THESIS PROTOCOL

THYROID FUNCTION STATUS IN CHILDREN WITH

EPILEPSY ON ANTIEPILEPTIC DRUG

Name of the Student:

Dr. Tumpa Dhar
MD Resident (Phase B)
Department of Pediatrics
Chittagong Medical College, Chattogram

Name of the Guide:

Dr. Mohammod Imrul Kayes
FCPS (Pediatrics)
Associate Professor
Department of Pediatric Nephrology
Chattogram Medical College & Hospital, Chattogram

Name of the Co-Guide:

Dr. Ayesha Begum

FCPS Pediatrics
Assistant Professor
Department of Pediatrics
Chattogram Medical College & Hospital, Chattogram

1
Date:

To
The Principal
Chittagong Medical College, Chattogram

Subject: Application for the approval of Thesis Protocol with the title, “Thyroid
function status in children with epilepsy on antiepileptic drug.”

Respected Sir,

With the above-mentioned subject, I have the honor to seek your kind permission to
submit the thesis protocol as part of my MD course curriculum hereby for your kind
pursual.

I therefore, like to request you to approve my protocol so that I can commence my work
in your esteemed institute to complete my thesis in due time.

Obediently Yours

Dr. Tumpa Dhar

MD Resident (Pediatrics)
Phase-B
Chittagong Medical College, Chattogram

2
 CMC Ethical Review Committee
Chittagong Medical College Hospital
Chittagong-4000, Bangladesh
Tel-031619400, Fax-630180

1. Name of the applicant : Dr. Tumpa Dhar

2. Course : MD Resident (Pediatrics)
3. Session : March 2023
4. Category : Government
5. Reg. no. 18101010130504
6. Mailing address & : Department of Pediatrics, CMCH
Telephone number 01837001054
7. Title of the study : "Thyroid function status in children with
epilepsy on antiepileptic drug."
8. Type of the study : Analytical Cross-sectional study
9. Duration of the study : One year
10. Any collaboration : No
11. Conflict of Interest : None
12. Name of the Guide : Dr. Mohammad Imrul Kayes
FCPS(Pediatrics)
Associate Professor
Department of Pediatrics Nephrology
Chattogram Medical College & Hospital

13. Co-Guide : Dr. Ayesha Begum

FCPS (Pediatrics)
Assistant Professor
Department of Pediatrics
Chattogram Medical College & Hospital

14. Abstract of study : Attached Here

3
Check Documents being submitted herewith to committee:

- Summary : Attached

-Umbrella proposal initially : Attached

-Protocol and CRF : Attached

- Informed consent form for subject : Attached

-Verbal consent form for subjects : Attached

-Procedure for Maintaining Confidentiality : Attached

- Schedule of the study : Attached

4
Declaration

I agree to obtain approval of the Ethical Review Committee for any changes involving
the rights and welfare of subjects or any changes of the methodology before making
any such changes.

Applicant: Dr. Tumpa Dhar

MD Resident (Pediatrics)
Phase- B
Chittagong Medical College Chattogram.

Date:

Forwarding of the guide/Supervisor.

Name of the Guide:

Dr. Mohammad Imrul Kayes

FCPS Pediatrics
Associate Professor
Department of Pediatrics Nephrology
Chattogram Medical College Hospital

5
 CHITTAGONG MEDICAL COLLEGE HOSPITAL
Application for the Ethical review of thesis protocol.

1. Name of the applicant : Dr. Tumpa Dhar

2. Course : MD (Pediatrics) phase B
3. Category : Government
4. Title of the study : "Thyroid function status in children with
epilepsy on antiepileptic drug".
5. Type of the study : Analytical Cross-sectional study
6. Duration of the study : One year
7. Any collaboration : No
8. Conflict of interest : None
9. Name of the guide : Dr. Mohammad Imrul Kayes
FCPS Pediatrics
Associate Professor
Department of Pediatrics Nephrology
Chattogram Medical College & Hospital

10. Co-guide : Dr. Ayesha Begum

FCPS Pediatrics
Assistant Professor
Department of Pediatrics
Chattogram Medical College & Hospital

11. Signature of the guide :

12. Signature of Co-guide :

13. Submission date :

14 Signature of the student :

For Official use:

Serial No: Received on: Reviewed on:
Comment:

Member-Secretary ERB Chairperson ERB

6
Circle the appropriate answer to each of the following

(If not Applicable write NA)

1. Source Population: 4. Are subjects clearly informed
about:
(a) Ill Subjects Yes No (a) Nature and Yes No
purpose of the study
(b) Non* ill subjects (b) Procedures to be
Yes No followed including Yes No
alternatives used
(c) Minors or persons Yes No (c) Physical risks No
Yes
under guardianship
(d) Private questions Yes No
2. Does the study involve: (e) Invasion of the No
Yes
Body
(a) Physical risks to Yes No (f) Benefits to be
Yes No
subjects Derived
(b) Social risks (g) Right to refuse to
participate or
Yes No Yes No
withdraw from the
study
(c) Psychological risks to (h) Confidential Yes
Yes No No
subjects handling of data
(d) Discomfort to (i) Compensation
Yes No
Subjects where there are risks
(e) Invasion of the body Yes No or loss of working No
Yes
(f) Invasion of privacy time or privacy is
Yes No involved in any
particular procedure
(g) Disclosure of 5. Will signed consent/verbal consent
information damaging to be required
Yes No
subject or others (a) From subject Yes No
(b) From parent or Yes No
Guardians
3. Does the study involve:
(a) Use of records 6. Will precautions Yes No
(hospital, medical, death, Yes will be taken to
No
birth or other) protect anonymity
of subjects
(b) Use of fetal tissue or
Yes No
abortus
(c) Use of organs or body
Yes No
fluids

