2008; 10(3) : 191

INDIAN JOURNAL OF IJPP PRACTICAL PEDIATRICS • IJPP is a quarterly subscription journal of the Indian Academy of Pediatrics committed to presenting practical pediatric issues and management updates in a simple and clear manner • Indexed in Excerpta Medica, CABI Publishing. Vol.10 No.3 JULY.-SEP.2008 Dr. K.Nedunchelian Dr. S. Thangavelu Editor-in-Chief Executive Editor

CONTENTS FROM THE EDITOR'S DESK 193 TOPICS FROM “IAP-IJPP CME 2008” Intractable epilepsies in children 196 - Kumaresan G Constipation in Children 201 - Bhaskar Raju B, Sumathi B How do I manage atopic dermatitis? 208 - Jayakar Thomas Surfactant therapy 213 - Lakshmi V Approach to neonatal sepsis 221 - Karthikeyan G Allergic rhinitis 227 - Shivbalan So, Gowrishankar NC Long term control of childhood asthma 235 - Balachandran A Urinary tract infection - When and how to evaluate? 242 - Vijayakumar M, Prahlad N

Journal Office and address for communications: Dr. K.Nedunchelian, Editor-in-Chief, Indian Journal of Practical Pediatrics, 1A, Block II, Krsna Apartments, 50, Halls Road, Egmore, Chennai - 600 008. Tamil Nadu, India. Tel.No. : 044-28190032 E.mail : [email protected]

1 Indian Journal of Practical Pediatrics 2008; 10(3) : 192

Antimicrobials in acute encephalitis 250 - Vishwanathan V GENERAL ARTICLES Cyclic vomiting syndrome 254 - Neelam Mohan Genetic counseling for preventable disorders 263 - Madhulika Kabra RADIOLOGIST TALKS TO YOU Intracranial hemorrhage and hypoxic ischemic encephalopathy in the neonate 279 - Vijayalakshmi G, Elavarasu E, Vijayalakshmi M, Venkatesan MD

PICTURE QUIZ 283 DERMATOLOGY Alopecia areata in children 284 - Madhu.R

BOOK REVIEW 220

NEWS AND NOTES 207,212,226,234,241,262,282,288

FOR YOUR KIND ATTENTION * The views expressed by the authors do not necessarily reflect those of the sponsor or publisher. Although every care has been taken to ensure technical accuracy, no responsibility is accepted for errors or omissions. * The claims of the manufacturers and efficacy of the products advertised in the journal are the responsibility of the advertiser. The journal does not own any responsibility for the guarantee of the products advertised. * Part or whole of the material published in this issue may be reproduced with the note "Acknowledgement" to "Indian Journal of Practical Pediatrics" without prior permission. - Editorial Board

Published on behalf of the Indian Academy of Pediatrics by Dr.K.Nedunchelian, Editor-in-Chief, Indian Journal of Practical Pediatrics from 1A, Block II, Krsna Apartments, 50, Halls Road, Egmore, Chennai - 600 008. Tamil Nadu, India and printed by Mr. D. Ramanathan, at Alamu Printing Works, 9, Iyyah Street, Royapettah, Chennai - 600 014.

2 2008; 10(3) : 193

FROM THE EDITOR’S DESK

In this issue we have included few topics revolutionalised the management of this covered in the “IAP - IJPP CME 2008” organised condition, especially the long term managment by “Indian Academy of Pediatrics” and “Indian and an article in this issue deals with this aspect. Journal of Practical Pediatrics”, conducted at Certain proportion of epilepsies even with regular Chennai on 15th June 2008. It was uniformly felt compliance of antiepileptic drugs become that topics covered were practical and most intractable. Intractable epilepsy is a nightmare useful in the present context. With the request to both parents and pediatrician or neurologist. for the proceedings of CME from all over the An article on “intractable epilepsies in children” country, this issue is dedicated to bring out some covers modalities of treatment for the same. of the articles from CME for the benefit of our Urinary tract infection is a condition, once readers. diagnosed, has to be evaluated thoroughly for underlying urological abnormalities. If under The static infant mortality rate (IMR) in our treated, urinary tract infection in young children country for the past few decades is contributed can lead on to end stage renal disease. mostly by the persistently high neonatal mortality. Among the neonatal morbidity, birth weight and Atopic dermatitis runs a protracted course gestational age related complications including with its associated significant morbidity.The immature lungs contribute to increased mortality clinical presentation and its management are in these groups. Surfactant therapy seems to be covered in the article “Atopic dermatitis in a promising solution to this problem. Description children”. Acute encephalitis is dreaded for its on surfactant, preparations available, indications, morbidity in the form of sequelae and high etc are given in the article “Surfactant therapy”. mortality. Mainstay of treatment is supportive Sepsis is one of the common causes of neonatal with antiedema measures and in a few conditions morbitity and mortality. “Approach to manage- antimicrobials have definite role, which are ment of neonatal sepsis” is also covered in this discussed in the article on “Antimicrobials in issue. encephalitis”. Apart from articles selected from “IAP-IJPP Constipation in children would lead to CME 2008”, there are two more interesting significant discomfort physical as well as articles, “Cyclic vomiting syndrome” and psychological, to the child and mental stress to “Genetic counseling”. These are important topics the parents. Conditions leading to constipation because the practicing pediatrician should know and management are brought out very well in the how to manage and when to refer for expert article “Constipation in children”. opinion. This prompted us to cover these two Rhinitis is the another condition, which if conditions. Under “Radiologist talks to you” persists or recurs causes significant morbidity. column “Radiological evaluation of intracranial Allergy as a cause of rhintis is most often not hemorrhage and HIE in the neonate” is covered appreciated by pediatrician. When to suspect this and “Alopecia areata” is included under and how to approach and manage this condition Dermatology Series, which deals with various are narrated in the article “Allergic rhinitis”. types and management strategies of the condition. Increasing awareness about “asthma”, better Dr. K.Nedunchelian, understanding of its pathogenesis, etc have Editor-in-Chief. 3 Indian Journal of Practical Pediatrics 2008; 10(3) : 194

INSTRUCTIONS TO AUTHORS General Print the manuscript on one side of standard size A4, white bond paper, with margins of at least 2.5 cm (1”) in double space typescript on each side. Use American English using Times New Roman font 12 size. Submit four complete sets of the manuscript. They are considered for publication on the understanding that they are contributed to this journal solely. All pages are numbered at the top of the right corner, beginning with the title page. All manuscripts should be sent to: The Editor-in-Chief, Indian Journal of Practical Pediatrics Manuscript 1st Page – Title Name of the author and affiliation Institution Address for correspondence (Email, Phone, Fax if any) Word count No. of figures (colour / black and white) No. of references Authors contribution 2nd Page – Abstract (unstructured, not exceeding 100 words) with key words (not exceeding 4) 3rd Page - Acknowledgement Points to remember (not more than 5 points) Text References Tables Figures – should be good quality, 4 copies black & white / colour, (4 x 6 inches – Maxi size) Glossy print. (Each colour image will be charged Rs.1,000/- separately) Legends Text Only generic names should be used Measurements must be in metric units with System International (SI) Equivalents given in parentheses. References Recent and relevant references only Strictly adhere to Vancouver style Should be identified in the text by Arabic numerals in parentheses. Type double-space on separate sheets and number consecutively as they appear in the text. Defective references will entail rejection of article Tables Numbered with Roman numerals and typed on separate sheets. Title should be centered above the table and explanatory notes below the table. Figures and legends Unmounted and with figure number, first author’s name and top location indicated on the back of each figure. Legends typed double-space on separate sheet. No title on figure.

4 2008; 10(3) : 195 Article Categories Review article Article should be informative covering the recent and practical aspects in that field. Main articles can be in 1500 – 2000 words with 12 – 15 recent references and abstract not exceeding 100 words. Case report (covering practical importance) 250 – 600 words, 8 – 10 recent references Clinical spotters section 100 – 150 words write up With 1 or 2 images of clinically recognizable condition (of which one could be in the form of clinical photograph / specimen photograph / investigation) Letters to the Editor 200 – 250 words pertaining to the articles published in the journal or practical viewpoints with scientific backing and appropriate references in Vancouver style. Selection procedures All articles including invited articles will be peer reviewed by two masked reviewers. The decision of the Editorial Board based on the reviewers’ comments is final. Check List Covering letter by corresponding author Declaration (as enclosed) signed by all authors ** Manuscript (4 copies) Accompanied by a copy in CD / or submit as an email attachment in addition to hard copy. Failing to comply with the requirement at the time of submission would lead to the rejection of the article. Author’s contribution / Authorship Criteria All persons designated as authors should qualify for the authorship. Authorship credit should be based on substantial contributions to i) concept and design, or collection of data, and interpretation of data; ii) drafting the article or revising it critically for important intellectual content; and iii) final approval of the version to be published. All conditions i), ii) and iii) must be met. **Declaration by authors I/We certify that the manuscript titled ‘……………………………….’ represents valid work and that neither this manuscript nor one with substantially similar content under my/our authorship has been published or is being considered for publication elsewhere. The author(s) undersigned hereby transfer(s), assign(s), or otherwise convey(s) all copyright ownership, including any and all rights incidental thereto, exclusively to the Indian Journal of Practical Pediatrics, in the event that such work is published in Indian Journal of Practical Pediatrics. I / we assume full responsibility for any infringement of copyright or plagiarism. Authors’ name(s) in order of appearance in the manuscript

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All manuscripts, which are rejected will not be returned to author. Those submitting articles should therefore ensure that they retain at least one copy and the illustrations, if any.

5 Indian Journal of Practical Pediatrics 2008; 10(3) : 196

IAP-IJPP CME 2008

INTRACTABLE EPILEPSIES IN (checked by drug assay) for atleast six months CHILDREN for each drug. The earlier definition of minimum of two years of drug trial is not acceptable as in * Kumaresan G catastrophic seizures where denying the benefits of early surgical therapy leads to loss of valuable Abstract : Despite effective newer drugs and time with permanent impact on quality of life. other treatment modalities, 20 - 25% epilepsies With many drugs now available no clear cut remain intractable. It is essential that real guidelines are established for order of selection intractability should be established. Treatment of drugs options available are anti epileptic drugs, surgery, ketogenic diet and vagal nerve Social disability: This will vary with patient’s stimulation. The indications and advantages of life style. While occasional mild complex partial each of these modalities are discussed. seizures is acceptable to a person doing routine Keywords : Intractable epilepsy, Drugs, Surgery, semiskilled job, even a brief absence attack will Non pharmacological methods. be unacceptable to a person appearing frequently in media. Hence the definition of social disability Refractory epilepsies,difficult to treat is individualised. epilepsies or intractable epilepsies refer to our inability to control seizures effectively.With the Subjective handicap : Refers to how much the introduction of sodium valproate in 1993 there seizures interfere with the person’s quality of was a hope that an ideal anti-convulsant has been life.This is particularly important in children as discovered. However despite the introduction of early control of seizures will give them better more than ten new drugs, the problem of opportunities for good education,social life and intractability exists. 20-25% of epilepsies remain employment. intractable, not responding to standard drugs with significant impairment in quality of life and The evaluation of intractable epilepsy begins unacceptable side effects of drugs and risks with a comprehensive re-evaluation of diagnosis associated with every episode of seizure. and past medical history. The diagnosis of epilepsy has to be clearly established, as many The definition of intractable epilepsy is not non-epileptic conditions may masquarade as clearly established.The three important intractable epilepsy (as high as 20% in many components include medical intractability, epileptic clinics). The drugs tried earlier have to subjective handicap and social disability. be checked as to their appropriateness to the type Medical intractability: Is defined as failure to of epilepsy or syndrome, the dose, the duration, respond to two primary drugs in correct dosage and possibilities of drug interactions due to wrong combinations.The possibilities of precipitating * Former Professor of Pediatric Neurology, Institute of Child Health and Hospital for factors including psycho-social factors Children, Egmore, Chennai - 8. contributing to intractability has to be excluded.

6 2008; 10(3) : 197 If these factors are present then the condition is given with valproate the starting dose will be recognised as pseudo-intractability. 0.15 to 0.6mg/kg/day and over two weeks increased to1-5mg/kg/day. If given alone the Once real intractability is establised the dose will be 0.6mg/kg/day to start with, followed options available include by 1-2mg/kg/day to 5-15 mg/kg/day. When 1. New anti–epileptic drugs introduced it was claimed as the ideal drug for 2. Epileptic surgery women inview of least toratogenicity but the dose 3. Vagal nerve stimulation needs to be monitored during pregnancy and 4. Ketogenic diet lactation. 5. Other non-pharmacological methods. Zonisamide: This drug has action against generalised seizures, focal seizures and epileptic New drugs encephalopathies. However side effect profile Since 1990 there has been a vigorous includes anhydrosis, Stevens-Johnson syndrome, research for a new ideal anti-epileptic drug and nephrolithiasis and effects on cognition. Dose in the last 10 years more than 10 new drugs have starts from 1-2mg/kg/day and increased upto been introduced. Of these, four drugs have been 4-8mg/kg/day. found to have broad spectrum action, effective Other new drugs, but with narrow spectrum against many types of seizures. This includes include ox-carbazepine, tigabin, felbamate, levitiracetam, topiramate, lamotrigene and sulthiam, vigabatrin and gabapentine. zonisamide. Ox-Carbazepine is the first among new drugs Levitiracetam: This drug is very close to ideal to be approved as first choice drug for focal antiepileptic drug.It is highly effective against seizures and approved by FDA for use in many types of seizures,with less adverse effects children. However it does not have a high profile and has no drug interaction.It can be titrated in combination therapy due to drug interaction. rapidly and needs no monitoring of laboratory It has less incidence of skin reactions compared tests.The dose is 5-10mg/kg/day up to a to its pro drug carbamazepine. maximum of 60mg/kg/day. Sulthiam is reemerging as a drug of choice for Topiramate: This drug is highly effective benign childhood focal seizures. Its mode of against many types of seizures including various action is similar to acetazolamide and its side childhood epileptic encephalopathies. But it has effects are hence similar to acetazolamide- a long list of side effects including effects on paresthesia, acidosis and hyperventilation. cognition and behaviour which restricts its use to intractable epilepsies not responding to other Felbamate was withdrawn soon after drugs.The dose is 0.5mg/kg/day to 5-9mg/kg/day. introduction due to occurence of aplastic anemia and liver toxicity. Its present use is cautiously Lamotrigine: This drug has broad spectrum of limited to severe cases of Lennox-Gastaut action in all types except myoclonic syndrome and should be withdrawn after two seizures.However it needs slow titration needing months if there is no response. a long time to build effective dose.It can cause serious skin lesions like Stevens-Johnson Vigabatrine is another drug with limited use due syndrome especially when started on high to unfavourable side effects profile. It causes doses.There is significant drug interaction with visual field defects which may be difficult to sodium valproate and carbamazepine. When recognise in mentally retarded children.Its use is 7 Indian Journal of Practical Pediatrics 2008; 10(3) : 198 restricted to infantile spasms and intractable focal it is found to be useful and safe in children.The seizures not responding to other drugs. early resort to surgery is indicated in catostrophic epilepsies to achieve early seizure control and Tigabine has a narrow spectrum against improve quality of life and prevent aggravation intractable focal seizures and spasms of epileptic of epilepsy through secondary epileptogenesis encephalopathies. It may aggravate absence or the extension of epileptogenic areas. seizures. The evaluation of a child for epileptic Gabapentine and pregabaline were found to surgery is done in stages. The first step is a be useful in focal seizures but are not promising comprehensive review of diagnosis and past and are used more often for relief of neuropathic therapy to exclude pseudo-refractoriness as pain. suitable modifications of these can lead to control Other drugs awaiting completion of clinical trials of seizures and surgery will not be needed. The include ganaxolone and caraberset in second step will be to evaluate for congruence phase 3 and valroceramide and telampanel in of data from various tests to see whether there is phase 2 trial stage. clinico-electrical correlation and whether there is a resectable focus in a non-eloquent region In general, newer drugs are believed to have predicting a possible successful outcome without lesser side effects but long term clinical trials residual deficits. The recognition of focal origin are needed . The various trials published are of seizures is made possible by advances in EEG mainly aimed at satisfying drug regulatory techniques, advances in neuro-imaging authorities and do not provide useful guidelines techniques and the EEG recordings from cortical to the clinician. There has been no head to head surface. comparison among the various new drugs. They are expensive. However ox-carbazepine, MR spectroscopy, PET studies, SPECT lamotrigine, topiramate and levitiracetam have studies and funtional MRI mapping help to established their places as first-line drugs. recognise epileptogenic zone on physiological basis even in the absence of anatomical evidence However the availability of many drugs has of structural damage. raised issues like (1) What is the initial drug of choice for various types of seizures to choose These studies have helped to recognise the from the long list of drugs available for the same role of surgery in some refractory forms of type of seizures? (2) What is the proper order childhood epilepsies like West syndrome with of drugs to be tried? (3) How long to try medical focal cortical malformations amenable to surgery. therapy in focal lesions before surgery? The possible local pathology is suspected in children presenting with focal infantile spasms, Epileptic surgery asymmetrical spasms, presence of partial The advances in neuro-imaging has ushered seizures, hemihypsarrythmia on EEG and in a new era of epileptic surgery. Epilepsy surgery presence of hemiplegia. is no longer considered a treatment of last resort Indications for surgery and has now become a realistic therapeutic option. Recent text books on therapy of epilepsy 1.Drug resistant epilepsy: The limitations are devote almost one third of their books to surgery. due to variable definitions. There are no It is found to be useful in 5-10% of intractable guidelines on order of drugs or combinations to epilepsies. With increasing experience in adults define this entity. 8 2008; 10(3) : 199 2. Surgically resectable epileptic syndromes: The overall prognosis depends on the These are well defined pathological substrates pathology. In general, low grade gliomas have with excellent prognosis after surgery. Eg: mesial 100% relief, followed by 62% relief in cortical temporal sclerosis, structural lesions and cortical dysplasia. “Poor results are seen in patients with developmental abnormalities. frontal epilepsy, poorly congruent pre operative data and no definite pathology”. 3. Catastrophic epilepsies: These are conditions with well defined pathological substrates Recent advances include use of gamma- associated with poor response to medical knife radiosurgery for cavernous angiomas and therapy and delay in seizure control leading to deep brain stimulation. poor outcome in relation to quality of life. Ketogenic diet Examples include Sturge-Weber syndrome, hemimegalencephaly and tuberous sclerosis. This mode of therapy was introduced 75 years ago and despite the availability of many Contra-indications new drugs still holds a place in treatment of epilepsy. It is a useful therapeutic alternative to (1) Primary generalised epilepsies (some be considered in difficult cases. This method of forms) and idiopathic focal epilepsies of therapy needs an organised set up involving a childhood. (2) Epilepsy caused by underlying dedicated team and is worthy of trial more widely. progressive brain disease. (3) Psychiatric The basic principle is to give 80% of calorie disorders and (4) Severely dysfunctional family. requirements through fat and create ketosis. The brain utilises the keto-acids thus formed in the Types of surgery Krebs cycle instead of pyruvate derived from (1) Lesionectomy includes removal of focal carbohydrates and the exact mode of action is lessions like cortical dysplasias,benign tumours not clearly established. The classical ketogenic or focal atrophic lesions. (2.) Resective surgeries diet introduced earlier with 4 to1 ratio of fats like anterior temporal lobe resection and was unpalatable. Modified diets with medium hemispherectomy. (3) Palliative surgical chain triglycerides and subsequent modified procedures like callosal resections and sub-pial MCT diet have been tried of late. Atkin diet with resections for conditions with no focal resectable less restrictions has been tried in a pilot study. lesions. The main draw back is the inability by the parents to maintain this schedule due to unpalatibility The disadvantages include (a) Too long a and only 35-47% could remain on the diet for waiting period, (b) Lengthy evaluation; at the end more than one year. The response was noted to of evaluation only 50% may be suitable for be more than 90% reduction in 32% of children surgery. In one series out of 120 patients referred, and about 50% reduction in about in 56% of only 83 were ultimately found to be suitable for children. 16% of cases are reported to have full surgery. (c) There is yet no uniformly accepted seizure control. This form of therapy is indicated guidelines on order of selection of drugs or in all forms of intractable epilepsy and certain duration of medical therapy before considering metabolic disorders like glucose transport surgical options. (d) Surgery is expensive and disorders and pyruvate de–carboxylase only very few centers perform surgery. In India, deficiency. The results are better in myoclonic Sri Chitra Tirunal Institute at Trivandrum and seizures and atonic seizures. It is contraindicated NIMHANS at Bangalore have done large series. in mitochondrial disorders and fatty oxidation 9 Indian Journal of Practical Pediatrics 2008; 10(3) : 200 disorders. Concomitant use of sodium valproate Points to remember and carbonic acid inhibitors like sulthiam, • 20-25% epilepsies remain intractable not topiramate, acetazolamide and zonisamide needs responding to standard drugs. to be avoided. The complications include constipation, gastro-esophageal reflux, growth • Levitiracetam, topiramate, lamotrigine and retardation, hyperlipidemia and bone zonisamide are the four drugs found to demineralisation. The exact duration of therapy have broad spectrum anti-epileptic action. is not clearly established. • Surgery for epilepsy is becoming a realistic Vagal nerve stimulation therapeutic option. This form of therapy may be tried in patients • Ketogenic diet still seems to be a useful who are unfit for surgical procedures. The therapeutic alternative for difficult cases. procedure consists of an implanted stimulator • Vagal nerve stimulation may be tried in which the patient switches on at the onset of patients unfit for surgery. symptoms with variable frequency. The success rate is reported to be more than 80% reduction Bibliography in one third, 30-50% reduction in another one 1. Conway JM, Kriel RL, Birnbaum AK. third, and no response in rest of the one third of Antiepileptic Drug Therapy in Children. patients. The procedure is very expensive and In: Pediatric Neurology: Principles &Practice, may be unsuitable for developing countries. The Eds, Kenneth F. Swainman, Stephen Ashwal, th complications include change in voice, throat Donna M. Ferriero, 4 Edn, Mosby Elsevier, pain and cough. Oxford, UK, 2006; pp 1105-1130. 2. Shinnar S, Dell CO. Treatment Decisions in The role of various forms of psycho- childhood Seizures. In: Pediatric Epilepsy- nd therapies are not well establised. They need an Diagnosis and Therapy, 2 Edn, Eds, Pellock organised set up and may be effective in a very JM, Dodson WE, Bourgeois BFD. Demos, few in whom known precipitating factors exist 2001; pp 291-300. or have warning premonitory symtoms. These 3. Medical Treatment. In: Epilepsy in Children, rd include bio-feed back therapy and various forms 3 Edn, Eds, Alexis Arzimanoglou Renzo, of relaxation therapy. These help to increase the Guerrini Jean Aicardi, Lipincott Williams morale of patients as methods of “self control”. &Wilkins, Philadelphia, USA 2004; pp 387- 396. Thus in summary, about 20-25% of children 4. Patasalos PN, Sander JWAS. Anti epileptic may have chronic epilepsy causing concern to Drugs in Clinical Trials. In: The Treatment of nd the physician and the parents. Early recognition Epilepsy, 2 Edn, Blackwell, UK 2004; pp 568- of this difficult group is important for counseling 576. 5. Wheless JW. The Ketogenic Diet. In: Pediatric the family. The warning signs for intractability th include the following. (a) onset of seizures in Neurology: Principles & Practice, 4 Edn, infancy, (b) seizure type - tonic, myoclonic, Eds, Kenneth F. Swainman, Stephen Ashwal, absence and multiple seizure pattern, (c) organic Donna M. Ferriero, Mosby Elsevier, Oxford, UK 2006;pp. 1131-1150. brain damage - sequelae of infections, cerebral 6. Panayiotopoulos CP. Principles of therapy in palsy and mental retardation, (d) long duration epilepsies: Vagus nerve stimulation. In: The of seizures, (e) bad epileptic syndromes - West Epilepsies: Seizures, Syndromes and Manage- syndrome, Rasmussen Syndrome, Lennox- ment. Ed, Panayiotopoulos CP, Bladon Medical Gastaut syndrome. Publishing; Oxford, UK 2005; pp 80-86. 10 2008; 10(3) : 201

