Ketogenic Diet: An Apparent Therapy For Pediatric Refractory Seizures

ABSTRACT

The ketogenic diet (KD) is a high fat, low carbohydrate, and restricted protein diet that was framed in the 1920’s as an alternative therapy for refractory epilepsy. Refractory epilepsy poses high risk of morbidity and mortality for pediatric population. It is a desirable treatment modality for refractory epilepsy in children. The ketogenic diet can be used by people of all ages. In the hospital setting, patients are administered with 1 g of protein per 1 kg of bodyweight, 5-10 g of carbohydrates, and the rest daily calories are given in the form of fat. The efficacy of ketogenic diet is more acknowledged than most of the new antiepileptic drugs. The neuroprotective activity of ketogenic diet can be applied beyond its treatment for epileptic conditions. The ketogenic diet is not heave of side effects. Despite of that, the side effects such as dehydration and hypoglycemia are foreseeable, avertable and treatable. Thus ketogenic diet can be considered as a safe intervention in comparison with other conventional antiepileptics. Pharmacists can play an important role in impeding the use of medications with high carbohydrate content. So along with the advancements in medical field, ketogenic diet can be considered as an apparent therapy for refractory seizures.

INTRODUCTION

The ketogenic diet (KD) is a high fat, low carbohydrate, and restricted protein diet that was framed in the 1920’s as an alternative therapy for refractory epilepsy [1]. Intractable or refractory epilepsy is a childhood neurological medical emergency defined by inadequate control of seizures despite its optimal treatment with conventional medications [2]. Wilder et al. introduced the concept of a diet consisting of “ketogenic” and “antiketogenic” components for the treatment of epilepsy [3, 4]. The International Ketogenic Diet Study Group recommends the therapy of KD in children who fail to respond to 2 or 3 anticonvulsant drugs regardless of age or gender [5]. In the hospital setting, patients are usually administered 1 g of protein per 1 kg of bodyweight, 5-10 g of carbohydrates, and rest daily calories are given in the form of fat [6].A ketogenic-diet team, including a trained neurologist and dietitian, is necessary for the therapy [5,7,8,].These dietary treatments are now also being considered for neurological disorders other than epilepsy, such as brain tumors, Parkinsonism, Alzheimer’s disease, and amyotrophic lateral sclerosis [1].

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TYPES OF KETOGENIC DIET

Classic ketogenic diet:

In classic KD the fat and protein is present in a ratio of 4:1 grams and rest with carbohydrate, 90% of the calories in the diet come from fat. Younger children are provided with a ratio of 3:1[9].

Modified Atkins diet:

The modified Atkins diet allows unlimited protein and fat intake. It is comprised of 60-70% long- chain fatty acid, 25–30% protein and 5% carbohydrate [10].

Low glycemic index treatment:

The low-glycemic index (low-GI) treatment diet restricts the patient’s carbohydrate intake to low-GI carbohydrates, allowing for a larger daily allowance of carbohydrates [10].

Medium chain triglyceride:

The MCT diet is comprised of 71% medium-chain fatty acid, 10% protein, and 19% carbohydrate [10]. Adverse effects like renal stones, acidosis, hypoglycemia, constipation, and growth retardation are less common [9].

Modified medium chain triglyceride:

The modified MCT diet distributes the calories as 30% MCT oil, 40-50%conventional or long-chain fatty acids, 10–20% protein, and 5–10% carbohydrates [10].

COMPOSITION OF KETOGENIC DIET

MECHANISM OF ACTION

The antiepileptic effects of KD are still unclear. The ketosis reduces the seizure activity by inducing changes in energy metabolism, lipid composition of cell membranes, brain water content, or brain pH [11].The anti-apoptotic activity is responsible for the neuroprotective activity of KD [12].The prolonged fasting resulted in detoxification of the gut, resulting in a decrease in the frequency of seizure occurrence [13].KD improves mitochondrial function by increasing metabolic efficiency, while lowering the production of reactive oxygen species (ROS), which then protects the brain from oxidative stress[14,15,16].

