months on the diet, he developed a virus-like syndrome with lethargy and shock. The evaluation was unrevealing; the diet was stopped, and a decision was made not to pursue future resuscitation. Two months after stopping the diet (at 23 months of age), he had another episode of lethargy and hypotension and subsequently died. No pathologic abnormalities were found in the heart by clinical, light, or electron microscopy. The cause of his underlying condition remains undetermined.

C. C. came to us at age 11 for initiation of the ketogenic diet. At age 10, she had developed viral meningoencephalitis with residual partial complex seizures, often with secondary generalization, and frequently related to menses. The seizures were thought to be of left frontotemporal origin. The ketogenic diet was discontinued after 4 months because of lack of seizure improvement and the rigidity of the diet. Four years later, at age 15, she underwent cortical mapping with a grid and resection of the left prefrontal and the anterior temporal lobe. Seizure frequency was decreased dramatically but occasionally recurred. She drowned in the bathtub 1.5 years after surgery, presumably as a result of a seizure.

P. H. had moderate developmental delays. She developed generalized tonic-clonic seizures at age 5, which averaged 20 to 30/mo and were refractory to multiple medications. Her seizures improved markedly on the diet with "improved attention and verbal skills." Six months and again 1 year after starting on the diet, she was noted to have had a 50% to 90% decrease in seizures and was on fewer medications. Eighteen months after initiation, the diet was discontinued "because it was not sufficiently effective"; and 18 months later, she died during a nocturnal seizure.

B. R. began to have generalized tonic-clonic and atonic seizures at 2 years of age. Evaluation had been unrevealing, and the seizures had been refractory to medications. At 4 years of age, the diet was initiated with marked improvement for 6 months. The generalized tonic-clonic seizures then returned, occurring in flurries. The "diet was helping, but his language was deteriorating," and when the diet was discontinued 23 months after initiation, multiple types of seizures recurred. Multiple subpial transections was performed elsewhere 7 months after diet discontinuation, and he died of a perforated gastric ulcer in the postoperative period.

Epilepsy Surgery

Nine children discontinued the diet and subsequently have undergone cortical resections. Four with known unilateral congenital structural brain lesions ultimately came to hemispherectomy. One child (T. K.) had perinatal problems and an extensive unilateral dysplasia. He had a 50% to 90% decrease in seizures during his 10 months on the diet but also had major feeding and behavioral problems. A right hemispherectomy was performed at 3.75 years of age, and he now is seizure-free with marked improvement in his developmental skills. Two children (D. N., S. S.) had congenital hemipareses due to middle cerebral artery thrombosis with early onset focal and atonic seizures refractory to medications. Both had a dramatic, although brief, success on the ketogenic diet, but the seizures recurred after several months and the diet was discontinued. Each have undergone a hemispherectomy with no subsequent seizures and excellent clinical function. One child with Rasmussen's encephalopathy was tried on the diet for 1 month without improvement and then underwent hemispherectomy with an excellent outcome. Five other children with focal seizures were tried on the ketogenic diet and ultimately have had focal cortical resections.

C. B., an 8-year-old with partial seizures and bilateral frontal spikes, failed multiple medications and developed a Lennox-Gastaut-like electroencephalographic pattern. She was weaned off prednisone and started on the diet. Her seizures decreased by 50%, but "she hated it." The diet was stopped after 3 months, and she later had a frontal lobectomy at another institution with a 90% reduction in her seizures.

J. W., a 12-year-old, had partial complex seizures starting at age 4. They were intractable to multiple medications. Because his school work was poor, the family wanted to see how he would do without medications. The electroencephalograms revealed independent multifocal spikes. The magnetic resonance imaging scan was reported as normal at that time. The ketogenic diet never produced good ketosis, had little effect on the seizure frequency, and was discontinued after 3 months. Subsequent evaluation at another institution at 16 years of age revealed an underlying cortical dysplasia and led to a right frontal lobectomy. He subsequently has remained seizure-free.

S. U. had moderate delays and intractable myoclonic and right-sided seizures often with secondary generalization. The seizures started at 8 months of age. At age 5, the ketogenic diet was attempted because the family wanted to avoid a surgical procedure. Six months after initiation, the diet had resulted in a 50% to 90% decrease in seizure frequency and intensity and allowed a decrease in medications. The seizures recurred over the next 6 months, and his intellectual function decreased. The diet was discontinued, and surgical evaluation with a grid resulted in a left prefrontal resection with multiple subpial transections of the motor strip. He continues to have moderate delays with occasional mild nocturnal seizures.

