ketogenic diet - epilepsy - diet therapy
dieta cetogênica - epilepsia - dietoterapia
Epilepsy is a devastating neurological disorder affecting approximately 50 million
people of the world’s population[1]. Pharmacotherapy with anti-epileptic drugs is the main strategy adopted for treatment,
but 20–40% of patients continue to struggle with recurrent seizures despite medications[2]. Because of the physical, social, and psychological impact of even a single seizure,
nonpharmacologic treatments such as dietary therapy have been considered to improve
the quality of life of patients with medically-refractory epilepsy[3].
Fasting has been used as a treatment for epilepsy since ancient times. The ketogenic
diet (KD) is a high-fat, low-carbohydrate, and restricted protein diet created in
1921 at the Mayo Clinic by Dr. R.M. Wilder to mimic the fasting state, which has been
found useful in patients with refractory epilepsy[4]. The mechanism by which the KD leads to a reduction in seizures in these patients
is not yet clear. In response to this diet and in the absence of glucose, ketone bodies
produced from fatty-acid metabolism are used as the main energy source in the brain,
maintaining a ketosis status[5]. Further evidence includes carbohydrate reduction, activation of adenosine triphosphate
(ATP)-sensitive potassium channels by mitochondrial metabolism, inhibition of the
mammalian target of rapamycin pathway, and inhibition of glutamatergic excitatory
synaptic transmission[5],[6].
Patients with epilepsy syndromes and conditions such as myoclonic-atonic epilepsy
(Doose syndrome), severe myoclonic epilepsy of infancy (Dravet syndrome), Rett syndrome,
infantile spasm, and tuberous sclerosis complex may particularly benefit from the
KD. In addition, the KD is the treatment of choice for glucose transporter protein
I deficiency and pyruvate dehydrogenase deficiency[3].
The KD has been used worldwide[7] and there are many alternative ketogenic diets such as the classical KD, medium
chain triglyceride diet, modified Atkins diet, and low glycemic index treatment[8]. The classical KD is calculated based on the ketogenic ratio, which refers to the
ratio of the amount of fat to the combined amounts of protein and carbohydrate and
is typically a 3:1 or 4:1 ratio. The amount of carbohydrates is minimal and every
meal is calculated based on the energy and protein requirements of the patient[9].
In Brazil, the KD is administered with solid foods and the most used ingredients are
mayonnaise, bacon, eggs, heavy cream, meat, and some vegetables and fruits[10]. Since the KD is a highly restricted diet, one of the biggest challenges is to maintain
patient adherence to the diet for at least two years. A formula-based KD can facilitate
and improve the introduction of and adherence to the KD treatment for long periods
in oral-fed children and can be especially practical and safe in tube-fed patients.
The objective of this study was to evaluate the acceptability, tolerance, and efficacy
of a formula-based KD in children with refractory epilepsy.
METHODS
Ten children with refractory epilepsy, who did not have remission of their seizures
despite appropriate trials of two tolerated and appropriately chosen antiepileptic
drugs, and who were referred to the KD program between October 2014 and June 2015
were included in the study. Children with disorders that contraindicated the use of
the KD were excluded[2]. This study was approved by the Research Ethics Committee at the Child Institute
of the Clinical Hospital, University of São Paulo, Brazil. An informed consent was
obtained from each parent or caregiver.
The KD was introduced in the outpatient setting. Before an initial screening visit,
the patients’ families were invited to a meeting to learn about the KD and the current
trial. Next, they came for a visit, when the clinical history of the child was recorded
and neurological and baseline exams were performed. Parents were instructed to record
in a diary the frequency of seizures for one month from baseline and for the three
months of treatment.
At the time of study entry, one child was taking one anti-epileptic medication, one
was taking two anti-epileptic medications, six children were taking three anti-epileptic
medications, one child was taking four anti-epileptic medications, and one child was
taking five anti-epileptic medications. The medications were not changed during the
three-month study period.
For orally fed patients, we introduced the KD at a ratio of fat to protein and carbohydrate
of 2:1 in the first week with solid foods distributed over four meals during the day.
In the second week, we introduced a 3:1 KD powdered formula at two meals plus two
meals with solid foods, and after another two weeks we introduced a 4:1 KD formula
at two meals plus two meals with solid foods.
For enterally fed patients, we introduced a modulated 3:1 KD formula exclusively and,
after two weeks, a 4:1 KD formula.
After starting the 4:1 diet, all children were reviewed as outpatients once a month,
for three months.