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CONSTIPATION IN CHILDREN constipation, such as Hirschsprung’s disease, pseudo-obstruction, spinal cord abnormality, * Bhaskar Raju B hypothyroidism, congenital anorectal malforma- ** Sumathi B tions, and rare conditions like diabetes insipidus, 2 Abstract: Constipation in children is a common cystic fibrosis, gluten enteropathy. A change problem encountered by the practicing from human milk to cow’s milk or cow’s milk or pediatrician and the primary care physicians soya based formula may lead to firmer stools and taking care of children. Functional constipation hence painful defecation in an infant. is the most common cause of inadequate Definition evacuation. History, clinical examination and a rectal examination are adequate for diagnosis Constipation has been defined as “delay or of functional constipation. However, organic difficulty in defecation, present for two or more causes will have to be sought for and ruled out if weeks, sufficient to cause significant distress to the presentation is atypical or therapy fails to the patient”.3 It is also defined by the occurrence elicit the desired response. Treatment of of any of the following characteristics, functional constipation consists of laxatives, independent of stool frequency: passage of hard, dietary modification and bowel training. scybalous, pebble like, or cylindrical cracked stools; straining or painful defecation; passage Key words: Functional habitual constipation of large stools that may clog the toilet; or stool children management. frequency less than 3 per week except in breast 4 Introduction fed infants. Constipation is a common problem in Epidemiology toddlers and preschool children. Constipation Worldwide 0.3% to 28% of children are seen in childhood is usually functional in constipated.5 Van den Berg gives 0.7% to 29.6% 97% of children, with equal frequency in boys as values for prevalence of constipation in and girls.1 In older children, situations that make children.6 Up to a third of children aged six to defecation uncomfortable or inconvenient such 12 years report constipation during any given as unpleasant toilet facilities at school or perianal year.7 25% of the pediatric gastroenterology pain results in infrequent bowel emptying. The consultations are constipation referred for further presence of red flag signs may indicate evaluation.8 uncommon but serious organic causes of * Professor, Causes of constipation ** Asst. Professor, Functional constipation is the most common Pediatric Gastro Enterology, Institute of Child Health and Hospital for cause of constipation. However one has to look Children, Chennai, Tamil Nadu. for congenital anorectal malformations, 11 Indian Journal of Practical Pediatrics 2008; 10(3) : 202 underlying neurological, endocrine and metabolic anal sphincter and gluteal muscles to withhold causes besides some miscellaneous ones stool and avoid pain of defecation. Child often (Table 1). adopts various postures including standing with legs crossed, and straining to hold stool-referred Pathogenesis of functional to as ‘fecal withholding’, or ‘functional fecal constipation retention’.12 In due course this will lead to Several mechanisms have been associated inhibition of reflex defecation and reduced rectal with constipation. Idiopathic / functional movement and the rectum will be filled with hard constipation often starts as a painful bowel stool and fecal soiling follows (Fig. 1). One third movement due to any reason which makes the of children with functional constipation will child withhold stools in fear of pain next time it present with encopresis. This leads to frustration, moves its bowels. This becomes a vicious cycle decreased self-esteem, depression, loss of coping 13 since withholding stools makes the stool even skills, anxiety and other affective disturbances. harder and more painful to push out next time. History and clinical examination This results in incomplete evacuation and chronic constipation. Other factors like genetic, dietary Each child should undergo a detailed history, habits especially low intake of fibre in the diet a thorough physical examination including digital and disturbances of intestinal motility may play rectal examination to identify presence of stool a role in causation and perpetuation of functional at anal verge, assess rectal tone and determine constipation.9, 10 The presence of methane in the presence of rectal distention or impaction.7 breath would suggest disturbed motility and Delayed passage of meconium may suggest consequent prolonged colonic transit time in hypothyroid or Hirschsprung’s disease. Fever, children with chronic constipation.11 In functional abdominal distension, anorexia, nausea, constipation the child responds to the urge to vomiting, weight loss or poor weight gain could defecate by voluntarily contracting the external be signs of an organic disorder (Red flag signs).

Table 1. Causes of constipation S. No. Causes Conditions 1. Idiopathic Functional (95%-97%) 2. Anal lesions and congenital Anal fissure, anteriorly placed anus, anal stenosis anorectal malformations 3. Neurological disorders Hirschsprung’s disease, spinal cord abnormalities: myelomeningocele, spina bifida, cerebral palsy, tethered cord 4. Endocrine/metabolic Hypothyroidism, hypercalcemia, hypokalemia, diabetes insipidus, diabetes mellitus 5. Drugs Anticonvulsants, heavy-metal (lead) poisoning, anti- diarrhoeals, antipsychotic agents. 6. Miscellaneous Prune Belly syndrome, Down’s, Cystic fibrosis, Cow milk protein allergy, connective tissue disorders, tumors

12 2008; 10(3) : 203

Fig.1. Mechanism of encopresis

Table 2. Comparison of functional fecal retention and Hirschsprung’s disease Symptom Functional fecal retention Hirschsprung disease Delayed meconium passage Rarely 60% Constipation as newborn Rarely Almost always Failure to thrive Uncommon Possible Enterocolitis None Possible Onset after age 2 years Common Sometimes Abdominal distension Rare Common Fecal incontinence Common Almost never Difficult bowel training Common Rare Avoidance of toilet Common Rare Withholding behavior Common Rare Stool in rectal ampulla Common Rare Fissure Common Rare Obstructive symptoms Rare Common Transition zone in barium enema Absent Present Aganglionosis on biopsy Absent Present

13 Indian Journal of Practical Pediatrics 2008; 10(3) : 204 Bloody diarrhea in an infant with a history of zone in a case of Hirschsprung’s disease and also constipation could be an indication of useful when other anatomic abnormalities such enterocolitis complicating Hirschsprung’s as a colonic or rectal stricture is suspected.15 disease. Presence of stool in the rectum on In the child with infrequent bowel movements Perrectal examination confirms the diagnosis of and no other signs of constipation, colonic transit functional constipation and generally needs no time can be evaluated with radio-opaque markers. further confirmatory imaging studies. The Presence of the markers throughout the colon presence of anal fissures is suggestive of indicate pancolonic delay.16 Assessment of functional constipation. Table 2 gives the segmental colonic transit time using radio opaque essential differences between functional markers may be indicated for children with constipation and constipation due to neurologic disorders, such as myelomeningocele Hirschsprung’s disease. Physical examination or cerebral palsy.17 Anal manometry is useful in should include neurological examination and Hirschsprung’s disease. 30% of childhood assessment of abdominal, cremasteric and lower constipation is associated with urinary infection extremity deep tendon reflexes, as well as the and a urine culture may be useful when indicated. presence of anal wink (the contraction of the anus when stroked). Abnormal physical findings Management suggesting organic causes like failure to thrive, Constipation due to functional etiology (also lack of lumbo-sacral curve, sacral agenesis, referred to as habitual constipation) is the most anteriorly placed anus and features of common type seen in clinical practice. Treatment hypothyroidism should be looked for. consist of stool disimpaction, prevention of further stool retention, promotion of regular Classic presentation bowel habit, dietary advice, psychosocial support and close follow up.18 Children who have functional constipation often present from pre-school to elementary Disimpaction school age with a history of infrequent stool, Whenever child has palpable fecal mass in prolonged defecation, abnormal posturing, the abdomen, loaded rectum identified by the painful act of defecation and withholding of stool. digital examination or rarely on plain x-ray Children who are older than 3 years of age most abdomen, disimpaction is indicated. This can be frequently present with soiling, impaction, and done by oral or by rectal route. Usually oral withholding.14 administration of medication (oral enema!) is Laboratory tests better than the rectal route as this is non-invasive and is not associated with discomfort or pain. Since functional constipation is the most Rectal administration of drug usually causes common cause and only 5% of children have discomfort to children, making stool retention organic etiology, special diagnostic tests are worse. Polyethelene glycol (PEG) orally is ideal rarely needed.15 If a rectal examination is not for oral disimpaction.19 The dose is 20ml/kg/hour possible, plain x-ray abdomen may be considered. for four hours and can be repeated the next day Loaded rectum in a plain radiograph of abdomen if necessary. Such lavaging can be done orally or is highly predictive of fecal impaction on digital by nasogastric tube (25ml/kg/hour). Single dose rectal examination. A barium enema in an of prokinetic agent namely 5 to 10 mg of unprepared colon will demonstrate a transition metaclopramide may be given half an hour

14 2008; 10(3) : 205 before lavaging. Phosphate enema, glycerine depend on the response seen and will need to be suppositories may be used rectally. modified constantly based upon the nature of the stool it results in. Maintenance therapy Dietary modification Once the impacted feces is dislodged and evacuated, treatment of constipation should aim Children with functional constipation to prevent fecal re-impaction by maintenance should be encouraged to consume diet rich in therapy with laxatives (Table 3), dietary fibre. The recommended amount of daily dietary modifications, bowel training and close follow- fibre for all children is equal to 5 g plus the child’s up. In general the dosage of drugs used would age in years.20 Fruits like apple, pear and prune

Table 3. Laxatives S. No Drug Dosage Side effects 1 Lactulose 1-3ml/kg/day, 1-2 doses. Abdominal cramps, flatulance Adjust dosage to response seen 2 Milk of magnesia 1-3ml/kg/day,1-2 doses Over dose-hypermagnesemia, Adjust dose to response seen hypophosphatemia, hypocalcemia 3 Sorbitol 1-3ml/kg/day,1-2 doses Abdominal cramps, flatulance 4 Mineral oil Disimpaction 15-30ml/year Lipoid pneumonia (Liquid Paraffin) of age.(max 240ml) Maintenance- 1-3 ml/kg/day 5 PEG (Poly Disimpaction-25ml/kg/hour Nausea, bloating, cramps, Ethylene Glycol) Maintenance-5-10ml/kg/day vomiting, anal irritation. or 0.5-1g/kg/day 6 Senna syrup: 8.8 g sennoside/ 5 ml Idiosyncratic hepatitis, 2–5 years: 2.5–7.5 ml/day melanosis coli, hypertrophic in two divided dosages. osteoarthropathy, analgesic 6–12 years 5–15 ml/day nephropathy, abdominal in two divided dosages cramping. Melanosis coli (Tablets and granules available) improves after medication stopped 7 Bisacodyl 5 mg tablets, 1–3 tablets/dosage Abdominal cramping, 1–2 times daily. diarrhea, hypokalemia 10 mg suppositories, 0.5–1 suppository, 1–2 times daily

15 Indian Journal of Practical Pediatrics 2008; 10(3) : 206 juices that contain nonabsorbable carbohydrates Points to Remember like sorbitol are helpful. Fluid intake should be encouraged. The diet should contain whole • Functional constipation is the most grains, fresh fruits and vegetables rich in fiber. common cause of constipation in children. Toilet training • Good history and thorough physical examination including per rectal (PR) are This is possible after 2 to 3 years of age. all that is needed for a diagnosis of Child should be encouraged to sit in the toilet functional constipation. for 5 to 10 minutes, 3 to 4 times per day immediately after meals for initial few months, • Laxative therapy is usually needed for regularly. The gastrocolic reflex that occurs after several months. meals can be made use of, to ease the bowel movement. Child should be rewarded whenever • Early withdrawal of therapy leads to there is no fecal soiling. This will act as a positive relapse. reinforcement and provide psychological support • Effective treatment depends on (a) child to these children. Re-education is an important and family education, (b) adequate part of bowel training. Child should be advised disimpaction (c) maintenance phase which not to strain excessively and never to ignore/ includes behavioral therapy, medication suppress the urge to defecate. and dietary modification. Outcome: In studies on functional constipation, recovery is defined as greater than three stools References per week with no soiling. However the response 1. Baucke VL. Prevalence, symptoms and depends on age of onset and associated outcome of constipation in infants and Toddlers, encopresis. Approximately two third of cases of J Pediatr 2005;146:359-363. functional constipation need laxative therapy for 2. Wendy S, Biggs, Dery WH. Evaluation and months to years and the rest require even longer Treatment of Constipation in Infants and term treatment. Significant number may continue Children, Am Fam Physician 2006;73:469-477. to have constipation into adulthood. In one study, 3. Baker SS, Liptak GS, Colletti RB, et al. 52 percent of children with constipation and Constipation in infants and children: evaluation encopresis, the symptoms persisted even after and treatment. A medical position statement of five years of treatment.21 Clayden has shown that the North American Society for Pediatric 22% of children required laxatives for less than Gastroenterology and Nutrition. [erratum 6 months, 44%for less than 12months, and the appears in J Pediatr Gastroenterol Nutr 2000 rest for more than 12 months.22 Jan;30(1):109]. J Pediatr Gastroenterol Nutr 1999; 29 : 612-626. Follow up 4. Hyams J, Colletti RB, Faure C, et al. Functional The successful management of functional gastrointestinal disorders, J Pediatr Gastro- constipation in childhood depends on close enterol Nutr 2002;35 (suppl):110-117. follow-up, till normal bowel movement is 5. Benninga MA, Voskuijl WP, Taminiau JA. achieved, followed by review every two to three Childhood constipation: is there new light in months for the next 2 years and then yearly the tunnel? J Pediatr Gastroenterol Nutr 2004; thereafter. 39 : 448-464.

16 2008; 10(3) : 207 6. Van den Berg, Maartje M, Benninga, et al. 14. Partin JC, Hamill SK, Fischel JE, et al. Painful Epidemiology of Childhood Constipation: defecation and fecal soiling in children. A Systematic Review. Am J Gastroenterol. Pediatrics 1992;89(6 Pt 1):1007-1009. October 2006, 101(10): 2401-2409. 15. Joseph M. Croffie Constipation In Children, 7. Felt B, Brown P, Coran A, et al. Functional Indian J Pediatr 2006;73:697-701. constipation and soiling in children. University 16. Padopoulou A, Clayden G S, Booth I W. The of Michigan Health System guidelines for clinical value of solid marker transit studies in clini-cal care 2003. Accessed online February childhood constipation and soiling. Eur J Pediatr 2, 2005 1994; 153: 560–564. 17. Youssef NN, Di Lorenzo C. Childhood 8. Taitz LS, Wales JK, Urwin OM, et al. Factors constipation: evaluation and treatment. J Clin associated with outcome in management of Gastroenterol 2001;33(3):199-205. defecation disorders, Arch Dis Child 1986;61(5):472-477. 18. Clinical Practice Guideline, Evaluation and Treatment of Constipation in Infants and 9. Morais MB, Vitolo MR, Aguirre ANC, et al. Children: Recommendations of the North Measurement of low dietary fibre intake as a American Society for Pediatric risk factor for chronic constipation in children, Gastroenterology, Hepatology and Nutrition, J J Pediatr Gastroenterol Nutr. 1999;29: 132-135. Pediatr Gastroenterol Nutr 2006;43: e1-e3. 10. Di Lorenzo C, Pediatric anorectal disorders, 19. Vincent R, Candy DCA. Movicol for the Gastroenterol Clin North Am.2001;30:269-287. treatment of faecal impaction in children – an audit of the first thirty patients. 11. Ana Christina FS, Henrique ML, Ulysses FN, Gastroenterology Today 2001; 11: 50–52. et al. Breath methane associated with slow 20. Position of the American Dietetic Association. colonic transit time in children with chronic Health implications of dietary fiber. J Am Diet constipation, J Clin Gastroenterol.volume 2, Assoc 1997;97(10):1157-1159. Oct-Dec 2005; 241-244. 21. Staiano A, Andreotti MR, Greco L, et al. Long- 12. D.C. A.Candy, D. Edwards. The management term follow-up of children with chronic of chronic constipation, Current Paediatrics, idiopathic constipation. Dig Dis Sci 1994; 2003; 13,101-106. 39:561-564. 13. Childhood constipation: Finally some hard data 22. Clayden GS. Management of chronic about hard stool. J Pediatr 2000; 136:4-7. constipation. Arch Dis Child 1992;67:340-344.

NEWS AND NOTES

JHARKHAND PEDICON 2008, DHANBAD November 22-23, 2008 Contact Dr.B.B.Sahni President, IAP Jharkhand State and Sr.Specialist, Department of Pediatrics, Tata Central Hospital,Dhanbad-828 301, India. Res:0326-2320769, 6612229, Office:03266612285, Mobile:09334015806 Email:[email protected]

17 Indian Journal of Practical Pediatrics 2008; 10(3) : 208

IAP-IJPP CME 2008

HOW DO I MANAGE ATOPIC TCS. Pimecrolimus is reserved for moderate DERMATITIS? eczema in children more than 2 years if uncontrolled by TCS. Never use TCIs: a)Under * Jayakar Thomas occlusion b)For eczema requiring long term use. Systemic treatment and phototherapy are for Abstract: Management of atopic dermatitis specialist only as last resort. (AD) should always commence with a global assessment of the disease in terms of severity, Key words: Atopic Dermatitis, Management, psychological well-being and checking TCSs, TCIs. adherence to optimal therapy. Counseling and education should include stepwise approach Atopic dermatitis (AD) is a common to management and demonstration on how to condition that affects more than one in ten use medications, how to recognise a flare and children and the incidence is increasing. There explanation of benefits and harms of are probably several reasons for this, including treatment. Emollients are applied all the time higher exposure to air pollution, smaller families and with all treatments. One must offer choice with less exposure to infections, more pets, higher of products, prescribe large quantities (more maternal age, a wider range of foods and the than 250g per week), to be applied liberally practice of evidence-based medicine. There is and frequently and after bathing. Topical clearly also an important hereditary component corticosteroids (TCS) of lowest potency to atopic eczema. This is complex because not capable of controlling symptoms are to be all affected children are atopic, though the genes used. They are to be applied to areas of active implicated in atopy are likely to be involved, AD only. One uses mild TCS to prevent flares. together with others as yet unknown. AD usually Mild potency only is used on face and neck presents during the first year of life and when it and thin skin, once or twice daily. One can is severe it is extremely disabling. It may also consider short course (7-10days) of potent cause major psychological problems. TCS to control symptoms. Never use a)Potent Diagnosis on children under 12 months b)Very potent on children under 12 years c)On face, axilla or There is no gold standard laboratory test for groin. diagnosis of AD. Several criteria have been suggested, as follows: Topical calcineurin inhibitors (TCI) are not first • Hanifin and Rajka line therapy on the body (limbs and trunk). Tacrolimus is used for moderate/ severe eczema • Schultz-Larsen in children more than 2 years if uncontrolled by • Danish Allergy Research Centre (DARC) * Senior Consultant Dermatologist, Kanchi Kamakoti CHILDS Trust Hospital, • Jan Bos’ millennium Chennai, INDIA • Doctor-based clinical diagnosis 18 2008; 10(3) : 209 Clinical diagnosis only is reliable and essential to find a suitable moisturizer that can consists of. be applied all over twice a day whether or not • Severe pruritus there is active eczema. Creams containing moisturizing agents, emulsifying ointment and • Classical morphology creams or ointments with lanolin can be used. • Typical distribution If a product stings the skin it must be abandoned. • Positive family history The most likely irritant in emollient creams is the

It is also observed that the first eczema, stabilizer propylene glycol.Products that contain during the first year, in the first born, is usually urea almost always sting broken skin and are atopic dermatitis. unsuitable in these children. Management1,2,3 Use of wet dressings Explanation and counseling are a vital part Wet dressings are useful in children with of the successful management of atopic severe widespread eczema. This is essentially an dermatitis. Parents would have received a barrage inpatient procedure but can be used for short of advice from a range of medical, paramedical periods at home. A water based emollient is and non-medical “experts” and require a clear applied all over; a corticosteroid cream (rather understanding of the nature of the condition, a than ointment in this case because cream is more long term management plan and a realistic water miscible) is applied to the areas of active expectation of the results of treatment. eczema. The creams are covered with a double Terminology is often confusing; the terms atopic layer of wrapping, the innermost of which is eczema and atopic dermatitis are often used wetted with tepid water. The material may be synonymously. It is essential to talk in terms of cotton sheeting covered with a crepe bandage, control rather than cure, otherwise parents will though an easier alternative is the use of a search for an end point after which care will no double layer of tubular elasticized bandage. longer be required and this is an unrealistic The procedure is repeated three times a day. expectation. The condition should be explained This treatment is usually effective in clearing the as a multifactorial disorder and it must be eczema in three or four days. appreciated that just as there is no “cure” there is no single “cause.” Often no explanation can Avoidance of allergens be found for a particular flare up of the condition, House dust mite is the most important and many factors are probably working in allergen. Avoidance measures have to be carried combination at all times. out assiduously and must include encasing the mattress and pillows as well as dealing with the Dealing with xerosis top covers, either by encasement or by hot (more Bath oils and products containing oatmeal than 60°C) washing. If food allergy is suspected, are useful and prevent the drying of the skin that the child should be referred to a pediatric bathing can induce. Bath oils that contain dietician. In general, it is children with severe antiseptic may have added benefit in certain cases atopic eczema who have food allergy or food but have a tendency to over-dry and sometimes intolerance. Children with flexural eczema are actually irritate the skin. The child should have unlikely to have food allergy, unless the history either a bath with additive or a short shower. It is suggests otherwise.