7
 CHITTAGONG MEDICAL COLLEGE HOSPITAL
Chittagong-4000, Bangladesh
Tel-031619400, Fax-630180
Research Proposal
For Post Graduate Thesis/Dissertation

Part-A

1. Thesis Title : "Thyroid function status in children with

epilepsy on antiepileptic drug. "
2. Name of the applicant : Dr. Tumpa Dhar
3. Course : MD (Pediatrics)
4. Place of study : Department of Pediatrics, Chittagong Medical
College
5. Sponsoring : Not Applicable
6. Duration of study : One year
7. Date of :
commencement
8. Date of completion : 1 year from the acceptance of protocol.
9. Total cost : 2,50,000/= taka only
10. Other support of proposed research
i. In this research project being supported by any other source? no

ii. Has an application for funding of this project has been submitted to any other
organization (s)? no

11. Date of submission :

12. Signature of student :
13. Signature of guide :
14. Endorsement of the :
course coordinator
:

Name and signature

:
Designation

Official seal :

8
Part-B
Student’s Information Sheet

1. Name : Dr. Tumpa Dhar

Designation : MD (Pediatrics) phase B

Official address with : Department of Pediatrics, Chattogram

telephone number Medical College Hospital, Chattogram.

Present residential address : Green Palace, Flat No.: 5A, Ali Newaj Lane,
Chalkbazar, Chattogram

2. Academic Background

Degree Institute University/Board Field Year

MBBS Cumilla Medical College University of Medical 2015
Chittagong Science
HSC Chittagong University Chittagong Science 2008
College
SSC Sultanpur High School Chittagong Science 2006

3. Field of Specialty : Pediatrics

4. (a) Research Experience : 3years

(b) Other Experience : None

5. Percentage of time to be devoted to this project : 100%

6. Number of Scientific Publication : None

Signature of the student

9
 PART-C

Title: “Thyroid function status in children with epilepsy on antiepileptic drug”

Summary

Background: Anti-epileptic drug (AED) therapy schemes can control seizures in

approximately 70% of patients, highlighting the significance of early AED initiation
and the need for substantial knowledge of the possible adverse events associated with
their use. AEDs have long been examined for their potential to induce thyroid
dysfunction. However, the lack of international consensus calls for additional studies
to establish practice guidelines for monitoring and managing thyroid dysfunction in
children taking AEDs.

Aims: This study aims to analyze thyroid function of epileptic children who are on
AEDs.

Patients and Methods:

➢ This Cross-sectional study will be carried out in the Department of Pediatrics

of Chittagong Medical College Hospital for one year after acceptance of the
protocol by the Ethical Review Committee.

➢ Children of pediatric age group with a diagnosis of epilepsy and on AEDs

(Valporate,carbamazepine,Phenobarbital,Phenytoin,Levetiracetam,Oxcarbaze
pine) either as monotheraphy or in combination for more than six months with
complete seizure control will be included by the Department of Pediatrics,
CMCH.

➢ Children with progressive neurologic disease, thyroid, metabolic and endocrine

diseases; children on long term medication that could affect thyroid function
other than AEDS and those with noncompliance will be excluded from this
study.

➢ Subjects meeting eligibility criteria will be evaluated clinically and Serum

levels of free thyroxine (FT4) and thyroid-stimulating hormone (TSH) will be
measured.

10
 ➢ Abnormal thyroid status will be determined and compared among different
AEDs. Data will be analyzed by using SPSS Windows version 29.0.

➢ The main outcome of this study will be to compare the impact of different AEDs
on thyroid function to determine the safest AED for long-term use.

Conclusion: The conclusion of the study may aid in establishing a follow up care
protocol to monitor thyroid function status in epileptic child receiving antiepileptic
theraphy to combat thyroid dysfunction.

11
 PART-D
1. Introduction:

Epilepsy is a chronic neurological condition that affects people of all ages and sexes
worldwide (Beghi et al., 2020). The prevalence of epilepsy is disproportionately
concentrated in low and middle-income countries (LMICs). The incidence of epilepsy
is almost threefold higher in LMICs (139 per 100,000) compared in high-income
countries (HICs) (48.9 per 100,000) (Fiest et al., 2017; Ngugi et al., 2010). Moreover,
premature mortality associated with epilepsy is significantly higher in LMIC compared
in HICs. The high burden of epilepsy in LMICs is largely attributed to inadequate
medical services, poor socioeconomic conditions, and traditional beliefs regarding the
treatment of epilepsy (WHO 2019). Epilepsy contributes to a significant disease burden
in children and adolescents worldwide. In 2017, more than 291 million children aged
less than 20 had epilepsy and intellectual disabilities of which 95% lived in low- and
middle-income countries (Olusanya et al., 2020).

