CHAPTER I

INTRODUCTION

1.1 Case Scenario

The incidence of epilepsy is greatest in the first 2 years of life. Early control
of seizures can be associated with better developmental outcome but many of the
epilepsies presenting in infancy are poorly responsive to antiepileptic medication.
The ketogenic diet (KD) is a high fat, low-carbohydrate diet designed to mimic
the effects starvation on the body. Dietary fat is converted into ketones in the
body and used as an energy source by the brain. The KD has been shown to be
and used as an energy source by the brain. The KD has been shown to be
successful in controlling seizures in many observational studies. However the
pediatric neurologist want to find the best evidence of KD in children.

1.2 Case Scenario Assessment

According to the case scenario, assessment to be accomplished are:
1. Formulation of the problem including PICO format and clinical research
question;
2. Finding the best evidence (i.e. journal) to answer the clinical research
question;
3. Critically appraise the evidence (i.e. journal) that already found form the
search;
4. Apply the evidence by integrate the results with clinical expertise and
patient values.

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 CHAPTER II
CONTENTS

2.1 Problem Formulation

2.1.1 The Formulation PICO Question
The essential first step in the Evidence-Based Meidicine practice is the
identification of uncertainty, or the need for information, and the translation of
this uncertainty into answerable clinical questions. Developing the ability to
formulate precise, structured, and answerable clinical questions has been
identified as one of the key tasks for clinicians. Well-formulated systematic
review questions use a structured format to improve the scientific rigor of an
systemic review. One of the method by using PICO which is stand for
population, intervention, comparation and outcomes.1
Based on the case scenario, the PICO question described as below:
Table 2.1 PICO Qustion Based on the Case Scenario
Population/Patient Infancy or Infant or Infants or Young Children or
First 2 Years or Children or Pediatric or Paediatric or
Pediatry or Paediatry
and
Epilepsy or Seizure or Seizures or Convulsion or
Convulsions
Intervention Ketogenic Diet or KD or Ketogenic
Control/Comparison Not Ketogenic Diet
Outcome Control Seizure or Control Seizures or Control
Epilepsy or Control or Remission

2.1.2 Clinical Research Question

A researchable question is an uncertainty about a problem that can be
challenged, examined, and analyzed to provide useful information. The
underlying questions of a research project provide important information to
decide whether the topic is relevant, researchable, and significant. A well-
formulated research question needs extreme specificity and preciseness which
guides the implementation of the project keeping in mind the identification of

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 variables and population of interest.2 A successful research project depends upon
how well the research question is being formulated.
Based on the case scenario above, the clinical reaserch question can be formed
as “In children under two years old with epilepsy, is ketogenic diet effective in
controlling seizures?”
2.2 Best Evidence
Searching for high quality clinical research evidence can be a daunting task
to many in the healthcare professionalism, yet it is an integral part of the
evidence-based practice process. It starts with a case scenario from which a
question is onstructed that is relevant to the case and is phrased in such a way as
to facilitate finding an answer. Once a well-structured question is formulated, it
will be in a better position to search the literature for evidence that will support
the original PICO question.

Figure 2.1 The Display of PubMed Advanced Search Builder

Planning a search strategy is started by determining which database to
search. One of the example is by using PubMed advance search builder. It
requieres to fill the form with PICO keywords. Each keyword need to be search
with the synonyms. Synonyms, words or phrases that mean exactly or nearly the
same as another word or phrase, can help expand the search appropriately. To
complete the search, the next step is combining the Population (those children
under 2 years old with epilepsy); the intervention (ketogenic diet) and the
outcome (controlling seizure). By using the database’s search history, it should be
able to combine these searches into one search showing results from all three of
previous searches. The next step is refining the results by adding limiters.

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Applying limiters will focusing the results to the most pertinent and relevant
content ensuring that no wasting time needed wading through content that may
not be useful. In this search, the limiter was conducted by adding the type of
publication which was clinical trial. As the final search result, it is only require to
choose the best one of the 14 journals (see figure 2.1).