19 Indian Journal of Practical Pediatrics 2008; 10(3) : 210 Topical corticosteroids ointment may be effective. To prevent infections it is useful to bathe the child in preparations It is often necessary to spend some time containing triclosan or benzalkonium chloride. counseling the parents that topical steroid preparations used appropriately are safe. The Topical immunosuppressant strength chosen depends on the severity of the eczema and the site affected. The frequency of Tacrolimus is a potent immunosuppressive application depends on the individual product. drug used in organ transplantation. A topical formulation has been shown to be effective in Class I trials in patients with moderate to severe atopic 1.Clobetasol diproprionate 0.05%, dermatitis. Studies specifically related to 2.Halbetasol proprionate 0.05%, childhood eczema have confirmed its efficacy. 3.Diflorasone diacetate 0.05% The main side effect is a sensation of burning. A concern has been raised as to whether Class II application to skin exposed to sun could increase 1. Fluocinonide 0.05%, the long term risk of skin cancer. Pimecrolimus 2. Halcinonide 0.05%, (an ascomycin derivative) is a newer immuno- 3.Amcinonide 0.05% suppressive agent, similar to tacrolimus. Studies

Class III in children are very encouraging. The approval 1. Mometasone furoate 0.1%, of topical calcineurin inhibitors for the treatment 2.Betamethasone diproprionate 0.05% of AD represents a significant advance in our management options for this disease. Class IV The distinction between pimecrolimus and 1. Fluocinolone acetonide 0.01-0.2%, tacrolimus is that the former is a cream while the 2. Hydrocortisone valerate 0.2% latter is an ointment. Tacrolimus is currently 3. Hydrocortisone butyrate 0.1% marketed as an ointment that is more potent but also more irritating. Importantly, there are Class V situations in which topical calcineurin inhibitors 1. Triamcinalone acetonide 0.1%, may be advantageous over topical corticosteroids 2. Fluticasone propionate 0.05%, and may be useful as first-line therapy. These 3. Desonide 0.05% would include treatment of patients who are Class VI poorly responsive to topical steroids or have 1. Prednicarbate 0.05%, steroid phobia and treatment of face and neck 2. Triamcinalone acetonide 0.025% dermatitis where ineffective, low-potency topical corticosteroids are usually used due to fears of Class VII steroid-induced skin atrophy. The potential use 1. Hydrocortisone 2.5%, of topical calcineurin inhibitors as maintenance 2.Hydrocortisone 1% therapy is also intriguing for prevention of AD flares and progression of the atopic march. Topical antibacterials However, although systemic absorption of these Staphylococcus aureus is commonly compounds is low, there is a need for careful cultured from eczematous skin and there may be surveillance to rule out the possibility that skin obvious signs of infection. For localized cancers and increased viral skin infections will infections, mupirocin, sisomycin and fusidic acid appear when such agents are used long-term. 20 2008; 10(3) : 211 Never use TCIs: Azathioprine is a safer drug for long term use, though it does have several side effects, • Under occlusion including nausea, fatigue, myalgia and liver • For eczema requiring long term use dysfunction. It is essential to assay for thiopurine Oral medications methyl transferase before treatment starts as children deficient in this enzyme will experience Immunosuppressive drugs : Severe atopic marked bone marrow suppression. In most eczema is a serious condition, with huge loss of children it is effective at low dosage. The main quality of life for the child on par with juvenile long term side effect that could theoretically occur rheumatoid arthritis. It is therefore essential that (as with cyclosporin) is the development of such children are treated adequately. The use of lymphoma. The advantage of this drug is that it oral steroids should be avoided because of severe can be used continuously. Other possibilities rebound of the eczema on withdrawal, the eczema include the leukotriene inhibitors zafirlukast and becoming unstable after several courses and the montelukast given orally. Chinese herbal long term side effects. There are generally two medicines have also been used successfully but alternatives for severe eczema, cyclosporin and are not without danger. azathioprine. Antihistamines : Sedating antihistamines such Cyclosporin: Recent studies have confirmed the as promethazine given at bedtime are useful. efficacy of cyclosporin in childhood atopic The sedation is an important feature of their eczema. Regrettably the improvement is often not antipruritic action. It is still debatable whether maintained after withdrawal of the drug. non-sedating antihistamines such as cetirizine and Continuous treatment is rarely justified in view loratadine are useful because generally the role of the long term risks (such as hypertension and of histamine in eczema is somewhat limited. renal dysfunction). However, it has a place as an However, a large study of the use of cetirizine in effective, safe and well tolerated short term option adults with atopic eczema showed a significant for the management of severe refractory disease reduction of clinical manifestations in those in children. treated.

Treatment may be summarized as follows : MILD MODERATE SEVERE 1. Bathing and moisturization 1. Bathing and moisturization 1. Bathing and moisturization 2. Avoidance of trigger factors 2. Avoidance of trigger factors 2. Avoidance of trigger factors 3. Treat superinfection 3. Treat superinfection 3. Treat superinfection 4. Intermittent short-term use 4. Intermittent short-term use 4. Intermittent short-term use of Class VI to VII topical of Class IV to V topical of Class II to III topical steroids + TCI steroids + TCI steroids + TCI 5. Oral antihistaminics 5. Oral antihistaminics 6. Consider oral rescue medication / UVB therapy

21 Indian Journal of Practical Pediatrics 2008; 10(3) : 212 Points to Remember Bibliography • Atopic dermatitis in children is a complex 1. Thomas Jayakar. Understanding Atopic condition . dermatitis and its management in Children. Pediatric Oncall [serial online] 2008;5. • Four in five children with atopic eczema Available from: http://www.pediatriconcall. have IgE mediated allergy to inhalants or com/fordoctor/diseasesandcondition/ foods. pediatric_dermatology/atopicdermatitis.asp • House dust mite and mosquitoes 2. Thomas Jayakar. Common Dermatological Problems in Adolescents. In: Bhave SY. Editor. exacerbates atopic dermatitis . st Textbook of Adolescent Medicine. 1 Edn. • Food allergy exacerbates eczema in less New Delhi: Jaypee Brothers; 2006. pp.554-576. than one in ten children. 3. Thomas Jayakar. Atopic Dermatitis. In: Thomas • To reduce the need for admission to hospital J. edit. Pediatric Dermatology Ward Rounds. st children with severe eczema can be treated 1 Edn. New Delhi: Jaypee Brothers, 2007; with topical or oral immuno-suppression. pp.17-19.

NEWS AND NOTES

IAP Drug Formulary

IAP Drug Formulary Web-Update 2008 (1) - Edition 10 The ninth web update of the IAP Drug Formulary, the first for 2008, is now available for download. These updates are being made available, free of cost, to all our esteemed users as IAP Executive Board considers this as a service to pediatric care in our country. This quarterly web publication of the IAP is possibly the first drug formulary in the world that provides such a facility. Users should to regularly update their formulary through the formulary installed in their computers as and when they receive the newsletter announcing the availability of an update The Formulary contains information, which, to the best of our knowledge, is accurate and up-to-date. But every practitioner must, as we have always insisted, take individual responsibility for taking all precautions when dispensing and administering drugs to children. We are looking forward to comments and criticism regarding the update. Useful and meaningful quarterly updates will continue to be made available so that this ongoing publication of IAP meets international standards and continues to be sought after by all those caring for children and adolescents. Those who have not yet bought the formulary could do so by sending a DD in favour of ‘IAP, Mumbai’ for Rs 350 (three hundred and fifty only) to the IAP office. Dr Jeeson C Unni MD, DCH, FIAP Editor-in-Chief, IAP Drug Formulary Consultant pediatrician, Dr Kunhalu’s Nursing Home, T D Road, Cochin – 682011

22 2008; 10(3) : 213

IAP-IJPP CME 2008

SURFACTANT THERAPY preterm babies. Surfactant is also used in the management of secondary surfactant deficiency * Lakshmi V states like meconium aspiration, pulmonary Abstract: The incidence of respiratory distress edema, congenital pneumonia and ARDS. syndrome increases with lower gestational age Avery and Mead in the year 1959 were the and surfactant is the standard of care in the first to demonstrate that surfactant was deficient management of Respiratory distress syndrome in the lungs of babies dying due to Hyaline (RDS). membrane disease (HMD). Aerosolized Large number of trials have come in surfactant Dipalmitoyl Phosphatidyl Choline (DPPC) tried therapy and many of them are still ongoing. in 1964 by Robillard and 1967 by Chuetal were Surfactant acts by lowering the alveolar surface unsuccessful. Fujiwara reported the first clinical tension thus preventing their end expiratory study of intratracheal surfactant in1980. In 1989 collapse and establishing functional residual commercial surfactant preparations were volume (FRV). Prophylactic surfactants are approved by FDA in USA. being given for <30 weeks gestation and they Composition of surfactant are quickly extubated to Nasal CPAP. Natural surfactants in adequate dose has improved the The mammalian surfactant contains morbidity and mortality. Babies requiring 80% phospholipids, 8% neutral lipids and surfactant and ventilation are monitored and 12% proteins. weaned rapidly once the compliance improves.Surfactant also has proved to be The phospholipid pool consists of effective in meconium aspiration babies who dipalmitoyl phosphatidyl choline 60%, have secondary surfactant deficiency. unsaturated phosphatidyl choline (PC) 25%, phosphatidyl glycerol(PG) 15% along with trace Key words: Preterm, RDS, Surfactant. amounts of phosphatidyl inositol, phosphatidyl ethanolamine, phosphatidyl serine, sphingo- Respiratory distress syndrome (RDS) is the myelins and neutral lipids like cholesterol. DPPC major cause of morbidity and mortality in preterm alone is primarily responsible for the function 1 babies. The incidence of RDS is inversely but is poorly adsorbable through the air liquid proportional to the gestational age occurring in interface and is facilitated by the surfactant 15-30% of babies between 32-36 weeks, 50% of proteins and other lipids like phosphatidyl the babies born before 30 weeks of gestation and glycerol. 60-80% of babies of less than 28 weeks of gestation.2 Surfactant therapy has become the About half of the protein content is the standard of care in the management of RDS in contaminating plasma and lung tissue and the rest * Consultant Neonatologist, are surfactant associated apopoteins Sp A, B, C Mehta Children’s Hospital, Chennai. and D (Table 1). 23 Indian Journal of Practical Pediatrics 2008; 10(3) : 214 Table 1. Surfactant apo proteins SPA 36000kDa, water soluble Regulates surfactant metabolism, formation of tubular Chromosome6 myelin, participate in host defense and phagocytosis SPB 8000kDa, hydrophobic Surface lowering property helps in absorption Chromosome2 SPC 3800kDa, hydrophobic Lines the airway in developing lung. helps in absorption SPD 43000kDa, hydrophilic Host defense

Synthesis and secretion Surfactant synthesis is reduced in the Surfactant is identified as early as 16 weeks following conditions: Birth asphyxia, hypoxia, in the fetal lung though its proper secretion begins caesarian section, acidosis, diabetic mothers, after 24 weeks of gestation and more abundantly hypotension, cold stress . after the 35th week of gestation. Surfactants are Accelerated production is observed with phospolipids synthesized and recycled by type II hormones like, catecholamines, glucocorticoids, pneumocytes which form the air liquid interface. thyroid hormone and fetal stress like intra uterine Proteins are synthesized on the rough growth retardation, preterm, prelabour rupture of endoplasmic reticulum and lipids in the membranes. endoplasmic reticulum and golgi bodies.The lipid Surfactant is released into the alveoli as soon content is stored in the membrane bound as the lungs are distended with the first few organelles called the lamellar bodies. breaths and surfactant synthesis and the release The contents are secreted through the apices of is enhanced by antenatal steroids.4 the type II cells into the extracellular aqueous lining of the alveoli by exocytosis .Here they unravel into tubular myelin which is a lipid bilayer membrane and also is the extracellular reservoir for DPPC monolayer at the air liquid interphase (Fig.1). The surfactant pool size varies with the gestational age. In a term baby the amniotic fluid contains 100mg/kg of surfactant.3 The pool size in a preterm baby is low and in a preterm baby with RDS have 2-10mg/kg. Half-life of surfactant is 30 hours. Exogenous surfactant increases alveolar and tissue pools. In babies with RDS there is a steady increase in phospatidyl choline levels to normal by 4-5 days. Ninety percent of the DPPC is taken back Fig.1. Surfactant production from type by type II cells and recycled. 10% is degraded II pneumocytes and secretion into by alveolar macrophages. alveolar surface 24 2008; 10(3) : 215 Reduced release and function are seen when Instillation and procedure there is meconium, blood, fluid in the alveoli. Surfactant is instilled directly into the lungs Surfactant functions through the endotracheal tube under strict aseptic conditions.Once intubated a smaller size (5 Fr) Surfactant molecules once released spread nasogastric tube cut short to the length of ETT to line the alveolar surface. These molecules are is introduced through the ETT after disconnecting pushed together during expiration and lower the the ventilator or through a side port adaptor or a surface tension, which prevents alveolar collapse dual lumen ETT (Fig.2). The desired dose is thus maintaining the residual volume and loaded into a sterile syringe given as a bolus over improving the lung compliance. As a result the 15 mts in 2-4 aliquots.Changing the position of lung can expand and oxygenate well and the work the baby than given in supine position had no of breathing is less.It also plays a role in host effect on the outcome and the spread is more defence mechanisms against infections. uniform in supine position.12 The baby may be Deficiency of surfactant results in collapse connected back to the ventilator or hand bagged of alveoli during expiration leading to difficulty for a few minutes. Precautions to be taken are to in re-expansion with the next breath. Thus the keep the endotracheal tube in position and patent inspiratory pressure to open the alveoli are prior to instillation. Adverse events reported were further increased and FRC is not established or reflux of solution in the tube, apnoea, low.The compliance decreases. As a result, the bradycardia, hypotension and desaturation which work of breathing is more with chest wall improves with positive pressure ventilation. retractions and grunt where endogenous PEEP Hence it is imperative to monitor these is produced to keep the alveoli open. V/Q mismatch ensues and eventually respiratory failure sets in. Timing Instillation of surfactant prior to the first breath has the better outcome5,6 as the spread is homogenous in fluid filled lungs. 1. Prophylactic treatment when started for babies more than 30 weeks, it was found to be beneficial and hence preferred over rescue7,8. But it also leads to unnecessry treatment in 30% of babies who maynot require it9,10. 2. Early rescue given to preterm babies with respiratory distress within 2 hours of age. 3. Late rescue in those with established RDS after 2 hours of life. Early rescue has better outcome in terms of Fig. 2. Surfactant being instilled mortality and airleaks and CLD than late through a NG tube into the endotra- treatment.11 cheal tube 25 Indian Journal of Practical Pediatrics 2008; 10(3) : 216 parameters during the procedure (Table 2). Avoid Dose ETT suctioning for atleast 2-4 hours unless Surfactant dose is 50-200mg/kg and is yet deemed necessary. to be standardized. Further exogenous surfactant Following surfactant there is a rapid does not inhibit endogenous production and is improvement in oxygenation and followed by thought to be reutilized in the lungs, hence it is very difficult to study the pharmaco dynamics. slow improvement in compliance. Hence FiO2, PIP and ventilator rate should be appropriately Different manufacturers recommend different weaned. Chest expansion, Blood gases, Chest doses as shown in the Table 3. x-ray and pulmonary graphics are useful guide Fujiwara showed FiO2 requirement was to improvement in oxygenation and compliance. higher with lower dose (51-58mg/kg). Higher If ventilation is not adjusted appropriately dose (120mg/ kg) has maximal beneficial effect alveolar over distention and hyperventilation lead regarding lesser duration of ventilation, intra to air leaks. cranial hemorrhage and bronchopulmonary dysplasia.14 Types of surfactant Number of doses Natural surfactants: Animal derived by either Some times repeat second or third dosing lung mince extract or by lung lavage extract. may be necessary especially when given as late It has phospolipids and surfactant proteins. rescue. The need for repeat dosage was lower Synthetic surfactant: Only with a higher initial dose and when used phospolipids. prophylactically. The criteria for repeat dosing may be low Newer surfactant: Synthetic surfactants with threshold (FiO >0.3 and still intubated) or high synthetic peptides modeled on surfactant 2 threshold (FiO2>0.4 and MAP>7cm H2O).But proteins. Aerosolized Surfactant. both regimen were found to be equally effective.15 Natural vs synthetic surfactant Again the timing of the second dose varies with the manufacturer’s recommendation as Both natural and synthetic surfactants are Survanta recommends 6 hours or earlier and beneficial for prevention and treatment of RDS. Curosurf recommends 12 hours gap between two But natural surfactant leads to lower mortality, doses. Neosurf recommends upto 3 doses in first airleaks and faster weaning from the ventilator13. 5 days of age.

Table 2. Monitoring

During the procedure Post surfactant Weaning

Colour Chest rise FiO 2

Heart rate SpO2 Ventilator rate Respirations Blood gas PIP Blood pressure Chest x-ray Pulmonary graphics

26 2008; 10(3) : 217 Ventilation strategies Blood gas criteria for ventilation : pH is <7.2 and hypoxemia PO <50-60mmHg despite Not all babies receiving surfactant therapy 2 FiO >0.6-0.7 and CPAP of 8cm H O. Target to need to be ventilated. Especially when given 2 2 achieve by ventilation should be a PO of 50- prophylactically or in early rescue where they 2 70mmHg and PCO 35-45mmHg. This should can be extubated to nasal CPAP. As endotracheal 2 tube ventilation is an important risk factor for be achieved with rapid rates, adequate PEEP, BPD, CPAP especially when given early support short IT, low tidal volumes of 4-6ml/kg with ventilation with minimal damage to the lungs.16 minimal PIP. INSURE (Intubate, surfactant and extubate to Weaning problems CPAP) therapy has reduced the need for mechanical ventilation.17 Inability to wean: Repeat dosage Indication for mechanical ventilation is Weaned but requires increase in setting by when the respiratory distress is severe with shock 24 hours: PDA or apnoea and when the baby has respiratory Sudden deterioration: Pulmonary hemorrhage / distress on CPAP. air leak

Table 3. Types of surfactant Surfactant Trade name Preparation Protein PL Dose family concentration Natural Survanta (bovine) DPPC,PG SPB,SPC 25mg/ml 4ml/kg Curosurf (porcine) DPPC,PG SPB.SPC 80mg/ml 2.5ml/kg 1.25ml/kg Neosurf (BLES) DPPC,PG SPB,SPC 27mg/ml 5ml/kg Infasurf (bovine) DPPC,PG SPB,SPC 35mg/ml 3ml/kg Alveofact(bovine) DPPC,PG SPB,SPC 4Omg/ml 1.2ml/kg Synthetic Surfact DPPC No 13.5mg/ml 5ml/kg Pumactant DPPC,PG No 40mg/ml 1.2ml/kg Exosurf DPPC No 13.5mg/ml 5ml/kg 9% Hexadecanol 6% Tyloxapol Newer Surfactants Surfaxin DPPC,POPG KL4 pepide 30mg/ml 5.8mg/ml as SPB Venticute DPPC,DOPG r-SPC 50mg/ml Aerosolized surfactant

27 Indian Journal of Practical Pediatrics 2008; 10(3) : 218 Secondary or acquired surfactant albumin, bilirubin, immunoglobulin, amniotic deficiency or dysfunction fluid,elastin and meconium. Quantitative deficiency of alveolar Meconium aspiration syndrome surfactant pool may develop secondary to lung (MAS) injury and inflammation resulting in loss of type II cells or impairment in their ability to In a dose dependent manner meconium produce surfactant. inhibits the function of surfactant by competitively displacing surfactant from the Surfactant metabolism may be affected alveolar monolayer in vitro. resulting in a change in the phospolipid panel like decrease in the surface active PC/PG than This inhibition is seen with hydrophobic and less surface-active compounds without altering hydrophilic extracts of meconium and can be the phospholipid pool. overcome by surfactant supplementation. Treatment with natural surfactant had improved Change in the more surface-active large oxygenation in full term babies with MAS.18,19 aggregates to small aggregates, which impairs the Earlier administration within 6 hours and higher function of surfactant. doses of 150mg/kg and repeated doses upto four were shown to reduce airleaks, ventilation Damage to the alveolar capillary membrane duration and hospital stay.20There was stepwise Inactivation of surfactant by disease or drugs nature of response to serial doses. There was also like hypothermia and acidosis significant reduction in the need for ECMO in term infants with MAS after treatment with Mechanism of surfactant surfactant.21 dysfunction in mature lungs Congenital diaphragmatic hernia • Quantitative deficiency : Decreased (CDH) synthesis / type II cell injury, increased clearance. There are conflicting data about whether patients with CDH actually are surfactant • Altered metabolism of surfactant : deficient. Studies have demonstrated normal Phospolipid composition, composition of lecithin sphingomyelin ratios and PC, PG in aggregate forms. bronchoalveolar lavage fluid in babies with CDH. • Biophysical alteration of surface active Wilcox, et al showed improvement in lung films: Altered phospolipid configuration, inflation, compliance and blood gases and Glick, adsorption of less surface-active agents. et al reported reduction in mortality when given only prophylactically. However controlled Biochemical degradation of surface active • clinical trial is still ongoing. compounds : Lytic enzymes and oxygen free radicals. Other condition where in surfactant is being Agents inhibiting surfactant administered is for Group B streptococcal function pneumonia as it also plays a role in antibacterial defense system of the lung. Bulk of the function Plasma/serum, hemoglobin, fibrin monomers, is provided by surfactant A and D which are RBC membrane lipids, fibrinogen, cholesterol, removed by processing of commercial

28 2008; 10(3) : 219 preparation, B and C which are retained also lambs with natural surfactant. J Clin Invest contribute to function. However there are no 1984;73:848-856. prospective trials. 7.. Sweet D, Bevilaqua G, Carnielli V, et al. European consensus Guidelines in the Points to Remember management of Neonatal Respiratory distress syndrome. J Perinat Med 2007;35:175-186. • Surfactant therapy is the standard of care 8. Soll RF, Moley CJ. Prophylactic vs selective for neonatal respiratory distress syndrome. use of surfactant in preventing morbidity and • Intense monitoring during instillation and mortality in preterm infants.Cochrane database rapid weaning from ventilator reduces the Syst Rev .2001;2:CD000510. complications. 9. Enhorning G, Shennon A, Possmayer F, et al. Prevention of Neonatal respiratory distress • Prophylactic surfactant in <30 weeks syndrome by Tracheal instillation of Surfactant: preterms is beneficial. A randomized clinical trial. Pediatrics • Treatment with natural surfactant and 1985;76:145-153. early rescue therapy has better outcome. 10. Kwong MS, Egan EA, Notter RH, et al. Double blind clinical trial of calf lung surfactant extract • INSURE therapy has reduced the need for for the prevention of Hyaline membrane disease mechanical ventilation. in extremely premature infants. Pediatrics 1985; • Early surfactant therapy has reduced the 76:585-592. need for ECMO in meconium aspiration 11. Yost CC,Soll RF. Early vs delayed selective syndrome. surfactant treatment for neonatal respiratory distress syndrome.Cochrane Database Syst References Rev.2000;2:CD001456. 1. Lemons JA, Bauer CR, Oh W, et al. Very low 12. Broadbent R, Fok TF, Dolovich M,et al. Chest birth weight infants outcome of NICHD position and pulmonary deposition of surfactant Neonatal Research Network. Jan 1995-Dec in surfactant deleted rabbits.Arch Dis Child 1996.Pediatrics 2001; 107: el-8. Fetal and Neonatal Ed 1995;72:F84-89. 2. Greenough A, Milner A.D, Roberton NRC. 13. Soll RF,Blanco F. Natural vs Synthetic Surfactant replacement therapy in Neonatal surfactant for neonatal RDS. Cochrane database Respiratory distress syndrome. Comparison of Syst Rev 2001;2:CD00014. high vs low does of surfactant TA. Euro J Pediatr 14. Konishi M, Fujiwara T, Naito T, et al. Surfactant 1998;147(1):20-25. replacement therapy in neonatal respiratory 3. Jobe AH, Ikegami M, Biology of distress syndrome.Comparison of High vs low Surfactant.Clin Perinatol 2001;28:655-669. dose of surfactant. Euro J Pediatr 1988;147(1): 20-25. 4. Crowley PA. Antenatal corticosteroid Therapy- A meta analysis of the Randomized trials 1972- 15. Kattwinkel J, Bloom BT, Delmore P, et al. High 1994.Am Jl Obst Gynec 1995;173:322-335. vs low threshold retreatment for neonatal 5. Jobe A, Ikegami M, Jacobs H, Jones S,Conaway respiratory distress syndrome. Pediatrics D. Permeability of premature lamb lungs to 2000;106:282-288. protein and the effect of surfactant on that 16. Ho JJ, Henderson Smart DJ, Davis PG. Early permeability. J Appl Physiol 1983 55:169-176. vs delayed initiation of continuous distending 6. Jobe A, Ikegami M, Jacobs H, Jones S. pressure for respiratory distress syndrome in Surfactant and pulmonary blood flow preterm infants. Cochrane database Syst Rev distributions following treatment of premature 2002; 2:CD002975. 29 Indian Journal of Practical Pediatrics 2008; 10(3) : 220

17. Bohlin K, GudmundsdottirT,Katz-Salamon M, severe respiratory failure. Pediatrics 1993;92: Jonsson B, Blennow M. Implementation of 135-139. surfactant treatment during continuous positive airway pressure. J Perinatol 2007;27:422-427. 20. Findlay RD, Taeusch HW, Walther FJ. 18. Auten RL, Notter RH, Kendig JW, et al. Surfactant replacement therapy for meconium Surfactant treatment of fullterm newborns aspiration syndrome.Pediatrics1996;97:48-52. with Respiratory failure. Pediatrics 1991;87: 21. Soll RF, Dargaville P. Surfactant for meconium 101-107. aspiration syndrome in full term infants. 19. Khammash H, Perlman M, Wojulewicz J, et al. Cochrane database of Syst Rev 2000;2: Surfactant therapy in full term neonates with CD002054.

