Brittany Cines, RD, LD, CNSC, CSP

Many patients with epilepsy are nonreponsive to medications. The ketogenic diet and other dietary therapies, such as the modified Atkins diet, are back in the forefront as viable nonpharmacological treatment options for medication refractory epilepsy. Following are illustrative fictional accounts of patients with medical problems with co-occurring epilepsy.Glucose Transporter Deficiency SyndromeThree-year-old Matt with history of motor delay presents with episodes of head drop and movement abnormality that seem to worsen with longer duration after a meal. Cerebrospinal fluid glucose is 304, with concurrent serum glucose of 90. Atonic seizures are ultimately controlled on a combination of 2 antiseizure medications, including a carbonic anhydrase inhibitor, although electroencephalogram remains abnormal. Genetic testing reveals SLC2A1 mutation.Matt is admitted to the hospital to initiate a 4:1 ketogenic diet. He is not fasted, however by the second day, he produces 4+ urine ketones, is not drinking well, and vomits with meals. Blood glucose nadir is 30 and bicarbonate level drops from 18 to 12. Intravenous hydration is provided and potassium citrate/citric acid is started. By hospital day 5, bicarbonate level has stabilized and he is discharged.The initial month is difficult for his family, as they struggle to find foods that Matt consistently enjoys. However, with the support of the dietitian and another “keto family,” as well as cookbooks and online recipes, he tolerates the diet. The family is also motivated by the observation that seizures are no longer seen and balance is improved. EEG normalizes and gradually he is weaned off of antiseizure medications.Dravet SyndromeFive-year-old TÃ©a with history of febrile seizures, intellectual disability, ataxia, and refractory myoclonic, generalized-tonic-clonic, and complex partial seizures, presents for transfer of care. She has an SCN1A mutation, and seizures persist despite numerous medication trials, often occurring as status epilepticus requiring multiple rescue medications. Height is at the 50th percentile for age; weight is at the 5th percentile for age.She is admitted for initiation of 4:1 KD. No short-term complications arise, however she is resistant to the foods offered to her. Authorization for a manufactured ketogenic formula is obtained and she accepts the drink. She is discharged home after family receives education regarding food preparation and use of an online program to assist with calculation of food proportions, and recipes and resources for further meal options. They suspect that once in familiar surroundings at home, she will be more willing to eat.At home she continues to be resistant to offered meals and will not drink plain water or flavored sugar-free drinks. She may have 4 days between bowel movements. She will not eat avocado or flaxseed, but will take polyethylene glycol (Miralax). Weight gain stagnates. The KD ratio is gradually decreased, to allow for greater amounts of protein/carbohydrate, and caloric goal is increased.At a subsequent visit, the dietary therapies program social worker elicits that there is inconsistency and disagreement at home between family members regarding the use of the KD. Treatment is changed to MAD, to allow for more flexibility since precise calculations and weighing of food is not necessary. However, administration continues to be difficult, the patient continues to resist foods given to her, and dietary changes are abandoned.Formula-Fed Patient with Epileptic EncephalopathySeven-year-old Robbie with diffuse cerebral malformation, and daily myoclonic and tonic seizures is referred by his primary neurologist. He has spastic quadriplegia, is non-ambulatory, and is on 3 antiseizure medications. Nutrition is provided via gastrostomy tube due to oral motor dyscoordination and aspiration.Robbie is admitted for initiation of 4:1 KD. No immediate complications arise, and his family is comfortable with formula preparation and monitoring of blood sugar and urine ketones. Robbie is discharged after 3 days, with multivitamin, calcium, and vitamin D3 supplementation. His family observes a 75% decrease in seizures within 2 weeks, however fat malabsorption and diarrhea occur. This improves with a decrease in the ratio, ultimately to 2.5:1. Seizure control decreases, however family observes that he is more alert and feel that the balance between benefits and adverse effects of the KD is positive.Within the next year, he has multiple femur fractures. Twenty-five-hydroxyvitamin D is low at 24. A Bone density scan demonstrates severely low bone density for age. He is weaned off of KD to minimize factors contributing to his fracture risk.Febrile Infection-Related Epilepsy SyndromeJennie, a 16-year-old, presents with fever, symptoms of upper respiratory infection, with progressive alteration of mental status and status epilepticus. A full evaluation, including testing for infectious, postinfectious, autoimmune, paraneoplastic, vascular, and structural etiologies is negative. Seizures persist despite medication trials including steroids, intravenous immunoglobulin, midazolam, pentobarbital, ketamine, plasma exchange, and rituximab. Medical complications includeÂ  transaminitis, elevated pancreatic enzymes, and hemodynamic instability.The initial attempt at enteral KD fails because of poor tolerance related to ileus. Subsequently, parenteral KD is attempted, however ratio is low due to limitation of lipid administration; significantly elevated triglycerides are seen and parenteral KD is aborted. When able to be enterally fed, enteral KD is re-attempted, with close monitoring of electrolytes, bicarbonate, liver functions, triglycerides. Ketone levels remain nil to trace; all potential sources of sugar are identified, and ultimately ketone levels rise to 3+ in the urine, confirmed by a betahydroxybutyrate level of 50 in the blood. Approximately one week after KD is initiated, pentobarbital is weaned. Two months later, Jennie is transferred to the rehabilitation unit.

Slideshows

The authors present illustrative fictional accounts of patients with medical problems with co-occurring epilepsy.