Figure 2.2 Search Result of PubMed Advanced Search Builder

Once after added limiters to combined search and run the results again.
Choosing and reviewing articles that are most relevant to the PICO question was
the last step in finding the best evidence. In this search, the study conducted by
Lambrechts et al. set as the best evidence (see figure 2.2).
The aim of the study in the journal is to evaluate the efficacy and tolerability
of the ketogenic diet (KD) during the first 4 months of a randomized controlled
trial (RCT) in refractory epilepsy patients aged 1–18 years. Children and
adolescents with refractory epilepsy, not eligible for epilepsy surgery, were
included. Following 1 month at baseline, patients were randomized to either the
KD or to care as usual (CAU). Primary outcome is the proportion of patients with
at least 50% reduction in seizure frequency at 4 months. Secondary outcomes are
mean percentage of baseline seizures, seizure severity, and side effects. Fifty-
seven patients were randomized; nine dropped out, leaving 48 for analysis. In an
intention-totreat analysis, 13 patients treated with the KD and four patients of the
CAU group were responders. This trial provides evidence that the KD is an
effective therapy in children and adolescents with refractory epilepsy compared
with CAU. Most often reported side effects are gastrointestinal symptoms.3
2.3 Critical Appraisal
Critical appraisal is regarded as a process of evaluating a research article
carefully and systematically to determine the reliability, validity and application
in clinical practice. Method of appraising information should be done
sistematically to provide a good conclusion, which is the best kind of information.

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It includes appraisal of various sources of information as well as appraising the
conclusion by providing supporting evidences. The components of critical
appraisal are consist of validity, importance, applicability.1
2.3.1 Validity
Validity review aim is to assess if its findings are true and accurate. This is a
crucial step in the validation process because it must determine whether the
article outcomes were influenced by known or unknown sources of bias.4 The
complishment of validity review is done by answering some questions (see
Table 2.2).
Table 2.2 Validity Review of The Critical Appraisal’s Component
Was the assignment of Yes, patients were randomized to either the KD or
patients to treatments to CAU after a 1-month baseline period. A software
randomized? package (ALEA) was used to support the
randomization, which was based on the
minimization method.
A total of 58 patients were included in the study.
Each group has almost equal amounts of patients.
The difference only the intervention.
Was the randomization list Yes, A software package (ALEA) was used to
concealed? support the randomization, which was based on the
minimization method. Computer software is an
adequate allocation concealment.
Was follow-up of patients Yes, there are no loss follow up of patients greater
sufficiently long and than 20%. 84.21% patients complete the clinical
complete? trial.
Based on a minimum detectable difference in
success rate of 35% between the KD group and
CAU, and assuming that alpha = 5% and power =
80%, it is needed 22 children for each group.
Were all patients analyzed Yes, An intention-to-treat (ITT) analysis was
in the groups to which performed.
they were randomized?

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 Were patients, clinicians, No, the project proposed an open-label, Ketogenic
and study personnel kept Diet has never been tested in a blinded manner.
“blind” to treatment? Morever it was stated that the KD was introduced
according to the Dutch guideline during a 5-day
hospitalization at the epilepsy center and the form
applied most frequently was the MCT diet after
asking what patient’s preference.
Were the groups treated Yes, before starting the experiment, all of the
equally, apart from the groups were taking AED regime as their treatment.
experimental treatment? When the experiment finished, consuming AED
regime was still continuing and change of the AED
regime was only allowed if medically necessary.
Were the groups similar at Yes, it was stated that children and adolescents,
the start of the trial apart aged between 1 and 18 years, with refractory
from the experimental epilepsy not eligible for epilepsy surgery, were
therapy? included. Patients were excluded if there were
medical contra-indications or the expectation that
compliance with the diet was not possible because
of severe behavioral or motivational problems.
Before starting the baseline, 1 was excluded due to
undetected dyslipidemia.