BOOK REVIEW

Name : Radiologist talks to you Editor : Dr.Elizabeth John Review : The most popular articles published under the column of “Radiologist talks to you” serially in IJPP is now brought out as the “IJPP Series - I”. Interpretation of X-ray has almost become a part of extended clinical examination. For clinicians having a vast knowledge in radiology is not sensible and a simple. It would be of immense help if salient and comprehensive practical guidelines to interpret skiagrams is given for day to day practice. This is a long felt need among pediatricians, which is being fulfilled by the “Radiologist Talks to you” as “IJPP series - I”. Normal X-rays and others that are likely to be missed in clinical practice are covered in this series. The X-ray picture quality is good. This book apart from imparting radiological interpretation skill to the reader, will definitely serve as an important desk top reference for the busy pediatric practioner and will be a must have book for every pediatrician. Publishers : Indian Journal of Practical Pediatrics 1A, Block-II, KRSNA Apartments, No.50, Halls Road, Egmore, Chennai-600 008. Tamil Nadu. India. Phone : 044 - 28190032 Price : Rs.200/-

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APPROACH TO NEONATAL value. Neonatal sepsis is a great mimic, its SEPSIS protean symptoms mimicking problems in almost every other organ system. This article will present * Karthikeyan G an evidence based approach to neonatal sepsis, its diagnosis, antibiotic treatment and other Abstract: Antibiotic treatment and aggressive adjunctive therapies like IV immunoglobulin, supportive care are the cornerstones in the colony stimulating factors and exchange management of neonatal sepsis. Early transfusion. recognition is very important but notoriously difficult as there are no specific clinical signs of Early versus late onset neonatal neonatal sepsis. Sepsis screen is useful to confirm sepsis the clinical suspicion of sepsis but search is still on for an ideal screening test that has 100% Sepsis onset within 48 – 72 hours after birth sensitivity and 100% negative predictive value. is termed as early onset sepsis and is presumably Intravenous immunoglobulin therapy is not cost acquired vertically from the flora of maternal effective in treating neonatal sepsis. Colony genital tract. The risk factors for early onset stimulating factors are useful only in the select sepsis are prematurity, prolonged rupture of subset of septic neonates with neutropenia. membranes, intra partum maternal pyrexia Exchange transfusion may be helpful in sepsis more than 38oC, asphyxia, maternal urinary tract complicated by disseminated intravascular infection or diarrhea 48-72 hours before delivery coagulation, sclerema or neutropenia. and positive high vaginal swabs. Sepsis onset after the first 48 – 72 hours is termed as late onset Key words: Neonatal sepsis, Antibiotic therapy, sepsis and is acquired horizontally from the Sepsis screen, Intravenous immunoglobulin, environment. The risk factors for late onset sepsis Colony stimulating factor, Exchange transfusion. are lack of hand washing, low birth weight, mechanical ventilation, indwelling intravenous Neonatal sepsis is a major neonatal problem catheters and cannulae, superficial infections etc. accounting for 1.6 million deaths annually in In a study on neonatal sepsis from Chennai developing countries1. Early recognition is very 50% of the cases of neonatal sepsis were of early important as delay can inevitably lead to death onset2. but this is notoriously difficult as there is no single specific clinical symptom or sign that is Pathogens causing neonatal sepsis unique to neonatal sepsis and no laboratory test can identify a baby with neonatal sepsis with Klebsiella pneumoniae, Staphylococcus 100% sensitivity and 100% negative predictive aureus and E. coli are the predominant pathogens causing neonatal sepsis in India3. This is in * Consultant Neonatologist, contrast to western countries where Group B G.K Baby Hospital, streptococcus (GBS) and coagulase negative Coimbatore. staphylococci are the predominant pathogens. 31 Indian Journal of Practical Pediatrics 2008; 10(3) : 222 Antibiotic resistance is very common with Two or more positive tests is taken as sensitivity to commonly used antibiotics like positive sepsis screen. ampicillin, gentamicin and cefotaxime being very low2,3. In the Chennai study 66% of the Apart from CRP, other acute phase reactants Staphylococcus aureus isolates were resistant to like fibrinogen, orosomucoid and procalcitonin methicillin (MRSA). have also been evaluated in some studies but CRP is the one commonly used in sepsis screen panels. Diagnostic challenge Polymerase chain reaction (PCR) has been evaluated in an Indian study7 and it was found to Blood culture considered the gold standard have a sensitivity of 100% and specificity of for diagnosis is positive in only about 50% of all 95.6%. Cytokines like Interleukin 6 (IL 6) and neonates with a clinical diagnosis of sepsis2,3. Tumour Necrosis Factor (TNF) have been Moreover test results with antibiotic sensitivity evaluated in experimental studies8. Interleukin 6 takes about 48–72 hours and hence the initial was raised very early in the course of the disease choice of antibiotics has to be empirical or based and levels reached normal values by the end of on sepsis screening. 24 hours. Hence it is an early and sensitive Sepsis screening marker. Future sepsis screens are predicted to comprise of interleukin 6 and CRP. Various hematological and non hematological parameters have been evaluated Antibiotic use and laboratory sepsis for rapid evaluation of neonatal sepsis termed as screen sepsis screening4,5. An ideal sepsis screen has to have 100% sensitivity and 100% negative 1. In the symptomatic newborn, antibiotics predictive value; that is, it should not miss any should not be withheld on the face of a negative case of neonatal sepsis while some overtreatment sepsis screen as none of the available screen has can be accepted. Further it should have a rapid 100% negative predictive value. A complete turn over time, be cost effective and results have sepsis work up including blood culture, lumbar to be consistent across different test centres. No puncture (LP) and a chest X-ray needs to be done single test fulfils these criteria and hence a battery before starting antibiotics. Antibiotics can be of tests is employed constituting a sepsis screen stopped in such a situation once the cultures panel. The National Neonatology Forum (NNF) (blood and CSF) are negative. has recommended the following 5 tests as 2. In the symptomatic newborn with a neonatal sepsis screen6. positive sepsis screen whose cultures are negative 1. Leucopenia (total leucocyte count less than antibiotics should be continued for 24 – 48 hours 5000) after the repeat screen is negative. 2. Neutropenia (total neutrophil count less than 3. In the asymptomatic newborn with a 1800) negative sepsis screen in whom antibiotics are started because of the presence of major or 3. Immature : Total neutrophil count ratio more multiple perinatal risk factors for sepsis, than 0.2 antibiotics can be safely stopped once cultures 4. C- Reactive Protein (CRP) more than are negative and a repeat screen is also negative. 6mg/L 4. In the asymptomatic newborn with a 5. Micro- ESR more than 15 mm in first hour negative sepsis screen in the presence of only 32 2008; 10(3) : 223 minor risk factors for sepsis, antibiotics can be Singh et al have recommended the use of withheld and the neonate should be observed for following seven clinical signs as having high the next 24 hours for symptoms and signs of predictive ability of neonatal sepsis in a NICU sepsis. setting10. 5. In the asymptomatic newborn with a 1. Abdominal distension positive sepsis screen antibiotics should be 2. Increased prefeed aspirates administered and continued until the cultures are reported negative or for 24 -48 hours after the 3. Hyperthermia (present on at least repeat screen is negative whichever is later. 2 occasions 1 hour apart) 6. For blood culture positive cases 4. Tachycardia (present on at least antibiotics are continued for 10 – 14 days and 2 occasions 1 hour apart) for meningitis cases intravenous antibiotics are 5. Chest retractions continued for 14 – 21 days or more depending on repeat CSF culture reports. 6. Grunting

Clinical sepsis screening 7. Lethargy Who is a symptomatic newborn? Lethargy, A cut off score of 1 had the highest negative feed intolerance, temperature instability and the predictive value and negative likelihood ratio gut feeling that the baby is just not alright are (85% and 0.44) whereas cut off score of 2 or more often the early presenting features of neonatal had the best positive predictive value and positive sepsis. Never ignore the concerns expressed by likelihood ratio (52 % and 2.65) in diagnosis of experienced nurses. Bleeding diathesis, purpura, late onset sepsis. In a subsequent study to validate shock and sclerema are more overt but late signs this clinical score in a cohort of VLBW babies, of neonatal sepsis. Recent studies have attempted the authors report that the clinical score when to validate different clinical signs and symptoms coupled with a laboratory sepsis screen (2 or more of neonatal sepsis. A WHO multicentric study positive of abnormal absolute neutrophil count, has identified the following nine clinical features immature: total neutrophil count, micro ESR and that can be recognized by community health CRP) had a sensitivity of 95 % and negative 11 workers as being predictive of a serious bacterial predictive value of 90.6 % . 9 illness in young infants . Role of lumbar puncture in the 1. Feeding ability reduced evaluation of neonatal sepsis 2. No spontaneous movement Meningitis is an important complication of 3. Temperature more than 38oC late onset neonatal sepsis and at least 15% of culture proven meningitis cases have negative 4. Prolonged capillary refill time blood cultures. Hence a recent review has 5. Lower chest wall retractions recommended that LP has to be part of routine 6. Respiratory rate more than 60 / min investigation in late onset neonatal sepsis (more 12 7. Grunting than 48 hours) . A recent review has concluded that meningitis is very uncommon in 8. Cyanosis asymptomatic neonates with only risk factors for 9. H/O convulsions early onset sepsis and LP can be safely omitted 33 Indian Journal of Practical Pediatrics 2008; 10(3) : 224 in this group of neonates13. LP still has to be A cochrane review on IVIG for prevention of undertaken in babies who are symptomatic with nosocomial sepsis in preterm or low birth weight early onset sepsis or those with strong suspicion neonates reports a meager 3% decrease in the of meningitis13. incidence of sepsis in the treated group with no decline in mortality or morbidity15. Another Guidelines for antibiotic therapy Cochrane review on IVIG for suspected or Antibiotic therapy has to be started subsequently proven infection in neonates found whenever there is a doubt of neonatal sepsis but borderline significant decrease in mortality and has to be stopped once it is reasonably certain concludes that there is need for further adequately 16 that the baby is not infected. Choice of antibiotics powered trials . The results of International depends on local sensitivity pattern of bacterial Neonatal Immunotherapy Study (INIS) that isolates. Wherever possible, narrow spectrum enrolled 3500 neonates with sepsis to IVIG antibiotics to which the isolates are sensitive have therapy in addition to antibiotics are expected in to be preferred to more broad spectrum antibiotics 2009 – 2010. Given the cost of IVIG and the to minimize chances of antibiotic resistance14. number needed to treat because of the small But on the face of a seriously ill neonate, there beneficial effect, it is not cost effective to should not be a hesitation to embark on broad administer IVIG for prevention or treatment of spectrum antibiotics like meropenam, neonatal sepsis in India and its use has to be fluroquinolones etc. Antibiotic rotation policies restricted to individual circumstances. The help to keep emergence of antibiotic resistance polyclonal non specific nature of the IVIG in check. preparations used in these trials could have been responsible for the not so bright results achieved Supportive therapy in neonatal and specific immunoglobulin therapy like anti sepsis staphylococcal immunoglobulin is being tried in some clinical trials. High level intensive supportive care is the cornerstone in the management of neonatal sepsis Colony stimulating factors (CSFs) in neonatal especially those cases with shock syndrome and sepsis: The granulocyte colony stimulating factor multi organ dysfunction syndrome. Respiratory (G- CSF) and granulocyte- monocyte colony support strategies, hemodynamic support using stimulating factor (GM- CSF) are naturally blood products, fluids and inotropes and occurring cytokines that stimulate the production nutritional support using total parenteral nutrition and antibacterial function of granulocytes and for those cases with necrotizing enterocolitis are monocytes. Neonates whose chemotaxis and crucial in the resuscitation and management of phagocytic abilities are reduced when compared septic shocked neonate with multiorgan to adults especially when complicated by dysfunction. neutropenia may benefit from the administration Novel adjunctive therapy in of CSFs. A cochrane review has suggested that neonatal sepsis G- CSF and GM- CSF decrease the mortality at day 14 in a sub group of 97 neonates with Intravenous immunoglobulin in neonatal systemic infection complicated by neutropenia sepsis: Intravenous immunoglobulin (IVIG) (< 1.7 x 109/l) but there is no evidence of any despite its theoretical benefits has failed to live beneficial role in the prevention of sepsis in high up to the expectations in the clinical trials so far. risk neonates as well as reducing mortality in

34 2008; 10(3) : 225 those with systemic infection uncomplicated by • Existing evidence does not support routine neutropenia17. The dose of G- CSF and GM- CSF use of intravenous immunoglobulin in used in the studies range from 5–10 mcg/kg/day neonatal sepsis. given subcutaneously or intravenously for • Colony stimulating factors are beneficial 3–21 days. in the select subset of septic babies with Exchange transfusion in neonatal neutropenia. sepsis • Exchange transfusion may be helpful in neonatal sepsis complicated by Fresh blood exchange transfusion can disseminated intravascular coagulation, replenish the clotting factors, correct anemia, sclerema or neutropenia. remove circulating bacterial toxins and provide opsonins and immunoglobulins. But there is no References large well conducted randomized controlled trial to validate its efficacy in treating neonatal sepsis. 1. Vergnanao S, Sharland M, Kazambe P, Mwansambo C, Heath PT. Neonatal sepsis: an Limited review of available studies18 has international perspective. Arch Dis Child Fetal suggested that exchange transfusion may be Neonatal Ed 2005; 90: 220 – 224. considered in severe neonatal sepsis complicated 2. Karthikeyan G, Premkumar K. Neonatal sepsis: by a) disseminated intravascular coagulation Staphylococcus aureus as the predominant b) sclerema c) neutropenia. pathogen. Indian J Pediatr 2001; 68: 715 – 717. Conclusions 3. Neonatal morbidity and mortality: Report of the National Neonatal – Perinatal Database. Indian Apart from antibiotic therapy and supportive Pediatr 1997; 34 :1039–1042. care no further definite therapeutic choices are 4. Chiesa C, Panero A, Osborn JF, Simonetti AF, available to treat neonatal sepsis. Given the risk Pacifico L. Diagnosis of neonatal sepsis: of increased mortality despite therapy and A clinical and laboratory challenge. Clinical sequelae like periventricular leukomalacia and Chemistry 2004 ; 50 : 279 – 287. Available the cost of treatment, it is wiser to emphasize on from http://www.clinchem.org/cgi/content/full/ preventive strategies of neonatal sepsis. Good 50/2/279 hand hygiene and exclusive breastfeeding are the 5. Rodwell RL, Leslie AL, Tudehope DI. Early major time tested preventive strategies and try diagnosis of neonatal sepsis using a haematological scoring system. J Pediatr to avoid the ‘give sepsis, treat sepsis’ cycle in 1988; 112 : 761 – 767. neonatal intensive care. 6. Neonatal sepsis. NNF teaching aids available Points to Remember from http://www.gujhealth.gov.in/family-wel/ pdf/Newborn%20Care/neonatalsepsis.pdf • Antibiotics should not be withheld in a accessed on 29.4.2008 symptomatic neonate even in the presence 7. Yadav AK, Wilson CG,Prasad PL, Menon PK. of a negative sepsis screen as none of the Polymerase chain reaction in rapid diagnosis available tests has 100% negative predictive of neonatal sepsis. Indian Pediatr 2005; 42 : value. 681–685. 8. Mishra UK, Jacobs SE, Doyle LW, Garland SM. • Lumbar puncture is mandated in all Newer approaches to the diagnosis of early neonates with late onset sepsis and in onset neonatal sepsis. Arch Dis Child Fetal symptomatic babies with early onset sepsis. Neonatal Ed 2006 ; 91 : F208 – 212. 35 Indian Journal of Practical Pediatrics 2008; 10(3) : 226

9. The WHO Young Infants Study Group. Clinical Arch Dis Child Fetal Neonatal Ed 2006; 91: prediction of serious bacterial infections in F72 – F74. young infants in developing countries. Pediatric 15. Ohlsson A, Lacy JB. Intravenous immuno- Infect Dis J 1999;18:S23 -31. globulin for preventing infection in preterm and/ 10. Singh AS, Dutta S, Narang A. Predictive clinical or low birth weight infants. Cochrane Database scores for diagnosis of late onset neonatal of Systematic Reviews 2004, Issue 1. Art. No.: septicemia. J Trop Pediatr 2003;49:235–239. CD000361. DOI: 10.1002/14651858. 11. Kudawala M, Dutta S, Narang A. Validation of CD000361.pub2. a clinical score for the diagnosis of late onset 16. Ohlsson A, Lacy JB. Intravenous immuno- neonatal septicemia in babies weighing 1000 – globulin for suspected or subsequently proven 2500 g. J Trop Pediatrics Advance access infection in neonates. Cochrane Database of published August 14, 2007. Systematic Reviews 2004, Issue 1. Art. No.: 12. Malbon K, Mohan R, Nicholl R. Should a CD001239. DOI:10.1002/14651858. neonate with possible late onset infection CD001239. pub2. always have a lumbar puncture? Arch Dis Child 17. Carr R, Modi N, Doré C. G-CSF and GM-CSF 2006; 91: 75 – 76. for treating or preventing neonatal infections. 13. Ray B, Mangalore J, Harikumar C, Tuladhar A. Cochrane Database of Systematic Reviews Is lumbar puncture necessary for evaluation of 2003, Issue 3. Art. No.: CD003066. DOI: early neonatal sepsis? Arch Dis Child 2006; 91: 10.1002/14651858.CD003066. 1033 – 1035. 18. Nangia S, Saili A. Exchange transfusion in 14. Isaacs D. Unnatural selection: reducing neonatal sepsis - Does it help? J Neonatol antibiotic resistance in neonatal units. 2006; 20: 333 – 337.

NEWS AND NOTES

BAI JERBAI WADIA HOSPITAL FOR CHILDREN PAREL, MUMBAI 400 012 Department of Pediatric Hematology & Oncology • 2 yrs Fellowship course in Pediatric Hematology and Oncology(PHO) is conducted under the auspices of National Board of Examination (NBE), Delhi • Four centres recognised / accredited by NBE are: B.J. Wadia Hospital for Children, Mumbai, Gangaram Hospital, Delhi, Rajiv Gandhi Cancer Centre, Delhi, Kasturba Medical College, Mangalore. • All the Head of Departments pediatric departments are requested to encourage their postgraduates to avail of this attractive Fellowship programme and appear for the entrance test conducted by NBE at various cities in November / December 2008. Please keep track of the details on their website (www.natboard.nic.in). Dr. Bharat Agarwal Head of Department, Paediatric Hematology & Oncology.

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ALLERGIC RHINITIS symptom rhinorrhea, nasal obstruction and itching of the eyes, nose and palate, occurring * Shivbalan So upon inhalation of allergens among individuals ** Gowrishankar NC previously exposed to such allergens and against Abstract : Allergic rhinitis (AR) is a symptom which they have IgE antibodies. complex characterised by paroxysmal sneezing, Pathogenesis rhinorrhea, nasal obstruction and itching of eyes, nose, palate on exposure to allergen. AR Allergic rhinitis (AR) occurs in a genetically is not uncommon and about a third of children hypersensitivity response. There is an increase with AR have asthma. AR interferes with feeding in circulating IgE levels with release of and sleep in very young children while it causes inflammatory mediators like, histamine, persistent nasal obstruction and chronic mouth prostaglandins and leukotrienes resulting in breathing in older children. Diagnosis is by symptoms within a few minutes of exposure history and physical examination while skin (early-phase response). In about half of patients, prick tests are rarely needed. Management symptoms recur two to eight hours after exposure includes avoidance of allergens, intranasal to allergen and without further exposure, corticosteroids and/or antihistamines. resulting from infiltration of inflammatory cells (late-phase response). Keywords : Allergic rhinitis, Clinical features, Intranasal cortico steroids. Clinical features An allergy is our body’s immune system Characteristic features of allergic rhinitis response to a substance that is usually harmless. include sneezing, watery rhinorrhea, and nasal Rhinitis is defined as an inflammation of the congestion. This may be accompanied by itchy mucus membrane lining the nose resulting in the watery eyes and intense itching of the nose and occurrence of annoying nasal symptoms soft palate. A family history of allergy is the including discharge, itching, sneezing, single-most important factor predisposing congestion, and pressure. Allergic reactions in children to the development of allergic diseases. the nose are frequent as inhaled allergens are AR generally begins in childhood or adolescence trapped by the nasal filtration system. and continues into adulthood. In fact, more than Allergic rhinitis (AR) is defined as one of two-thirds of people with AR are diagnosed at the rhinitis syndromes, associated with a younger than 20 years of age. Most cases of allergic rhinitis begin in the teens or early adult * Consultant Pediatrician and Pulmonologist, Sundaram Medical Foundation, Chennai. life. ** Asst. Professor of Pediatrics, Symptoms are less common in infants or Dept. of Pulmonology, Institute of Child Health and Hospital for very young children. When they do occur, Children, Chennai - 8. obstruction may interfere with feeding and 37 Indian Journal of Practical Pediatrics 2008; 10(3) : 228 contribute to irritability. Children are particularly periorbital edema, periorbital “shiners” or dark affected by the consequences of this illness circles under the eyes attributed to venous stasis especially because nasal obstruction often leads resulting from interference with blood flow to disturbed sleep patterns, poor quality sleep, caused by edematous nasal mucous membrane. fatigue, daytime sleepiness, poor concentration, Pattern of AR hearing difficulty, poor appetite and poor growth. Persistent nasal obstruction predisposes to Traditionally AR has been described as chronic mouth breathing, which in turn in a being either seasonal (hay fever) or perennial, growing child causes abnormal development of although both types often coexist. Seasonal AR the mouth and teeth associated with changes in occurs at defined yearly intervals in response to facial features. About one-third of people with wind borne outdoor allergens such as tree, grass AR have asthma. Treating AR with systemic or and weed pollens. Plants that rely on insect local agents can alleviate the symptoms of pollination rarely cause AR. Perennial AR are asthma. AR may be associated with allergic triggered by exposure to allergen present all year conjunctivitis, chronic sinusitis or rhinosinusitis round like house dust mite, animal dander or due to blockage of the osteomeatal unit and moulds. repeated bouts of otitis media with or without The World Health Organization in its effusion due to eustachian tube inflammation. guidelines, “Allergic Rhinitis and Its Impact on Allergic rhinitis can also be associated with Asthma,” proposed that AR no longer be uncontrolled asthma, halitosis, husky voice, sore classified as seasonal or perennial (occupational) throat and recurrent eye infections. Allergic but rather be categorized as either persistent or rhinitis should be considered in children with intermittent, and that symptoms be graded continuous or recurrent upper respiratory relative to severity. This is in relation to the infections, frequent sore throat, mouth breathing concept of one airway and one disease that the and snoring, recurrent infective sinusitis, chronic inflammatory reactions in the nose, eyes, headaches, recurrent upper respiratory tract or and upper airways of people with AR are middle ear infections. identical to those that occur in the lower airways of people with asthma, and that the two Physical examination conditions are inextricably linked. Intermittent Focus the physical examination on the AR is defined as symptoms less than 4 days per patient’s nose, eyes, throat, ears, lungs and week or less than 4 weeks at a time. Persistent skin. Observe the patient for “allergic salute” AR is defined as symptoms more than 4 days per (ie., repeated nose wiggling, wiping, pushing, week or more than 4 weeks at a time. Mild to etc., usually with an open, upward-facing palm) severe AR is categorized based on any and mouth breathing (chronic). Transverse nasal impairment of sleep and daily activities (Fig.1). crease and Dennie-Morgan infra orbital crease occurs secondary to allergic salute. Nasal Differential diagnosis examination usually reveals clear nasal • Nonallergic perennial rhinitis (vasomotor secretions, edematous, boggy nasal mucous rhinitis) membranes with little or no erythema and • Non-allergic rhinitis with eosinophilia swollen, purple turbinates that may block the syndrome (NARES) nasal airway. Thick nasal secretions may indicate infection. AR often reveals conjunctival, • Rhinitis medicamentosa.