AED remains the treatment of choice for epilepsy in childhood in the absence of a
structural brain abnormality amenable to epilepsy surgery and treatment for a period no
shorter than two to three years is often required (Cansu 2010). AEDs are classified as
older (first‐) generation or newer (second‐ and third‐) generation agents. The older‐
generation AEDs introduced into clinical practice more than four decades ago include
phenobarbital, phenytoin, primidone, ethosuximide, valproate, carbamazepine,
clonazepam, and clobazam. The “second‐generation” AEDs which have been approved
for the treatment of epilepsy since the late 1980s include in chronological order,
vigabatrin, oxcarbazepine, lamotrigine, gabapentin, felbamate, topiramate, tiagabine,
levetiracetam, and zonisamide. The third‐generation AEDs include, pregabalin,
fosphenytoin, lacosamide, rufinamide, eslicarbazepine, retigabine (also known as
ezogabine), perampanel, brivaracetam, cannabidiol, stiripentol, cenobamate, and
fenfluramine (Hakami 2021). The newer ASDs differ substantially in their mechanisms
of action, spectra of activity, pharmacokinetics, and adverse effects profiles (Hakami
2021).

12
Long-term treatments with AED highlight the need for substantial knowledge of the
possible adverse events associated with their use. These are more commonly mild
adverse events in clinical practice such as gastrointestinal problems, signs of transient
sedation or other neurological signs, endocrinological and haematological dysfunction,
weight loss or gain, and behavioural abnormalities which only exceptionally constitute
reasons for drug discontinuation (Mir et al., 2023; Perucca and Gilliam 2012).

The occurrence of thyroid dysfunction following AED initiation and the various
biochemical abnormalities regarding the thyroid hormone and TSH concentrations have
been widely speculated, reported and reviewed in the literature (Hakami, 2021; Han et
al., 2022; Ilia et al., 2022; Zhang et al., 2016). Nevertheless, the mechanism of the
underlying positive association between AEDs and thyroid hormones is still unclear. It
is known that more than 99% of circulating thyroid hormones (T3 and T4) are bound
to plasma proteins and FT3 and FT4 do not appear to interfere with thyroxin-binding
globulin with higher accuracy and sensitivity in clinical practice. By changing their
biosynthesis, secretion, transport, metabolism, and/or excretion AEDs can cause
several degrees of impairment in thyroid-hormone homeostasis (Cansu 2010).
According to current literature, it is most likely that AEDs affect hepatic microsomal
enzyme systems and accelerate the metabolism of thyroid hormones. Particularly, liver
enzyme-inducing AEDs such as carbamazepine and phenytoin induced the hepatic
P450 enzyme system resulting in the reduction of T4 and FT4. Moreover, human
uridine diphosphate glucuronosyltransferase could also be responsible for
glucuronidation and play a role in metabolism of thyroid hormones, as high levels of
UGT have been observed after AED exposure in some studies (Benedetti, et al., 2005;
Shorvon 2000). Positive feedback mechanism of the hypothalamic-pituitary-thyroid
axis is then activated by the decrease in T4 and FT4 levels (Yılmaz et al., 2014).
Furthermore, another effect of AEDs on thyroid hormones may be due to the
interference of competitive binding of thyroid hormones to thyroxin-binding globulin.
Peripheral conversion of T4 to active T4 also increased, consequently leading to a
decrease of FT4 (Zhan et al., 2016).

Thyroid hormones play a pivotal role in brain development and central myelination
specially during the first three years of life and in various metabolic pathways, bone

13
maturation, and growth (Counts and Varma 2009; Stepien and Huttner 2019).
Therefore, any overt thyroid abnormality may result in growth and cognitive
impairment (Pimentel et al., 2016). Furthermore, subclinical thyroid dysfunction has
been associated with serum lipid and proatherogenic abnormalities in children and
increased cardiovascular risk in adults, with similar data for children being scarce to
date (Witte et al., 2015).

Recent meta-analyses (Han et al., 2022; Ilia et al., 2022; Zhang et al., 2016) suggested
that carbamazepine, phenytoin, and valproate were the drugs most strongly associated
with decreases in T4 and T3 level while topiramate had the greatest elevating effect on
TSH. The AEDs with the least disruptive effect on thyroid hormone levels were found
to be lamotrigine and levetiracetam (Han et al., 2022).

The implications of such thyroid dysfunction have been examined in the current
literature. The alterations in thyroid hormone concentrations of patients under AED
treatment are often of minimal clinical significance but may further precipitate
subclinical or even overt hypothyroidism in patients with a history of thyroid disease
or levothyroxine-supplemented individuals (Verrotti, et al., 2018). In a literature
review, Cansu (2010) indicated that thyroid abnormalities post-AED can further cause
long-term memory abnormalities, cognitive impairment or subtle neuromuscular
disorders. Finally, in their review on the causes and implications of AED on thyroid
function, Hamed (2015) concluded that subclinical hypothyroidism caused by AED
could lead to metabolic and lipid disturbances and neurodevelopmental adverse events,
which, however, can be reversible either upon AED discontinuation or upon
levothyroxine supplementation, as additionally supported by the review of Crisafulli et
al. (2019).

The presence of biochemical thyroid alterations and subclinical hypothyroidism and

their implications in the pediatric population under AED therapy has raised many
questions regarding the necessity of monitoring and treatment for which international
consensus is currently lacking, which demand studies to establish practice guidelines
for the monitoring and management of subclinical thyroid dysfunction in children
taking AED (Ilia et al., 2022). Moreover, However, there are still limited data about the

14
influence of AEDs on thyroid function in children, especially in Bangladesh. In this
context, present study aims to analyze thyroid function of epileptic children who are on
AED therapy.

