Dietary therapies Flashcards
Ketogenic diet
The KD simulates the ketosis seen with starva- tion while providing necessary calories for growth and development. When a “normal” diet is consumed, glucose is the sole source of energy for the brain; fatty acids do not cross the blood– brain barrier. When carbohydrate consumption is limited, glucose supplies are low, so fat is then used as the alternative source of energy. Specif- ically, when glucose is low, oxaloacetate is shunted from the Krebs cycle to gluconeogene- sis, to produce and maintain glucose levels. This decreases the efficiency of the Krebs cycle to metabolize the abundant acetyl-coA generated from fatty acid metabolism, so acetyl-coA is instead converted to ketone bodies, specifically to acetoacetate, which is then degraded to ace- tone and also converted to beta-hydroxybutyrate. Ketone bodies can cross the blood–brain barrier and so are used instead of glucose for energy [2]. The “classic” KD utilizes long-chain fatty acids (as opposed to medium-chain fatty acids) and is the most widely used dietary treatment. The composition of the diet is calculated using a ratio of the weight of fat (in grams) to the sum of the weight of protein and carbohydrates. Typical ratios are 3:1 or 4:1 (compared to the ratio in a standard North American diet which is 0.3:1). In a 3:1 ratio, there are 3 grams of fat for every 1 g of protein plus carbohydrate combined. The amount of protein is calculated to meet dietary reference intake which is 1 g per kilogram body weight, so a 3:1 ratio is typically used for older children with greater body mass. Calories are also measured, such that they are sufficient to support growth but controlled to prevent excessive weight gain. Roughly 90 % of the calories are obtained from
fat consumption in the classic KD.
Historically, caloric restriction, fluid restric-
tion, and an initial fasting period of 24–48 h, until large ketones are demonstrated, have been features of the KD, but there is limited evidence that these are necessary. Initial fasting seems to shorten the time to the first reported seizure reduction, but long-term outcomes are not impacted. A randomized controlled trial com- paring fasting versus gradual initiation (gradually increasing ratios from 1:1 to 2:1 to 3:1 to 4:1) showed equivalent efficacy at 3 months, with decreased weight loss, decreased episodes of hypoglycemia, and decreased treatment neces- sary for acidosis or dehydration in those children initiated without fasting [3].
Medium chain triglyceride (MCT) diet
In 1971, Peter Huttenlocher at the University of Chicago introduced the MCT Diet. Whereas the classic KD uses standard foods as source of fat, this utilizes MCT oil as a source of medium-chain fatty acids, which is more easily absorbed and delivered directly to the liver; thereby, more efficiently generating ketones and allowing greater consumption of protein and
carbohydrates. The MCT diet provides 60–70% calories from fat. The downside of the MCT diet is gastrointestinal side effects including diarrhea, vomiting, and abdominal pain [4]. However, a randomized controlled trial comparing the toler- ability and efficacy of the MCT diet versus classical KD showed no significant differences in either [5].
Low-Glycemic-Index Treatment (LGIT)
This is the least restrictive dietary therapy pre- sently used in epilepsy management and, thus, may be seen as more palatable and better toler- ated than the other diets. It is also initiated in the outpatient setting, without weighing of foods. It was first reported in 2005 at Massachusetts General Hospital, based upon the theory that one mechanism of the KD could be stabilization of blood sugar levels. This arose from observations that seizure control of children on the KD can be very sensitive to intake of extra carbohydrates, and that blood glucose levels are extremely stable in children on the KD. The LGIT allows higher carbohydrate intake than the other 2 diets but limits the type of carbohydrates to those that are low in glycemic index, foods that result in lower postprandial blood sugar and insulin pro- files. Larger particle size, less gelatinization of a starch, presence of fat, higher acidity, and increased fiber content lead to lower glycemic indices. The type of starch is also a factor. In LGIT, fat contributes 60% of calories, protein 20–30%, and carbohydrates are limited to 40– 60 g per day. All carbohydrates are foods with glycemic index less than 50 [8].