We evaluated the acceptability, tolerance, and efficacy of the formula-based KD by
the frequency of seizures, adverse events, level of ketosis, and intake of formula
for the three-month period.
The frequency of seizures, adverse events, level of ketosis (whole blood βHB testing
with a portable bedside machine or urine), and acceptability of the diet were recorded
by the patient’s parents. During the medical/dietitian visit, the records were checked
and the parents were asked to rate the overall acceptability of the product and list
any adverse events. Children received KetoCal® 4:1 (Nutricia North America Inc., Gaithesburg, MD, USA).
RESULTS
Ten children (five boys) participated in the study. The age at the KD onset ranged
from nine months to 16 years (mean: 6.3 years). All patients completed the three months
of treatment ([Table 1]).
Table 1
Demographic and clinical features.
|
Case
|
Gender
|
Age at epilepsy onset
|
Etiology
|
Epilepsy type/Syndrome
|
|
1
|
M
|
1.5y
|
Unknown
|
Lennox Gastaut syndrome
|
|
2
|
M
|
9m
|
Unknown
|
Generalized and partial
|
|
3
|
F
|
4m
|
Unknown
|
Generalized
|
|
4
|
F
|
3y
|
Encephalitis
|
Lennox Gastaut syndrome
|
|
5
|
M
|
7m
|
Unknown
|
Lennox Gastaut syndrome
|
|
6
|
F
|
1y
|
Unknown
|
Generalized
|
|
7
|
M
|
4m
|
Asphyxia
|
West syndrome
|
|
8
|
F
|
3m
|
Lyssencephaly
|
Lennox Gastaut syndrome/Lissencephaly
|
|
9
|
M
|
2y
|
Unknown
|
Lennox Gastaut syndrome
|
|
10
|
M
|
4m
|
Asphyxia
|
Partial
|
M: male; F: female; y: year; m: month
Ketone levels were measured in blood in six patients and a level of 3–5 mmol/L was
achieved in 7–10 days. In four patients, ketone urine levels were measured and rated
++/+++ on the 7th and 15th days in two children each. Two children did not have their ketosis level measured
in the first three weeks. After three months, the responder rate (more than 50% seizure
frequency reduction) was 6/10 (60%) and 10% (1/10) of patients were seizure-free.
The most frequently reported adverse effects were hunger, constipation, drowsiness,
and hypoactivity, and one patient who received the formula exclusively presented with
an intense perineal rash following the contact between the patient’s feces and skin.
Eight children reported improved attention and activity.
The formula was well accepted and tolerated by most patients and only one patient
did not like its taste. Parents and clinicians considered that the formula was easy
to use and facilitated the introduction of and adherence to the KD treatment. These
results are shown in [Table 2].
Table 2
Results.
|
Case
|
Age of KD onset
|
Administration
|
Ketosis
|
Days to reach ketosis
|
Response
|
Acceptability
|
Adverse effects
|
|
1
|
6y
|
Oral feeding
|
4-5
|
10
|
Decreased < 50%
|
Good
|
Hungry, obstipation and hypoactivity
|
|
2
|
9y
|
Tube feeding
|
3-5
|
8
|
Decreased > 75%
|
Good
|
Perineal rash
|
|
3
|
3y
|
Oral feeding
|
3-5
|
7
|
Decreased < 50%
|
Good
|
Hungry, somnolence, obstipation, lack of energy and improved QoL
|
|
4
|
16y
|
Oral feeding
|
2-3
|
7
|
Decreased < 50%
|
Good
|
Drowsiness, hypoactivity and improved QoL
|
|
5
|
3y
|
Tube feeding
|
4-5
|
10
|
Decreased < 50%
|
Good
|
Constipation and improved QoL
|
|
6
|
2y
|
Oral feeding
|
4-5
|
8
|
Decreased 100%
|
Good
|
Improved QoL
|
|
7
|
9m
|
Tube feeding
|
+++
|
NA
|
Decreased > 75%
|
Good
|
Hypoactivity, obstipation and improved QoL
|
|
8
|
6y
|
Oral feeding
|
+++
|
NA
|
Decreased > 75%
|
Good
|
Improved QoL
|
|
9
|
5y
|
Oral feeding
|
++/+++
|
7
|
Decreased > 50%
|
Good
|
Hungry and obstipation and improved QoL
|
|
10
|
4y
|
Oral feeding
|
++/+++
|
15
|
Decreased > 50%
|
Didn’t like
|
Hungry and improved QoL
|
KD: ketogenic diet; y: year; m: month QoL: quality of life.