38 2008; 10(3) : 229 • Gustatory rhinitis to differentiate allergic and nonallergic rhinitis • Anatomic nasal obstruction (eg, polyps, when they are not adequately controlled by deviated septum, enlarged turbinates, medication and trigger avoidance. Presence of adenoid hypertrophy, tumor) eosinophils in nasal smear is usually in favor of allergic origin but does not conclusively • Nasal foreign bodies (particularly in young differentiate AR from nonallergic eosinophilic children) rhinitis. • Infectious rhinitis, atrophic rhinitis, rhinosinusitis. Allergy testing • Environmental/ Occupational rhinitis Allergy testing is performed in order to (eg. animal exposure, woods dusts, industrial confirm the diagnosis in difficult cases and to enzymes, food processing, latex). identify the allergens that could be avoided or be • Rarely: Malignancy, vasculitis included in immunotherapy regimens. Culpable (eg. Wegeners granulomatosis), sarcoidosis, allergens can be identified by skin prick test or hypothyroidism. in vitro tests to test the presence of allergen- specific IgE antibodies. Diagnosis In vitro tests for serum IgE antibody to History and physical examination are allergens by radioallergosorbent test (RAST) and usually sufficient to diagnosis and manage AR. enzyme-linked immunosorbent assay (ELISA), In select situations skin prick tests or serum estimate the amount of allergen-specific IgE assays for allergen- specific IgE may be required antibody in a patient’s serum. Intermittent Pers (Symptoms) (Symp • < 4days/ Wk • > 4 days • or < 4 Wks • and > 4

Mild Modera (All of the following) (One or m • Normal sleep • Abnormal s • No impairment of daily • Impairment activities, sport, leisure activities, s • No impairment of work & • Impaired w school school • No troublesome symptoms • Troublesom

Fig.1. Classification of AR

39 Indian Journal of Practical Pediatrics 2008; 10(3) : 230 Management not intended to relieve acute symptoms, hence they need to be used on a regular basis. The Five general approaches can be used in the United States Food and Drug Administration management of allergic diseases: identification (FDA) has approved six intranasal steroids for of allergens, patient education, avoiding or use in AR: beclomethasone, budesonide, minimizing exposure to allergens, pharmaco- flunisolide, fluticasone, mometasone, and therapy and allergen immunotherapy. triamcinolone. All work by down-regulating Allergen avoidance numerous steps in the inflammatory process. When used prophylactically, they attenuate both Allergen identification and avoidance are early- and late-phase reactions. Most agents in critical first steps in treatment, particularly in this drug class are administered once or twice patients with perennial symptoms. Neither daily and have an onset of action of 12 to medications nor immunotherapy should be used 24 hours. Maximum benefit can take days or as substitutes for, but rather as adjuncts to, weeks to manifest. Once control of symptoms reducing exposure to allergic triggers. has been achieved the dosage should be reduced The common allergens are: (a) Pollen, progressively to the minimum dose to control (b) Molds/Fungi, (c) Dust Mites: Air cleaners symptoms. Daily use is required in most patients. with high-energy particulate air (HEPA) filters In clinical practice for children, INGCs can may reduce particulate air matter. (d) Animal be started with the maximal dose for age. Once Dander: The root of the problem is the protein symptoms are adequately controlled, “step down” secreted primarily by sebaceous glands which is the dose at one week intervals to the lowest also found in urine and saliva. Dander becomes effective dose. Patients with severe symptoms easily airborne and accumulates in upholstered will require daily use on a chronic basis. furniture and carpets. For patients allergic to pet dander, the only way to completely eliminate Step on how to use INGCs; symptoms is to remove the pet from the home. (e) Cockroaches, (f) Viral upper respiratory • Shake the bottle. infections can aggravate allergies. They should • Blow your nose so that your nostrils are avoid contact with people who have viral upper clear. respiratory illnesses, if possible, wash hands frequently, and refrain from sharing food, drink, • Wash your hands. etc. • Take the lid off the bottle. Pharmacotherapy • Tilt your head slightly forward. The therapeutic options in AR management • Close one nostril by gently pressing are shown in Table 1 and topical medications are against the side of your nose with your given in Table 2. finger. Inhaled nasal glucocorticosteroids (INGCs) • Insert the tip of the nasal spray away have been shown to be effective in the from the septum into the other nostril and management of allergic rhinitis. They relieve start to breathe in slowly through your nasal blockage, discharge, sneezing, nasal itch, nose. While you are still breathing in post-nasal drip and eye symptoms. Corticosteroid squirt one spray into the nostril keeping nasal sprays act as prophylactic agents and are the bottle upright. 40 2008; 10(3) : 231 Table 1. Therapies for allergic rhinitis Agent Action Indication Example Side effects

Second- Blocks H1 Reduces sneezing, Fexofenadine; Mild sedation, dry generation receptors ocular and Cetrizine, mouth in antihistamine and inhibits- nasopharyngeal- Loratadine minorityof autacoid release itching, rhinorrhea Azelastine* patients Intra nasal Inhibits influx Reduces sneezing, Beclomethasone Nosebleed, corticosteroid* of inflammatory ocular and Budesonide nasal septal cells nasopharyngeal- Fluticasone perforation itching, rhinorrhea, Mometasone mucosal congestion Leukotriene- Blocks Reduces mucosal Montelukast Elevated levels of receptor leukotriene inflammation AST, ALT, antagonist receptors Bilirubin Anticholinergic Blocks Reduces copious Ipratropium* Headache, agent acetylcholine rhinorrhea nosebleed receptors

α adrenergic Vasoconstrictor Relieves nasal Pseudoephedrine, Arrhythmias, agonist congestion Phenylephrine hypertension, (decongestant) nervousness, insomnia

* Intranasal application

Table 2. Dosage of nasal topical medication Azelastine 5-11 yrs, 1 spray each nostril BD ≥12 yrs, 2 spray each nostril BD Beclomethasone ≥6 yrs, 1-2 spray each nostril BD Budesonide ≥6 yrs, 1-2 spray each nostril OD (≥12 yrs max of 4 spray each nostril OD) Fluticasone ≥4 yrs, 1-2 spray each nostril OD Mometasone 2-11 yrs, 1 spray each nostril OD ≥12 yrs, 1-2 spray each nostril BD Ipratropium ≥5 yrs, 2 spray each nostril 2-3 times/ day.

41 Indian Journal of Practical Pediatrics 2008; 10(3) : 232 • Remove the spray from the nostril and Leukotriene antagonists (montelukast), while breathe out through your mouth. topical nasal steroids appear to provide superior symptoms control, these drugs may provide • Repeat the same for the other nostril. additional relief in selected patients. • Replace the lid on the bottle. Non medicated treatment with steam and salt • Once daily preparations may be more water (saline) sprays when used on a regular basis effective if administered in the evening, can help to relieve nasal blockage and thick as nasal inflammation is greater at night secretions. than during the day Diet has only a minor influence on symptoms in most people. The results from strict Antihistamine nasal sprays or eye drops “elimination diets” are usually disappointing and (azelastine) act rapidly (within minutes) to relieve may affect nutrition. sneezing or itching and are generally well tolerated. In general, they are less effective at The stepwise algorithm for management of relieving severe nasal congestion. AR is depicted in Fig.2.

Decongestant nasal sprays or drops provide quick Immunotherapy relief, but should only be used in the short-term (up to a maximum of 5 days) to clear excessive Immunotherapy (desensitisation) is the nasal blockage. In patients with severe nasal closest thing to a cure for allergic rhinitis and an obstruction, they may be used for a few days to effective adjunct to drug therapy in selected open the air passages to allow access to the nasal patients. Immunotherapy, or the repeated, mucosa by corticosteroid nasal sprays. Repeated controlled administration of specific allergens to or long term use of this can lead to rhinitis patients with IgE-mediated conditions and is medicamentosa. Intranasal decongestants usually given to patients as weekly or biweekly (eg.phenylephrine, oxymetolazine, xylometola- injection over a period of years. zine, and naphazoline), which act more rapidly Immunotherapy decreases early and late and have fewer systemic side effects than oral phase response to nasal allergen challenge. The counterparts, continue to be used widely by major risk with the use of immunotherapy is patients with AR, but use for more than seven to anaphylaxis, and serum sickness too can occur eight days causes rebound congestion upon drug rarely. withdrawal. Allergy prevention in children Anticholinergic sprays (Ipratropium) are very effective in reducing watery rhinorrhoea. Allergies are often life-long and although treatable, they are not curable. To prevent Mast cell stabilising nasal sprays or eye drops allergies in children with a strong family history cromolyn sodium reduce inflammation with of allergies it is suggested to exclusively breast regular use. feed infants till 6 months, starting complimentary Oral medication feeding after 6 months with hypoallergenic diet, avoid exposure to environmental tobacco smoke, Systemic corticosteroids are indicated for allergic delay introduction of allergenic foods and rhinitis only in exceptional circumstances. minimise exposure to dust mites.

42 2008; 10(3) : 233

Fig.2. Management of AR

43 Indian Journal of Practical Pediatrics 2008; 10(3) : 234 Points to Remember Bibliography • Allergic rhinitis is not uncommon in 1. Greiner AN. Allergic rhinitis: impact of the children disease and considerations for management. Med Clin North Am, 2006;90:17-38. • Allergies are often life-long and although treatable, they are not curable 2. Lai L, Casale TB, Stokes J. Pediatric allergic rhinitis: treatment. Immunol Allergy Clin North • AR is most often a clinical diagnosis and Am, 2005;25:283-299. investigations are rarely required 3. Plaut M, Valentine MD. Clinical practice. • Allergen avoidance is the first step in AR Allergic rhinitis. N Engl J Med 2005;353:1934- management. 1944. 4. ARIA, At-A-Glance Pocket Reference 2007. • INGCs and 2nd generation antihistaminics New aria update based on the allergic rhinitis are the main stay of pharmacotherapy and its impact on asthma workshop report In • Skin testing and immunotherapy is used as collaboration with the World Health 2 a last resort in difficult cases Organisation, GA LEN, and allergen.

NEWS AND NOTES

“THILLAI NEOCON 2008” VI Annual Convention of National Neonatology Forum TamilNadu Chapter

Venue: Rajah Muthiah Medical College Annamalai University Annamalai Nagar – 608 002 Date : 4th & 5th October 2008. Organised by : Rajah Muthiah Medical College and Indian Academy of Pediatrics – Cuddalore District For details contact: Dr.S.Ramesh Professor & H.O.D of Pediatrics Rajah Muthiah Medical College & Hospital Annamalai University Annamalai Nagar – 608 002 E.mail: doc_ramesh [email protected] [email protected] Fax : 04144 - 237333 Phone No: 04144 – 237333 Mobile No: 9443271734, 9486223289

44 2008; 10(3) : 235

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LONG TERM CONTROL OF Clinical evaluation CHILDHOOD ASTHMA The diagnosis of asthma is based * Balachandran A predominantly on history, clinical examination and laboratory investigations. Abstract : Asthma, an inflammatory disorder of airway is known for its episodic presentation. History Clincial evaluation is based on history, clinical 1. A complete description of the symptoms: examination and laboratory investigations. Long term management comprises of allergen control, a. Symptoms such as recurrent cough or aerosol therapy and follow up. wheeze or breathlessness, chest discomfort, post tussive vomiting Keywords : Asthma, Clinical evaluation, Chronic managment, Children. b. Pattern of symptoms with regards to onset, severity, duration, character, diurnal Asthma is defined as a chronic inflammatory variation, sleep disturbance and child’s disorder of the tracheobronchial tree activity. characterized by reversible recurrent airway c. Precipitating factors such as allergens, obstruction either spontaneously or with therapy. infections, nonspecific exposure to irritants, Asthma is characteristically episodic hence there weather changes, emotional factors and may not be signs and symptoms of airway physical stress (exercise) which may induce obstruction at the time of evaluation. These cough and wheeze. patients have airway hypersensitivity to a variety of stimuli. 2. History of associated illness, rhinitis, sinusitis, The pathologic changes include anatomic atopic dermatitis and nasal polyps. narrowing of the tracheobronchial airway causing 3. Details of previous episodes and medications increased resistance to air flow, over inflation of and the response to bronchodilators or steroids. the lung, uneven distribution of ventilation with regional hypoventilation in relation to pulmonary 4. Environment of the child at home, school, play blood flow (reduced V/Q) causing hypoxemia area, presence of pets or pollutants. and increased ventilation drive. This is secondary 5. Impact of the disease on the child and family, to airway inflammation, mucus plugging and both at home and around in consideration of epithelial injury. In uncontrolled persistent socioeconomic and emotional factors. asthma, over a period of time these changes lead to airway remodeling. 6. Family history of allergy, asthma or other significant medical problems. * Consultant Pediatric Pulmonologist, Mehta Children’s Hospital, Also look for evidence of atopy like eczema, Chennai bilateral pale hypertrophied inferior turbinate and

45 Indian Journal of Practical Pediatrics 2008; 10(3) : 236 insect bite allergy. Look for the shape of chest in symptoms are not present), and supportive persistent asthma, there may be an increase in laboratory tests like spirometry. anteroposterior diameter. Grading of asthma severity It is important to remember that asthma is History of inability to eat due to symptoms, characteristically episodic and children may not sleep disturbance, restriction of play and activity, have signs or symptoms at the time of frequency of school absenteeism along with the examination. Diagnosis of asthma is based on number of emergency room visits and detailed history and clinical examination and hospitalization need to be taken into account for absence of wheeze during examination does not assessing the severity of asthma. Based on exclude a diagnosis of asthma. Hence it is symptoms, severity of chronic asthma can be necessary to know the symptoms and signs of classified (Table 1). airway obstruction and to assess them in evaluation to make a diagnosis of asthma. However, for practical purposes grading severity of asthma is done by assessing symptoms Symptoms suggestive of airway obstruction (day and night) with or without peak expiratory are: recurrent wheeze, recurrent isolated cough, flow (PEF) over a period of time (eg. last recurrent breathlessness, nocturnal cough, 3 months). tightness of chest and/ or exercise induced cough/ wheeze. Asthma symptoms tend to cluster in later Aerosol therapy is the cornerstone in asthma part of the night. Hormonal changes are attributed management. There are number of delivery to play a role in night time symptoms of asthma. systems available that are suitable for different The serum cortisol and epinephrine levels are at ages. The advantages of aerosol therapy are their nadir in early morning causing increased smaller dose, target delivery, quick action, safety airway resistance and nocturnal symptoms. and fewer side-effects. The delivery systems that are commonly utilized are: metered dose inhalers Signs suggestive of airway obstruction are: (MDI), dry powder inhalers (DPI) and nebulisers generalised rhonchi, prolonged expiration and/ (Table 2). or chest hyperinflation (increased anteroposterior diameter of the chest). Successful pharmacologic management of asthma should incorporate two major strategies: It is important to remember that all reversal of acute and chronic airway obstruction, asthmatics need not have wheeze. Cough long-term attenuation and prophylaxis of the responding to bronchodilators may be an intrabronchial sequelae due to inflammatory cells evidence of reversible bronchospasm. Asthma and their mediators. The current treatment of can manifest either as acute exacerbations or asthma involves two major classes of drugs: chronic asthma. a) Relievers, i.e. bronchodilators used for Diagnosis immediate relief of symptoms. e.g. salbutamol, terbutaline. No definitive diagnostic test for asthma exists and the diagnosis of asthma is based on a b) Controllers, i.e. anti-inflammatory drugs that clinical constellation of symptoms, the patient’s help in stopping bronchial wall remodelling and personal and family history, physical examination in prevention of excacerbations. They can be findings (which are often absent when acute either inhaled or oral medications. 46 2008; 10(3) : 237 Table 1. Severity of asthma Grade of severity Day time Night time Peak expiratory symptoms symptoms flow(PEF)* Intermittent · < twice a week · < twice a month · > 80% of personal best · Brief exacerbation · <20% diurnal variation** Mild persistent · > twice a week but · > twice a month · >80% of personal best < twice a day · 20-30% diurnal variation · Exacerbation may affect sleep and activity Moderate persistent · Daily · > once a week · > 60%-<80% of personal · Exacerbation may best or affect sleep and · > 30% diurnal variation** activity Severe persistent · Daily · Frequent · < 60% of personal best · Limited physical · > 30% diurnal variation** activity · Frequent exacerbation * Not essential ** A diurnal variation of < 10% in PEF values is normal. Lowest PEF levels are seen on waking and highest levels about 12 hours later. Table 2. Age appropriate devices Inhaled drugs are inhaled corticosteroids Device Suitable age % of drug (ICS) like beclomethasone, budesonide, delivery fluticasone and ciclesonide, long acting beta agonists (LABA) like salmeterol and formoterol MDI + <4 years 10-15% and mast cell stabilizer like cromolyn sodium. Spacer + (preschool) Face mask Oral medications are leukotriene antogonists MDI + >4 –6 years 10-15% (LTRA) like montelukast, sustained release Spacer (early school age) (SR) theophylline and oral steroids. Controllers only control but do not cure asthma and there is DPI >7-8 years 5-10% no role for controller therapy in intermittent (late childhood) asthma. MDI adolescence 5-10% Long term management of asthma consists Home all ages 1-5% of environmental control of dust and pollution, nebuliser* management of chronic asthma with aerosol * Not recommended routinely except in acute therapy and treatment of acute episodes of severe exacerbations or where other modalities asthma, regular follow up and effective parent/ of drug delivery had failed especially in infants. patient education. 47 Indian Journal of Practical Pediatrics 2008; 10(3) : 238 Specific goals of asthma management are: and severity has to be reassessed on every follow • Control of symptoms up visit. • No emergency room visits or On follow up hospitalizations Follow up is basically to reassess the child • No school absenteeism for symptom control or exacerbations, checking • No exercise limitations reinforcing drug compliance and technique. • No sleep disturbance Therapy is initiated based on the degree of • Optimal lung function symptoms, airflow limitation, and lung function • Limited side effects due to drugs variability which have allowed asthma to be classified by severity as intermittent, mild • Normal day to day life like their peers. persistent, moderate persistent, or severe Normal growth persistent asthma. However, it is important to recognize that asthma severity involves both the Once a diagnosis of asthma has been made severity of the underlying disease and its appropriate management should be instituted. responsiveness to treatment. The severity of Assessment of severity of asthma should be made asthma may change over months or years. based on duration, frequency and severity of Therefore, for subsequent ongoing management symptoms. Peak flow rate is not always required of asthma, the more relevant and useful and is an additional objective measurement for classification of asthma would be by the level of grading and diagnosis. The latest trend in the control. management of asthma is aerosol therapy i.e. inhaled drugs are better than systemic drugs The goal of asthma care is to achieve and because of target delivery, smaller dose, rapid maintain control of the clinical manifestations action and fewer side effects. For the inhaled drug of the disease for prolonged periods. When to be effective it should reach the lungs in asthma is controlled, patients can prevent most sufficient amount. The penetration and deposition attacks, avoid troublesome symptoms at day and of aerosol depends upon the particle size, night, and be physically active. velocity, type of device and ventilatory pattern. To reach this goal, four interrelated Initiation of aerosol therapy: Once diagnosis components of therapy are required: (1) Develop has been reached appropriate management should patient/ family and doctor partnership, be instituted. Assess severity of asthma. There (2) Identify and reduce exposure to risk factors, are two methods in practice: one is “step down” (3) Assess, treat, and monitor asthma, method, where control is achieved by starting (4) Manage acute episodes of asthma. the regime suitable to higher severity and titrated Assess, treat and monitor asthma down. Other method is step up method in which the regime appropriate to the grade assessed is The ultimate goal of asthma management is started and titrated upwards if control is not to achieve and maintain clinical control. This can achieved. The drug and dosage for asthma be achieved during regular follow-up by management are given in Table 3 and 4. assessing asthma control, accordingly treating to Medication plans must accommodate the fact that achieve control and monitoring further to asthma is both a chronic and a dynamic condition maintain control 48 2008; 10(3) : 239 Table 3. Drugs used in asthma management Grade* First choice Alternate choice

Intermittent Short acting β2 agonist when required No controllers Mild Persistent Low dose ICS LTRA/ SR theophylline Moderate Persistent Low dose ICS + LABA or Low dose ICS+ LTRA/ Medium dose ICS SR theophylline (SRT) Severe persistent Medium dose ICS + LABA High dose ICS + LABA Then add LTRA/ SRT If needed add oral steroid Anti-IgE (Omalizumab) • At every grade of severity, avoid allergens / irritants and acute episodes should be managed with reliever drugs as appropriate.

