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The ketogenic diet

Author
Eric HW Kossoff, MD

Section Editor
Douglas R Nordli, Jr, MD

Deputy Editor
Janet L Wilterdink, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2013. | This topic last updated: Sep 16, 2013.

INTRODUCTION—Antiepileptic drugs (AEDs) are the primary treatment for epileptic seizures, and are effective in controlling seizures in most patients. However, approximately one-third of patients will not become seizure-free with medications and require nonpharmacologic treatments [1]. Although epilepsy surgery is usually considered for these patients, there are many families and patients who are either unwilling to consider or are not candidates for epilepsy surgery, either because surgery would lead to intolerable motor, language, or memory deficits or for other reasons. In these patients, treatments such as vagus nerve stimulation (VNS) and diets are then considered.

This topic will review the ketogenic diet and alternative diets for the treatment of epilepsy. Some of the preliminary evidence for use of the ketogenic diet in other neurologic conditions will also be briefly reviewed. Other treatments for seizures and epilepsy in adults and children with epilepsy are reviewed separately. (See "Overview of the management of epilepsy in adults" and "Overview of the treatment of seizures and epileptic syndromes in children" and "Vagus nerve stimulation therapy for the treatment of epilepsy" and "Initial treatment of epilepsy in adults" and "Surgical therapy of epilepsy in adults".)

MECHANISMS OF ACTION—Published reports of the ketogenic diet as an effective treatment for epilepsy date to the early 1920s [2]. However, the mechanism(s) by which the ketogenic diet suppresses seizures remains unclear and is likely multifactorial [3].

The ketogenic diet utilizes a high fat, adequate-protein (1 gram/kg), low-carbohydrate diet that produces metabolic changes often associated with the starvation state. Often started with a brief fasting period, changes in plasma ketones, insulin, glucose, glucagon, and free fatty acids can occur within hours of starting the diet and can be quite profound [3].

Which of these metabolic changes are responsible for the improvement in seizure frequency is not known. The ketogenic diet was so called based upon the theory that ketone bodies (acetoacetate, acetone, and beta-hydroxybutyrate), created in the liver from long and medium-chain fatty acids, are directly anticonvulsant when crossing the blood-brain barrier. Urine and occasionally serum ketone levels are generally checked in patients on the ketogenic diet to ensure the diet is being managed correctly, in a manner analogous to following antiepileptic drug levels [4].

However, the importance of ketosis in the mechanism of action of the ketogenic diet is increasingly questioned. Increased mitochondrial biogenesis, oxidative phosphorylation, enhanced gamma aminobutyric acid (GABA) levels, reduced neuronal excitability and firing, and stabilized synaptic function have been shown to occur in patients on the ketogenic diet [3,5]. While these may be induced by ketosis, alternative mechanisms proposed include elevated plasma free fatty acids (including polyunsaturated fatty acids), reduced glucose fluctuations, increased activation of ATP-sensitive potassium channels, caloric restriction, and elevated brain amino acids. Inhibition of the mammalian target of rapamycin pathway and decreased glutamatergic synaptic transmission have also been implicated [6]. It is probable that the ketogenic diet has multiple mechanisms of action, with some more important than others for different forms or etiologies of epilepsy.

INDICATIONS

Efficacy—The ketogenic diet is an effective treatment for patients with epilepsy, regardless of age or seizure type [4]. A 2006 meta-analysis of 19 observational studies (1084 patients) found that after six months, approximately 60 percent of children started on the ketogenic diet had a greater than 50 percent seizure reduction, with 30 percent having greater than 90 percent seizure reduction [7]. Other meta-analyses and reviews have come to similar conclusions [7-9]. While more often considered a treatment in children rather than adults with epilepsy, the growing available (nonrandomized) evidence suggests that adults may also achieve benefit while on the diet; adults are more commonly offered the modified Atkins diet [10,11]. (See 'Modifed Atkins diet' below.)

The first randomized trial of the ketogenic diet was reported in 2008 [12]. One hundred and forty-five children (ages 2 to 16 years) with intractable epilepsy (failure of at least two AEDs) were assigned to immediate implementation of the ketogenic diet or to a control group in whom implementation was delayed for three months [12]. At three months, 103 remained in the trial, 54 in the active treatment group. In these patients, treatment with the diet was associated with a lower mean percentage of baseline seizures (62 versus 137 percent) and a higher percentage with greater than 50 percent seizure reduction (38 versus 6 percent).