Modified Atkins Diet (MAD)
The MAD was developed at Johns Hopkins Hospital, first reported in 2003, and aimed at children with behavioral difficulties, adolescents, and adults [6]. The standard Atkins diet has a goal of weight loss and includes an induction phase in which there is limitation of carbohy- drates to induce ketosis. In the MAD, this initial phase of carbohydrate restriction is continued, and weight loss is not encouraged unless nutri- tionally indicated.
The fat to protein plus carbohydrate ratio of the MAD is 0.9:1, providing approximately 60– 65% of calories from fat, 30% from protein (higher than the KD and “normal” diet), and 10% from carbohydrates (higher than the KD). Based upon the protocol at Johns Hopkins, in children, initial carbohydrate restriction is to 10 grams per day for a month, with liberalization to 15 g, then 20–30 g per day. Adults are started at 15 g of carbohydrates per day and then increased to 20–30 g per day after a month. This initial stricter period is based upon data from a ran- domized, prospective cross-over design study which showed higher incidence of >50% seizure reduction at 3 months in patients who initially consumed 10 grams per day (60%) versus 20 g per day (10%). The glycemic index of carbohy- drates is not controlled. Fiber is subtracted from the total carbohydrate count.
Initiation of the MAD is done as an outpatient process and no weighing of foods is required, although counting carbohydrates is required. Low-carbohydrate multivitamin and calcium supplementation is prescribed. Medications may be changed to lowest carbohydrate formulations. Urine ketones are checked twice per week and may be elevated to the “large” level, but some- times are lower than those generated by the KD. Monitoring includes phone follow-up in a month and clinic follow-up at 3 and 6 months, with complete blood count (CBC), complete meta- bolic panel (CMP), fasting lipid profile at base- line, 3 and 6 months [7].
Patient selection for dietary therapies
In December 2006, the Charlie Foundation commissioned a panel of 26 pediatric epileptol- ogists and dietitians from 9 countries with expertise in the KD, to create a consensus statement on the clinical management of the KD. It was endorsed by the Child Neurology Society and serves as an excellent reference for a wide
breadth of issues regarding the KD including the practical details of management.
This consensus statement states that the “KD should be strongly considered in a child who has failed 2–3 anticonvulsant therapies, regardless of age or gender, and particularly in those with symptomatic generalized epilepsies.” In addition, the committee members reviewed publications on efficacy in particular conditions. For the KD to be considered as having probable benefit in that condition, the existence of at least 2 publi- cations was required; those included myoclonic astatic epilepsy, Dravet syndrome, tuberous sclerosis, Rett syndrome, and infantile spasms. Formula feeding through gastrostomy tube or bottle would also be a favorable factor, as it would simplify food preparation and minimize chances of intolerance.
Also, based upon specific metabolic abnor- malities, 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 would be glucose transporter defi- ciency 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.
Other conditions in which the KD may pos- sibly be beneficial (based upon single case report or case series) include such conditions as Landau Kleffner syndrome, Lafora body disease, suba- cute sclerosing panencephalitis, mitochondrial respiratory chain complex disorders, phospho- fructokinase deficiency, febrile infection-related epilepsy syndrome (FIRES)/status epilepticus, Lennox-Gastaut syndrome, hypoxic-ischemic encephalopathy, and focal malformations of cortical development.
Contraindications are essentially disorders that involve fatty acid metabolism defects due to various enzyme deficiencies. Long-chain fatty acids are shuttled across the outer and inner mitochondrial membranes by carnitine, facili- tated by first carnitine palmitoyltransferase I, then carnitine translocase, then CPT2, after which beta oxidation occurs within the mito- chondrion, generating acetyl-coA, which then enters the Krebs cycle or forms ketones. Pyruvate
Mechanisms of dietary therapies
The exact mechanisms by which dietary thera- pies treat seizures have not been precisely delineated. Much research, including animal
model studies, has investigated this. Proposed mechanisms have included numerous processes, such as direct anticonvulsant effect of ketones/ free fatty acids, antioxidant/anti-inflammatory effects by decreasing reactive oxygen species, action on mitochondrial uncoupling proteins, increase of mitochondrial biogenesis, decrease of glutamate, and increase of GABA.