2. Rationale:

A normal thyroid status is critical to maintain normal body homeostasis. Alteration in

thyroid status can itself act as a provocating factor for seizures in epileptic children.
Moreover, hypothyroidism leads to various health hazards like dyslipidemia and
diastolic hypertension, which ultimately lead to coronary artery diseases and increase
the morbidity of epileptic children. Achievement of developmental milestone is also
delayed in hypothyroidism.

Whether biochemical thyroid alterations and subclinical hypothyroidism are cause for
significant clinical concern in children receiving AED is yet to be ascertained. Further
studies on different populations are necessary to build up an international consensus
regarding the necessity of monitoring and treatment of thyroid alterations and
subclinical hypothyroidism.

Through the present study, it could be determined whether it is necessary to build up a

monitoring schedule for epileptic children receiving AEDs to evaluate their thyroid
function for early diagnosis and management of thyroid dysfunction.

15
3. Research question:

• What is the thyroid function status of the children with epilepsy on AED
therapy?

4. Objectives:

A. Primary objective:
➢ To investigate the thyroid hormone levels (serum FT4 and TSH) of the
children on AED therapy.
B. Secondary objectives:
1. To compare serum FT4 and TSH among children receiving different AED.
2. To compare serum FT4 and TSH between children receiving first and
second-generation AEDs,
3. To determine the thyroid status of the children receiving different AEDs.

16
5. Materials and method:

5.1. Type of study: Cross-sectional study with analytical component.

5.2. Place of Study: Department of Pediatrics, Chattogram Medical College Hospital,

Chattogram, Bangladesh.

5.3. Study period: One year from acceptance of protocol.

5.4. Study population: Children with an epilepsy attended to the Department of

Pediatrics during the study period.

5.5. Sample Technique: Convenient sampling.

5.6. Sample size: Sample size will be determined by the following formula:

𝑧2 × 𝑝 × 𝑞
𝑛=
𝑑2
Where,
n= Expected sample size
z= 1.96, the standard normal deviation set as1.96 with 95% confidence interval.
p= 50% = 0.50 [The proportion of epileptic children with biochemical thyroid
abnormalities varies widely among studies with different AEDs from 0% to
52.9% (Ilia et al., 2022)].
q=1-p =1- 0.50= 0.50
d= is degree of accuracy desired or maximum allowable difference from true
proportion. Ideally it should be 10% of p = 0.05.
So,
1.962 × 0.50 × 0.50
𝑛= ≈ 385
0.052

17
5.7. Selection criteria:
5.7.1 Inclusion criteria:

1. Diagnosed case of epilepsy

2. Pediatric age group up to 12 years

3. On AEDs
(Valproate,Carbamazepine,Phenobarbital,Phenytoin,Levetiracetam,oxcarbaze
pine) either as monotheraphy or in combination for more than six months

4. Children with complete seizure control.

5.7.2 Exclusion criteria:

1. Child with progressive neurological disease, thyroid, metabolic and endocrine

disease

2. Children on long-term medication that could affect thyroid function other than
AEDs

3. Non-compliance with AED.

5.8 List of variables:

1. Demographic variables: Age, Sex.

2. Relevant antenatal, perinatal and neonatal history.
3. Clinical variables: Seizure type, age of seizure onset, drug type , drug dose,
drug duration, blood pressure, body mass index, OFC, developmental
milestone.
4. Laboratory parameters: Serum TSH and Serum FT4 level.
5. Outcome parameter: Euthyroid status, Hypothyroidism, Subclinical
hypothyroidism, hyperthyroidism.

18
5.9. Operational definition

➢ Epilepsy: According to ILAE (International League Against Epilepsy)

2017, Epilepsy is considered to be a disease of the brain defined by any of
the following conditions:

1. At least two unprovoked seizure occurring more than 24 hours apart;

2. One unprovoked seizure and a probability of further seizure similar to

the general recurrence risk (at least 60%) after two unprovoked seizures,
occurring over the next 10 years;

3. Diagnosis of an epilepsy syndrome.

➢ Seizure: A seizure is a transient occurrence of signs and/or symptoms

due to abnormal excessive or synchronous neuronal activity in the brain.

➢ Children with epilepsy: In this study children who will have a previous
diagnosis of epilepsy either focal onset, generalized onset, unknown case
of epilepsy.
➢ AEDs (Antiepileptic Drugs): Antiepileptic drugs are a diverse group of
pharmacological agents used in the treatment of epileptic seizures.
➢ Complete seizure control: Means that patient is seizure free for at least
6 months.
➢ Progressive neurological disorders: Are conditions where there is a
progressive deterioration of brain functioning which includes Genetic,
Metabolic, Ischemic, Infectious, Degenerative and Demyelinating
diseases.
➢ Hypothyroidism: Hypothyroidism is a state of insufficient circulating
thyroid hormone almost always results from deficient production of
thyroid hormone caused either by a defect in thyroid gland itself or a by
reduced thyrotropin (TSH) stimulation.
➢ Subclinical hypothyroidism: Subclinical hypothyroidism (SCH), also
called mild thyroid failure, is diagnosed when peripheral thyroid hormone
levels are within normal reference laboratory range but serum thyroid-

19
 stimulating hormone (TSH) levels are mildly elevated. This condition
occurs in 3% to 8% of the general population.
➢ Euthyroidism: The state of having normal thyroid gland function is
called Euthyroidism.
➢ Hyperthyroidism: Hyperthyroidism is defined as excessive synthesis
and secretion of thyroid hormone from thyroid gland.
➢ Normal thyroid hormone status:
1. Serum TSH: 5 months -20 years: 0.5-5.5 mIU/L
2. Serum FT4:
Infants: 0.9-2.6 ng/dl
Prepubertal children: 0.8-2.2 ng/dl
Pubertal children: 0.8-2.3 ng/dl

5.10 Data collection method:

All relevant information for each individual study subject will be recorded after getting
informed written consent in a pre-prepared data sheet/case record form. Collected data
will be checked again. Data will be collected by researcher herself by interviewing the
care givers, examining the child, and reviewing the medical records.

