RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

Synopsis of Dissertation

IRON DEFICIENCY ANAEMIA AS A RISK FACTOR FOR FIRST FEBRILE SEIZURE

Submitted by:

Dr. RAHUL MAJUMDAR, MBBS

Post Graduate Student in Paediatrics

Department of Paediatrics Adichunchanagiri Institute of Medical Sciences, B.G. Nagara, Nagamangala Taluk, Mandya District -571 448.

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION Dr. RAHUL MAJUMDAR

P.G.IN PAEDIATRICS, 1. NAME OF THE CANDIDATE AND ADDRESS DEPARTMENT OF PAEDIATRICS, (IN BLOCK LETTERS) A.I.M.S, B.G.NAGARA, NAGAMANGALA TALUK, MANDYA DISTRICT-571 448.

ADICHUNCHANAGIRI INSTITUTE OF 2. NAME OF THE INSTITUTION MEDICAL SCIENCES, B.G.NAGARA.

3. COURSE OF STUDY AND SUBJECT M.D IN PAEDIATRICS

4. DATE OF ADDMISSION TO COURSE 02-05-2009

“IRON DEFICIENCY ANAEMIA AS A RISK 5. TITLE OF THE DISSERTATION FACTOR FOR FIRST FEBRILE SEIZURE”

BRIEF RESUME OF INTENDED WORK APPENDIX-I

6.1 NEED FOR THE STUDY APPENDIX-IA 6. 6.2 REVIEW OF LITERATURE APPENDIX-IB

6.3 OBJECTIVES OF THE STUDY APPENDIX-IC

MATERIALS AND METHODS APPENDIX-II

7.1 SOURCE OF DATA APPENDIX-IIA

7.2 METHOD OF COLLECTION OF DATA: APPENDIX-IIB (INCLUDING SAMPLING PROCEDURE IF ANY)

7. 7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER YES ANIMALS, IF SO PLEASE DESCRIBE BRIEFLY. APPENDIX-IIC

7.4 HAS ETHICAL CLEARENCE BEEN OBTAINED YES FROM YOUR INSTITUTION IN CASE OF 7.3 APPENDIX-IID

8. LIST OF REFERENCES APPENDIX-III

SIGNATURE OF THE CANDIDATE 9. Since Febrile convulsion is a common clinical condition in paediatric age group, the risk factors associated with it needs to be REMARKS OF THE GUIDE 10. evaluated. The study will help to identify if Iron Deficiency Anemia, a treatable condition is a risk factor for febrile convulsion.

Dr. VENKATAMURTHY M, MBBS, MD PROFESSOR AND H.O.D, 11.1 NAME AND DESIGNATION OF GUIDE DEPARTMENT OF PAEDIATRICS, (IN BLOCK LETTERS) ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA.

11.2 SIGNATURE

NO 11.3 CO-GUIDE (IF ANY)

11.

11.4 SIGNATURE

Dr. VENKATAMURTHY M, MBBS, MD PROFESSOR AND H.O.D, DEPARTMENT OF PAEDIATRICS, 11.5 HEAD OF THE DEPARTMENT ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES, B.G.NAGARA.

11.6 SIGNATURE

12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL 12.

12.2 SIGNATURE APPENDIX-I

6. BRIEF RESUME OF THE INTENDED WORK:

APPENDIX-IA

6.1 NEED FOR THE STUDY

Febrile seizures are the most common seizure disorder during childhood. Febrile seizures are age dependent and are rare before 9 months and after 5 years of age. The peak onset being 14-18 months of age and the incidence approaches 3-4% of young children. Febrile seizures are frequently genetically determined. A strong family history of febrile convulsions in siblings and parents suggests genetic predisposition .1

Owing to their association with epilepsy in future, various studies have attempted to identify the risk factor associated with them viz, family history of febrile seizures, epilepsy, perinatal factors, temperature peak, maternal smoking and alcohol consumption during pregnancy, but risk factors remains largely unknown.2,3

Convulsions due to neurological damage may also be precipitated by fever as the cerebral threshold for seizures is reduced with the elevation of temperature. These are distinct from febrile convulsions which occur in a neurodevelopmentally normal child.4