2.3.2 Importance
Determining importance review is needed to assess whether the result of
study will make an impact in society.4 This review is consist of two question
which are asking about magnitude of the treatment effect and the precise
estimating the treatment effect (see Table 2.3).
Table 2.3 Importance Review of The Critical Appraisal’s Component
What is the There is a significant decrease of seizure frequency in
magnitude of the Ketogenic Diet (KD) group after 4 months. In KD grup the
treatment effect? mean seizure frequency is 56% to baseline. In CAU group
the mean seizure frequency is 99% to baseline. It means
that there is no significant decrease of seizure frequency on

6
 CAU group. This study also evaluates the changes in
seizure severity according to NHS3 score. After 6 weeks
of intervention, 15 patients of KD group (57.7%) showed
the improvement of NHS3 score while in the CAU group
only 4 patients (18.2%) that showed the improvement of
NHS3 score. After 4 months of intervention, 65.2% of KD
group had improvement in the severity of seizure,
meanwhile in CAU group the improvement occurred in
36.8% patients. Besides the positive effect of the ketogenic
diet, this study also showed that the ketogenic diet give a
higher gastrointestinal symptom after 4 months and higher
total cholesterol level after 6 weeks compare to baseline.
Other founding such as asymptomatic microscopic
hematuria and antropometric changes were also stated but
not statistically analyzed.
How precise is the Statistical analysis of this study showed a significant
estimate of the difference of the mean percentage of baseline seizure after
treatment effect? 4 months between KD group and CAU group (p=0.024).
This study also found a significant difference of the
improvement of seizure severity between KD group and
CAU group after 6 weeks of the intervention (p=0.006).

2.3.3 Calculation
Table 2.4 Calculation Results and Interpretation
Occurance of seizure at 4 Relative risk Absolute Number
months among children after reduction risk needed to
given ketogenic diet and AED (RRR) reduction treat (NNT)
only in the RCT trial (ARR)
Patients given Patients given
AED only ketogenic diet
CER – EER
control event experimental CER – EER 1/ARR
CER
rate event rate
(CER) (EER)

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 99% - 56%
99% - 56% 1/43%
99% 56% 99%
= 43% = 3 patients
= 43,4%
23.6% to
95% CI 1.6 to 4.2
62.4%

95% confidence interval (CI) on an NNT=1/(limits on the CI of its ARR)

 CER  1  CER    EER  1  EER  

 1.96   
 number of control patients   number of experimental patients 
 0.96  0.904   0.028  0.972 
 1.96  0.99 𝑥 0.01   0.56 𝑥 0.44
= ±1.96√( 730 ) +
 ( 711 )
22 26
 2.4%
= ±19.4%
Interpretation :
Relative Risk Reduction (RRR) is 43.4%, means that ketogenic diet if given to
children for 4 months could reduce the seizure occurence for 43.4% compared
to AED given. Absolute Risk Reduction (ARR) is 43%, means that the
difference of failure of ketogenic diet given compared to AED given is 43%.
Number Needed to Treat (NNT) is 3 patients, means that 3 children are needed
to get ketogenic diet for 4 months in order to prevent 1 child get seizure.
2.3.4 Applicability
Determining the practical application of study results is an important step
that is frequently overlooked. If the study is applicable to patient care, the
overall potential benefit for the patient must be assessed. Every treatment has its
risks and benefits. More importantly, the patient’s feelings and perceptions must
be taken into account.4 Questions that physicians practicing EBM would ask to
determine the practical use of study results might include the following (see
Table 2.5).
Table 2.5 Aplicability Review of The Critical Appraisal’s Component
Do these results apply to our Yes, the study conducted by Lambrechts et al. is
patient? using children samples whom age ranges from 1
to 18 years old. The samples are both also