Table 4. Equipotent daily dose ICS and LABA in children Relievers Low dose Medium dose High dose (μg / day) (μg / day) (μg / day) Budesonide/ Beclomethasone 100-200 >200-400 >400 Fluticasone 100- 200 >200-500 >500 Ciclesonide 80-160 >160-320 >320

Salmetrerol Max 150 μg / day Formoterol Max 24 μg / day

For children 5 years and younger, the best Monitoring is essential to maintain control and treatment to control asthma is inhaled establish the lowest step and dose of treatment glucocorticosteroids. to minimize cost and maximize safety. Typically, Exacerbations of asthma (asthma attacks or patients should be seen one to three months after acute asthma) are episodes of progressive the initial visit, and every three months thereafter. increase in shortness of breath, cough, wheezing, After an exacerbation, follow-up should be or chest tightness, or some combination of these offered within two weeks to one month symptoms. Respiratory distress is common but (Table 5). need not be always present. a) If asthma is not controlled on the current In children above 5 years, after initiation of treatment regimen, step up treatment. Generally, treatment as discussed before, further dosing has improvement should be seen within 1 month. to be titrated depending on the level of control. If the control is not good, reassess and reconfirm 49 Indian Journal of Practical Pediatrics 2008; 10(3) : 240 Table 5. Assessment of levels of asthma control Controlled Partly controlled Uncontrolled (All of the following) (Any measure present in any week) Daytime symptoms None More than twice/ week Three or more (twice or less/ week) features of partly Limitation of activities None Any controlled asthma present in any week Nocturnal symptoms/ awakening None Any Need for reliever None More than twice/ week medications (twice or less/ week) Lung function Normal <80% predicted or

(PEF/FEV1) personal best Exacerbations None One or more/ year†† One in any week** Management options Continue the same/ Look up# or Step up Step down #Check on compliance, trigger avoidance, diagnosis and co-morbid conditions ††Any exacerbation should prompt review of maintenance treatment to ensure that it is adequate. **An exacerbation in any week makes that an uncontrolled asthma week. the diagnosis, check compliance, eliminate reduction in dose of ICS and stopping medication triggers, treat concurrent medical conditions, treat on the principle of last in first out basis. The goal exacerbation and if required seek a second is to decrease treatment to the minimum opinion. medication necessary to maintain control. b) If asthma is partly controlled, consider In most patients, the increase from a medium stepping up treatment, depending on safety, cost to a high-dose of inhaled cocorticosteroid (ICS) and patient’s satisfaction with the level of control provides relatively little additional benefit. achieved. If nothing is contributory, increase the Controller treatment can be stopped if the dose of steroids by 50% to a maximum dose then patient’s asthma remains controlled on the lowest add on inhaled long acting β2 agonist/ Oral dose of controller and no recurrence of symptoms sustained release theophylline/ Oral steroid. Then occurs for one year. immunotherapy/ immunomodulators agents like methotrexate or anti IgE therapy (Omalizumab) In asthma, control is equated to cure and it can be tried. is considered to be in control (remission) if the patient is free from symptoms or not on any form c) If control is maintained for at least of reliever or controller therapy for the last 3 months, step down with a gradual, stepwise 12 months. Monitoring is still necessary even reduction to minimum dose possible in treatment, after control is achieved, as asthma is a dynamic with the principle of tapering by 25-50% disease and relapse or recurrence can happen. 50 2008; 10(3) : 241 Points to Remember College of Paediatrics and Child Health. The British guidelines on asthma management • As asthma is characteristically episodic 1995 review and position statement. Thorax there may not be any symptom or sign of 1997; 52(suppl 1): s1-21. asthma. 4. Global strategy for Asthma Management and • Proper clinical evaluation and Prevention — revised 2006 (in www.ginasthma.org categorisation of cases is important for management. 5. National Institutes of Health, National Health, Lung, and Blood Institute, National Asthma • The ultimate goal of asthma management Education and Prevention Program, Expert is to achieve and maintain clinicl control. Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. Washington, DC: • Successful pharmacologic management U.S. Government Printing Office; 1997. NIH aims at reversal and prevention of Publication No. 97-4051. (a) acute and chronic airway obstruction, 6. National Institutes of Health, National Health, (b) avoidence of intra bronchial sequelae. Lung, and Blood Institute, NAEPP Expert Panel Bibliography Report. Guidelines for the Diagnosis and Management of Asthma: Update on Selected 1. Mathur SK, Busse WW. Asthma: diagnosis and Topics 2003. Washington, DC: U.S. management. Med Clin North Am 2006; 90: Government Printing Office; 2002. NIH 39-60. Publication No. 02-5075. 2. Carroll W, Lenney W. Drug therapy in the 7. C Lemière, T Bai, M Balter, et al. On behalf of management of acute asthma. Arch Dis Child the Canadian Adult Consensus Group of the Educ Pract Ed. 2007; 92:82-86. Canadian Thoracic Society. Adult Asthma 3. British Thoracic Society, National Asthma Consensus Guidelines Update 2003. Can Respir Campaign, Royal College of Physicians of J 2004; 11(Suppl A):9A-18A. London in association with the General 8. Indian Academy of Pediatrics- National Practitioners in Asthma Group, British guideline. Asthma by Consensus. Consensus Association of Accident and Emergency statement on the diagnosis and management of Medicine, British Paediatric Society, Royal asthma in children- Update 2007.

NEWS AND NOTES

1ST CENTRAL ZONE CONFERENCE AND XXIX AP STATE CONFERENCE, ANDHRA PRADESH November 14-16, 2008 Contact Dr.P.Venugopal Organizing Secretary, Department of Pediatrics, KGH, Maharanipeta, Visakhapatnam-530 002. Andhra Pradesh, India. Tel: 09848027203 Email: [email protected]

51 Indian Journal of Practical Pediatrics 2008; 10(3) : 242

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URINARY TRACT INFECTION – in children. UTI in children is peculiar with its WHEN AND HOW TO EVALUATE? variable symptomatology. Acute presentation as septicemia is commonly seen with UTI in the * Vijayakumar M neonatal period. Both acute and chronic * Prahlad N presentations of UTI are seen in infants and older children. It is characterized by recurrences in Abstract: Urinary tract infection in a growing infants and young children and various urinary child can result in parenchymal damage and lead anomalies and voiding dysfunctions, which aid on to renal scars with resultant hypertension and in chronicity are commonly seen in childhood end stage renal disease. Upper tract UTI and UTI. High morbidity is usual with renal scarring, complicated UTI needs early and aggressive hypertension and chronic renal failure in chronic management to reduce morbidity and mortality. UTI1,2. Early diagnosis, most of the times on Essential evaluation with ultrasonography, suspicion, is mandatory for better management voiding cystourethrography and radionuclide so as to prevent the resultant mortality and imaging is the need of the day. Follow-up morbidity. Management of UTI in children is imaging to assess the progression of the disease not treatment alone and it involves steps to and to document the efficacy of therapeutic identify the severity of acute damage and to intervention should be remembered. Correct document associated anatomical or functional usage of intravenous urogram and direct anomalies. Steps includes investigations at the radionuclide cystogram is needed. Voiding initial stage for treating acute UTI followed by dysfunction needing urodynamic studies and subsequent evaluation to prevent scarring of the uroflow EMG should not be forgotten in recurrent growing kidney in infants and young children. and complicated UTI. Asymptomatic bacteriuria Investigations like ultrasonography, voiding in adolescent girls needs at least a good cystourethrography and radio isotope imaging ultrasound to document anatomical anomalies have become useful and mandatory for a proper as renal scars are being documented in few of management of UTI in children3. Consensus them. statement on management of UTI from Indian Keywords: Urinary tract infection, Pediatric Nephrology Group has given clear ultrasonogram, radionuclide imaging, voiding guidelines to aim at correct management of UTI cystourethrogram in children4. Individual unit’s experience is added Introduction to the existing knowledge on evaluation of childhood UTI so that every child gets the priority Urinary tract infection (UTI) and respiratory of adequate and aggressive initial management tract infections are common bacterial infections followed by essential evaluation to make kidneys * Consultant Pediatric Nephrologist, of children grow normally into adult kidneys. Mehta Children’s Hospital, UTI in a child up to 2 years of age and if feasible Chennai 600 031. even up to 5 years of age should be treated and 52 2008; 10(3) : 243 evaluated completely so as to reduce the recurrence of symptoms and significant bacteri parenchymal damage to the growing kidney. uria in a child who had previously recovered clinically with appropriate treatment. The second Why should we evaluate UTI? episode (recurrence) may be early (relapse: Delay in diagnosis results in delayed within 2 weeks) or late (re-infection)6. treatment which causes extensive morbidity. Unless the child with UTI is evaluated Most of the times, this is due to vague completely treatment will not be adequate. For symptomatology of UTI in infants and young example, radio nuclide scan using Dimercapto children. Young age, delay in initiating succinic acid (DMSA) to document nucleopenic antibacterial therapy, wrong choice of antibiotics, areas will be needed to document acute pyelo short duration of therapy, recurrences and nephritis in a child. This investigation is the gold associated disorders like vesicoureteric reflux are standard for evidence of pyelonephritis. But for essential risk factors for renal scarring1,5. About this investigation the child will not be treated 50% of the children with symptomatic UTI have adequately for sufficient duration with the recurrences5. It was also documented that 10-25% presumption that it is a simple UTI. This is of children with asymptomatic bacteriuria especially so when the child becomes afebrile acquire focal renal scars and a proportion develop and asymptomatic within 3 or 4 days of renal stones, hypertension, chronic renal failure appropriate antibiotic therapy only to make the or complications of pregnancy1. Hospital child develop parenchymal damage and the acquired infection should be always kept in mind resultant scars. DMSA scans are found useful especially with indwelling urinary catheter. even in culture negative UTI to document acute UTI with lower tract symptoms like urgency, pyelonephritis7. A prospective study was done dysuria and pollakiuria due to inflammation of by us to assess the frequency of acute bladder mucosa is called lower tract UTI or pyelonephritis (APN) documented by Tc99m cystitis and is being described as dysuria- DMSA scintigraphy (DMSA) and the frequency frequency syndrome. Usually fever is not the of vesicoureteric reflux (VUR) in febrile children rule. On the contrary features of upper tract with positive urine culture.We also determined infection include fever, flank pain and systemic the frequency of APN, in febrile children with symptoms. Upper tract infection is bacterial supportive evidence for UTI but with negative infection of renal parenchyma and is termed acute urine culture, as documented by DMSA and pyelonephritis. Lower tract infection is common frequency of VUR in them. This study stressed in females and can be benign with less chance of the utility of DMSA to diagnose APN in urine associated anomalies. But upper tract infection culture negative febrile children and suggested should always be considered as malignant DMSA as a clinical tool in evaluation of fever of infection and is usually associated with urinary unknown origin (FUO). This study included tract anomalies. Asymptomatic bacteriuria is 42 children with positive urine culture and significant bacteriuria without classical 26 children with negative urine culture who had symptoms and diagnosed on routine screening. clinico-biological features of UTI as determined This is commonly seen in school going and by the predetermined criteria and diagnosed to adolescent girls. Upper tract infections, UTI have APN by DMSA. The clinico-biological associated with anomalies and recurrent UTI features included febrile illness, renal angle constitute complicated UTI. Second attack of UTI tenderness, toxic child, positive acute phase is usually termed as recurrent UTI. It is the reactants, elevated total counts of WBC and 53 Indian Journal of Practical Pediatrics 2008; 10(3) : 244 polymorphonuclear leucocytosis. All of them had Repeat cultures are indicated when contami- ultrasonogram (USG), DMSA and micturating nation is suspected with mixed growth as well cystourethro-gram (MCU). They were followed as with growth of organisms normally up for a minimum period of 6 months. Out of the constituting the periurethral flora like 42 children with positive urine culture 92.9% had lactobacillus in healthy girls and enterococci in features of APN in the DMSA of whom 82.1% infants and toddlers4. had vesicoureteric relux (VUR). The DMSA was Urinalysis: Mild proteinuria, leukocyturia (more abnormal in 26 children with negative urine than 5 WBC/HPF in centrifuged urine and more culture, of whom 65.4% had VUR. Ultrasound than 10 WBC/mm3 in uncentrifuged urine) and suggestive of parenchymal change was observed bacteria on Gram stain can indicate UTI4. in 47.6% in the culture positive group and Enhanced urinalysis using uncentrifuged urine 65.4% in the culture negative group. and Neubauer counting chamber along with In conclusion, it was suggested, that DMSA is Gram staining of urine sediment is found useful a useful investigation for the diagnosis of APN to get at the suspicion of UTI early. More than in febrile UTI. DMSA is indicated in febrile 10 WBCs/mm3 with a positive gram staining will children with negative urine culture but with indicate the possibility of UTI to a very supportive evidence of UTI and in FUO. reasonable extent. An abnormal DMSA is a strong indication for work up for VUR7. Others investigations Rapid tests: The popular rapid tests like nitrite like ultrasonogram done with the help of or Greiss test and leucocyte esterase tests have a knowledgeable sonologist, voiding problems of false positivity and negativity. cystourethrogram, direct radionuclide cystogram, Bacterial enzyme nitrate reductase can convert intravenous urogram, MRI urograms, etc are very the urinary nitrate to nitrite, which can be useful to document associated anomalies and to detected. If sufficient time is not allowed for prevent morbidity in the form of renal scars, incubation of bacteria with urine, the tests hypertension and end stage renal disease. become negative as in children with increased Appropriate usage of these imaging modalities frequency. If UTI is caused by a bacterium that should be done for a better treatment of childhood does not contain nitrate reductase as in UTI. streptococcal species, false negative results are seen. Similarly leucocyte esterase test detects Investigations leucocytes in urine, which can be present in UTI as well as in other conditions like interstitial Collection of urine sample: Ideally clean catch nephritis or glomerulonephritis. A better method midstream urine specimen is useful and of utilizing these rapid tests is by getting a contamination from periurethral flora should be combined positive test for leucocyte esterase and avoided. If it cannot reach laboratory nitrite in a child with clinico-biological features immediately, it should be stored at a temperature of upper tract UTI. A positive enhanced urinalysis of 4-80 C. In infants and young children when with positive rapid test will definitely indicate collection of midstream urine sample is difficult UTI with certainty. or when contamination of culture is noted, suprapubic aspiration is ideal. Due to high false Initial evaluation: This evaluation becomes positive rates bag samples are not useful1. More mandatory even at the stage of initial diagnosis than the positive culture the negative culture from of UTI as this will give clues towards underlying a bag specimen is found useful in ruling out UTI. anomalies and seriousness of the UTI1,4.

54 2008; 10(3) : 245 Estimation of total and differential counts of organisms grown in culture is increasingly being WBC, peripheral smear study, ESR and documented and it needs adequate and aggressive C-reactive protein (CRP) as acute phase therapy. After making urine sterile there is a role reactants, are done for pointers for infection. for chemoprophylaxis in recurrent UTI, Blood culture is done if acute pyelonephritis is complicated UTI, UTI with VUR and/or DMSA considered. Renal dysfunction is assessed by showing nucleopenic areas. The duration of blood urea and serum creatinine estimation. chemoprophylaxis is at least for 6 months to Ultrasound (USG) examination can be done at 2 years or for up to the age of 5 years depending this stage itself to rule out underlying anatomical on the background illness1,2. defects to a reasonable extent in the beginning itself, which will help us to plan further Subsequent evaluation : In the recent past, management (Fig. 1-3). Good sonologist can give diagnostic radiology has revolutionized the ideas on acute pyelonephritis by differential evaluation of childhood UTI dramatically. More nephromegaly or with increased echotexture of importance is given to children less than 5 years one or both the kidneys which will guide us for with UTI to reduce the renal damage in growing early suspicion on acute pyelonephritis. Presence kidney. One should note that evaluation after the of VUR and scars can be documented by first episode and with recurrent episodes differs. ultrasound but a normal ultrasound will not rule Diagnostic radiology is aimed at identifying the out them as USG is a poor test to indicate VUR underlying anatomical defect predisposing to and renal scarring8. recurrent attacks of UTI and hence decides future follow-up strategy. Child gets adequate treatment for UTI as per documentation of it as acute pyenlonephritis or First episode: Ultrasound is needed in every not and as per age and symptomatology. Extended child with first attack of UTI1,3. MCU and DMSA spectrum beta lactamases (ESBL) producing are mandatory in children less than 2 years of

First UTI

Ultrasound

Normal Abnormal

< 2 yrs 2-5 yrs > 5 yrs > 5 yrs

MCU and DMSA scan No further MCU and DMSA scan MCU if scar on DMSA evaluation DMSA scan or if DMSA not available

Fig 1. Investigation plan for UTI4

55 Indian Journal of Practical Pediatrics 2008; 10(3) : 246 age even if USG is normal for the first attack of radionuclide cystogram (DRNC) is usually done febrile UTI1,3. We also feel that this principle can to pick up VUR as it is more sensitive than MCU be used even up to 5 years of age in whom the in documenting VUR (Fig 9). It is always safer underlying defects are being increasingly and wiser to do classical initially and only as per detected which made us believe that in 2-5 years need DRNC should be done in the initial age group even if USG is normal one has to do evaluation. Unfortunately the grading of VUR DMSA scan. MCU is indicated if there is scar cannot be done precisely and posterior urethral on DMSA scan or if DMSA scan facilities are anomalies cannot be detected by DRNC. not available. In more than 5 years age group Recurrent UTI: It is very clear to every one that with first UTI with normal USG, no further children with recurrent UTI should have USG, evaluation is usually needed. If USG is abnormal DMSA and MCU irrespective of age to detect in this group of more than 5 years of age, MCU underlying anatomical anomalies without and DMSA scan should be done4 (Fig.1). ambiguity. In hydronephrosis, DTPA (diuretic The advantage of USG is that it can be used renography using 99mTc-labelled diethylene at any stage of illness and can be done even triamine penta acetic acid) scan to assess the during acute UTI and forms part of initial function of individual kidney and drainage of the evaluation. Posterior urethral valve, post void dilated collecting system will be useful. residual urine, bladder hypertrophy, dilatation of Intravenous urogram (IVU) is being replaced by ureters, ureterocele, hydronephrosis as well as DTPA for this purpose. pelvicalyceal anomalies can be detected. VUR also can be detected by an experienced Other investigations: Spinal dysraphism and ultrasonologist. radio opaque calculi are detected by X-ray of the KUB region. Need for IVU in UTI is very much MCU is useful in detecting VUR, posterior less with the availability of DMSA and DTPA urethral valve (Fig.4&5), ureterocele and bladder scans. It is useful in double collecting system or urethral diverticuli. For the fear of introducing evaluation and for delineating the level of sepsis, it is better avoided during acute UTI. After obstruction in obstructive uropathy associated making urine sterile child is started on with UTI (Fig 10). Areas of loss of renal chemoprophylaxis and after 1-2 weeks MCU can parenchyma and clubbing and distortion of bedonesafely. A single dose of 1 mg/kg/dose of calyces as pointers for renal cortical scars can be gentamicin given 60 minutes before doing MCU identified by IVU. Voiding dysfunction should is found to be useful in our experience. be remembered with recurrent and complicated Renal scintigraphy using 99mTc- radio labeled UTI and will need uroflow EMG and urodynamic dimercapto succinic acid (DMSA scan) should studies. be performed in every child below 2 years or Follow-up: Urine culture negativity indicates a as indicated.(Fig. 6-8). It can be done even during successful treatment. Urine culture every month acute phase and even with renal failure. It is for 3 months and then every 3 months for the becoming a gold standard test for detecting acute first year is found useful. Urine culture is always pyelonephritis with documentation of cold areas. mandatory when child gets fever without focus DMSA scan is an excellent method for detecting and presenting with urinary symptoms with or 1 renal cortical scars . without fever1. Children kept on long-term If DMSA is showing cold areas/cortical chemoprophylaxis need periodic follow-up. scars but VUR is absent in MCU, direct Repeat DMSA is done after 6 months to 56 2008; 10(3) : 247

Fig 2. USG showing dilated posterior urethra, distended bladder with thick Fig 3. USG showing left ureterocele and trabeculated urinary bladder wall

Fig 4. MCU showing posterior Fig 5. MCU showing bilateral grade5 urethral valve and secondary VUR vesicoureteric reflux

Fig 7. Repeat DMSA after 6months Fig 6. DMSA showing bilateral pyelo- showing healing of acute pyelone- nephritis with nucleopenic areas phritis shown in Fig.6 57 Indian Journal of Practical Pediatrics 2008; 10(3) : 248

Fig 8. DMSA showing small right Fig 9. DRNC showing bilateral kidney with scars massive VUR even in prevoid films

Fig 10. Right megaureter in IVU document resolution of inflammation and for Conclusion delineating scars if any. Follow-up DMSAs are UTI in children is not uncommon. Think of needed as and when indicated and following UTI in children with fever without focus or with infection suggesting acute pyelonephritis. Repeat MCU or DRNC is needed after 1 year of follow- failure to thrive. Urine culture is still the gold up to see for down grading of reflux and later standard to diagnose UTI. USG in the initial repeated as per need. Repeat ultrasonogram to evaluation of UTI is very much needed but is not assess the growth of the kidneys is done at a good tool for ruling out VUR and renal scars. periodic intervals of at least once a year for up to DMSA radionuclide scan is the gold standard test 5-7 years of age, if child had renal scars in DMSA for acute pyelonephritis. We evaluate children and/or VUR in MCU or DRNC in initial with first attack of febrile UTI with USG, DMSA evaluation. and MCU as per indication. Consider DRNC 58 2008; 10(3) : 249 for follow-up of VUR children and in girls if the • Children with positive DMSA with negative parents refuse MCU at the initial stage after VUR by MCU should have DRNC to explaining the inadequacies of DRNC in document VUR in them. documenting bladder and urethral anatomy. Voiding dysfunction is a problem to be References considered in recurrent UTI and needs adequate 1. Vijayakumar M, Prahlad N, Sharma NL, evaluation. Nammalwar BR. Urinary tract infection (UTI). In: Suraj Gupte Ed, Recent advances in st Acknowledgement Pediatrics-17 - Hot topics. 1 Edn, Ed. Jaypee We are thankful to Dr.BR Nammalwar, Brothers Medical Publishers, New Delhi, 2007; pp 240-260. Pediatric Nephrologist, Mehta Children’s Hospital, Chennai and Dr.V.Sripathi, Pediatric 2. Vijayakumar M, Prahlad N. Urinary tract infection in children. In: Nammalwar BR, Urologist, Mehta Children’s Hospital, Chennai Vijayakumar M, (eds) Principles and Practice for their kind contribution in providing material st of Pediatric Nephrology, 1 Edn. Jaypee for various figures quoted in the article. Brothers, New Delhi, 2004; pp 348-356. Points to remember 3. Kher KK, Leichter HE, Urinary tract infection. In: Kher KK, Makker SP (eds). Clinical • Every child less than two years with first Pediatric Nephrology. International edn, Mc attack of UTI should have USG, MCU and Graw Hill, Inc Health Professions Division, DMSA to detect parenchymal damage and New York, 1992; pp 277-321. to document associated anatomical 4. Indian Pediatric Nephrology Group: Indian anomalies. This strategy can be followed Academy of Pediatrics, Consensus statement on up to 5 years of age as increasing numbers management of urinary tract infection. Indian of associated anomalies are being identified Pediatr 2001; 38:1106-1115. even with fist attack of UTI in 2-5 years of 5. Bagga A, Sharma J. Urinary tract infection: age group also. Clinical features, evaluation and treatment. Pediatr Today 2000; 6:395-401. • Children above five years of age with first 6. Vijayakumar M, Bagga A. Reader’s Forum: attack of UTI should have MCU and Definition of recurrent UTI. Indian Pediatr DMSA scan if ultrasound evaluation is 2006; 43: 148-149. abnormal. 7. Nammalwar BR, Vijayakumar M, Sankar J, Ramnath B, Prahlad N. Evaluation of the use • Children with recurrent UTI irrespective of DMSA in culture positive UTI and culture of age should have USG, MCU and DMSA negative acute pyelonephritis. Indian Pediatr as a policy. 2005; 42: 691-696. 8. Veyrac C, Kotzki PO, Lopez C, etal. • Direct radio nuclide cystogram (DRNC) Comparison of ultrasound and dimercapto- can be used for follow-up of VUR children succinic acid scintigraphy changes in acute and not as the initial screening test as it is pyelonephritis. Pediatr Nephrol 1999;13: not going to delineate urethral anatomy. 219-222.

