Cost-effectiveness of a ketogenic diet in children with intractable epilepsy: a Dutch randomized controlled trial

Up to 30 % of patients with uncontrolled seizures do not respond to drug
therapy. An alternative therapy especially for children is the KD. The*re a lot
of literature confirming the efficacy of the KD. Literature is nevertheless
limited to class 3 and 4 data with the exception of one randomized controlled
trial published in 2008. A cost effectiveness study is never performed.
The KD is used only in a minority of children who could potentially benefit
from it.
In order to optimize therapy for children with uncontrolled seizures, the KD
should be prescribed for more children with intractable epilepsy.
Implementation can be facilitated by a better understanding of the
cost-effectiveness of this dietary treatment.
Benefit for the child is the possibility to have better seizure control with
the KD.
A substantial amount of children with therapy resistant epilepsy do also have a
mental disability and other handicaps as different symptoms of the underlying
brain damage.
Epilepsy has been shown to have the greatest impact on quality of life when
children have intractable seizures and additional disabilities (26). Groups
relatedness is a fact since this are the children who can have benefit from the
KD.

Primary Objective:
To demonstrate the cost-effectiveness of treatment with a ketogenic diet
compared to usual care in children with drug-resistant epilepsy who are not
eligible for epilepsy surgery. Usual care is defined as: the child continuous
to take his or her anti-epileptic drugs and no changes will be made to the
anti-epileptic drugs treatment except when medically indicated.
Research questions are: What are the societal costs of the KD compared to usual
care? What are the effects of the KD compared to usual care (changes in seizure
frequency and seizure severity; side effects/complaints, psychological
functioning; quality of life)? What is the incremental cost-effectiveness ratio
of the KD compared to usual care (cost per QALY).
Secondary Objectives are:
In our proposed study, we will pay great attention to enhance and assess
compliance for example by regular monitoring of ketone bodies with urine
sticks, a standardized protocol including frequent contacts (face-to-face;
telephonic; e-mail) with dietician, nurse, paediatrician and neurologist, and
Internet communication (seizure and cost diaries, ketosis measurements). We
also aim to improve the commitment of the child and parents by using the
Internet to be in contact with them and to exchange information.

Design:
The cost-effectiveness study is designed as a randomized controlled trial (see
Appendix 5 and 16). After informed consent all patients will start with a
4-week baseline period. Then, patients will be randomized to start a KD either
immediately (KD group) or after a 4-month delay (control group).

Randomization - using the minimization method - will be stratified according to
age (1-6 years, 7-12 years, 13-18 years) and whether the child is at the
residential centre (epilepsy centre Kempenhaeghe) or not (child attends the
epilepsy centre as an outpatient while s/he lives at home).
The KD group immediately starts with a KD for a 4-month study period, with a
follow-up of another one year. Since a KD is a last resort treatment, the
children in the control group will also receive a KD after a 4-month delay. The
controls will be treated and monitored according to good clinical practice.

Neither the multidisciplinary team nor the (parents of the) children will be
blinded to which group the children are randomized to. The anti-epileptic drugs
the children use at the time of inclusion in the study will be continued and no
changes will be made to the anti-epileptic drugs during the 4-week baseline
period and the 4-month study period (except when medically indicated).

