A pilot study on the use of Ketocal Infant in administering the ketogenic diet

The aetiology of epilepsy in infancy is extremely varied and in some cases
unknown. Infancy is the most critical period for brain maturation. Frequent
seizures during this period can be a poor prognostic factor for epileptic
encephalopathy and neurodevelopment, underscoring the urgency of controlling
seizures [1]. In the majority of cases, severe epilepsy syndromes are
initially treated with pharmacologic intervention. However, due to poor
response, non-pharmacological options (i.e vagal nerve stimulation, ketogenic
diet and epileptic surgery) remain an important part of treatment for these
patients. Thus, the use of the KD in the infant population is increasing
following reports that it is a safe and effective therapy in certain infantile
epilepsies [2;3].

The classical KD has a long history of use in the treatment of refractory
epilepsy, but lost favour in the mid 1900*s with the evolution of
anti-epileptic medications. Its use has now increased dramatically, initially
at the Johns Hopkins Institute and now worldwide [4], primarily when
anti-epileptic drugs have failed or there are unacceptable side effects from
their use [5].

The KD causes the metabolic equivalent of fasting. The very high LCT fat
content of the classical KD means that the body has to derive energy from fat
rather than from carbohydrate. Energy is derived from fat by b oxidation
producing ketone bodies such as b hydroxybutyrate (BHB). These ketone bodies
are used as a metabolic fuel by the body including the brain for energy giving
rise to plasma ketosis [5;6]. The KD*s mechanism of action is unknown.
Various theories exist such as: the change in brain energy metabolism resulting
in the production of ketone bodies which may be anti-convulsant; change in
neuronal cells which may reduce neuronal excitability and hence be
anti-epileptic or a change in brain acidosis [7-9].

The classical KD is a high long chain triglyceride (LCT) fat, adequate protein
and low carbohydrate diet. Most commonly, the classical diet provides a 4:1
ratio of 4 grams of fat to every 1 gram of non-fat (protein and carbohydrate)
energy, although the ratio can be modified to individual tolerances. In the
infant population, it is common practice to reduce the ratio, often to 3:1
[1;10;11]. There are several reasons why the ratio is often reduced in this
younger population; the infant brain has a greater ability to extract and
utilise ketone bodies than older children[12-14]; gastrointestinal tolerance
can be improved with a lower fat intake; and more protein can be incorporated
into the diet, which is essential for the growth needs of the infant.

The ketogenic diet - use and efficacy in epilepsy

Multiple studies are available in the literature that show the KD is
efficacious in terms of seizure reduction in children with refractory epilepsy
[15-19]. In these studies, the diet has been found to be comparable or better
than the efficacy seen with current anti-epileptic medications (i.e. greater
than 50% reduction in seizures in 50% of subjects) [20]

More recently, a number of reviews of the KD have been published which also
show positive outcomes. In 2006, Henderson published a meta-analysis on the
efficacy of the KD as a treatment option for epilepsy [21]. The analysis
included 19 studies with a total of 1084 patients and concluded that *the
calculated odds ratio is significant, clearly indicating benefit*. Two
systematic reviews [22;23] have been published on the efficacy of the KD. In
the latter, Keene reported in 2006 that 49% of children achieved a greater than
50% reduction in seizures based on a total collective patient population of 972
from 14 studies [23]. Since new anti-convulsant medications are deemed
effective if they reduce seizures by 50%, the evidence strongly supports the
effectiveness of the diet [24]. Any reduction in seizures can only be
beneficial as continued seizures have a detrimental effect on development.

Following on from the successful use of the diet in children, several studies
in the literature now support the use of the KD in infants (table 2). Nordli
et al [11] conducted a retrospective review of 32 infants with refractory
epilepsy who were treated with the KD in 2001. Seventeen of the subjects had
infantile spasms. The results reported effectiveness similar to that in the
literature for older children: 19% became seizure free and an additional 36%
had a >50% reduction in seizure frequency. Similarly, Kossoff et al, [10]
studied the tolerance, safety and efficacy of the KD in 23 infants with
infantile spasm in 2002. He found that after 3 months on diet, 61% of subjects
had a >50% reduction in seizures, with 13% of these being seizure free. This is
further supported in a retrospective study by Rubenstein et al 2005 [25]. This
study identified 13 patients that had been started on the ketogenic diet for
treatment of epilepsy seizures, between 1994 and 2005, before use of any
anticonvulsant or in whom only one anticonvulsant had been tried. In those
patients that remained on the diet at 6 months (10 patients), 60% of patients
had >90% seizure reduction, and for those that remained on the diet at 12
months (6 patients), 100% had a >90%. The study concluded that the ketogenic
diet can a valuable therapy before epilepsy becomes intractable.
More recently, Eun et al, 2006 [1] undertook a retrospective analysis of 43
subjects with infantile spasms. Eun*s results showed that at 3 months, 70% of
subjects had a >50% reduction in seizures, and of these, 35% were seizure
free. These results are consistent with the fore mentioned reviews of the
diet, and may even be suggestive of better efficacy in the infant population.
(page 5 and 6 of study protocol)

Evaluation of tolerance to Ketocal Infant as measured by intake and effect on
GI symptoms.
To show that the growth of infants using Ketocal Infant is acceptable compared
to infants with epilepsy.
To evaluate teh ability of Ketocal Infant to attain an maintain ketosis (and
thus seizure control) in subjects with a clinical indication for use of the
ketogenic diet

Open label prospectiv pilot study; a international multicentre study (UK,
Danmark, the Netherlands) with a least 6 infants using the ketogenic diet by
using Ketocal Infant.

Replacement of the usual formula into Ketocal Infant formula and therefore
changing from carbohydrate to fat burning for energy supply. This results in
state of ketosis which can influence the seizures frequency and severness.

By replacing the usual formula into Ketocal Infant the infant the ketogenic
diet will be initiated.
Monitoring the ketosis is essential to ensure the diet works and the ketosis is
adequate (3+-4+ bloodketones is accepted as adequate) Frequent control of
ketosis is necessary at start of the ketogenic diet until adequate ketose is
reached . After that only at clinic visits or in case of illnes eci .
If the child becames capable of taking oral ketogenic foods during the study
they will be encouraged to do so.