5.11 Data collection procedure:

Detailed history-taking, including demographic data, seizure type, epileptic syndrome,
seizure aetiology, onset age of epilepsy, selected AEDs, the dosage of antiepileptic
drugs, and duration of AED therapy, will be performed. Blood pressure, height/length,
and weight will be measured following standard operating procedures. Careful
examination of thyroid glands for the presence of goitre will be carried out.

Analysis of Thyroid Function

A 5-mL venous blood sample will be taken from each participant while taking aseptic
precautions. Blood samples will be collected between 8 a.m. and 10 a.m. after overnight
fasting. The samples will be then centrifuged to separate the serum. The serum will be
analyzed using a Chemiluminescence autoanalyzer (Siemens ADVIA Centaur XPT) to
assess fT4 and TSH concentrations properly.

20
The parents or caregivers will be referred for appropriate management if any alteration
of thyroid function will be detected.

5.12 Data analysis:

After collection data will be entered in to Microsoft Excel data sheet to generate a
master sheet. Later they will be fed into SPSS version 29.0 for processing and analysis.
Continuous variables will be presented as mean±SD. Categorical variables are
presented as frequency (%). Oneway analysis of variance (ANOVA), followed by post
hoc test will be used to evaluate significant differences among the the AED groups.Chi-
square test will be used to assess association between thyroid status and AEDs. P < 0.05
will be considered statistically significant.

5.11 Data presentation/Result:

Data will be presented by appropriate method by frequency table, frequency curve, bar
chart, pie chart, scatter/dot diagram, histogram etc. which will be appropriate, in a
simplified, self-explanatory, and informative manner.

5.12 Recommendation: Recommendation will be given on the basis of findings

regarding the safest AED in terms of thyroid function alteration.

6. Utilization of result:

• The study results could be used in the management of children with epilepsy.
• The study will be submitted to respective University as part of the requirement
for the MD (Paediatric Medicine ) examination purpose.
• The results of the study will be presented to the Department of Paediatrics
CMCH.
• Effort will also be made to present these results at conferences and publish them
in peer review journals.
7. Ethical Implication:

The study protocol will be submitted to the ethical review committee of Chittagong
Medical College and an ethical clearance certificate will be obtained. Informed written
consent will be obtained from the caregivers of the patients. Participants will be

21
 volunteered. All participants will be free to take part or refuse to be a part of the study.
Measures will be taken to protect the data confidentiality and anonymity of the collected
data.

8. Time schedule:

1 2 3 4 5 6 7 8 9 10 11 12
Month
Problem definition
Approach to problem
Protocol development
Data collection
Data analysis

Report writing & preliminary

presentation to supervisor/department

Submission

22
9. Flow Chart of Study Design:

Assessment of the children with epilepsy for the eligibility in the study
↓
Any exclusion criteria--→ will exclude from study
↓ (Fulfills inclusion criteria)
Consent given→ No →exclude
↓yes
History, Physical examinations will be recorded in CRF
↓
Collection of blood samples for thyroid function evaluation
↓
Collection of report and completion of CRF
↓
Data Analysis
↓
Result and discussion writing
↓
Presentation of thesis in the department
↓
Will be submitted to the university.

23
10. References:

Amer, M.E., Abdo, M.A., Mahmoud, R.A. and Ahmed Ibrahem, A.M., 2024. Relation
between Antiepileptic Drugs and Thyroid Function in Children with Epilepsy. Zagazig
University Medical Journal. doi: 10.21608/zumj.2024.262088.3107

Aziz, R.A.A. and ELela, M.A.A., 2018. Is it necessary to measure thyroid hormone
levels in children receiving antiepileptic drugs?. Journal of Pediatric Epilepsy, 7(04),
pp.136-141.

Beghi, E., 2020. The epidemiology of epilepsy. Neuroepidemiology, 54(2), pp.185-

191.

Benedetti, M.S., Whomsley, R., Baltes, E. and Tonner, F., 2005. Alteration of thyroid
hormone homeostasis by antiepileptic drugs in humans: involvement of
glucuronosyltransferase induction. European journal of clinical pharmacology, 61,
pp.863-872.

Cansu, A., 2010. Antiepileptic drugs and hormones in children. Epilepsy

research, 89(1), pp.89-95.

Crisafulli, G., Aversa, T., De Luca, F. and Wasniewska, M., 2019. Subclinical
hypothyroidism in children: when a replacement hormonal treatment might be
advisable. Frontiers in Endocrinology, 10, p.443393.

Counts, D. and Varma, S.K., 2009. Hypothyroidism in children. Pediatrics in

review, 30(7), pp.251-258.