59 Indian Journal of Practical Pediatrics 2008; 10(3) : 250

IAP-IJPP CME 2008

ANTIMICROBIALS IN ACUTE Pathophysiology ENCEPHALTIS Spread of infection can be through the blood * Viswanathan V stream or through the endoneurium or the perineurium of the neuron as in the case of HSV, Abstract:Encephalitis in children is a common rabies or poliomyelitis. cause for admissions to hospitals in India and they present usually with fever, altered sensorium, Etiology seizures and other neurological signs. The most Acute encephalitis can occur in epidemics common causes are usually viral like Herpes, (Japanese B encephalitis, Chandipura Japanese B, mumps, varicella etc. More recently encephalitis) or sporadic of which Herpes it has been recognized that Mycoplasma simplex virus type I and II, cytomegalovirus, pnenumonia can present with encephalitis and mumps, measles, varicella zoster, Epstein Barr these children respond to treatment with Virus are most common.1 Mycoplasma Azithromycin. Management of these children is mainly supportive apart from acyclovir in children with suspected herpes encephalitis. Table 1. Encephalitis - Etiology and prodrome Keywords: Antimicrobials, Encephalitis, Mycoplasma infection • Japanese encephalitis (Epidemics) - high fever, headache Encephalitis and meningitis are common causes of admission to hospitals in India. The • HSV I and II - Fronto-temporal regions - etiology for encephalitis and the differential olfactory, gustatory, bizzare behaviour, diagnosis for these in our country differs slightly personality and memory alterations from the western world although he overall • Enterovirus - cold, diarrhea, rash, clinical picture is very similar. abdominal pain The word encephalitis is used when there is • Enterovirus 70 - preceding conjunctivitis, involvement of the brain parenchyma, cerebellum rash or the brain stem, where as in meningitis there is • Adenovirus - respiratory symptoms, rash inflammation of the meninges only. Quite often involvement of both occurs and the term • Measles - rash, conjunctivitis meningoencephalitis is used. • Mumps, EBV - parotitis • CMV, Varicella - hepatitis, pneumonia, * Consultant Pediatric Neurologist varicella inf. Kanchi Kamakoti Childs Trust Hospital, Chennai - 600 034. • HIV - parotitis, lymphadenopathy

60 2008; 10(3) : 251 pneumoniae was reported as a probable or Serology : Paired samples of blood or CSF are possible etiologic agent in 70% of the children required for a clear diagnosis and many a times who presented with acute encephalitis from have limited value, useful only for retrospective whom an etiologic agent was identified in a study diagnosis. from Canada2. Neuro-imaging : CT brain may be easier to get Clinical features for practical reasons. Studies reveal that initial CT brain scans may be abnormal in 44% of the Fever, altered sensorium, focal findings like cases but subsequent scans increased the aphasia, ataxia, hemiparesis, involuntary proportion of abnormalities to 69% during the movements, cranial nerve palsies, seizures, etc. period of hospitalization.5 MRI brain scans are are the usual findings. The prodromal features particularly helpful for differentiating acute during the illness may give a clue to the etiology disseminated encephalomyelitis.6 Temporal lobe in these children as outlined in Table 1. These was commonly affected in children with HSV children may develop temperature dysregulation, encephalitis although there were multifocal SIADH or diabetes insipidus. involvement in many as compared to adults who showed typical localization to temporal lobes.7 Seizures are usually in the form of recurrent partial seizures or status epileptics with or EEG : Very sensitive tool for diagnosing children without secondary generalization and associated with encephalitis; showed abnormalities in more altered mental status requiring hospitalization. than 87% of patients initially and in 96% during The seizures are seen mostly during the acute the course of their illness.2 Diffuse slowing phase of the illness but can be difficult to control typically bilateral, was the most common in some cases. finding.8 Periodic lateralized epileptiform discharges (PLEDs) and Frontal or occipital Studies suggest that most children who rhythmic delta activity (FIRDA or OIRDA) often develop M.pneumoniae infection were older than occur with HSV encephalitis.5 5 years of age, where as children who were diagnosed to have HSV encephalitis were Differential diagnosis younger than 2.8 years of age.2 Two main conditions that are treatable and Investigations mimic viral encephalitis are mycoplasma pneumoniae encephalitis and cerebral malaria. CSF examination: Shows lymphocytic pleocytosis3,4 raised protein, normal sugar. RBC’s Mycoplasma pneumoniae in the CSF may be seen in children with HSV encephalitis encephalitis. The timing of the lumbar puncture (LP) is the difficult decision in these children as Mycoplasma pneumoniae, a common it may not be possible to consider the LP when respiratory pathogen has been implicated as an the child presents with altered sensorium and etiology of encephalitis. Clinically they are features of raised intra-cranial pressure. similar to enterovirus encephalitis, although they frequently require intensive care with prolonged CSF PCR for HSV, CMV, Varicella Zoster, EBV hospitalization.9 Studies suggest that 1% - 10% and entero-viruses is most helpful for of cases of acute childhood encephalitis are confirmation of diagnosis. caused by this organism.10

61 Indian Journal of Practical Pediatrics 2008; 10(3) : 252 Fever, lethargy, altered sensorium with monitoring of the level of consciousness can be associated respiratory infection are the usual done along with anticipatory care for potential presentation. The criteria for diagnosis of complications. Supportive management is the probable M.pneumoniae encephalitis included most important treatment in acute encephalitis. the detection of M.pneumoniae by culture or PCR of specimens from the throat, the CSF, or both to Seizures are common in these children and eliminate the potential impact of false-positive benzodiazepines, phenytoin or phenobarbitone serologic test results. The clinical manifestations, are the anticonvulsants of choice as needed. CSF abnormalities, EEG and neuroimaging These are given as a loading dose followed by findings associated with M.pneumoniae maintenance doses. encephalitis are indistinguishable from those of Increased intra cranial pressure contributes 2 other viral encephalitis , Antibiotic therapy has substantially to the mortality and morbidity in been shown to suggest earlier recovery in these encephalitis. Mechanical ventilation and children although conclusive evidence is still intravenous Mannitol 1g/kg initially followed by lacking due to the small number of cases in the 0.25g/kg 4 to 6 hourly are very useful measures 10 studies so far. Macrolide antibiotics such as in reducing ICP. close monitoring of the CVP, erythromycin and azithromycin, doxycycline or BP, fluid and electrolyte balance are important chloramphenicol have all been used for treatment. in these children. Neurologic sequelae have been reported in up to 64% of the survivors in some studies following Patients with suspected or confirmed HSV mycoplasma encephalitis.10 encephalitis should receive IV Acycolovir 10mg/ kg for 10 to 14 days at the earliest. varicella Cerebral malaria encephalitis an uncommon complication of AIDs or immuno-compromised children should be Common problem in our country, nearly treated with IV acyclovir in the same way for 10 40% of all the malaria is caused by plasmodium to 14 days. Gancyclovir is used if a child is falciparum which is resistant to chloroquine.11 suspected to have CMV encephalitis. Mortality occurs mainly in children less than 5 years. Fever altered sensorium, seizures, Points to Remember encephalopathy, retinal hemorrhages and involvement of other systems are the usual • Viral encephalitis is a common problem in presenting features. The detection of the parasites our country. in the thick blood smear is the gold standard for • CSF PCR for specific viruses is valuable diagnosis. Hypoglycemia is seen in close to 25% tool in diagnosis. of these children and so needs to be watched for MRI brain scans may show multiple patchy and corrected if it occurs. Apart from supportive • changes in children with HSV encephalitis treatment quinine and artemesinin derivatives are unlike adults. effective in treating this condition. • EEG is a very useful tool for diagnosis of Management encephalitis. Any child with suspected encephalitis • Mycoplasma pneumoniae encephalitis and requires admission and close monitoring in an cerebral malaria are important to consider intensive care unit preferably, where frequent in the differential diagnosis.

62 2008; 10(3) : 253 References 6. Caldemeyer KS, Simth RR, harris TM, Edwards MK. MRI in acute disseminated encephalo- 1. Rao PN, Kumar PA, Rao TA, et al. Role of myelitis. Neuro-radiology 1994;36:216-220. chandipura virus in an epidemic brain attack in 7. Whitley RJ, Lakeman F. Herpes simplex virus Andhra Pradesh. Indian J Paediatr Neurol infections of the central nervous system: 2004; 2: 131-143. therapeutic and diagnostic considerations. Clin 2. KolskiH Ford Jones, Richardson S, Prteic S, Infect Dis J 1995; 20:414-420. Nelson F, et al. Etiology of acute childhood 8. Kennard C, SwashM. Acute viral encephalitis; encephalitis at the hospital for Sick Children, its diagnosis and outcome. Brain 1981;104:129- Toronto, 1994-1995. Clin Infect Dis J 148. 1998;26:398-409. 9. laura JC, Honarmand S, deborah F, et al. 3. Cizman M, Jazbec J. Etiology of acute Pediatric Encephalitis: What is the role of encephalitis in childhood in Slovenia. Paediatr mycoplasma pneumoniae? Pediatrics Infect Dis J 1993;12:903-908. 2007;120:305-333. 10. Bitnun A, Lee E, Petric M, et al. Acute 4. Rantala H, Uhari M. Occurrence of childhood childhood encephalitis and mycoplasma encephalitis: a population based study. Paediatr pneumoniae. Clin Infect Dis J 2001;32:1674- Infect Dis J 1989;8:426-430. 1684. 5. Miller JD, Ross CA. Encephalitis: f afour year 11. Kalra V. Practical paediatric neurology. Arya survey. Lancet 1968;1:1121-1126. Publications.2002;pp97-99.

NEWS AND NOTES

APLS: THE PEDIATRIC EMERGENCY MEDICINE COURSE

6th-7th December 2008 Organizer: IAP, Delhi and Center for Child Health, Sir Ganga Ram Hospital, Delhi Venue: Auditorium, Working Women Hostel, Sir Ganga Ram Hospital, Delhi Registration: Limited to 40 delegates, Registration Fee: Rs 2000/- in favor of “Ambulatory Pediatrics”. Course Director and Mailing Address Dr Suresh Gupta, Consultant, Pediatric Emergency Medicine, Centre for Child Health, Sir Ganga Ram Hospital, Rajender Nagar, Delhi 110060 Email: [email protected], Phone: 9811426628, 28312591, 42251156

63 Indian Journal of Practical Pediatrics 2008; 10(3) : 254

GENERAL ARTICLE

CYCLIC VOMITING SYNDROME Cyclic vomiting syndrome (CVS) is a paroxysmal, severe, recurrent vomiting disorder * Neelam Mohan of unknown etiology. It was first described in the ** Bhat NK 19th century with earliest references being that *** Amit Gupta of Dr W Heberden in 1806 (French literature) 1,2 Abstract : Cyclic vomiting is a syndrome and Dr Simuel Gee in 1882 (English literature). charecterised by recurrent episodes of vomiting Li in 1995, described CVS as a unique temporal interspersed with well intervals. It is considered pattern of recurrent, discrete, and stereotypical as a migraine variant with no clear etiology. episodes of explosive vomiting that punctuate 3 Among various causes, altered intestinal motility periods of completely normal health. and mitochondrial DNA mutations are thought to play a role. Median age of onset is between Definition 5-7 years with slight female preponderance. Associated symptoms are abdominal pain, Consensus diagnostic criteria were headache and autonomic symptoms. Infection, established in 1994 at the First International psychological stress and food products are some symposium on CVS.4 identifiable precipitating factors. There is a long list of differential diagnosis including surgical Essential criteria : (a) Recurrent, severe, and non-surgical causes of acute abdomen, CNS discrete episodes of vomiting, (b) Varying disorders like brain tumor, ICP and porphyria. intervals of normal health between episodes, It is a diagnosis of exclusion by history, physicial (c) Vomiting episodes lasting from hours to days examination and laboratory studies. and (d) No apparent cause of vomiting with Management includes rehydration and negative laboratory, radiographic, and antiemetics such as ondansetran. Majority of endoscopic evaluation. them improve as they grow into adolescence and one third of patients tranform themselves to Supportive criteria : (a) Vomiting pattern is migraine headaches. stereotypical, and each episode is similar in terms of time of onset, intensity, duration, frequency, Key words : Cyclic vomiting, Migraine, Acute associated symptoms, and signs within an abdomen, Ondansetron. individual, (b) Vomiting pattern is self-limited and episodes resolve spontaneously if left * Consultant Pediatric Gastroenterologist, untreated, (c) Associated symptoms include ** Associate Consultant Pediatric Gastroenterology, Hepatology, nausea, abdominal pain, headache, motion Nutrition and Liver transplantation unit, sickness, photophobia and lethargy and Center for Child Health, (d) Associated signs include fever, pallor, Sir Ganga Ram Hospital diarrhea, dehydration, excess salivation, and *** Senior Resident, GTB Hospital, NewDelhi social withdrawal.

64 2008; 10(3) : 255 Associations between CVS, Endocrine factors abdominal migraine and migraine Infectious, psychological and physical stress CVS, abdominal migraine and migraine are known triggers of episodes of CVS.4,9,10. headache all seem to be manifestations of the It has been shown that ACTH, cortisol, and spectrum of migraine diathesis.5 Each is a catecholamine levels are elevated just prior to functional, episodic disorder with attacks vomiting episodes in patients with CVS.8,9,11 seperated by symptom-free intervals. A patient According to Tache’s corticotropin-releasing- with any of these disorders may experience factor hypothesis, physical or psychological headache, abdominal pain, nausea and vomiting stress releases corticotropin releasing factor during their attack. However, the distinction of (CRF) from the hypothalamus which induces these three syndromes is based on their gastric stasis, nausea and vomiting.6 CRF also predominant symptoms: headache predominates stimulates the anterior pituitary to secrete ACTH, in migraine; intense, sustained, midline thereby activating the hypophyseal-pituitary- abdominal pain predominates in abdominal adrenal axis (HPA) and the stress response. Basal migraine; and nausea and vomiting predominate secretion of CRF has a diurnal rhythm with in CVS. increasing secretion beginning at 1 am, reaching its peak at 6am. This may account for the Etio-pathophysiology predominance of night and morning times of onset of CVS episodes. The CRF may be The etiology, pathophysiology, and target potential brain-gut mediator of CVS and CRF organ in CVS remain unknown. Renewed interest receptor antagonists (currently under develop- in CVS since 1990 has led to a flurry of research ment) can theoretically ablate an attack of CVS.6 over the last decade. Existing pathophysiological evidence points to CVS as a brain-gut disorder Gastrointestinal motility disorders involving neuroendocrine pathways in Gastrointestinal motility dysfunction is genetically predisposed individual.6,7,8 Support postulated as a possible etiology in CVS. It has exists for migraine-related mechanisms, as been shown that gastrointestinal dysmotility patients with CVS have a significantly higher (hypermotility, hypomotility, or dysrhythmia) prevalence of family members with migraine involving either the stomach or the small bowel headaches epidodes5. Furthermore, one third of is present even during asymptomatic periods in patients with CVS whose vomiting resolved, CVS patients.10 Also, the number of emeses in subsequently developed migraine headaches. children with CVS has been reported to decrease Also 80% of CVS patients with positive family by administration of prokinetic agents.12 history of migraine respond to antimigraine therapy. Autonomic nervous system Proposed mechanisms by which CVS occurs Autonomic dysfunction has been observed are based primarily on clinical observations of in patients with CVS and migraine.13,14 Many of CVS and related conditions.9 The commonly the associated symptoms, such as pallor, flushing, proposed etiologies for CVS include hormonal fever, lethargy, salivation and diarrhea are dysfunction, gastrointestinal dysrhythmias, mediated by the autonomic nervous system. autonomic dysfunction, food allergy, mitochon- However, it is unclear whether primary ANS drial DNA mutation and ion channelopathies. abnormality results in CVS and migraine or if

65 Indian Journal of Practical Pediatrics 2008; 10(3) : 256 another disorder leads to an ANS abnormality in to significant clinical improvement in their CVS combination with either CVS or migraine. symptoms. Genetic associations Mitochondrial enzymopathies Mitochondrial DNA mutations may be Renewed interest in mitochondrial involved in the pathogenesis of CVS. enzymopathies and CVS, suggested that energy Boles et al have demonstrated that, among supply and demand might not be met under children with CVS and neuromuscular disease, certain circumstances in predisposed 15,16 80% have maternal-side migraines. Most individuals.15-19,22,23 This energy deficit can alter cases of CVS have been described as sporadic, voltage-gated membrane channels for calcium, but family history may be an important factor. magnesium, and other ions. Some patients may Several families, have been described with have genetic mutations of various ion channels. 17-19 multiple members involved. In these familial Perturbations in delicate cellular electrochemical cases of CVS, the mode of inheritance is gradients can result in depolarization and predominantly matrilineal. This supports the hyperexcitability of neurons that in turn could Boles’ hypothesis that defects in mitochondrial lead to any of the above-mentioned energy production due to mutations may neuroendocrine phenomena. predispose to onset of episodes of vomiting during periods of heightened demands for energy; Demographics and epidemiology for example, stress or excitement, in patients who may be well compensated for usual daily CVS has been described in all races and 8,15-20 ethnicities, although whites appear to be affected demands. Because the functional integrity 24 of the gastrointestinal tract involves a great deal to a greater degree than other races. The prevalence of CVS is not well studied . It is of interplay between smooth muscle and nervous 24,25 tissues, gastrointestinal symptoms are often estimated to be 0.04% to 1.9% in children. prominent in mitochondrial DNA disorders.16,20 CVS occurs in all age groups. Children as young as 6 months and adults as old as 73 years have Although universal genetic associations of been described as having CVS.10,24 The median CVS are yet to be identified, case studies of age at onset of symptoms ranges from 5.2 to patients and/or families have shown an A3243G 6.9 years.9,26 There is a slight female mitochondrial DNA mutation along with several predominance (M:F 45:55).9 other less well-characterized mitochondrial DNA mutations exhibiting vomiting as a common Symptoms 15,19 feature. Each attack of CVS can be divided into four Allergy phases. Recognition of this phasic pattern helps in making the diagnosis and in management. Food allergy has been suggested as a possible etiology of CVS. Lucarelli, et al. 1. Prodrome phase: The patient senses the evaluated eight children with CVS but no approach of an episode during the prodromal symptoms of food allergy.21 Most of these phase, but is still able to take and retain oral children had a positive skin prick test and the medications. Prodromal symptoms consist of specific IgE present for various foods, including nausea, lethargy, anorexia, and pallor. This phase, cow’s milk proteins, soy, and egg white. which is often marked by abdominal pain, can Elimination of the offending foods from diet led last from few minutes to several hours. 66 2008; 10(3) : 257 2. Vomiting phase: This consists of nausea c. Retching and nausea are frequent and vomiting; inability to eat, drink or take accompaniments. medicines without vomiting; paleness; drowsiness and exhaustion. d. Signs and symptoms of an intense stress response are common, including increased heart 3. Recovery phase: The recovery phase rate and blood pressure, drenching diaphoresis, begins as soon as nausea remits and ends when minor loose stooling, low-grade fever and the patient has recovered appetite,color, strength neutrophilia. and body weight lost during the vomiting phase. e. Autonomic symptoms are also common, 4. Interepisodic symptom-free phase. particularly lethargy, pallor, anorexia, increased salivation and social withdrawal. Lethargy may The frequency of CVS episodes ranges from be profound, and patients may be unable to walk, 1 to 70 episodes per year with an average of talk or may appear comatose. 12 episodes a year.26,27 The severity of CVS is mild if the illness doesn’t interfere with work or f. Many patients with CVS have school, moderate if attendance at work or school neurologic symptoms, which supports the is in jeopardy, and severe if the patient is relationship between migraine and CVS. frequently disabled and sick. Symptoms include headache, photophobia, phonophobia and vertigo. The symptoms which occur during the attack of CVS are as follows:9,26-30 Precipitating events4,9,10,24,26,27,31

a. Vomiting: It is present in all cases. The Most children (68-80%) can identify a vomiting in CVS typically is severe and specific condition or event that triggered an intermittent with a peak rate of 12.6 emeses per episode.The most common precipitating event is hour. The median peak rate of emeses is 6 times infection, particularly chronic sinusitis. per hour during the attack. Only Bacillus cereus Psychological stresses and food products, food poisoning matches this high intensity of including chocolate, cheese, and monosodium emesis. The emesis is often projectile and glutamate (MSG), rank close behind chronic frequently contains bile, mucus, and blood. sinusitis. Others recognize physical exhaustion Vomiting peaks in the first hour and then begins or lack of sleep, atopic events, motion sickness to decline over the ensuing 4-8 hours, lasting a and menses as triggers. mean of 24 hours. Episodes commonly occur in Differential diagnosis32-41 the early morning (2-4 am) or upon awakening (6-8 am). Forceful vomiting and retching often 1. Gastrointestinal disorders (nonsurgical): cause hematemesis due to prolapse gastropathy Peptic ulcer disease, hepatitis, pancreatitis with or Mallory-Weiss tears. Peptic esophagitis and or without pseudocyst, motility disorders, hemorrhagic lesions of the gastric mucosa are inflammatory bowel disease, infections typical endoscopic findings that result from, (giardiasis, entamoeba, pinworms). rather than cause, vomiting episodes. 2. Gastrointestinal disorders (surgical): b. Abdominal pain is present in 5%-80% Pancreatic pseudocyst, recurrent subacute of children and may initially be severe enough appendicitis, bowel obstruction, intermittent to mimic acute abdomen. duodenal intussusception, duodenal web/atresia/