Description of the ketogenic diet:
The ketogenic diet is introduced during a hospitalization for one week or
longer if medically indicated. The diet is calculated on an individual basis
by the dietitian. The intake is calculated with a computer program from a
24-hour food record. The initial calorie prescription for the ketogenic diet is
based on an average between the pre-diet intake and the recommendations for
energy requirements, taking into account current and previous weight and
height, recommended calorific requirements and levels of physical activity.
The diets begin with 25% extra fat intake, including 10 grams of MCT fat. In
four days the fat-intake is built up to 100% of the calculated fat, given in
LCT fat (diary cream) and a very slowly increasing amount of MCT fat, going up
to a level of 60% of total dietary energy of MCT fat in the final diet. In
about 3 weeks the total quantity of MCT fat is achieved and the LCT fat is left
at 11% of total dietary energy. When the extra fat intake is at 100% the
calculated diet is introduced. The diet then consists of protein (WHO minimum
requirements for age, 10% of total dietary energy), fat (71% of total dietary
energy) and carbohydrate (19% of total dietary energy). Depending on the
tolerance of the MCT fat the diet may need some adjustments. The diet is fully
supplemented with vitamins and minerals. Sometimes the MCT diet is not possible
and the classical ketogenic diet (3:1 or 4:1 ratio) is advised. Also children
with a PEG/tube feed are treated with the ketogenic diet. The diet is then
adjusted to a fluid version.
Down titration of antiepileptic drugs is possible in responders from six months
after initiation of the ketogenic diet. The KD is a high-fat, low carbohydrate,
normocaloric diet that mimics the metabolic state of fasting. During a
prolonged fast, body energy requirements are met by lipolysis and ß-oxidation
of fatty acids rather than by the breakdown of carbohydrates.
Thus, the KD maintains an anabolic nutritional state in a metabolic situation
of fasting. Any diet providing nutritional fat for the generation of ketones
that serve as an alternative fuel to body tissues may be called *ketogenic*.
Ketones may produce an anticonvulsant effect, presumably due to changes in
cerebral energy metabolism, cell properties decreasing excitability,
neurotransmitter function, circulating factors acting as neuromodulators and
brain extracellular milieu [20].
Most studies report the use of the classical ketogenic diet [18,19] that has
been used since the 1920s and is based on a ratio of fat to carbohydrate and
protein combined of 3:1 or 4:1 [33]. A modification to this diet that uses
medium-chain triglycerides (MCT) as an alternative fat source was introduced in
the 1970s [34]. The MCT diet yields more ketones per kilocalorie of energy
provided than long-chain triglycerides (LCT) do, they are absorbed more
efficiently, and are carried directly from the digestive system to the liver by
the portal vein. The increased ketogenic potential of MCT means that less total
fat is needed in the MCT diet, which enables the inclusion of more carbohydrate
and protein [23]. In a 4:1 ratio, there are 4 grams of fat for every 1 gram of
protein and carbohydrate combined. Protein is provided to meet dietary
reference intake, which is approximately 1 g per kilogram of body weight.
Carbohydrates complete the remaining allowance of the ratio. A medium-chain
triglyceride (MCT) diet contains 70% calories from fat, using MCT as the main
source
(50%) and 20% from polyunsaturated sources [35]. In a randomized controlled
trial [36], 145 children were randomized to receive a classical or an MCT diet.
At 3, 6 and 12 months, there were no statistically significant differences in
seizure reduction between the two diet groups. There were also no significant
differences in tolerability except increased reports in the classical group of
lack of energy after 3 months and vomiting after 12 months.
The KD is generally used for a period of up to 3 years. Seizure control
benefits are typically seen within 1-3 months of initiation of the diet. The
international study group reports that the diet should be trialed for at least
for 3* months before deciding to discontinue it [37]. The diet can be
discontinued earlier if seizures worsen beyond expectations or adverse effects
cannot be corrected [35]. Medications are tapered once efficacy of the diet has
established (usually within 3-6 months of diet initiation). The diet is
gradually tapered by lowering its fat content and increasing the carbohydrate
and protein portion of the diet until ketosis is eliminated. Tapering starts
after 2 years of treatment or in case of intolerable side effects. the Dutch
guideline: *Dieetbehandelingsrichtlijn ketogeen dieet voor kinderen (0-18 jaar)
met refractaire epilepsie. Evidence-based handleiding voor een
multidisciplinaire behandeling* will be used.

Potential side effects of the KD are especially in the beginning of the diet
gastro-intestinal symptoms (nausea, vomiting, diarrhoea or constipation) and
hypoglycaemia can occur. In a later faze there*s an elevated risk of kidney
stones en growth deceleration. Growth normalises after termination of the KD.
There*s a higher risk of lever dysfunction, pancreatitis, hypercholesterolemia,
metabolic acidosis, hypocarnitinaemia, hypocalcaemia, hyponatriemia. In older
female menstruation can become irregular. Prolonged QT time is described during
treatment with the KD. Risk of the blood and urine examinations and the ECG are
limited. A venapunction can cause an ecchymosis. One can have an allergic
reaction on disinfectants or adhesive of ECG electrodes. There are no specific
risks about neuropsychological examination. During each visit at the policlinic
the children and their parents visit the neurologist, paediatrician, dietician
and epilepsy nurse. These visits will be scheduled on the same day. The
following assessments will take place: fysical examination with special
interest to weight and length, vena puncture, urine analyses and ECG. This
takes 2 to 3 hours. Neuropsychological examination consist of questionaires
filled in by the parents which take maximum an hour and psychological
assessment of the child. Cognitive tests will be performed as fare as the
mental development of the child allows. During the testing the child wears an
actimeter on his/her wrist (*bracelet* that detects movements). These testings
will takes a maximum of one hour. Neuropsychologic examinations will take place
during baseline, after four months and one year later for the children of the
intervention group. During the baseline of four weeks all parents/patients fill
in cost diaries and seizure diaries. Patients starting immediatly after
randomistion with the ketogenic diet are completing the cost diaries and
seizure diaries during the first sixteen months, patients of the control group
during 4 months. Filling in the cost diary takes approximately 5 to 10 minutes
per week. Filling in the seizure diaries takes 5 minutes per day or week
depending on seizure frequency.