C. C. (discussed above) had partial complex seizures secondary to viral meningoencephalitis. The ketogenic diet was of no clear benefit. Four years later, she had a resection of the premotor frontal cortex with seizure improvement. She drowned in the bathtub 1.5 years after surgery, presumably as a result of a seizure.

P. G. was normal to age 4.5 years, when he developed severe focal motor seizures involving the face and arm with epilepsia partialis continua. Extensive workup, including a biopsy for Rasmussen's encephalopathy, was negative. At age 5, he was started on the ketogenic diet, which was discontinued 3 months later having been <50% effective. He has undergone two subsequent large frontal cortical resections at another institution for a cortical dysplasia; although improved, he has ongoing seizures.

Growth

Forty-one percent of parents who responded believed that their children did not grow as well on the diet. Most equated growth with lack of weight gain. Careful serial measurements⁷ indicate that height, in general, increases at a low but normal rate. Weight gain is controlled carefully to maintain adequate ketosis and is permitted only to increase proportional to the increase in height. The child thus remains close to his or her ideal body weight.

Kidney Stones

Kidney stones are a widely known complication of the ketogenic diet. They usually are uric acid or a mixture of calcium and uric acid. In a prospective study of 112 children who started the diet,⁸ 6 had developed stones (0.8/100 mo at risk). The combination of acid urine, low urinary citrate excretion, and hypercalcuria, in conjunction with low fluid intakes, places these children at high risk for uric acid and calcium stone formation.

Satisfaction With Diet

The 107 parents who answered the questionnaire were asked to rank their satisfaction with the diet on a Likert scale of 1 to 10. Forty-two (39%) were extremely satisfied with the diet (8-10 on the scale). For almost all of these patients, the diet had been effective in substantially reducing seizures. Thirty-four (31%) were only moderately satisfied with the diet, ranking it 4-7 out of 10 on the scale. Twenty-two (20%) were dissatisfied, scoring the diet at 3 or less. In 14 of these 22 children, the diet had been ineffective. Nine families did not respond to the question.

When asked whether they would recommend the diet to other parents, 97 of 107 respondents (90%) said that they would, and 60 parents (56%) said that they would be prepared to try the diet again. Even those for whom the diet had been ineffective and who said that they were dissatisfied were likely to recommend it to another parent. They believed that it had been worth the try.

Alternative Therapies

Many of those who failed the diet went on to try the newer anticonvulsant medications or alternative therapies. Some regularly administered homeopathic therapy, some families claimed that acupuncture had benefited their child, and others found benefit from craniosacral stimulation or magnetic impulses. Only 2 of the patients had had a vagal nerve stimulator implanted, with moderate benefit.

	DISCUSSION

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Efficacy of the Diet

Most epilepsy in children can be controlled with 1 medication. Those whose seizures cannot be controlled with the first medication, properly used, have a <20% chance of their seizures being controlled with the second medication.⁹ Children who have seizures that are difficult to control with 2 medications have only a 25% to 40% chance of their seizures being controlled with other medications.^9-12 It is this latter population of children who have failed >3 medications that some¹² have termed "intractable," or that we call "difficult to control." The 150 children who entered our ketogenic diet study all were intractable. They averaged 410 seizures per month and had failed an average of 6 medications before the time of starting on the diet.

One year after starting the ketogenic diet, 11 (7%) of these children had become seizure-free and an additional 30 children (20%) had a >90% decrease in seizures (Table 1). Three to 6 years later, 27% of the 150 had a >90% decrease in their seizures, and most had discontinued the diet. Half of those (13%) were seizure-free. This 27% with marked improvement in seizure control is the same percentage as we had found after 1 year on the diet,² although they are not necessarily the same children. Three to 6 years after starting the diet, a higher percentage (13%) have become free of seizures.

Medications

Although our primary aim was to allow the children to be as free of seizures as possible, many parents were more concerned about the side effects of the medication than about the consequences of the seizures. Parents often pushed for a decrease in the medications despite ongoing seizures and continued their children on the diet despite continued seizures because the child "functioned better" with fewer medication side effects.

Although we improved seizure control, we also were able to reduce the medications. The children were taking a mean of 1.97 medications at diet initiation. Three to 6 years after diet initiation (Table 2), 30 of the 83 children who had remained on the diet for 1 year (36%) were off all medications and 28 (34%) were taking only 1 medication. Seventeen of the 41 (41%) who have had a >90% reduction in seizures have discontinued all medications (Table 2), and an additional 12 (29%) are taking only 1 medication. The mean number of medications at the 3- to 6-year follow-up was 1.0. In response to the frequent parent query, "Can the diet allow my child to be seizure-free and free of all medications?" 13 of the 150 children achieved this goal (Table 5). Eight other children were off all medication and had a 90% to 99% decrease in their seizures. An additional 14 of the original 150 children achieved a >90% to 99% decrease and were taking only 1 medication. Thus, 35 of the original 150 children (23%) had achieved a >90% control of their seizures and were taking 1 or no medication 3 to 6 years after starting the diet. Most of these also had discontinued the diet by that time.