Elshorbagy, H.H., Barseem, N.F., Suliman, H.A., Talaat, E., AlSHOKARY, A.H.,
Abdelghani, W.E., Abdulsamea, S.E., Maksoud, Y.H.A., Azab, S.M., Elsadek, A.E.
and El Din, D.M.N., 2020. The impact of antiepileptic drugs on thyroid function in
children with epilepsy: new versus old. Iranian Journal of Child Neurology, 14(1),
pp.31-41.

Fiest, K.M., Sauro, K.M., Wiebe, S., Patten, S.B., Kwon, C.S., Dykeman, J.,
Pringsheim, T., Lorenzetti, D.L. and Jetté, N., 2017. Prevalence and incidence of

24
epilepsy: a systematic review and meta-analysis of international
studies. Neurology, 88(3), pp.296-303.

Hakami, T., 2021. Neuropharmacology of antiseizure

drugs. Neuropsychopharmacology reports, 41(3), pp.336-351.

Hamed, S.A., 2015. The effect of antiepileptic drugs on thyroid hormonal function:
causes and implications. Expert review of clinical pharmacology, 8(6), pp.741-750.

Han, Y., Yang, J., Zhong, R., Guo, X., Cai, M. and Lin, W., 2022. Side effects of long-
term oral anti-seizure drugs on thyroid hormones in patients with epilepsy: a systematic
review and network meta-analysis. Neurological Sciences, 43(9), pp.5217-5227.

Hanc, F., Türay, S., Bala, K.A., Tunçlar, A., Dilek, M. and Kabakuş, N., 2021. Effects
of 12-month Antiepileptic Drug Use on Thyroid Functions in Children: A Retrospective
Observational Study. Journal of Pediatric Research, 8(4), pp.389-393.

Ilia, T.S., Dragoumi, P., Papanikolopoulou, S., Goulis, D.G., Pavlou, E. and Zafeiriou,
D., 2022. Is the prevalence of thyroid disease higher in children receiving antiepileptic
medication? A systematic review and meta-analysis. Seizure, 94, pp.117-125.

Mir, M.A., Malik, A.B., Qadrie, Z. and Dar, M.A., 2023. Adverse Reactions Caused by
Antiepileptic Medications in Real-World Medical Settings. International Journal of
Current Research in Physiology and Pharmacology, pp.25-35.

Ngugi, A.K., Bottomley, C., Kleinschmidt, I., Sander, J.W. and Newton, C.R., 2010.
Estimation of the burden of active and life‐time epilepsy: a meta‐analytic
approach. Epilepsia, 51(5), pp.883-890.

Nelson Textbook of Pediatrics, 21st Edition.

Olusanya, B.O., Wright, S.M., Nair, M.K.C., Boo, N.Y., Halpern, R., Kuper, H.,
Abubakar, A.A., Almasri, N.A., Arabloo, J., Arora, N.K. and Backhaus, S., 2020.
Global burden of childhood epilepsy, intellectual disability, and sensory
impairments. Pediatrics, 146(1).

25
Perucca, P. and Gilliam, F.G., 2012. Adverse effects of antiepileptic drugs. The lancet
neurology, 11(9), pp.792-802.

Pimentel, J., Chambers, M., Shahid, M., Chawla, R. and Kapadia, C., 2016.
Comorbidities of thyroid disease in children. Advances in Pediatrics, 63(1), pp.211-
226.

Rafik, A., El-Din, N.S., El Khayat, N.M., Nada, M. and Abushady, E.M., 2024. Effect
of anti-epileptic drugs usage on thyroid profile in Egyptian epileptic children. The
Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 60(1), pp.1-18.

Rochmah, N., Faizi, M., Nur Nailul, N. and Gunawan, P.I., 2020. How common is
Hypothyroidism in Children with Epilepsy on Antiepileptic Drugs. Asia Pac J Paediatr
Child Health, 3.pp.76-81.

Shorvon, S., 2000. Oxcarbazepine: a review. Seizure-European Journal of

Epilepsy, 9(2), pp.75-79.

Stepien, B.K. and Huttner, W.B., 2019. Transport, metabolism, and function of thyroid
hormones in the developing mammalian brain. Frontiers in endocrinology, 10,
p.449733.

Verrotti, A., Scardapane, A., Manco, R. and Chiarelli, F., 2008. Anti-epileptic Drugs
and Thyroid Function. Journal of Pediatric Endocrinology and Metabolism, 21(5),
pp.401-408.

Witte, T., Ittermann, T., Thamm, M., Riblet, N.B. and Völzke, H., 2015. Association
between serum thyroid-stimulating hormone levels and serum lipids in children and
adolescents: a population-based study of german youth. The Journal of Clinical
Endocrinology & Metabolism, 100(5), pp.2090-2097.

World Health Organization, 2019. Epilepsy. A public health imperative. World Health
Organization.

Yılmaz, Ü., Yılmaz, T.S., Akıncı, G., Korkmaz, H.A. and Tekgül, H., 2014. The effect
of antiepileptic drugs on thyroid function in children. Seizure, 23(1), pp.29-35.

26
Zhang YX, Shen CH, Lai QL, Fang GL, Ming WJ, Lu RY, Ding MP. Effects of
antiepileptic drug on thyroid hormones in patients with epilepsy: a meta-analysis.
Seizure. 2016 Feb 1;35:72-9.