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 currentlytaking epileptic medications even though
their epilepsy is the refractory type, which is not
controlled adequately with optimal epileptic
treatment (> 2 AEDs).
Is our patient so different Our patients are not so different with the ones in
from those in the study that the study, having the same age interval, situation,
its results cannot apply? and condition. Even they are still classified in the
same category, which are pediatric patients, the
age span between 1 to 18 years old is still too
wide, based on their behavior, body biochemistry,
and susceptibility. Furthermore, there is possibly a
minor difference in the types of epilepsy in each
patients (whether it is tonic, clonic, tonic-clonic,
absence, and etc.), which is not classified in this
study. Even so, this study is still considered
relevant and applicable to our patient.
Is the treatment feasible in Yes, according to the study, both classical
our setting? ketogenic diet and Medium-Chain Triglyceride
(MCT) ketogenic diet didn’t require any specific
food or suplement for the intervention to be done
and thus ketogenic diet may be done in our setting
using local ingredients that are familiar to our
people, as long as the fat-protein-carbohydrate
composition follow those of the study. In this
study, the most frequently used ketogenic diet
type is the Medium-Chain Triglyceride (MCT)
diet. MCT are mostly sourced from coconut oil.
Since coconut oil are generally used on daily
home-cooking in our setting, the ingredient are
readily accessible and may more likely to be
accepted for consumption.
What are our patient’s For potential benefits, ketogenic diet had been

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potential benefits and harms
from the therapy?
Method I: f
f = risk of death
f = 50% = 0.5
Method II: 1/(PEERRRR)
RR = EER/CER = 0.57
RRR = 1- RR = 0.43
shown in the study to reduce frequency of seizure
by ≥50% in 50% of patient by the third month,
and as much as 3,8 to 11,5% of patients
experience seizure free each month. Mean seizure
frequency at 4 months compared to baseline, was
significantly lower in patient with ketogenic diet
(56%) than in those without ketogenic diet (99%).
After 6 weeks of intervention, patient with
ketogenic diet also tend to have improvement in
NHS3 score compare to patient without ketogenic
diet (57,7% vs 18,2%).
As for harms, the ketogenic diet mainly cause
gastrointestinal symptoms and increase of total
cholesterol level. Since in our setting patients are
used to having rice as a staple food, it is expected
that ketogenic diet may result in phycologically
feeling hungry or not satisfied as carbohydrate
intake are low. Other harm such as asymptomatic
microscopic hematuria and reduce in height or
weight need to be studied further.
Risk of the outcome in our patient, relative to
patients in the trial.
Expressed as a decimal:
NNT/f= 3 / 0.5 = 6
(NNT for patients like ours)
Our patient’s expected event rate if they received
the control treatment (PEER)
1/(PEERRRR)
=1/(1.5 x 0.43)
= 1.55
(NNT for patients like ours)
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Are our patient’s values and Yes. Samples are children and adolescents, aged
preference satisfied by the between 1 and 18 years, with refractory epilepsy
regimen and its not eligible for epilepsy surgery, were included.
consequences?
Do we and our patient have
a clear assessment of their
values and preferences?
Patients were excluded if there were medical
contra-indications or the expectation that
compliance with the diet was not possible because
of severe behavioral or motivational problems.
Patients were randomized to either the KD or to
CAU after a 1-month baseline period. CAU is
defined as the child continuing to take his or her
AEDs. Patients whom randomized into the KD
group were studied during 4-month period and
followed up for a further 12 months. Patiens
whom randomized into the CAU group were
treated with the KD according to good clinical
practice after a delay of 4 months.
Yes. Children and adolescents with refractory
epilepsy were included. Following 1 month at
baseline, patients were randomized. Fifty-seven
patients were randomized; nine dropped out,
leaving 48 patients for analysis. There were two
type of outcomes from this study. Primary
outcome is the proportion of patients with at least
50% reduction in seizure frequency at 4 months.
Secondary outcomes are mean percentage of
baseline seizures, seizure severity, and side
effects. Mean seizure frequency at 4 months
compared to baseline, after removal of two
outliers in the KD group, was significantly lower
(P – 0.024) in the KD group (56%) (95% CI: 36–
76) than in the CAU group (99%)(95% CI: 65–
133%).
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 Are they met by this Yes. Twice as many patients in the KD group had
regimen and its a relevant decrease in seizure severity score. Thus,
consequences? this KD trial provides the evidence that KD is
more effective therapy than CAU, both with
regard to seizure frequency and severity, in
children and adolescents. However, this therapy
increase gastrointestinal symptoms as its side
effect that can be controlled by fine-tuning the
diet.