Febrile seizures occur in young children at a time in their development when the seizure threshold is low. This is a time when young children are susceptible to frequent childhood infections such as upper respiratory infection, otitis media, viral syndrome, and they respond with comparably higher temperatures. Animal studies suggest a possible role of endogenous pyrogens, such as interleukin 1, that, by increasing neuronal excitability, may link fever and seizure activity. Preliminary studies in children appear to support the hypothesis that the cytokine network is activated and may have a role in the pathogenesis of febrile seizures, but the precise clinical and pathological significance of these observations is not yet clear.5,6

Genetics: Febrile convulsions tend to occur in families, although the exact mode of inheritance is not known and varies between families. Febrile convulsion susceptibility trait is inherited by autosomal dominant pattern with reduced penetrance.7

The risk of another child having febrile convulsions is one in five with one affected sibling and one in three if both parents and a previous child had febrile convulsions. The seizure incidence in offspring of individuals with a history of febrile convulsion was 10%.8 APPENDIX –IB

6.2 REVIEW OF LITERATURE:

A simple febrile convulsion is usually associated with core temperature that increases rapidly to 100.2 degree Fahrenheit. The direct cause of a febrile seizure is not known; however, it is normally precipitated by a recent upper respiratory infection or gastroenteritis. It is initially generalized and tonic clonic in nature lasts a few seconds and rarely upto 15 minutes, followed by brief post ictal period of drowsiness, and occur only once in 24hrs.1

Essential criteria for diagnosing typical/simple/ benign febrile convulsions 4  Fits occur within 24 hrs of onset of fever  Fits lasts less than 10 minutes and are usually single per febrile episodes.  Convulsions are generalized; 4-18 % may show focal convulsions.  No post ictal or neurological deficits  Family history of febrile convulsions in the siblings.

Essential criteria for diagnosing atypical/ complex partial seizures

 Age, neurological status before the illness, and fever are the same as for simple febrile seizure  This seizure is either focal or prolonged ( >15 min), or multiple seizures occur in close succession

Approximately 30-50% children have recurrent seizures with later episodes of fever and a small minority has numerous recurrent febrile seizures1

Factors associated with increased recurrence risk include-

 Age <12 months  Lower temperature before seizure onset,  Positive family history of febrile seizures & complex features. Factors associated with greater risk of later epilepsy include-

 Presence of complex feature during the seizure or post ictal period  Positive family history of epilepsy  Initial febrile seizure before 12 months of age  Delayed developmental milestones  Pre-existing neurological disorders

An Electroencephalogram and neuroimaging studies are not warranted after a simple febrile seizure but is useful for evaluating patients with complex or atypical features or with other risk factors for later epilepsy.1

Iron is involved in the metabolism of several neurotransmitters, and monoamine and aldehyde oxidase are reduced in iron deficiency anemia, which is a common cause during second and third year of life and has been associated with behavioral and development disturbances.9,10

Lower levels of plasma ferritin in patients with febrile seizures may suggest a role for iron insufficiency in febrile seizure disorders11 which have been concluded in several studies as done below:

In a study by Hartfield et al., children with febrile seizures were almost twice as likely to be iron deficient as those with febrile illness alone suggesting that screening for iron deficiency should be considered in children presenting with febrile seizures.12

Naveen-ur-Rehman et al., reported that plasma ferritin level was significantly lower in cases as compared to control suggesting that iron deficient children are more prone to febrile seizures.13

Daoud AS et al., stated that Plasma ferritin level was significantly lower in children with first febrile seizures than in reference group, suggesting a possible role for iron insufficiency in febrile seizures.11

Rajwanth K Vaswani et al., found the mean serum ferritin level was significantly low in cases (31.9 +/- 31.0) as compared to controls (53.9 +/- 56.5) with P value= 0.003 Iron deficiency could be a potential risk factor for febrile seizure in children.14

Pisacane et al., stated that fever can worsen the negative effect of anemia or of iron deficiency on the brain and a seizure can occur as a consequence, alternatively anemia can be associated with severity of febrile illness, and more severe cases could be more likely to get seizures.15

Parks Y A et al., found that levels of neurotransmitters and mitochondrial enzymes essential for behavioral and psychomotor development are all altered during iron deficiency.9

Kobrinsky et al., reported that iron deficiency raises the threshold for seizures.16 APPENDIX-IC

6.3 OBJECTIVES OF THE STUDY

Estimation of Iron status in children with first febrile convulsion.

