Dietary treatment of children with Angelman Syndrome and refractory epilepsy

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder
characterized by impairments in cognitive, neurological and motor functioning
leading to a postulated neurological and behavioural profile. Its prevalence
among children and young adults is estimated at 1:24.580 new borns[
AS has been recognized during 1960*s by paediatrician Dr. Angelman who
published his landmark report on *puppet children* in 1965 with the discovery
of which became known as the *happy puppet syndrome*. The name Angelman
syndrome was introduced in 1982 .
The phenotype features are mouthing behaviour, sleep difficulties, fascination
with water, absent or minimal speech development, abnormal electroencephalogram
results, epilepsy and ataxic of broad based gait. Additional features as
feeding difficulties, gastrointestinal reflux, hand flapping, easily provoked
laughter, short attention span, hyperactivity and microcephaly are described in
63-80% of the cases .
AS is caused by the lack of UBE3A gene expression from the maternally inherited
chromosome 15 due to various 15q11-q13 abnormalities.
Over 90% of patients with AS develop epilepsy. Many different seizure types are
seen and non- convulsive status epilepticus is common.

Ketogenic diet treatment in refractory epilepsy in children:
Despite the availability of a large number of anti epileptic drugs (AED)
seizures in 50% of children with AS do not respond adequately or children
suffer from serious side effects from pharmacological treatment. These children
are in need of additional treatment options. The latest Cochrane review based
on data from several clinical trials show the ketogenic diet (KD) to be a
successful, non-pharmacological, treatment option in treating seizures in
children with refractory epilepsy. Various studies showed an efficacy rate in
the range of 27-62% at three months after diet initiation, with success being
defined as >= 50% seizure reduction. Most studies reported success rates at
three months and to a lesser extend at 12 months after diet initiation.
Reported efficacy rates at 12 months range between 9-83%.
Treatment with KD is compliance demanding and requires a high degree of medical
and dietetic monitoring because of its side effects and limits. On KD ketone
bodies appear in the blood which proves the metabolism has switched from
carbohydrate buring to fat burning for energy supply. To achieve and maintain
this delicate metabolic balance the menu's have to be calculated and prepared
strictly on a daily basis by parents. It takes efforts to incorporate this
diet into daily life. Therefore efforts were made to design dietary regimes
that are more liberal as the Modified Atkins Diet (MAD) and LGID. Studies
mention parents and caregivers of patients do confirm these diet to be more
liberal . On LGID the intake of fat and protein is calculated, the
carbohydrates with glycemic index > 50 are restricted. On MAD only the
carbohydrates are restricted, the intake of fat and protein being ad libitum,
this gives parents the opportunity to be flexible and to adjust to their
child*s personal needs and capabilities. These diets do not achieve a notable
level of ketosis but still seizure reduction is achieved.
The KD is based on high intake (90 energy%) of long chain fat (LCT). Medium
chain fat (MCT ) utilizes fast and more ketone bodies than LCT, which may
benefit efficacy of the diet and makes it possible to maximize the amount of
carbohydrates into the diet. When adding MCT into the diet becomes more diverse
and palatable.
Recent research indicates decanoic acid (C10) as part of MCT fat may mimic the
mitochondrial proliferation associated with the KD. This suggests adding MCT
benefits efficacy on seizure reduction.
.
Refractory epilepsy in AS:
In children with AS epilepsy starts often in infancy and generally before the
age of 4. Although no direct correlation is proven between epilepsy severity
and degree of cognitive impairment, recurrent and prolonged seizure activity in
AS has been hypothesized to have a large impact on cognitive outcomes. ]. In a
significant proportion of patients (23-77%) seizures are inadequately
responding to well dosed pharmacological treatment with AED of first choice
and/or a combination of AED. Several studies and retrospective chart reviews
report monotherapy of valproate or clonazepam or both drugs in combination to
be most effective Additionally used AED are phenobarbital, topiramate,
carbamazepine, lamotrigine and levetiracetam with a lower efficacy.

Ketogenic diet in AS:
Non-pharmacological treatment options like the KD and LIGD have produced
promising results in reducing seizures in children with AS.
Two case reports of children with AS show a almost immediate and notable
success of KD on seizure reduction [
A prospective trial of the LGID in small cohort of six children (mean age 3.3
y) with AS, showed a > 80% seizure reduction in five of them after four months
of treatment. After one year five patients maintained having > 90% seizure
reduction
As the underlying working mechanism of the KD treatment is not fully understood
yet, the question arises how important it is to reach ketosis to achieve
seizure reduction. Patients do not achieve a significant level of ketosis
whilst on the more moderate types of KD like LGID or MAD. Past studies have
shown that ketosis does not improve seizure outcome with the LGID
Using the LGID and MAD is described by parents and caregivers (from AS patients
and children with refractory epilepsy ) as more palatable and easier to
incorporate in daily life than the original KD. This is important, taking into
account the behavior and feeding difficulties seen in AS. There are no studies
on MAD in AS.