Based upon the available evidence, most (21 of 26) members of a 2009 expert consensus panel felt that the ketogenic diet should be considered in children with intractable epilepsy after unsuccessful treatment trials of two or three AEDs [4]. One unanswered question is whether the ketogenic diet is better than a third or fourth medication. Although the data would suggest that the diet is more likely to be of benefit (50 percent chance of >50 percent seizure reduction, compared with approximately 30 percent chance with an additional medication), this has never been formally studied in a randomized, prospective manner.

For patients with specific conditions that appear to be particularly responsive to the ketogenic diet, it is reasonable to consider this treatment earlier. The expert consensus group identified conditions with strong versus suggested evidence of benefit of the ketogenic diet [4]. These are discussed below.

Specific conditions—Conditions with a probable indication (multiple reports of benefit) for the ketogenic diet include [4]:

●Infantile spasms — A number of case series have shown that the ketogenic diet may control infantile spasms in patients refractory to first-line treatments [13]. This is discussed in detail separately. (See "Management and prognosis of infantile spasms", section on 'Ketogenic diet'.)

●Myoclonic-astatic epilepsy (Doose syndrome) — A generalized epilepsy of early childhood with a high frequency of intractability, myoclonic-astatic epilepsy and head-drop seizures has been reported to respond rapidly and often completely to the ketogenic diet in a number of case series [14-16]. Up to 5 percent of patients with syndrome may have GLUT-1 deficiency, another condition that responds to the ketogenic diet as discussed below [17].

●Rett syndrome — The ketogenic diet may improve intractable seizures in patients with Rett syndrome [18-20]. However, in view of the frequent occurrence of growth failure in this syndrome, a ketogenic diet should be used with some caution. (See "Rett syndrome", section on 'Seizures'.)

●Tuberous sclerosis complex — Many patients with tuberous sclerosis complex are refractory to medical treatment but have multiple tubers that can be epileptogenic making surgery impossible. In these patients, a ketogenic diet may help control seizures and should be considered along with other nonpharmacologic interventions [21-24]. (See "Tuberous sclerosis complex: Management", section on 'Epilepsy'.)

●Severe myoclonic epilepsy of infancy (Dravet syndrome) — Intractable epilepsy is one of the characteristics of the Dravet syndrome. Case series suggest that the ketogenic diet may reduce seizure frequency in many of these patients, especially the atypical absence seizures noted in this condition [25-29]. (See "Epilepsy syndromes in children".)

●GLUT1 deficiency — GLUT1 deficiency syndrome is a genetic disorder characterized by impaired glucose transport across the blood brain barrier resulting in generalized epilepsy, developmental delay, and an associated movement disorder [17,30-33]. A low cerebrospinal fluid glucose level suggests this diagnosis. It may also present with early-onset absence epilepsy. The diagnosis can be confirmed in most cases with genetic testing (SLC2A1 mutation).
The ketogenic diet is a first-line treatment for this disorder and provides ketones as an alternative energy source for the brain. While seizures typically remit with this treatment, the effects on neurodevelopment are less apparent [34,35]. However, the diagnosis of GLUT-1 deficiency is often delayed, and developmental outcomes may be better with early initiation of dietary therapy [36].

●Pyruvate dehydrogenase (PDH) deficiency — The ketogenic diet may also serve to provide an alternative energy source for the brain in PDH deficiency, a mitochondrial disease characterized by lactic acidosis, severe neurologic impairments, and occasionally, intractable epilepsy [37,38]. In uncontrolled reports, patients on the ketogenic diet appear to have an improved neurologic outcome.

●Gastrostomy-tube or formula fed children — Poor compliance, a major limiting factor in the effective use of the ketogenic diet, is not a significant problem in patients who receive all of their nutrition via formula or gastrostomy feedings. In one case series, 12 patients with intractable epilepsy and a static encephalopathy were maintained on the ketogenic diet administered via a gastrostomy tube; only two patients did not improve; six patients achieved a more than 90 percent reduction in seizures [39]. A retrospective study found that 61 children who were administered the ketogenic diet via formula (31 formula fed infants; 30 gastrostomy tube fed children) had better rates of >90 percent seizure remission with the diet than children administered the diet through solid food: 59 versus 27 percent [40].