DISCUSSION
Due to the KD strictness, patient compliance depends on the type of diet and the patient
population[3]. In Brazil, the KD was administered orally, or tube fed to children, using solid
foods, and the most-used ingredients include mayonnaise, bacon, eggs, heavy cream,
meat, and some vegetables and fruits. Despite the small number of patients in this
study, the use of a formula-based KD was well accepted, tolerated and facilitated
the compliance to the treatment.
The goal of the KD treatment is to bring the brain into a state of ketosis to control
seizures. The traditional method of initiating the KD involves a period of fasting
of 12–48 hours, depending on the urine ketone levels[9]. A prospective randomized study showed that fasting is not necessary for achieving
ketosis. In that study, the fasting KD group became ketotic earlier, but after six
days, no difference was found in the degree of ketosis between the two treatment groups,
and gradual initiation protocols offered the same results at three months, with lower
frequency and severity of early side effects[11]. Fasting has the same effect as a “loading dose” of medication; however, acute adverse
effects requiring patient hospitalization are more frequent[11]. Gradual KD onset allows the diet to be followed with less adverse effects on an
outpatient basis, which is especially welcome where the availability of hospital beds
is restricted. In the current study, satisfactory ketone levels were achieved, on
average, 10 days after gradual KD onset for patients who were receiving a 3:1 KD formula.
A major limitation of the current study is the small cohort of patients, due to the
limited quantity of the formula available for testing.
Besides that, not all patients measured ketosis in the same way and two children did
not have their ketosis level measured in the first three weeks. Ketosis measured in
the blood or urine is a reliable parameter. The two patients who did not measure ketosis
had more than 75% of their seizures improved, which leads us to infer that they reached
a good ketosis level, although we cannot determine the onset.
A randomized controlled trial that tested the efficacy of the KD in children with
intractable epilepsy found that 62% of patients in the KD group had less than 50%
reduction in seizures, 38% had more than 50% reduction in seizures, and 7% had more
than 90% reduction in seizures at three months[12]. In our sample, 60% of patients had more than 50% seizure frequency reduction and
10% were seizure-free, which is a high response rate despite the small number of patients
studied. Our sample population included five patients (50%) with Lennox-Gastaut syndrome,
who are more likely to experience a reduction in seizure frequency when receiving
KD treatment[13].
The KD powdered formula tested herein is nutritionally complete and has been successfully
used in KDs, in Europe and in the United States of America, in patients with drug-resistant
epilepsy, but in Brazil has only recently become available. Although we describe a
small cohort of patients, this study was important to evaluate the acceptance of the
formula in our population, facilitating the introduction of an already well-established,
but not yet prescribed, treatment that is often misinterpreted by medical professionals,
dieticians and the general population as laborious and difficult to adhere to.
We observed only mild KD-related adverse events and they were not responsible for
diet discontinuation. Gradual KD initiation protocols are, in general, associated
with fewer and milder adverse events[14],[15]. One patient had an intense perineal rash by contact that resolved with immediate
hygiene after evacuation. This is the first report of this KD-related adverse event.
A well-balanced diet usually contains vitamins and minerals, but supplementation is
essential for children receiving the KD due to the limited quantities of fruits and
vegetables they can eat, making the use of a standard multivitamin necessary. Nevertheless,
ketogenic formulas are enriched with vitamins and minerals and supplementation may
not be necessary, depending on the amount of formula prescribed per day. Formula-based
KD can be used in enterally fed patients to facilitate KD management and reduces administration
mistakes in preparation when administered orally. Indeed, using a formula-based KD
is simpler for dieticians to calculate, requires less family teaching, ketosis is
easily maintained, and preparation errors are less common[3]. However, children with epilepsy usually have several daily appointments, such as
medical and nutritional consultations, tests, and therapies. Thus, homemade foods
may not always be a practical solution since they are highly perishable and ketogenic
formulas serve as a better dietary option for these patients. Moreover, introducing
a successful KD in the outpatient setting can also reduce medical costs, as well as
improving the quality of life of children with medically-refractory epilepsy as the
number of seizures subsides. A barrier to the use of the formula in Brazil is the
cost, making its use sporadic or limited to special situations.
In conclusion, epilepsy can have a high impact on the quality of life in children
with intractable seizures and additional disabilities.
The ketogenic diet was effective in reducing the frequency of seizures and improving
cognition and the quality of life of patients.
Homemade foods are normally used in the KD, but ketogenic formulas can be recommended
to improve treatment acceptance and adherence.