2.4 Integrating the Results with Clinical Expertise and Patient Values
According to the critical appraisal in 2.3, it is obtained that ketogenic diet
accompanied by continued use of anti-epileptic drugs (AEDs) was more effective
at controlling seizure in children and adolescents with refractory epilepsy than
continued use of AEDs alone (refractory epilepsy was defined as seizures not
adequately controlled by optimal treatment with ≥2 AEDs). The result of
ketogenic diet effectiveness in the study can be seen in tables below, showing
comparison of seizure frequency reduction each month, mean and median
percentage of baseline seizure after 4 months, and improvement of National
Hospital Seizure Severity Scale (NHS3) score between ketogenic diet group and
care as usual (CAU) group which don't receive ketogenic diet.3

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Although the study show positive outcome of the ketogenic diet compared to
CAU group, there are some consideration that need to be taken into account
regarding its integration with clinical expetise and patient values. These
consideration include :
2.4.1 Patients consideration and preparation before starting ketogenic diet
Treatment with the ketogenic diet (KD) is demanding on families and
requires a high degree of medical and diet monitoring because of possible side
effects and restrictiveness, therefor a multidisciplinary team (consisting of
pediatric neurologist/paediatrician, epilepsy nurse, dietitian and pharmacist) is
highly needed. Before proceeding to dietary intervention, verification is needed
to check the suitability of KD as a treatment option for an individual patient.
During an informative discussion, the dietitian provides the parents / caregivers
with information about the dietary treatment, the possibilities and practicalities
of the KD and risks of short and long term adverse effects. Dietitian also reviews
expectations of the dietary treatment, financial considerations, the dietary
patterns, social circumstances and the practical and technical skills for applying
the KD. The treating physicians (pediatric neurologist/paediatrician) determines
the indication of KD and rule out medical disorders that are contraindicated with
the diet. Based on all of these data, the multidisciplinary team then assesses the
suitability of the dietary treatment.
Indication for KD treatment are refractory epilepsy after use of 2 AEDs, patients
experiencing adverse effects of AEDs, or patients waiting for epilepsy surgery.
While contraindication for KD treatment include: 5
a. Absolute contraindications: Fatty acid oxidation deficiencies; Pyruvate
carboxylase deficiency and other gluconeogenesis defects; Glycogen storage
diseases (except type 2), Ketolysis defects; Ketogenisis defects; Porphyria;
Prolonged QT syndrome or other cardiac diseases; Liver, kidney or pancreatic
insufficiency; and Hyperinsulinism
b. Relative contraindications: Inability to maintain adequate nutrition;Surgical
focus identified by neuroimaging and video EEG monitoring;Parent or
caregiver noncompliance; Growth retardation; Severe gastrointestinal reflux;
and familiair hypercholesterolemia

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2.4.2 Ketogenic diet type and ratio
There are two main versions of the traditional KD: 5
a. Classical KD : Consists of 85-90 % energy from fat, mainly long chain
triglycerides (LCT). Protein and carbohydrates combined provide a total of
10 %-15% of energy. The classical KD is implemented using a ratio system.
Ratio means grams fat: grams (protein + carbohydrates). A ketogenic ratio of
3:1 or 4:1 is usually used in infants. This version of the KD is well tolerated
by infants.
b. Ketogenic diet with medium chain triglycerides (MCT) : Consists of 71-75
% energy from fat, of which 50-60 % energy is from MCT and 11-25 %
energy is from LCT. This version of the KD provides more protein (10 %
energy) and carbohydrates (15-19 % energy). This version is not generally
used in infants who have poor tolerance of high amounts of MCT.
Based on level of ketosis and tolerance, the diet can be adjusted to a lower
ratio (2.5 or 2:1) or higherratio (3.5 or 4:1). The KD formula Ketocal ®3:1 is
specially developed for infants and (young) children to meet the nutritional
requirements. Ketocal 3:1® is based on the Classical KD and well tolerated by
infants. If using breastmilk it is recommended to start combined use with
Ketocal 3:1®, since using Ketocal 4:1® may not fully match with requirements
and careful calculation on an individual basis is highly needed. 5
More liberal versions of the traditional KD, such as Modified Atkins diet
(10-30 grams of carbohydrates, free fat and protein intake) and the Low
Glycemic Index Diet (60 % energy from fat, 30 % energy from protein and 40-
60 grams of carbohydrates with a glycemic index of 50 or lower), are not
suitable for the infant based on the high amount of protein and need forstrict
control.5
2.4.3 Ketogenic dietinitiation
The KD is usually initiated in infants during an admission of at least 3-5
days in an academic hospital or epilepsy centre. In older infants initiation at
home may be possible with close communication and support of the KD team
after thorough education of parents/caregivers. This includes teaching on how to
monitor ketone and glucose levels at home. There is no evidence that fasting is