Specific epilepsy disorders in which there have been somewhat more isolated reports of efficacy using the ketogenic diet include [4]:

●Landau Kleffner syndrome or acquired epileptic aphasia is sometimes associated with intractable epilepsy that has been reported to benefit from the ketogenic diet [41]. (See "Epilepsy syndromes in children", section on 'Syndromes with electrical status epilepticus during sleep'.)

●Lennox Gastaut syndrome (LGS) has many causes and is characterized by intractable epilepsy with multiple seizure types. (See "Epilepsy syndromes in children", section on 'Lennox-Gastaut syndrome'.) The ketogenic diet appears to be helpful in some cases [26,42]. In one case series of 71 children with LGS, 50 percent achieved a greater than 50 percent seizure reduction after six months on the diet; while 23 percent achieved a greater than 90 percent seizure reduction [43]. Seizure freedom was rare.
In a blinded-crossover study in 20 children with LGS and intractable seizures, patients were treated with the ketogenic diet after a 36 hour fast and randomized to a treatment solution of 60 g per day of glucose (to negate the effects of the diet) versus saccharin [44,45]. Ketosis was incompletely eliminated in the glucose-added group. Patients in the saccharin group had somewhat fewer seizures than did those in the glucose arm, but this did not quite achieve statistical significance (p = 0.07).

●Absence Epilepsy may respond to the ketogenic diet, when antiepileptic drugs are incompletely effective [29,46]. In a case series of 21 patients with childhood and juvenile absence epilepsy, use of the ketogenic or modified Atkins diet was associated with a >50 percent seizure reduction in 82 percent and compete seizure remission in 19 percent [46]. In the same report, a review of published studies that included 133 patients with absence epilepsy found similar results; 69 percent had a >50 percent seizure reduction and 34 percent became seizure free.

●Subacute sclerosis panencephalitis (SSPE) is a progressive neurologic disorder that can occur as a late complication of measles infection. Intractable myoclonus is a common feature. In one case, implementation of the ketogenic diet appeared to be associated with reduced myoclonic jerks, but the apparent benefit was only temporary [47]. (See "Clinical presentation and diagnosis of measles", section on 'Subacute sclerosing panencephalitis'.)

●Mitochondrial respiratory chain complex defects — In a case series of 14 patients with epilepsy associated with one of the mitochondrial respiratory chain complex defects who were treated with the ketogenic diet, seven patients became seizure free, four showed no response or could not tolerate the diet [48]. There were no severe adverse effects. Many epileptologists consider mitochondrial disorders to be an indication at this time.

●Refractory status epilepticus — There have been several case reports of the ketogenic diet successfully treating prolonged, medically refractory nonconvulsive and partial status epilepticus in adults and children [49-51]. One case series describes efficacious use of the ketogenic diet in seven of nine patients with febrile infection-related refractory epileptic encephalopathy (FIRES) [52]. An additional case report describes successful use of the modified Atkins diet in two children with nonconvulsive status epilepticus [53]. These cases all use ketogenic formulas provided through enteral (eg, gastric) tubes to administer the ketogenic diet and achieve ketosis. A multicenter, open-label trial of the ketogenic diet for adults with refractory status epilepticus is underway.
One study also found that the ketogenic diet was a useful adjunctive treatment in patients with intractable focal epilepsy who had had a recent (within the past month) worsening of seizure control and neurologic deterioration [54].

●Some studies also suggest that patients taking zonisamide or those having a vagus nerve stimulator are particularly likely to respond to the ketogenic diet at diet onset [55,56].

●In one single center case series, other syndromes responsive to the ketogenic diet included migrating partial epilepsy of infancy and epilepsy with myoclonic-atonic seizures [29]. Children with lissencephaly and hypoxic ischemic encephalopathy (four and eight patients, respectively) were also often likely to respond to the diet.