Dietary Therapy to Improve Epilepsy Outcomes: Case Vignettes

Treatments for epilepsy have come a long way since the use of fasting dating back to 500 BC. Neurologists started using the ketogenic diet (KD) to treat seizures as early as the 1920s; however, with the development of modern anticonvulsant medications, people lost interest. Between 20% and 30% of persons with epilepsy are refractory to medications. Thus KD and other dietary therapies, such as the modified Atkins diet (MAD), have returned to the spotlight as viable nonpharmacological treatment options for medication refractory epilepsy.

The ketogenic diet is a high-fat diet, which is described as ratios of grams of fat to grams of non-fat (protein and carbohydrates) foods, typically 3:1 or 4:1. The ratio of the MAD is 0.9:1, providing approximately 60% of calories from fat, 30% from protein (higher than the KD and “normal” diet), and 10% from carbohydrates (higher than the KD). The consensus statement published in 2009 by the International Ketogenic Diet Study Group recommends “KD should be strongly considered in a child who has failed 2 to 3 anticonvulsant therapies, regardless of age or gender, and particularly in those with symptomatic generalized epilepsies.”

A Cochrane Review in 2016 yielded 7 randomized controlled trials. The variables of interest were heterogeneous: one trial compared 3:1 and 4:1 ratios of the KD; another compared 2.5:1 and 4:1 ratios. Another trial compared KD versus regular diet, and then classical KD with KD utilizing medium-chain triglycerides as the source of fat. One trial compared fasting versus gradual initiation of the KD. One trial compared MAD with 10 versus 20 grams of carbohydrates per day. Another trial compared MAD, KD, and regular diet, while one trial compared MAD to regular diet. Taken together, all showed that at least 38% of patients had more than a 50% decrease in seizures at 3 months, with the benefit maintained at 1 year. The rate of seizure freedom on KD reached 55% in the 4:1 ratio after 3 months, and 10% in the MAD.

There have been several publications supporting the particular efficacy of KD in certain epilepsy syndromes and causes, including myoclonic-astatic epilepsy (Doose syndrome), severe myoclonic epilepsy of infancy (Dravet syndrome), tuberous sclerosis, infantile spasms, and Rett syndrome. Formula-feeding through tube or bottle would also be a favorable factor, as it would simplify food preparation and minimize chances of intolerance.

Based on specific metabolic abnormalities, there are 2 conditions in which the KD could be considered treatment of choice, to be used before 2 or 3 antiseizure medications have failed. Those are glucose transporter deficiency syndrome, in which glucose transport across the blood-brain barrier is impaired, and pyruvate dehydrogenase deficiency in which pyruvate cannot be metabolized into acetyl-coA.

 Moreover, findings suggest that other etiologies may benefit from dietary therapy, including genetic generalized epilepsies such as juvenile myoclonic and absence epilepsy, and epilepsies that are often considered catastrophic, including those due to malformations such as lissencephaly, hypoxic-ischemic injury, migrating focal seizures of infancy, and febrile infection-related epilepsy syndrome.

Contraindications to dietary therapy include disorders that involve fatty acid metabolism defects due to various enzyme deficiencies, specifically primary carnitine deficiency, carnitine palmitoyltransferase I or II deficiency, carnitine translocase deficiency, Beta-oxidation defects (medium-chain acyl dehydrogenase deficiency, long-chain acyl dehydrogenase deficiency, short-chain acyl dehydrogenase deficiency), and pyruvate carboxylase deficiency. The lack of carbohydrates in KD can also exacerbate acute intermittent porphyria. Relative contraindications include “failure to thrive,” an identifiable surgical focus, and predictors of noncompliance such as lack of supervision, access to or tendency towards forbidden foods, and lack of parental readiness and commitment.

Dietary therapies should be administered under the supervision of a program with particular expertise to allow for discussion of most appropriate dietary options, monitoring of short- and long-term adverse effects, and support of the patient and family through a change in lifestyle. The team’s essential providers are dietitian and physician (neurologist), however the team may also include a nurse, a nurse practitioner, a social worker, and an authorization specialist.

Complications during initiation of the diet may include vomiting, dehydration, hypoglycemia, and excessive acidosis. Use of carbonic anhydrase inhibitors such as topiramate and zonisamide increases the likelihood of acidosis. Constipation is a frequent adverse effect, which is treated by increasing hydration, giving foods such as avocado, or using laxatives.

Monitoring for long-term adverse effects should occur on a standard basis, including monitoring for weight and height, hyperlipidemia (fasting lipid profile), nutritional/electrolyte deficiencies (bicarbonate, calcium, magnesium, phosphorous, free/total carnitine, zinc, selenium, liver function, vitamin D), and kidney stones (urinalysis, urine calcium/creatinine). Serum betahydroxybutyrate levels may be drawn, to correlate with home urine ketones. Bone mineral density scan may be considered, particularly in high-risk patients (eg, immobile, multiple antiseizure medications, history of fractures).

Dr Kao is Attending Neurologist and Director of the Dietary Therapies Clinic of the Comprehensive Pediatric Epilepsy Program,Center for Neurosciences and Behavioral Medicine, Children’s National Medical Center, Washington, DC; Ms Cines is a Registered Dietician at Children’s National Medical Center; she specializes in gastrointestinal diseases and ketogenic diets.

1. Wheless JW. History of the ketogenic diet. 

2. Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. 

3. Martin K, Jackson CF, Levy RG, Cooper PN. Ketogenic diet and other dietary treatments for epilepsy. 

4. Thammongkol S, Vears DF, Bicknell-Royle J, et al. Efficacy of the ketogenic diet: which epilepsies respond? 

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