Ketogenic diet in the treatment of refractory continuous spikes and waves during slow sleep

Purpose: To evaluate the effect of the ketogenic diet on electroclinical characteristics and cognitive function in children with continuous spikes and waves during slow sleep (CSWS). Methods: Five children (four boys, one girl) aged between 8 and 13 years with CSWS refractory to conventional antiepileptic drugs (AEDs), including levetiracetam, and steroids were included. The prospective electroclinical assessment was performed prior to the ketogenic diet and once every 6 months post initiation during the 2‐year period. All children underwent neuropsychological testing prior to the ketogenic diet and four of the children again 12 months after the diet’s introduction. In case 4 the testing has been performed after 7 months and the diet was withdrawn after 9 months because of the lack of efficacy and the parent’s wishes. In two patients the cognitive functions were also evaluated after 24 months since the diet’s initiation. During the period on the ketogenic diet the concomitant AED treatment was unchanged. Results: Electrographic evaluation after 24 months on the ketogenic diet showed CSWS resolution in one patient, mild decrease of the spike–wave index in one, and lack of response in three patients. The ketogenic diet did not influence the neuropsychological outcome, and intelligence quotient (IQ) scores remained low at the end of the follow‐up period. However, in two patients an improvement in attention and behavior was demonstrated. Discussion: This is the first study evaluating the efficacy of the ketogenic diet in children with CSWS. Five presented cases were refractory to AEDs and steroids. Only one case responded with complete CSWS disappearance; in one the effect of the ketogenic diet was partial and intermittent, whereas in three patients no response has been observed. These results show that the ketogenic diet did not appear to influence the neuropsychological outcome; however, the absence of a control group makes it impossible to conclude with certainty.     

Ketogene Diäten

The exact mode of action of the ketogenic diet is still unknown. The classical ketogenic diet and the modified Atkins diet are the therapies of choice in glucose transporter-1 (GLUT1) deficiency syndrome and pyruvate dehydrogenase deficiency. Furthermore, they are an alternative therapeutic option in all therapy resistant forms of epilepsy, especially in infants (infantile spasms) as well as in young and school age children and adolescents. In adults the results are less favorable and the diet often fails because of lack of compliance. The responder rate of the ketogenic diet is syndrome-dependent. The best results are seen in the treatment of epilepsy in tuberous sclerosis (TSC) patients, followed by those with Dravet and Doose syndrome. The diet is also effective in all epilepsies attributed to structural causes or of unknown etiology. In infantile spasms an early initiation of the diet is helpful even as a first line treatment. In Europe first experiences with this strategy have been made and the use of the ketogenic diets is now widespread. Good results have been reported even in autism, tumors, brain injuries, pain, Alzheimer‘s disease, amyotrophic lateral sclerosis and diabetes mellitus.     

The neuropharmacology of the ketogenic diet

The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.     

Efficacy of the Ketogenic Diet for Intractable Seizure Disorders: Review of 58 Cases

The ketogenic diet was developed in the 1920s as a treatment for intractable childhood seizures when few antiepileptic drugs (AEDs) were available. There are still children whose seizures are refractory even to modern therapy, but use of the ketogenic diet appears to be waning. At Johns Hopkins, we continue to believe that the diet is very effective and well accepted by patients and families. To reevaluate our opinion of the efficacy and acceptability of this form of therapy in patients cared for in the 1980s with the newer AEDs, we analyzed the records of 58 consecutive patients who had been started on the diet. Before using the diet, 80% of the patients had multiple seizure types and 88% were treated with multiple AEDs; these children were among our most intractable patients. Despite this, seizure control improved in 67% of patients with the ketogenic diet, and actuarial analysis indicated that 75% of these improved patients continued the diet for at least 18 months. Sixty-four percent had AEDs reduced, 36% became more alert, and 23% had improved behavior. The improvement in these patients with intractable seizures and the length of time that families maintained the regimen indicate that the ketogenic diet continues to have a very useful therapeutic role in selected patients and their families.     

Dietary therapy is the best option for refractory nonsurgical epilepsy

Ketogenic diet therapies for epilepsy have been described since the fifth century and published in scientific literature since the early 1900s. Since that time, the diet's popularity has waxed and waned as newer drugs and other treatments have been introduced. However, in recent years, dietary therapy for epilepsy has been increasingly accepted by physicians and desired by patients as an alternative to new drugs and neurostimulation. The introduction of less restrictive versions of the classic ketogenic diet, such as the modified Atkins diet (MAD), have led to increased numbers of adult patients with refractory epilepsy who are initiating dietary treatment. Approximately half of adults and children who start a ketogenic diet have a >50% seizure reduction, which is impressive given that these patients typically have medically refractory epilepsy. We believe that ketogenic dietary treatment is the best option for children and adults with refractory nonsurgical epilepsy due to its efficacy, rapid seizure reduction, synergistic effects with other antiseizure treatments, known and treatable side effects, potential to treat comorbid medical conditions, and worldwide availability.     