The diet now has been shown to be effective in controlling the seizures in many children with difficult-to-control seizures. It is "more effective in controlling seizures (in these children) than newer anticonvulsants."⁴ Still, many physicians have remained skeptical about its effectiveness and its side effects (C. Hemingway, P. L. Pyzik, J. M. Freeman, manuscript in preparation) and use it only when all other (newer) medications have failed. New medications usually are evaluated in adults with medically refractory complex partial seizures, most have mesial temporal lobe epilepsy, and 50% of them have a 50% reduction in seizures.¹³ Engel's comments are made in the context of the need for better and earlier evaluation of adults with mesial temporal lobe epilepsy for surgery. The need for more adequate evaluation of all new therapies also should apply to children with difficult-to-control seizures, in whom "a 50% decrease in seizures in 50% of the cases" also is not enough.

As shown by the 9 children in our group who failed the diet and ultimately went to successful surgery, the ketogenic diet is less likely to control seizures completely in children with focal structural lesions. However, for some, the diet may provide a respite while surgery is evaluated. Occasionally, the diet has controlled seizures successfully even in children with structural lesions.

Acceptability of the Diet

The effectiveness of the diet and the likelihood of tolerating the diet are integrally linked. That the patients with the best results are likely to tolerate the diet best is no surprise. The highest attrition rate of those who start the diet is within the first year. Fifty-five percent of those who start the diet remain on it for 1 year. Patients who remain on the diet for the first year are likely to remain on it for a second year. Only 25 of the 83 children who were on the diet at 12 months (30%) discontinued it in the second 12 months, and 6 of those were because they had a >90% improvement. Forty percent of the later discontinuations were because of the diet's success rather than dissatisfaction with the diet.

Of interest was the response to the question, "Would you recommend the diet to someone else?" An overwhelming majority (90%) of parents said that they would, although 20% claimed to be dissatisfied with the diet for their child. Despite the fact that the diet is extremely restrictive and time consuming and requires rigid maintenance, the majority of parents saw that the potential benefits of the diet outweighed its drawbacks. Most parents were grateful for the opportunity to assess whether their child could have fewer seizures without the side effects of the medications. Fifty-five percent stated that they would consider trying the diet again.

Complications of the Diet

Forty-one percent of parents believed that their children did not grow as well on the diet but were mistaking the lack of weight gain for lack of linear growth. The diet is calculated and adjusted carefully so that children gain weight only in proportion to the increase in their height. Children grow on the diet, although ongoing studies⁷ are indicating that this linear growth may occur at a lowbut normalrate. Compared with the problems posed by the seizures and the medications, growth was believed by parents to be the lesser problem.

Kidney stones occur in approximately 10% of children who are on the diet⁸ and can be treated and perhaps prevented by providing adequate fluid intake and alkalinization of the urine. All children were screened weekly for blood in the urine by Hemastix (Bayer Corp, Elkhart, IN). Repeated positive tests were evaluated by the family physician and, if needed, by a urologist. Ultrasound was performed when deemed necessary. Occasionally, patients need lithotripsy or surgical removal of the stones. The occurrence of stones has not been reason for discontinuing the diet in children whose seizures have been improved. These children were treated with increased fluids and alkalinization of the urine and usually elected to remain on the diet.

Cardiomyopathy has been reported in patients who are on the ketogenic diet,^5,6 although it has not been recognized in any of the children in this series or in any of the other approximately 300 patients under our care.

Hyperlipidemia and subsequent atherosclerosis have caused concerns. A preliminary report¹⁴ suggested that there rarely is substantial hyperlipidemia, and if and when it occurs, adjustment of the diet ratio will bring the lipid levels toward normal. We have not had to stop the diet because of lipid abnormalities in any child for whom it has been successful in controlling seizures. Long-term effects of the diet on the cardiovascular system remain to be determined.

For those for whom the diet failed to provide adequate seizure control or for whom there continued to be perceived side effects of medications, parents continued to search for solutions. This was evident by the number of children who at the time of follow-up were using homeopathy, osteopathy, acupuncture, and magnet stimulation therapies, among others.