Experience dietary treatment i fn Erasmus Medical Center Sophia Children's
Hospital Rotterdam:
Since 2001, 155 young children with refractory epilepsy have started the KD
(all types of diets) in Erasmus MC Sophia Children*s hospital. Among them, four
children with AS started LGID. This type of diet was chosen based on previous
publications .Of our parents, one stopped the LGID after three months due to
lack of efficacy. Three patients achieved moderate seizure reduction after one
month LGID treatment, which did not improve further over time. Of these three
patients, two showed significant improvement after switching over to KD and one
reached seizure freedom after adding 10 energy% MCT fat to the LGID diet. Most
parents still had the need for close monitoring the daily intake, diet
calculation and preparation
Four patients with refractory epilepsy and behavior problems started MAD and
were all able to reach > 50% seizure reduction.
Feedback from parents of our AS patients shows that switching over to the KD to
try improving seizure reduction was accepted very well by the patients and
seemed not to increase the level of parental stress. Also to our experience the
MAD fits better to Dutch eating habits than LGID and parents had the
opportunity to be more flexible and adjust to the needs and capacities of their
child on daily basis.


Based on literature and our clinical exiperiences the aim of our study is to
maximize the effect on seizure reduction of dietary treatment but minimize the
burden for patients and parents by starting strictly (with ketosis) and end
easy (with decreased ketosis).

Primary objective:
- 50% seizure reduction or more at 3 months of dietary treatment .

Secondary objectives:
-level of ketosis on KD and MAD.
-number of patients maintaining >50% seizure reduction on MAD.
-number of withdrawals (not able to continue any dietary treatment and/or
insufficient seizure reduction after 3 months of dietary treatment)
- quantification of growht deviation (both height for age and weight for height)
-(change of) level of parental stress and coping during different study periods.
- incidence, kind of feeding difficulties
- change in eating behaviour during study periods, acceptance of change in diet.
- incidence, kind of behaviour problems and change in behaviour during study
periods.
- changes of QoL during study periods.
- incidence of adverse effects (i.e gastro-intestinal problems, constipation,
vomiting )
- toxicity (i.e. adverse events CTCAE grade >= 2).

This concerns a prospective trial of 10 months consisting of an observational
period of 1 month followed by randomized trial of 3 months. After this period
an additional observational study of 6 months is performed.

During study patients use adequately dosed AED in depended to kind of study
group.
First period:
After a run-in period of 1 month in which patients follow normal
diet and AED will be continued and optimized whenever necessary, randomization
will take place.

Second period; 3 months
Randomisation into
1. Diet group: KD (5 energy% carbohydrates), containing 15 energy% MCT fat and
AED.
2. Control group: continue normal diet (patient related) .

Third period: 3 months
1. Diet group;
- patients with > 50 % seizure reduction switch to a MAD (10 energy %
range 20-40 grams carbohydrates ), energy from fat and protein is
unrestricted,
15 energy% MCT fat supplemented.
- patients with < 50% seizure reduction terminate dietary treatment and restart
their
normal diet.
2. Control group ;
- patients with < 50 % seizure reduction start postponed KD (5 energy%
carbohydrates), 15 energy % MCT fat .

Fourth period: 3 months
1. Control group:
- patients with > 50% seizure reduction switch to a MAD (10 energy %
range 20-40 grams carbohydrates ), energy from fat and protein is
unrestricted,
15 energy% MCT fat supplemented.
- patients with < 50% seizure reduction terminate dietary treatment and restart
their
normal diet.
- Patients from diet group continue MAD for additional 3 months

During the trial period of 10 months all patients will be closely monitored by
a specialized dietitian and specialized nurse. During both dietary treatments
adverse effects are seen like constipation, deviated lipid profile, nausea,
food refusal, low blood sugar. These effects are in general temporarily, mild
and seldom reason for diet termination. The patient related possible risks of
the KD are classified as moderate and on MAD are classified as low based on a
previous explorative studies . Based on the fact this study concerns young
children with psychomotoric retardation the overall classification of this
study is moderate.
During the study period efficacy, safety, feasibility, QoL, (eating) behavior,
parental stress and compliance will be assessed by registering the effect on
seizures, adverse effects of standard AED treatment and dietary treatment and
protocol compliance.