14
required at the onset of the KD, and studies have established that fasting prior to
the diet intervention had no significant influence on the effectiveness of the KD.
In the international consensus statement, only diet initiation based on
increased ratios from 1:1, 2:1, 3:1 to 4:1 is mentioned in general. No specific
advice for infants is given. While in several studies, a non-fasting gradual
initiation protocol based on full calories was built up over a period of 3-4 days
by increasing the ratio 1:1, 2:1 etc until reaching target ratios. In other study,
instead using full calories since day one, non-fasting KD protocol based on
increasing calorie amount in three days are used; day one 1/3, day two 2/3 and
day three full calories.5
During diet initiation, close monitoring on glucose, ketones, and adverse
effects should be done.There is a risk of hypoglycaemia during diet initiation
although uncommon in the absence of ametabolic disease, thus blood glucose
should be checked twice daily (or more based onsymptoms of hypoglycemia)
and frequency must be adjusted based on tolerance. Glucose levels of 2-2.5
mmol/l (approximately 40mg/dl) should be treated immediately with 2-4 grams
of carbohydrates by adding a small amount of breast milk or normal infant
formula or glucose 10% solution (young infants <4 months). Older infants (> 4
months) can be given other sources of rapidly absorbed carbohydrate such as a
couple of tablespoons (30-60ml) of pure fruit juice. Infants with blood glucose >
3mmol/l but showing symptoms of hypoglycaemia (see Box 1) should also be
treated in the same way. Blood glucose should be re-checked 15-20 minutes
after treatment and if not improved, a further dose of breast milk or formula is
given (or fruit juice if appropriate).5
During transition to a ketogenic feeding regime, the level of ketone bodies
in the blood will increase. Monitoring of ketones will ensure a therapeutic level
is reached without risking symptoms of excess ketosis. Ketones can be measured
in blood or urine. Blood testing using a ketometer is recommended than urine
dipstick during diet initiation as this is more accurate and unaffected by urine
dilution or any possible alterations in water homeostasis that may occur in very
young infants. Blood ketones should be checked twice daily using a finger or
heel prick. Ideal range of ketones on ketogenic diet with blood ketometer are 2-

15
 5mmol/L and with urine dipstick are 8-16mmol/L or 3-4+ (the range depends on
the type of urine dipsticks). When blood ketones are too high (>5.0 mmol/l)
adjustment is done by decreasing ratio (add 1-2% protein and 1-2%
carbohydrate), replace 5% energy from MCT into LCT, or increase 5-10 % of
calories while maintaining same diet ratio.Medical advice should always be
sought for persistent hypoglycaemia or excess ketosis.5
2.4.4 Ketogenic diet prescription
In order to achieve an adequate ketosis, an individual KD prescription is
calculated. This involves the practical implementation (orally or by enteral
feeding tube) of the KD. Some of considerations in KD prescription describe as
below:
Table 2.6 Indicators of Ketogenic Diet Prescription5
Energy Recommendation daily energy intake for an infant with KD:
Age/months Weight/kg Kcal/kg/day
1-3 3.8-5.9 100-95
4-6 6.0-7.9 95-85
7-12 8.0-10.0 85-80
The energy requirements have to be based on the intake
recorded in the food diary, compared with the RDA for age and
gender and recent growth.
If there is a recent decline in the growth curve or failure to
thrive an additional amount of energy is necessary. Using the
ideal weight/age or weight/height should be considered to
ensure catch up growth.
Fat Most infants use the classical KD at a ratio of 3:1. This means
that for every 3 grams of fat there is 1 gram of combined
protein and carbohydrate.
Based on individual tolerance and/or level of ketosis, a different
ratio may be used (2:1 – 4:1).
Protein Recommended daily protein intake for an infant on the KD:
Age/months Weight/kg g/kg/day
1-3 3.8-5.9 2.0-1.6