Kidney stones,carbonic anhydrase inhibitors,and the ketogenic diet

PURPOSE: Because carbonic anhydrase inhibitors and the ketogenic diet are each known risk factors for kidney stones, simultaneous use of these therapies has been discouraged. The objective of this study was to establish the prevalence of nephrolithiasis in children in this combination-therapy population. METHODS: Since 1996, 301 children have been started on the ketogenic diet at our institution. A retrospective cohort study of renal calculi in ketogenic diet patients was performed to evaluate the increased risk with combined use of a carbonic anhydrase inhibitor. RESULTS: In 15 (6.7%) of 221 children on the ketogenic diet without the use of carbonic anhydrase inhibitors, stones developed. In five (6.3%) of the 80 children on the diet in combination with topiramate or zonisamide, stones developed. There was no difference between these two groups (p = 0.82). No child was treated with either acetazolamide or more than one carbonic anhydrase inhibitor simultaneously. Prior ketogenic diet duration was shorter (10.4 vs. 22.4 months; p = 0.03), and more children had either a family history of renal stones or significant urologic abnormalities (80 vs. 27%; p = 0.04) in the combination-therapy group. CONCLUSIONS: The combined use of carbonic anhydrase inhibitors and the ketogenic diet does not increase the risk of kidney stones. We recommend that all patients treated with combination therapy should be treated with increased hydration. Urine alkalinization should be considered for children with previous renal abnormalities, family histories of kidney stones, hematuria, or elevated urine calcium-to-creatinine ratios. If renal stones are found, we advocate discontinuation of the carbonic anhydrase inhibitor.     

Therapeutic Plasma Exchange for Malignant Refractory Status Epilepticus: A Case Report

BackgroundRefractory status epilepticus is a prolongation of status epilepticus despite anticonvulsant therapy with two or three medications in proper doses; it is defined as malignant status epilepticus if it takes weeks or months. Intravenous immunoglobulin, high-dose steroids, magnesium infusion, pyridoxine, hypothermia, ketogenic diet, electroconvulsive therapy, and surgical therapy are the other treatment options for status epilepticus.PatientOur 5-year-old male patient was hospitalized at our pediatric intensive care unit because of status epilepticus secondary to meningoencephalitis. No response could be obtained with many medical and nonmedical therapies in our patient, who developed malignant status epilepticus with unknown etiology. Therapeutic plasma exchange was applied as convulsions continued.ResultOurs is the first child for whom therapeutic plasma exchange was successfully applied because of malignant refractory status epilepticus secondary to meningoencephalitis.ConclusionTherapeutic plasma exchange may be a treatment option for children with refractory status epilepticus following presumed meningoencephalitis.     

Changing Physician Attitudes Toward the Ketogenic Diet: A "Parent-Centered" Approach to Physician Education about a Medication Alternative

Alternative medical therapies such as the ketogenic diet are often dismissed by the medical community. We used a “parent-centered” approach to make physicians aware of the ketogenic diet, an alternative therapy for difficult-to control seizures in children. Parents became aware of the diet through national TV and film. Written and video information was made available to them and they were encouraged to ask their physicians about the potential usefulness of the ketogenic diet for their child. Between 1994 and 1999 we assessed the success of this approach with three surveys of all U.S. child neurologists. This “parent-centered” approach increased physician knowledge about the diet, but had little effect on its use. Despite evidence of its effectiveness, physicians continued to reserve its use until children had failed most new anticonvulsants. Physicians say they would use it more often if “it worked better” and if they “had a dietitian with more experience.”     

Dietary treatments for epilepsy: management guidelines for the general practitioner

As ketogenic diets become more frequently used as a standard treatment for epilepsy in children and adults, hospital and community neurologists, pediatricians, intensivists, general practitioners, and house officers will readily encounter patients who are receiving these dietary treatments. A growing body of evidence demonstrates that dietary therapies for epilepsy (classic ketogenic diet, medium-chain triglyceride diet, modified Atkins diet, and low-glycemic-index treatment) are highly effective, with approximately 30-60% of children overall having at least a 50% reduction in seizures after 6 months of treatment. However, as would be true of any other medical anticonvulsant therapy, these treatments have known side effects and complications requiring recognition and timely action. In addition, the ketogenic diet is a significant intervention requiring rigorous daily adherence; not every family is willing or able to make the necessary commitment to this therapy. We provide herein a survey of the most common situations faced in both the inpatient and outpatient settings, including a discussion of triage and management based on our center's experience as well as the recent 2009 International Consensus Guideline.     

Dietary therapies for epilepsy: future research

Since 1921, dietary therapies have remained valuable options in the treatment of intractable childhood epilepsy. The traditional ketogenic diet has been well demonstrated, including in a recent randomized, controlled trial, as being highly effective. More recent alternative diets such as the medium-chain triglyceride diet, modified Atkins diet, and low-glycemic-index treatment have expanded the use of this modality to more children as well as adults. In this review, we discuss our top 10 most pressing research topics related to the ketogenic diet that warrant future study. As well, two promising ketogenic diet clinical researchers discuss their past and current research to help answer some of these questions.