	CONCLUSION

Top Abstract Methods Results Discussion Conclusion References

Three to 6 years after initiating the ketogenic diet, 13% of the 150 children who had difficult-to-control seizures and initiated the ketogenic diet were seizure-free. An additional 14% have had a >90% reduction in their seizures. Many had decreased or discontinued their anticonvulsant medications, and most had discontinued the diet. The mechanisms by which the ketogenic diet seems to be effective in controlling the difficult-to-control seizures are unknown^15,16 but are under active investigation.^17,18 The large number of children who now are free (or nearly free) of medications, are free (or nearly free) of seizures, and have discontinued the diet should encourage the search for the mechanisms by which the diet not only suppresses seizures but perhaps also alters the underlying epileptogenicity of the brain.

	ACKNOWLEDGMENTS

This study was supported in part by the Charlie Foundation to Cure Pediatric Epilepsy (Santa Monica, CA), by Jim and Nancy Abrahams, and by the Roxanne Fund.

These studies and the treatment of these patients could not have been carried out without the hard work of a dedicated staff, which included Eileen P. G. Vining, MD; Jane McGrogan, nutritionist; Heather Hladky and Jane Casey, nurse associates; and Diana Pillas, counselor-coordinator.

	FOOTNOTES

Dr Hemingway was the 1999 Roxanne Fellow in Pediatric Epilepsy at Johns Hopkins.

Received for publication Nov 21, 2000; accepted Mar 21, 2001.

Reprint requests to (J.M.F.) Meyer 2-147, Johns Hopkins Medical Institutions, 600 N Wolfe St, Baltimore, MD 21287-7247. E-mail: jfreema{at}jhmi.edu

	REFERENCES

Top Abstract Methods Results Discussion Conclusion References

1. Swink TD, Vining EPG, Freeman JM The ketogenic diet: 1997. Adv Pediatr. 1997; 44:297-329 [Medline]
2. Freeman JM, Vining EPG, Pillas DJ, Pyzik P, Casey J, Kelly M The efficacy of the ketogenic diet1998: a prospective evaluation of intervention in 150 children. Pediatrics. 1998; 102:1358-1363 [Abstract/Free Full Text]
3. Freeman JM, Kelly MJ, Freeman JB. The Ketogenic Diet. A Treatment for Epilepsy. New York, NY: Demos Publications; 2000
4. LeFever F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics. 2000;105(4). Available at: http://www.pediatrics.org/cgi/content/full/105/4/e46
5. Ballaban-Gil K, Callahan C, O'Dell C, Pappo M, Moshe S, Shinnar S Complications of the ketogenic diet. Epilepsia 1998; 39:744-748 [CrossRef][Medline]
6. Best TH, Franz DN, Gilbert DL, Nelson DP, Epstein MR Cardiac complications in pediatric patients on the ketogenic diet. Neurology 2000; 54:2328-2330 [Abstract/Free Full Text]
7. Vining EPG, Casey JC, McGrogan JR, Pyzik PR, Schwert PR, Freeman JM Children grow on the ketogenic diet [abstract]. Epilepsia. 1998; 39:168
8. Furth SL, Casey JC, Pyzik PL, Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol 2000; 15:126-128
9. Kwan P, Brodie MJ Early Identification of refractory epilepsy. N Engl J Med. 2000; 342:314-319 [Abstract/Free Full Text]
10. Hauser A, Hessdorfer DC. The natural history of seizures. In: Wylie E, ed. The Treatment of Epilepsy: Principles and Practice. 2nd ed. Philadelphia, PA: Lea & Febinger; 1997:173-178
11. Carpay HA, Arts WF, Geerts AT, Epilepsy in childhood: an audit of clinical practice. Arch Neurol. 1998; 55:668-673 [Abstract/Free Full Text]
12. Camfield PR, Camfield CS Antiepileptic drug therapy: when is it truly intractable? Epilepsia 1996; 37:S60-S65
13. Engel J Jr Epilepsy surgery for seizures. N Engl J Med. 1996; 334:647-652 [Free Full Text]
14. Vining EPG, Freeman JM, Kwiterovitch JR, The ketogenic diet induces dyslipidemia. Epilepsia. 1999; 40:122
15. Wheless J The ketogenic diet: fact or fiction. J Child Neurol 1995; 10:419-423 [Free Full Text]
16. Nordli DR, De Vivo D The ketogenic diet revisited: back to the future. Epilepsia 1997; 38:743-749 [CrossRef][Medline]
17. Schwartzkroin PA Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet. Epilepsy Res 1999; 37:171-180 [CrossRef][Medline]
18. Stafstrom CE, Spencer S The ketogenic diet: a therapy in search of an explanation. Neurology 2000; 54:282-283 [Free Full Text]