Iron status will be evaluated by including the following parameters:

Hemoglobin Serum ferritin MCV MCH APPENDIX-II

7. MATERIALS AND METHODS:

APPENDIX-II A:

7.1 SOURCE OF DATA

The study will be a case control prospective study conducted on all children with first febrile seizures and febrile illnesses in Pediatrics Intensive Care Unit and Pediatrics Wards of Sri Adichunchanagiri Institute of Medical Sciences, B.G.Nagara from January 2010 to June 2011

APPENDIX-II B

7.2 METHOD OF COLLECTION OF DATA

The study will include two groups:

The case group: It will include 50 consecutive children admitted in pediatrics ward fulfilling the following:

Inclusion criteria:

 Aged between 6 months to 6 years

First febrile seizures( Febrile seizures being defined as a seizure occurring in association with a febrile illness, in the absence of CNS infection or any other defined cause of seizures)

Exclusion criteria:

 Children with previous febrile seizures

 Neurological infections

 Developmental delay

 Children on Iron therapy The control group:

It will include 50 children aged 6 months to 6 years who get admitted with febrile illness without febrile seizures.

All children included in the study will have the following done:

Demographic data, seizure details, nature of febrile illness, family history of epilepsy/ febrile seizures, temperature at admission and nutrition status will be recorded and protein energy malnutrition will be graded as per the IAP classification.

Estimation of haemoglobin, red blood cell indices and serum ferritin will be done.

Iron deficiency anemia will be defined as haemoglobin < 11g/dl, MCV <70 fl, MCH <27 pg and serum ferritin <12microgram/dl(6).

APPENDIX-II C

7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER ANIMALS; IF SO PLEASE DESCRIBE BRIEFLY.

YES.

The children included in the study (both cases and controls) will have the following investigations done:

 Hemoglobin  Mean corpuscular Volume  Mean Corpuscular Hemoglobin  Serum ferritin

Hemoglobin, Mean Corpuscular volume and Mean Corpuscular Hemoglobin will be estimated by Semi Automatic Analyser Machine of Sysmex KX-21 model and Serum Ferritin will be estimated by CLIA ELISA method using Lilac Automatic Analyser Machine.

Other relevant investigations as required for the management of the case will be carried out (Lumbar puncture/ Imaging studies).

APPENDIX-II D

7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3?

YES. APPENDIX-III

LIST OF REFERENCES

1) Johnston MV. Seizures in childhood: Febrile seizures. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson’s Textbook of Pediatrics. 17thed. Pennsylvania: Saunders; 2004. p. 1994-1995.

2) Nelson KB, Ellenberg JH. Prenatal and perinatal antecedents of febrile seizures. Ann Neurol 1990;27:127-31.

3) Cassano PA, Koepsell TD, Farwell JR. Risk of febrile seizures in childhood in relation to prenatal maternal cigarette smoking and alcohol intake. Am J Epidemiol 1990;132:462-73

4) Veena Kalra. Febrile Convulsions.. In: Ghai OP, Gupta P, Paul VK, editors. Ghai Essential Pediatrics. 7th ed. New Delhi: CBS Publishers & Distributors; 2004.p. 528.

5) Gatti S, Vezzani A, Bartfai T. Mechanisms of fever and febrile seizures: putative role of the interleukin-1 system. In: Baram TZ, Shinnar S eds. Febrile Seizures. San Diego, Ca: Academic Press; 2002:169-88.

6) Haspolat S, Mihci E, Coskun M, et al. Interleukin-1beta, tumor necrosis factor- alpha, and nitrite levels in febrile seizures. J Child Neurol. Oct 2002;17(10):749

7) Iwasaki N, Nakayama J, Hamano K, Matsui A, Arinami T. Molecular genetics of febrile convulsion. Epilepsia 2002; 43 Suppl 9: 32-35.

8) Doose H, Maurer A. Seizure risk in offspring of individuals with a history of febrile convulsion. Eur J Pediatr 1997; 156: 476-481

9) Parks YA, Wharton BA. Iron deficiency and the brain. Acta Paediatr Scand 1989;55(suppl 361):71-7.

10)Walter T, De Andraca I, Chadud P, Perales CG. Iron deficiency anemia: adverse effects on infant psychomotor development. Pediatrics 1989;84:7-17.

11)Daoud AS, Batieha A, Abu Etiesh F, Gharaibeh N, Ajlouni S, Hijazi S. Iron status : a possible risk factor for first febrile seizure. Epilepsia 2002; 43: 740-743.