Partial versus generalized epilepsy—Some anecdotal and published evidence have suggested that the ketogenic diet may be less effective in partial compared with generalized epilepsy [57]. However, there are many reports in which patients with focal epilepsy appear to respond to the ketogenic diet [29,54,58-60], and in the randomized clinical trial discussed above, the subgroups of partial versus generalized epileptic syndromes appeared to experience similar benefit [12].

However, it is important to note that patients with intractable focal epilepsy who are candidates for epilepsy surgery are more likely to achieve complete seizure remission with epilepsy surgery than with the ketogenic diet [59,60]. It is not unreasonable to attempt the ketogenic diet for children who are candidates for surgery, however, if the family is not ready or the child is very young.

CONTRAINDICATIONS AND SCREENING EVALUATIONS—Fasting or implementation of the ketogenic diet in individuals with inborn errors of metabolism that affect the transport or oxidation of long chain fatty acids can lead to a devastating catabolic crisis. The ketogenic diet can also exacerbate acute intermittent porphyria.

Absolute contraindications to the ketogenic diet include [4]:

●Primary carnitine deficiency

●Carnitine palmitoyltransferase I or II deficiency

●Carnitine translocase deficiency

●Porphyria

●Fatty acid oxidation defects

●Pyruvate carboxylase deficiency

Patients with clinical features suggesting one of these diagnoses (cardiomyopathy, hypotonia, exercise intolerance, myoglobinuria, easy fatigability) should be tested in order to exclude one of these conditions [4]. Recommended tests are included in the Table (table 1). (See "Inborn errors of metabolism: Metabolic emergencies".)

In contrast, patients with mitochondrial respiratory chain complex defects and epilepsy have been safely and effectively treated with the ketogenic diet [48]. (See 'Specific conditions' above.)

A number of other conditions may make the diet difficult to implement, interfere with compliance, increase the risk of adverse events, or suggest that alternative treatments may be more effective:

●Epilepsy surgery candidates — Patients with intractable focal epilepsy who are candidates for epilepsy surgery are likely to have a better response to epilepsy surgery than to the ketogenic diet [59]. An EEG and MRI are useful in the evaluation of potential epilepsy surgery candidates, but are likely to have been performed prior to consideration of the ketogenic diet.

●Inability to ensure adequate nutritional status (poor oral intake), failure to thrive — Baseline weight, height, body mass index should be measured and compared with age-specific norms [4].

●Special dietary requirements or preferences (eg, vegan diet) — Potential food allergies or intolerances, cultural/religious dietary needs should also be carefully reviewed [4]. A review of a three-day food record can also be helpful in identifying potential problems. Most religions and cultures can be successfully accommodated with the ketogenic diet, however.

●Parent or caregiver noncompliance — A discussion should be held with family to ensure they understand the complexity of diet management and the importance of strict adherence to the diet as well as vitamin and mineral supplements [4]. If there is disagreement between parents or caregivers about using the diet, it is probably not worth starting.

●Medical conditions that may be aggravated by the diet — These include a history of kidney stones, dyslipidemia, liver disease, gastroesophageal reflux disease, constipation, cardiomyopathy, and chronic metabolic acidosis. A renal ultrasound and nephrology consult are recommended if there is a personal or family history of kidney stones [4]. These conditions do not preclude the diet’s use, but make it more difficult. Prior history of pancreatitis or elevated cholesterol should be discussed at length with the family before initiating the diet.

●Certain antiepileptic drug regimens — There is one report suggesting that patients taking phenobarbital may be less likely to respond to the ketogenic diet [55].

IMPLEMENTATION

Initiation—The ketogenic diet should be supervised by a trained dietitian in an epilepsy center who is familiar with the ketogenic diet.

The traditional ketogenic diet is started in the hospital following a 24 to 48 hour fasting period [4]. Then, daily calorie intake and/or the ketogenic diet ratio is gradually increased until the full ketogenic diet for home use is achieved. After an average hospital duration of four days, the child is discharged home.

During the hospitalization, serum glucose is often monitored every six to eight hours and urine ketones are monitored daily [4]. If serum glucose falls below 30 mg/dl, small quantities of orange juice are provided. Medications are usually left unchanged for the first month on the diet, although changed to carbohydrate-free preparations [61].