Duration
When the KD is the effective, evidence of benefit occurs fairly quickly. The range of time until benefit is 1–65 days and is typically within the first 2 weeks after initiation. Similarly, in a prospective study in adults on the MAD, median time to improvement was 2 weeks (range 1–8 weeks) [10]. Based on these data, continued KD administration for 3 months is encouraged before deciding if the KD should be resumed or discontinued.
If seizure freedom is obtained on the KD, weaning and discontinuation of the KD is con- sidered after 2 years, similar to the approach with antiseizure medications. If seizure freedom is not obtained, but improved seizure control occurs, the balance between benefit and long-term risks needs to be considered when discussing duration of the KD.
Complications of dietary therapies
hort-term complications of the KD may include vomiting, dehydration, hypoglycemia, and excessive acidosis. Therefore, patients are typi- cally hospitalized for initiation of the KD. Con- stipation is a frequent side effect, which is treated by increasing hydration, giving conducive foods such as avocado, or using bulk-forming laxatives.
Monitoring for long-term side effects of the KD must take place on a standard basis, at least every 3 months. This includes measurements and laboratory testing for weight and height, hyper- lipidemia (fasting lipid profile), nutritional and electrolyte deficiencies (electrolytes with bicar- bonate, calcium, magnesium, phosphorous, mplete blood count with platelets, free and total carnitine, zinc selenium, liver function tests, vitamin D), and kidney stones (urinalysis, urine calcium and creatinine). Also, as urine ketone testing is less accurate than serum testing, serum beta-hydroxybutyrate levels may be drawn to correlate with home urine results. Bone mineral density scan, to assess for osteopenia/ osteoporosis, may be considered, particularly in patients who are high risk (immobile, multiple antiseizure medications, history of fractures) and on the KD longer than 2 years.
Evidence of longer-term adverse events with the MAD is limited. In theory, risk of growth limitation, kidney stones, dyslipidemia, and gastroesophageal reflux would be less common than with the KD. Approximately, 25–50 mg/dl increases in total cholesterol have been noted. Blood urea nitrogen also has been shown to increase, likely related to increased protein intake [7(p39)]
Outcomes of dietary therapies
A Cochrane Review in 2012 yielded 4 random- ized controlled trials (versus no randomized controlled trials in a similar review in 2003). These trials were heterogeneous, namely one compared 3:1 and 4:1 ratios of the KD, one compared MCT and classical KD, one KD versus no diet, one fasting versus gradual initiation, and one MAD with 10 versus 20 grams of carbohy- drates. However, taken together, all showed that at least 38% of patients had a 50% decrease in seizures at 3 months, with the benefit maintained at 1 year.
Modified Atkins Diet
Efficacy of the MAD may be comparable to the KD in children and adults. In two studies including children, 43–65% had at least >50% reduction of seizures at 6 months, with 35–36% having >90% seizure reduction [7(p38)]. Meta-analysis of existing literature as of 2008 showed 45% of patients on the MAD with 50–90% seizure reduction and 28% with >90% sei- zure reduction. In an adult study, efficacy was quick if present (median 2 weeks), with 47% experiencing >50% seizure reduction by 3 months and 33% by 6 months [7(p39)].
Low-Glycemic-IndexTreatment
Review of 60 patients has shown 38% of patients with a >50% decrease in seizures at 1 month, with 24% having >90% seizure decrease. Of the patients who continued on LGIT through 6 months, 60% had a >50% seizure decrease, and 38% had a >90% decrease in seizures [8 (p43)].
Future directions in dietary therapies
The use of the KD is being investigated in sev- eral neurologic conditions beyond epilepsy, and in traumatic brain injury, Alzheimer’s disease, amyotrophic lateral sclerosis, autism, glial tumors, diabetic nephropathy, and Parkinson’s disease. In addition, in development is 2-deoxy- (D)-glucose (2-DG), an agent which is a non- metabolizable glucose analog that inhibits glycolysis.