12) Hartfield DS, Tan J, Yager JY, Rosychuk RJ, Spady D, Haines C, Craig WR. The association between iron deficiency and febrile seizures in childhood. Clinical pediatrics vol 48;2009 420-426 13)Naveed-ur-Rehman, Billoo AG. Association between iron deficiency anemia and febrile seizures.J Coll Physicians Surg Pak 2005; Jan (6) 338-40

14)Rajwanti K Vaswani, Praveen G Dharaskar, Swati Kulkarni, K Ghosh. Iron deficiency as the first risk factor for febrile convulsion: Case control study in children between 6 months to 6 years. Indian pediatrics e-pub

15) Pisacane A, Sansone R, Impagliazzo N, Coppola A,Rolando P, D’Apuzzo A, et al. Iron deficiency anemia and febrile convulsion: Case control study in children under 2 years. BMJ 1996; 313: 343.

16) Kobrinsky NL, Yager JY, Cheang MS, Yatscoff RW, Tenenbein M. Does iron deficiency raise the seizure threshold? J Child Neurol 1995; 10: 105-109.

17) De Gruchy GC. Clinical Hematology in Medical Practice, 5th ed. Victoria: Blackwell Science Ltd; 2004.

. APPENDIX-IID

PROFORMA APPLICATION FOR ETHICS COMMITTEE APPROVAL

SECTION A

“IRON DEFICIENCY ANAEMIA AS A RISK A. Title of the study FACTOR FOR FIRST FEBRILE SEIZURE”

Dr. RAHUL MAJUMDAR P.G.IN PAEDIATRICS, Principal investigator DEPARTMENT OF PAEDIATRICS, B. (Name and Designation) A.I.M.S, B.G.NAGARA, NAGAMANGALA TALUK, MANDYA DISTRICT-571 448.

Co-investigator C. (Name and Designation) NIL

Name of the collaborator D. NA Department / institute

Whether permission has been obtained E. from the head of the collaborating NA department and institution SECTION-B APPENDIX-II Summary of the project

SECTION-C APPENDIX-IC Objective of the study

SECTION –D APPENDIX-IIB Methodology SRI ADICHUNCHANAGIRI HOSPITAL Where the proposed study will be A. AND RESEARCH CENTRE, Undertaken B.G.NAGARA.

B. Duration of the project 18 MONTHS Nature of the subject : Does the study involve adult patients? NO Does the study involve children? YES C. Does the study involve normal volunteers? NO Does the study involves psychiatric NO Patients? Does the study involve pregnant women? NO

If the study involves healthy volunteers NA 1. Will they be institute students? NO D. 2. Will they be institute employees? NO 3. Will they be paid? NA 4. If they are to be paid, how much per person? NA

E. Is the study multi central trial? NO

If yes, who is the coordinator? NA (name and designation) NA Has the trial been approved by the ethical committee of other centers? NA If the study involves the usage of drugs: Please indicate whether,

1. the drug is marketed in India for the indication NA in which it will be used in the study.

2. the drug is marketed in India but not NA for the indication in which it will be used in the F. study. NA 3. the drug is only used for experimental use in humans. NA 4.clearance of the drug controller of India has been obtained for : NA -Use of the drug in the healthy volunteers

-Use of drug in-patients for a new indication. NA -phase one and two clinical trials.

-experimental use in-patients and healthy NA volunteers. How do you propose to obtain the drug to be used in the study? NA -Gift from a drug company G. -hospital supplies -patients will be asked to purchase -other sources (Explain) Funding (if any) for the project. Please state. -None H. -Amount NONE -Source -To whom payable

Does any agency have a vested interest in I. NO the outcome of the project?

Will data relating to subjects/controls be J. YES stored in a computer? Will the data analysis be done by

-The researcher? YES K. -The funding agency NO

Will technical / nursing help be required for the staff of hospital, if yes, NO

Will it interfere with their duties? NO

Will you recruit other staff for the duration of the NO L. study? If yes give details of I Designation NA II Qualification NA III Number NA IV Duration of employment NA Will informed consent be taken? YES If yes, Will it be written informed consent? YES M. Will it be oral consent? YES Will it be taken from the subjects themselves? NO Will it be from the legal guardian? YES If no, give reason: NA

Describe design, Methodology and N. APPENDIX-II Techniques

Ethical clearance has been accorded.

Date: Place: B.G. NAGARA

Chairman PG Training-cum research committee A.I.M.S., B.G.Nagara.