EFFICACY OF KETOGENIC DIET

The efficacy of KD is better than most of the new antiepileptic drugs [17]. Neal et al. randomized children to receive KD, after one month (treatment group) or four-month delay (control group) with no changes in the anti-epileptic drugs. The seizure frequency after four months was significantly lower in diet group compared to controls [18, 19].KDs have also been found to reduce neuronal cell death and the generation of seizure activity in experimental models of stroke and cerebral ischemia [20, 21]. KD has been also indicated in deficiencies in spatial learning and memory, as well as impaired brain growth [22]. The introduction of KD in Alzheimer’s patients augments the cognitive activity [23].

PREPARATION AND INITIATION OF KETOGENIC DIET

The patients growth, nutritional parameters, inborn errors of metabolism, family history of renal stones must be reviewed and those with severe neurological impairments should be assessed for ability to chew and swallow and any evidence of gastro esophageal reflux[7].The child’s medications should be reviewed and Type of KD Macronutrient content (% total daily calories) changed to carbohydrate free preparations. Corticosteroids and ACTH should be abstained at least one week prior to diet initiation [5]. For adjusting ketogenic therapy and maximizing ketosis, the monitoring of patient weight and serum titers (lactate, glucose, and beta hydroxybutyrate) was beneficial [24]. Families are taught to check urine ketones and monitor for other illnesses if there is an increase in seizure frequency [25]. On a regularly basis the patient should be monitored by medical and dietary staff who is knowledgeable about the diet and its risks [26].

Initiation of a ketogenic diet most often occurs in a hospital setting at an epilepsy center in order to safely monitor glucose levels and urine ketone levels. Traditionally, a 24-48-hour fasting period marks the initiation of KD. Supplements with multivitamin plus minerals (including trace minerals) and preparations containing calcium with vitamin D are administered to children who are on KD [5].

MONITORING, FOLLOW UP AND DISCONTINUATION OF KETOGENIC DIET

The duration of the ketogenic diet fluctuate among patients. A six week treatment period is usually adequate to determine success or failure. When the seizure control is optimized after a few months, AED therapy may be tapered or discontinued [5, 27]. In order to assess seizure control parents are advised to maintain a daily seizure and urine ketone chart. The blood tests (hematological and biochemical tests, and fasting lipid profile) and urinary spot calcium to creatinine ratio should be reasoned every six months.KD can be terminated immediately in cases of emergency or more slowly over weeks/months by reducing the ratio cautiously in those who have been treated for years [5].

SIDE EFFECTS OF KETOGENIC DIET

The ketogenic diet is not heave of side effects [28, 29] Frequent side effects include constipation or nausea and vomiting [25]. Some effects are very foreseeable, avertable, and treatable, such as dehydration and hypoglycemia[30, 31, 32].Nephrolithiasis is treated by increasing fluid intake, alkalization of urine, and discontinuation of carbonic anhydrase inhibitors; depending on the patient’s symptoms, timely referral is made to Urology [33]. Vitamin and mineral supplementation is provided to prevent known deficiencies. Gastrointestinal complaints can be treated with fluid intake, dietary adjustments and laxatives [25].

ROLE OF PHARMACIST IN KETOGENIC DIET THERAPY

Pharmacists can play an important role in regulating the use of medications with high carbohydrate content [34]. Carbamazpine suspension, ethosuximide syrup, phenobarbital elixir, and valproic acid syrup contain the highest amounts of carbohydrate and should be avoided in ketogenic diet patients [35].Providing pharmacists with a system to find out high carbohydrate content medications during order entry or via a software alert system can secure the patient from seizure recurrence and the re initiation of a ketogenic diet [36].

CONCLUSION

Ketogenic diet is a better therapeutic option for the treatment of refractory epilepsy. Ketogenic diet can be used by people of all ages. Even though the ketogenic diets are having side effects, they are preventable and treatable. Other than epilepsy it can also be used for Parkinson’s disease, Alzheimer’s disease, hypercholesterolemia etc. Other treatment alternatives may achieve control of seizure but potential for morbidity is higher. The pharmacist is also having a greater role in regulating high carbohydrate content medicines, thereby avoiding unwanted effects and improving effectiveness of ketogenic diet.

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