27
 Part –E

BUDGET

1. Total Budget : Tk. 1, 50, 00000

2. Detailed Budget:

●Personal cost (Professional scientific staff,

Technical and other staff) : Not applicable

●Investigation cost : 70,000/=

●Internet search : 2,000/=

●Office items : 10,000/=

●Travel cost : Not applicable

●Data analysis, processing and compose : Not applicable

●Printing and reproduction : 10,000/=

●Contractual service : Not applicable

● Administrative overhead : Not applicable

● Miscellaneous : 10,000/=

28
Appendix-A
Case record form

Protocol Title: “Thyroid function status in children on antiepileptic drug

monotherapy ”
A Patient identification

1 ID No.:

2 Hospital Registration No.:

3 Name

4 Address

5 Contact no.

6 Date of enrollment

B Demographic information:

1 Age ..years

2 Sex Male=1 Female=2

C Clinical information
1 Duration of epilepsy
2 Age of onset of epilepsy
3 Type of seizure
4 Height/Length
5 Weight
6 Blood pressure

C AED

Drug name Dose Duration

D Laboratory report

29
 fT4

TSH

E Thyroid status Euthyroid =1 Subclinical hypo=2

Hypo=3

Signature of the researcher

30
Appendix – B
Information Sheet
(For the respondents)
Protocol ID:
Title of the research: “Thyroid function status in children with epilepsy on
antiepileptic drug.”
Researcher’s name: Dr. Tumpa Dhar
Institution: Department of Pediatric, Chattogram Medical College Hospital,
Chattogram, Bangladesh.

1. About the research:

I have decided to do a Thesis for MD (Paediatrics) Phase B examination on “ Thyroid
function status in children with epilepsy on antiepileptic drug .” I want to include
your child as a research participant after receiving a written consent from you. I will
explain you in a moment what are the components and your and your patient’s role in
the research.
2. Purpose and nature of the research:
Antiepileptic drugs are the standard treatment for epilepsy. Antiepileptic drugs should
be taken for a prolonged period. In this regard, monitoring the children is required for
any drug related adverse events. Few studies demonstrated that Antiepileptic drugs
could alter thyroid hormone status in children with epilepsy. Nevertheless, the thyroid
hormone levels are not routinely monitored during the treatment with Antiepileptic
drugs.
3. Selection of the participant: As your children is suffering from epilepsy and on
Antiepileptic drug your child is being selected as a subject of the research. However,
only the parents or guardian who will provide written informed consent will be
included.
4. Privacy, anonymity and confidentiality:
Information will be collected at your convenient time and privacy will be strictly
maintained. Collected information will be kept confidential unless permitted by you.
This information will be used only for research purpose. Your child’s personal
information will not be disclosed to anyone.
5. Right to refuse or withdraw:

31
You have all the right to refuse to participate in this research if you do not wish to do
so and refusing to participate will not affect your baby’s treatment in any way. You
may stop participating in this research at any time you wish without showing any reason
and without losing any of your baby’s rights as a patient here.
6. What are the risk/or discomfort in the research?
The research will be observational research. So, there will be no additional physical
risk or discomfort from being in this research.
7. Incentives:
You or your children will not be provided any incentives to take part in the research.
8. Benefits:
Your children will get a free thyroid screening from the participation in the research.
9.The researcher’s responsibility:
I will act only as a researcher and treatment of your children will be carried out by the
respective doctor’s of the hospital.
10. Procedure of research:
If you agree, we will enroll your relative as a research participant and will adopt the
following procedures for your participation-
i. We will take signature/thumb impression from you in the attached consent form
in duplicate and a copy will be returned to you.
ii. We will ask some questions about the patient’s condition and perform a basic
physical examination and fill out a printed are record form.
iii. We will collect blood samples from your patients for laboratory investigations.

If you agree to participate in the research, please sign this form.

Interviewer Withness Guardian of patient

Name: Name: Name:

Signature: Signature: Signature:

Date: Date: Date:

32
 গবেষণা বেষবে তথ্য পত্র
গবেষণার শিবরানাম: "মৃ গী ররাবগ আক্রান্ত শিশু যারা একটি এশিশিবেিটিক ঔষধ িাবে তাবের থাইরব়েড হরবমাবনর অেস্থা শনণণব়ে
গবেষণা ।"
গবেষবকর নামঃ ডাঃ টুম্পা ধর
প্রশতষ্ঠান: শিশু শেভাগ, চট্টগ্রাম রমশডবকে কবেজ হাসিাতাে, চট্টগ্রাম, োাংোবেি।