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 4-6 6.0-7.9 1.5-1.3
7-12 8.0-10.0 1.2-1.1
If there is a recent decline in the growth curve or failure to
thrive an adequate intake of protein is important. Using the
ideal weight/age or weight/height should be considered to
ensure catch up growth.
Carbohydrate The permitted quantity of carbohydrate follows from the
calculation of energy and protein requirements and the
establishment of the necessary quantity of fat.
The allowed quantity of carbohydrate is divided throughout the
day to prevent adverse effects such as hypoglycaemia or
excessive ketosis.
Fluid Recommended daily fluid intake for an infant on the KD:
Age/months Weight/kg ml/kg/day
1-3 3.8-5.9 150-140
4-6 6.0-7.9 120-110
7-12 8.0-10.0 100-90
The fluid intake should be individually calculated and adjusted
frequently based on weight gain and biochemistry results (e.g.
urine calcium: creatinine ratio).
Vitamins, By means of adequate supplemention, the intake of
minerals and micronutrients should be individually calculated corresponding
trace to reference intakes for age and weight.
elements

2.4.5 Adverse effect of ketogenic diet

Table 2.7 Adverse Effects of Ketogenic Diet5
Adverse effects of the ketogenic diet in infants during diet initiation.
Glucose/ketons There is a risk of hypoglycaemia, acidosis, dehydration and
high levels of ketones on commencing a KD with increased
risk of excess ketosis and metabolic acidosis with concurrent
use of carbonic anhydrase inhibitors (for example, topiramate
or zonisamide).

17
Gastro Vomiting, nausea, diarrhea, and abdominal discomfort.
intestinal There is a risk that children with pre-existing gastro
complaints oesophageal reflux will have symptoms exacerbated by a high
fat regime in view of delayed gastric emptying.
Constipation is the most common reported complication of the
KD.
Adverse effects of the ketogenic diet in infants during follow up.
Gastro Vomiting, nausea, diarrhea and abdominal discomfort.
intestinal
complaints
Growth Impaired growth. A prescribed protein-to-energy ratio of at
least 1.5g protein/100kcal has been suggested to help prevent
growth faltering.
Nutritional Decline in both whole body and spine bone mineral content,
deficiencies selenium deficiency, hypomagnesemia and vitamin C
deficiency.
Cardiovascular Elevation of plasma lipid levels.
Kidney stone Increase the risk of kidney stones. The daily oral intake of
citrate potassium that theoretically alkalinizes the urine and
solubilizes urine calcium can be suggested to prevent kidney
stones
Others Increased infection risk, bruising, raised serum uric acid,
fractures, pancreatitis, lipid-aspiration pneumonia, and cardiac
abnormalities, but usually rare.

18
 CHAPTER III
CONCLUSION

Critical appraisal is extremely needed as an assessment of information

found in scientific journal articles before convinced to apply the information as
guidelines in clinical practice. The level of reliability of a study tremendously
depends on the study design, which places clinical trial as the highest in rank.
Critical appraisal evaluates all components in a research article including the
introduction, method and results. A good knowledge about how to evaluate each
component is very necessary to perform a good critical appraisal.
Based on the scenario the study conducted by Lambrechts et al. provides
evidence that the ketogenic diet is an effective therapy compared with care as
usual, both with regard to seizure frequency and severity, in children and
adolescents with refractory epilepsy. Most frequently reported side effects are
gastrointestinal symptoms that can largely be reduced by fine-tuning the diet.

19
 REFERENCES

1. Abdullah M, Firmansyah MA. Critical appraisal on journal of clinical trials.

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