1. গবেষণা সম্পবকণ :
আশম "মৃ গী ররাবগ আক্রান্ত শিশু যারা একটি এশিশিবেিটিক ঔষধ িাবে তাবের থাইরব়েড হরবমাবনর অেস্থা শনণণব়ে গবেষণা" শেষব়ে
এমশড (রিশড়োট্রিক্স) রেজ শে িরীক্ষার জনয একটি শথশসস করার শসদ্ধান্ত শনব়েশি। আিনার কাি রথবক শেশিত সম্মশত িাও়োর ির
আশম আিনার সন্তানবক একজন গবেষণা়ে অাংিগ্রহণকারী শহবসবে অন্তভুণক্ত করবত চাই। আশম আিনাবক শকিু ক্ষবণর মবধয েযািযা
করে উিাোনগুশে কী এোং গবেষণা়ে আিনার এোং আিনার ররাগীর ভূশমকা কী।
2. গবেষণার উবেিয এোং প্রকৃশত:
অযাশিশিবেিটিক ওষু ধ হে মৃ গীবরাবগর জনয আেিণ শচশকৎসা। অযাশিশিবেিটিক ওষু ধগুশে েীর্ণ সমব়ের জনয গ্রহণ করা উশচত। এই
শেষব়ে, ঔষধ সম্পশকণ ত রয রকানও প্রশতকূে র্টনার জনয শিশুবের িযণবেক্ষণ করা প্রব়োজন। শকিু গবেষণা়ে রেিা রগবি রয
অযাশিশিবেিটিক ওষু ধ মৃ গী ররাবগ আক্রান্ত শিশুবের থাইরব়েড হরবমাবনর অেস্থা িশরেতণ ন করবত িাবর। তা সবেও, থাইরব়েড
হরবমাবনর মাত্রা শন়েশমতভাবে অযাশিশিবেিটিক ওষুধ শেব়ে শচশকত্সার সম়ে িযণবেক্ষণ করা হ়ে না।
3. অাংিগ্রহণকারী শনেণাচন: রযবহতু আিনার শিশু মৃ গীবরাবগ ভুগবি এোং অযাশিশিবেিটিক-ড্রাগ গ্রহণ করবি , তাই আিনার
সন্তানবক গবেষণার অাংিগ্রহণকারী শহবসবে রেবি রনও়ো হবে। যাইবহাক, শুধু মাত্র শিতামাতা ো অশভভােক যারা শেশিত অেশহত
সম্মশত প্রোন করবেন তাবের অন্তভুণক্ত করা হবে।
4. রগািনী়েতা, রেনামী এোং রগািনী়েতা:
আিনার সু শেধাজনক সমব়ে তথয সাংগ্রহ করা হবে এোং রগািনী়েতা কব ারভাবে েজা়ে রািা হবে। আিনার অনু মশত না থাকবে
সাংগৃ হীত তথয রগািন রািা হবে। এই তথয শুধু মাত্র গবেষণা উবেবিয েযেহার করা হবে. আিনার সন্তাবনর েযশক্তগত তথয কাবরা
কাবি প্রকাি করা হবে না।
5. প্রতযািযান ো প্রতযাহার করার অশধকার:
আিশন যশে এটি করবত না চান তবে এই গবেষণা়ে অাংিগ্রহণ করবত অস্বীকার করার সমস্ত অশধকার আিনার আবি, এোং অাংিগ্রহণ
করবত অস্বীকার করা আিনার শিশুর শচশকৎসাবক রকাবনাভাবেই প্রভাশেত করবে না। আিশন রকাবনা কারণ না রেশিব়ে এোং এিাবন
ররাগী শহবসবে আিনার শিশুর রকাবনা অশধকার হারাবনা িাডাই আিশন রয রকাবনা সমব়ে এই গবেষণা়ে অাংিগ্রহণ করা েন্ধ করবত
িাবরন।
6. গবেষণা়ে ঝুুঁ শক/ো অস্বশস্ত শক?
গবেষণাটি একটি িযণবেক্ষণমূ েক গবেষণা হবে। সু তরাাং, এই গবেষণা়ে থাকা রথবক রকানও অশতশরক্ত িারীশরক ঝুুঁ শক ো অস্বশস্ত হবে
না।
7. প্রবণােনা:
গবেষণা়ে অাংি শনবত আিনাবক ো আিনার সন্তানবের রকাবনা প্রবণােনা রেও়ো হবে না।
8. সু শেধা:

33
গবেষণা়ে অাংিগ্রহণ রথবক আিনার শিশুরা শেনামূ বেয থাইরব়েড স্ক্রীশনাং িাবে।
9. গবেষবকর োশ়েত্ব:
আশম শুধু মাত্র একজন গবেষক শহবসবে কাজ করে এোং আিনার সন্তানবের শচশকৎসা সাংশিষ্ট হাসিাতাবের শচশকৎসবকর দ্বারা
িশরচাশেত হবে।
10. গবেষণার িদ্ধশত:
আিশন যশে সম্মত হন, আমরা আিনার আত্মী়েবক একজন গবেষণা অাংিগ্রহণকারী শহসাবে নশথভুক্ত করে এোং আিনার অাংিগ্রহবণর
জনয শনম্নশেশিত িদ্ধশতগুশে গ্রহণ করে-
i. আমরা ডু শিবকট সাংযুক্ত সম্মশত েবমণ আিনার কাি রথবক স্বাক্ষর/আঙু বের িাি রনে এোং একটি অনু শেশি আিনাবক রেরত
রেও়ো হবে।
ii. আমরা ররাগীর অেস্থা সম্পবকণ শকিু প্রশ্ন শজজ্ঞাসা করে এোং একটি প্রাথশমক িারীশরক িরীক্ষা করে এোং একটি মু শিত ররকডণ েমণ
িূ রণ করে।
iii. েযােবরটশর তেবন্তর জনয আমরা আিনার ররাগীবের রথবক রবক্তর নমু না সাংগ্রহ করে।

আিশন যশে গবেষণা়ে অাংি শনবত সম্মত হন, অনু গ্রহ কবর এই েমণটিবত স্বাক্ষর করুন।

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bvgt
bvgt bvgt
¯^v¶it
¯^v¶it ¯^v¶it
ZvwiLt
ZvwiLt ZvwiLt

34