67 Indian Journal of Practical Pediatrics 2008; 10(3) : 258 diverticulum, adhesions, choledochal cyst, endoscopic gastro duodenoscopy (EGD) needs cholelithiasis/gallbladder dyskinesia. to be performed in patients with acute vomiting, often for hematemesis or on clinical suspicion 3. Urologic/renal/gynecologic disorders: of peptic ulcer disease. Urolithiasis, reteropelvic junction obstruction, ovarian cyst, pregnancy, premenstrual syndrome. If the above tests are negative, structural lesions need to be excluded with imaging studies 4. Neurological disorders: Hydrocephalus, such as head and abdominal/pelvis CT. An EEG brain tumors, Arnold Chiari malformations, may be obtained depending upon the clinical epilepsy, subdural hematomas or effusions, suspicion of seizure disorder. familial dysautonomia. In the case of patients presenting with cyclic 5. Endocrine disorders: Diabetes mellitus, symptoms of vomiting, metabolic disorders adrenal insufficiency, pheochromocytoma. including pituitary-adrenal disorders, organic acid and amino acid disorders need to be screened 6. Miscellaneous disorders: Abdominal, for. migraine/abdominal epilepsy, hypothalamic surge, paroxysmal asthma, chronic sinusitis, Complications benign positional vertigo, anxiety, depression, secondary gain, Munchasen-by-proxy. Possible complications include dehydration, hypovolemic shock, electrolyte depletion, peptic A common diagnostic dilemma is to esophagitis, hematemesis, Mallory-Weiss tear, differentiate CVS from chronic vomiting. Most tooth decay and secretion of inappropriate patients with the chronic vomiting do not have a antidiuretic hormone. cyclic pattern, usually vomit less then four times an hour, are less likely to have autonomic Treatment symptoms and often have no family history of In the absence of known pathophysiology, migraine headaches.26,29,30 treatment of CVS remains empiric. Treatment is Diagnostic evaluation usually individualized and often is a trial and error process.9,26,27 Treatment is applied according CVS is a diagnosis of exclusion and to the phase the patient is in at the time of requires that other known and treatable causes presentation. The goal during the prodromal of vomiting be excluded. When a patient presents phase is to abort the oncoming vomiting phase. with acute vomiting, severe disorders can usually The goal during the vomiting phase is to prevent be excluded by history, physical examination, and dehydration and terminate the nausea and basic laboratory studies (such as a complete blood vomiting. The goal of the recovery phase is to count and a complete metabolic panel including refeed the patient without causing a relapse of liver function tests,renal function tests, amylase, nausea.42 The therapeutic goal during the and lipase, urinalysis, pregnancy test and an interepisodic phase is prophylaxis of further upper GI series/small bowel follow through). episodes. Abdominal ultrasound of the liver, gall Prophylactic therapy to prevent CVS bladder, pancreas, kidneys, and adrenals may help in evaluation of possible gallstones, pancreatitis, Daily prophylactic pharmacotherapy may and ureteropelvic junction obstruction. An be used to prevent episodes that occur more than

68 2008; 10(3) : 259 once per month or if they are extremely severe Treatment during the vomiting phase and disabling, (eg, lasting >3 days).42,43 Along with medical therapy, predisposing factors should Dehydration requires correction with be identified and prevented. Prophylactic appropriate intravenous fluids. Serotonin antimigraine medication should be considered, antagonists, e.g., ondansetron, may be especially if patient has a family history of administered as soon as restoration of migraine headaches or if the episode is associated intravascular volume is well under way. When with symptoms of photophobia, phonophobia, the patient is normovolemic, attempt to terminate scotomas, headache, or diplopia.9,44 The the vomiting phase with intravenous lorazepam mainstays of prophylactic therapy include and ondansetron. If these measures abolish the cyproheptadine, amitriptyline, propranolol, symptoms of the vomiting phase, and if relief is phenobarbital, and erythromycin.13,45-50 The North sustained, the episode will have been terminated. American Society for Pediatric Gastroenterology, If the episode cannot be terminated, the Hepatology, and Nutrition guidelines recommend patient must then be relieved by giving sedatives. cyproheptadine as first-line therapy in children (e.g., chlorpromazine combined with younger than 5 years. However, cyproheptadine diphenhydramine).41 Try not to interrupt sleep for can cause substantial weight gain because of an routine vital signs and other procedures. increase in appetite. Amitriptyline is the first-line choice in children older than 5 years and Psychiatric aspects of care adolescents.26 Help of a mental health professional In sleep-deprived patients, restoration of a experienced with CVS should be sought for the normal sleep pattern aids in preventing attacks. patient and entire family.52 If a CVS patient has an abnormal EEG, antiepileptic drugs such as phenobarbital, Prognosis27,31,52,53 carbamazapine, and pizotifen have been shown Shared observations suggest that two-third to be effective.49,50 of patients cease to have emetic episodes and Abortive therapy for CVS remain asymptomatic whereas one-third patients appear to transform emeses to migraine Abortive therapy is used during the headaches. Some patients progress through all prodromal phase when the patient begins to sense the three disorders: from CVS to abdominal early nausea signaling the approach of vomiting, migraine to migraine headaches. but is still able to take and retain oral medications.9,44,51 Most published series indicate that CVS Patients should be kept in a dark, quiet lasts an average of 2.5-5.5 years, resolving in late nonstimulating environment.29 Many antiemetic childhood or early adolescence. However, agents have been proven to be clinically younger age at onset of CVS is likely correlated beneficial; specifically ondansetron and with a longer duration of illness. For age at CVS promethazine. Benzodiazepines may be used to onset less than 3 year, 3-8 year, and greater that help induce sleep and terminate the episode.9,45 8 year reported lengths of illness are 5.8 year, Symptomatic treatment for pain, hypertension, 4.9 year, and 2.9 year respectively and about 75% diarrhea, headache, and heartburn may also be of patients eventually cease to vomit and have necessary. migraines by 18 year of age.

69 Indian Journal of Practical Pediatrics 2008; 10(3) : 260 78% parents felt that the provision of a References positive diagnosis and information made a 1. Heberden W. Commentaries on the history and significant impact on the severity of vomiting. causes of diseases, 3rd Edn. London: Payne and Foss, 1806. Summary 2. Gee S. On fitful or recurrent vomiting. St Bart Hosp Rep 1882;18:1-6. CVS is an intermittent functional vomiting disorder that affects individuals of all ages and 3. Li BUK. Cyclic vomiting: the pattern and syndrome paradigm. J Pediatr Gastroenterol is punctuated by variable duration of Nutr 1995; 21 Suppl 1: S6-10 asymptomatic periods. Etiology is yet to be identified but present evidence points to maternal 4. Li BUK (Ed). Cyclic vomiting syndrome. Proceedings of the 1st international scientific inheritance and mitochondrial DNA mutations symposium on cyclic vomiting syndrome held in some. A large number of CVS patients and/or at St. Bartholomen’s Hospital, London, family members are affected by other similar England, July 1994. J Ped Gastro Nutr 1995; episodic disorders of unknown etiology. SZI and Li BUK, Sarna S, Issenman R (Ed). Advanced CVS symptoms are more difficult to Proceedings of the 2nd International Scientific treat; therefore, clinicians should start Symposium on CVS. Held at the Medical symptomatic treatment as soon as possible after College of Wisconsin, April 1998. Dig Dis Sci ruling out other potential life-threatening causes 1999;44:S1-120. of vomiting. Some CVS patients live relatively 5. Li BUK, Murray RD. Is cyclic vomiting related normal lives and are free of symptoms in their to migraine? J Pediatr 1999;134:567-572. adulthood while others develop either abdominal 6. Tache Y. Cyclic vomiting syndrome: The migraine or migraine headaches. Renewed corticotrophin-releasing-factor hypothesis. Dig interest and research shall lead to more Dis Sci 1999;44:S79-86. knowledge and insight into CVS symptoms as 7. Sato T, Igarashi N, Minami S, et al. Recurrent well as better options for prevention and attacks of vomiting, hypertension and psychotic treatment in the future. depression: A syndrome of periodic catecholamine and prostaglandin discharge. Points to Remember Acta Endocrinol (Copenh) 1988;117:189-197. 8. Boles RG, Adams K, Li BU. Maternal • Consider cyclic vomiting in any child inheritance in cyclic vomiting syndrome. Am J presenting with recurrent vomiting. Med Genetics 2005;133A:71-77. • It is a diagnosis of exclusion after ruling 9. Fleisher DR, Gornowicz B, Adams K, et al. Cyclic vomiting syndrome in 41 adults: The out serious causes of acute abdomen and illness, the patients and problems of ICP. management. BMC Med 2005;3:20. • Usual onset of symptoms is between 5-7 10. Prakash C, Staiano A, Rothbaum RJ, et al. years of age. Similarities in cyclic vomiting syndrome across age groups. Am J Gastroenterol 2001;96:684- • Between the episodes child will enjoy 688. normal health. 11. Pasricha PJ, Schuster MM, Saudek CD, et al. Cyclic vomiting: Association with multiple • In majority of them symptoms resolve by homeostatic abnormalities and response to adolescence. One third of them develop ketorolac. Am J Gastroenterol 1996;91:2228- migraine headace. 2232.

70 2008; 10(3) : 261 12. Vanderhoof JA, Young R, Kaufman SS, et al. stroke like episodes (MELAS): Current Treatment of cyclic vomiting in childhood with concepts. J Child Neurol 1993;9:4-15. erythromycin. J Pediatr Gastroenterol Nutr 24. Li BUK, Misiewicz L. Cyclic vomiting: A brain- 1993;17:387-391. gut disorder. Gastroenterol Clin N Am 13. Rashed R, Familioni BO, Abell TL, et al. 2003;32:997-1019. Autonomic function in cyclic vomiting 25. Abu-Arafeh I, Russel G. Cyclical vomiting syndrome and classic migraine. Dig Dis Sci syndrome in children: A population based study. 1999;44:S74-78. J Pediatr Gastroenterol Nutr 1995;21:454-458. 14. To J, Issenman RM, Kamath MV. Evaluation 26. Li BUK, Balint JP. Cyclic vomiting syndrome: of neurocardiac signals in pediatric patients with Evolution in our understanding of a brain-gut cyclic vomiting syndrome through power disorder. Adv Pediatr 2000;47:1-44. spectral analysis of heart rate variability. J 27. Fleisher DR, Matar M. The cyclic vomiting Pediatr 1999;135:363-366. syndrome: A report of 71 cases and literature 15. Boles RG, Williams JC. Mitochondrial disease review. J Pediatr Gastroenterol Nutr and cyclic vomiting syndrome. Dig Dis Sci 1993;17:361-369. 1999;44:S103-107. 28. Stickler GB. Relationship between cyclic 16. Boles RG, Adams K, Ito M, et al. Maternal vomiting syndrome and migraine. Clin Pediatr inheritance in cyclic vomiting syndrome with 2005;44:505-508. neuromuscular disease. Am J Med Geneti 29. Pfau BT, Li BU, Murray RD, et al. 2003;120A:4744-4782. Differentiating cyclic from chronic vomiting 17. Haan J, Kores EE, Ferrari MD. Familial cyclic patterns in children: Quantitative criteria and vomiting syndrome. Cephalagia 2002;22:552- diagnostic implications. Pediatr 1996;97:364- 554. 369. 18. Boles RG, Chun N, Senadheera D, et al. Cyclic 30. Li BUK, Fleisher DR. Cyclic vomiting vomiting syndrome and mitochondrial DNA syndrome. Dig Dis Sci 1999;44:S13-18. mutations. Lancet 1997;350:1299-1300. 31. Li BUK, Hayes JR. Unpublished data, 1999. 19. Salpietro CD, Briuglia S, Merlino MV, et al. A Cited by Li, BUK and Misiewicz, L. Cyclic mitochondrial DNA mutation (A3243G vomiting: A brain-gut disorder. Gastroenterol mtDNA) in a family with cyclic vomiting. Am Clin N Am 2003;32:997-1019. J Pediatr 2003;162:727-728. 32. Selimoglu MA. Myopathic cyclic vomiting 20. Wang Q, Ito M, Adams K, et al. Mitochondrial syndrome associated with gastroesophageal DNA control region sequence variation in reflux and chronic sinusitis. J Pediatr migraine headache and cyclic vomiting 2003;143:545. syndrome. Am J Med Genet A 2004;131:50- 33. Rasquin-Weber A, Hyman PE, Cucchiara S, et 58. al. Childhood functional gastrointestinal 21. Lucarelli S, Corrado G, Pelliccia A, et al. Cyclic disorders. Gut 1999;45:SII60-1168. vomiting syndrome and food allergy/intolerance 34. Coker SB. Cyclic vomiting and the slit ventricle in seven children: A possible association. Eur J syndrome. Pediatr Neurol 1987;187:297-299. Pediatr 2000;159:360-363. 35. Jhonston JM, Harnsberger JK. Episodic 22. Goto Y, Nonaka I, Horai S. A mutation in the vomiting due to intermittent duodenal tRNA Leu gene associated with the MELAS intussusception. J Pediatr Gastroenterol Nutr subgroup of mitochondrial encephalomyo- 1990;10:405-408. pathies. Nature 1990;348:651-653. 36. Mira E, Piacentino G, Lanzi G, et al. Benign 23. Hirano M, Pavlakis SG. Mitochondrial paroxysmal vertigo in childhood. Acta myopathy, encephalopathy, lactic acidosis and Otolaryngol 1984;406:S271-274. 71 Indian Journal of Practical Pediatrics 2008; 10(3) : 262

37. Meyers FA, Dempsy D, Caroline D, et al. 1997;100:977-981. Duodenal diverticulum as cause of cyclic 46. Weitz R. Prophylaxis of cyclic vomiting with vomiting. Dig Dis Sci 1989;34:1148-1149. propranolol. Drug Intellig Clin Pharmacol 38. Schulte-Bockholt A, Kuqathasan S Mesrobian 1982;16:161-162. HG, et al. Ureteropelvic junction obstruction: 47. Forbes D, Withers G. Prophylactic therapy in An overlooked cause of cyclic vomiting. Am J cyclic vomiting syndrome. J Pediatr Gastroenterol 2002;97:1043-1045. Gastroenterol Nutr 1995;21:S57-59. 39. Vinograd I, Lernau OZ, Frand M, et al. 48. Prakash C, Clause RE. Cyclic vomiting Fundoplication and pyloroplasty - a surgical syndrome in adults: Clinical features and treatment for intractable “cyclic vomiting” in response to tricyclic antidepressants. Am J familial dysautonomia. J Pediatr Surg Gastroenterol 1999;94:2857-2860. 1982;17:80-81. 49. Gokhale R, Huttenlocher PR, Brady L, et al. 40. Li BUK, Murray RD, Heitlinger LA, et al. Use of barbiturates in the treatment of cyclic Heterogeneity of diagnoses presenting as cyclic vomiting during childhood. J Pediatr vomiting. Pediatrie 1998;103:583-587. Gastroenterol Nutr 1997;25:64-67. 41. Fleisher DR. Empiric guidelines for the 50. Symon DN, Russell G. Double blind placebo management of cyclic vomiting syndrome. controlled trial of pizotifen syrup in the Available at: http://www.ch.missouri.edu/ treatment of abdominal migraine. Arch Dis fleisher. Childhood 1995;72:48-50. 42. Li BU. Cyclic vomiting syndrome: a pediatric 51. Forbes D, Withers G, Silburn S, et al. Rorschach test. J Pediatr Gastroenterol Nutr Psychological and social characteristics and 1993 Nov; 17(4): 351-353 precipitants of vomiting in children with cyclic 43. Li BU. Cyclic vomiting: new understanding of vomiting syndrome. Dig Dis Sci 1999;44:S19- an old disorder. Contemp Pediatr 1996; 13: 48- 22. 62. 52. Hoyt CS, Stickler GB. A study of 44 children 44. Fleisher DR. Cyclic vomiting syndrome and with the syndrome of recurrent (cyclic) migraine. J Pediatr 1999;134:533-535. vomiting. Pediatr 1960;25:775-780. 45. Anderson J. Effective prophylactic therapy for 53. Hammond J. The late sequelae of recurrent cyclic vomiting syndrome in children using vomiting of childhood. Develop Med Child amitriptyline or cyproheptadine. Pediatrie Neurol 1974;16:15-22.

NEWS AND NOTES

5TH NATIONAL CONFERENCE OF CHILDHOOD DISABILITY GROUP, MEERUT, UP October 11-12, 2008 Contact Dr.Priyanka Jain (Developmental Pediatrician), Organising Chairperson, Jain Medical Center, 166, Civil Lines, Meerut (UP), India. Mobile: 09927008961, Web: http://www.iapcdg2008.com E-mail: [email protected]

72 2008; 10(3) : 263

GENERAL ARTICLE

GENETIC COUNSELING FOR means of most families. Genetic services are an PREVENTABLE DISORDERS excellent example of preventive medicine. The genetic facilities are widespread in developed *Neerja Gupta countries. But in most of the developing countries * *Madhulika Kabra genetic services are still unavailable or under developed.The prevention of genetic disorders Abstract: Rapid advances in the field of medicine could be effective at two levels, (a) General has led to recognition of more and more genetic population and (b) Families and individuals at disorders. Most of the genetic disorders present risk. in childhood and the pediatricians are the primary physicians involved in the diagnosis and Prevention of genetic disorders may be management. Hence, there is a strong need to achieved by understand the principles of genetic counseling which incorporates the knowledge about the A. Identification of risk factors genetic basis of these disorders, chances of recurrence for individual disorders , the various 1. Consanguinity genetic tests available and also the preventive strategies. Since relatives share some of their genes by common descent, consanguineous mating Key words : Genetic counseling, Preventable influences the incidence of some inherited disorders disease. The frequency of children with recessive and multifactorial diseases in consanguineous Advances in molecular genetics have led to matings is high compared with nonconsan- the completion of human genome project in guineous matings. 2000-2003. New inventions are affecting medical understanding of common as well as rare Consanguinity rate remains high in non- diseases. A major contribution of these advances industrial countries which may be over 50% with has been in diagnosis, management and prenatal a high inbreeding coefficient. diagnosis of genetic disorders as treatment in most cases is multidisciplinary, difficult, or 2. Advanced maternal age impossible and where available beyond the Relation between advanced maternal age * Senior Research Officer, and the occurrence of chromosomal Genetics Division, abnormalities is present in all ethnic groups. Department of Pediatrics ** Additional Professor, 3. Previous affected family members Department of Pediatrics, All India Institute of Medical Sciences, In these situations it may be easier to New Delhi.-110029, India. convince relatives for genetic counseling.

73 Indian Journal of Practical Pediatrics 2008; 10(3) : 264 B. Screening Programmes screening programme should be implemented in population with high frequency of carriers of a Population screening particular disorder. This is defined as the presumptive Following screening, carriers should be identification of the unrecognized diseases or counseled regarding the genetic and medical risks defects by certain tests, examination or other of the disease and provided with information procedure that can be applied to sort out regarding the various reproductive alternatives. apparently well persons who probably have the Carrier couple should have access to appropriate disease, from those who probably do not have genetic counseling and prenatal diagnosis. In our the disease. With better understanding of various country most couples come to know about their genetic diseases public health applications have carrier status after having an affected child. been developed. It is reasoned that all members Unless an active carrier screening program is in of a population at risk should be screened for a place it is unusual for a couple to learn that they given defect if treatment or preventive measures are at risk of having affected children. Premarital are possible. Screening of certain genetic carrier knowledge of carrier status also is not free of states has been recommended to allow genetic challenges as the carrier state may be taken as a counseling. These programmes are distinct from taboo and decision of a carrier not marrying a the usual retrospective genetic counseling. As carrier, avoid having children or using alternative consanguinity is important, a number of recessive reproductive options is too personal an issue. The diseases attain high frequencies in special only viable option remains that if a carrier marries population groups; hemoglobinopathies are another carrier the couple should voluntarily opt frequent in most South-Mediterranean , Arab and for prenatal testing and selective termination of African countries (Table 1). affected pregnancies. Couple should get Newborn screening counseling before conception or early in pregnancy. The objective is to screen all newborns for disorders in which symptoms are not clinically Prenatal screening evident until irreversible damage results and Various screening tests either invasive or early treatment can prevent or atleast ameliorate noninvasive can be done in any couple depending the consequences. For disorders like upon the indication phenylketonuria, congenital hypothyroidism, hemoglobinopathies and congenital adrenal Indications hyperplasia, newborn screening is universally adapted by most developed countries. Such 1. Advanced maternal age programs are going on in a few non industrialised 2. Previous child with any chromosomal countries, and remain limited to regions or to abnormality small size populations in developing countries. 3. Previous child with a common single gene disorder like thalassemia, Cystic Carrier/Heterozygote screening Fibrosis(CF), duchenne muscular dystrophy Aim of the screeing is to identify all the (DMD), spinal muscular atrophy (SMA) or individuals who themselves are healthy but are multifactorial disorder like neural tube defects at risk of having children with a severe autosomal (NTD), cleft lip/palate recessive or X linked illness. A heterozygote 4. Abnormal USG in pregnancy 74 2008; 10(3) : 265 Table 1. Disorders requiring heterozygote screening programme in various populations Disorder Population Carrier frequency Tay Sachs Disease Ashkenazi Jews 1/30 B thalassemia India,Greek/Italian, Cyprus Sardinia 1/25-1/30,1/30 Alpha thal South East Asia 1/25 Cystic Fibrosis (CF) Caucasians( N Europe) 1/25 Phenylketonuria (PKU) Caucasians( N Europe) 1/50 Sickle cell disease African- American 1/12

5. Abnormal maternal screening anencephaly, iniencephaly, acrania, total 6. Maternal infection craniospinal rachisis or prognosis may be variable depending upon type of defect. 7. Teratogen exposure b) Ultrasound screening: Anencephaly is Prenatal screening for common detectable at 11-12 weeks of gestation; spina genetic disorders bifida is detectable between 16 and 20 weeks; 1. Neural Tube defects (NTD) large defects may be visible earlier. a) Maternal serum α fetoprotein (AFP) levels: Counseling: Most of the NTDs are isolated These are measured at 16-18 weeks of gestation. and thought to be multifactorial in inheritance. A cut off >2.5 MoM (Multiple of Median) detects The risk of recurrence of NTD after the birth of > 90% cases of anencephaly and 80 % cases of an affected child is 3-5% and increases to about spina bifida cystica. Though the specificity of 10% after birth of two affected children. the test is not very high,being increased in abortion, twin pregnancy, exomphalos etc yet it Prevention: Oral folic acid supplementation has been implemented widely and has led to a (4 mg per day) started 1 month before to three striking decline in the incidence of open NTD. months after conception (periconceptional) The prevalence of NTDs in different parts of prevents recurrence in about 70% of cases. India varies from 0.5-11 per 1000 live births. Primary prevention (about 50%) by use of Most cases are straightforward and involve an 0.4 mg of folic acid periconceptionally has also isolated NTD, either anencephaly or spina bifida, been recommended. or both. Care is needed to ensure that one is 2. Chromosomal abnormalities dealing with a primary NTD or NTD is a part of (Down syndrome) syndrome, teratogenic exposure or chromosomal anomaly. Vertebral anomalies and a) Maternal serum screening : Second hydronephrosis are commonly seen in isolated trimester screening (Triple test/ Multimarker NTDs. It can be uniformly fatal as in screening) 75 Indian Journal of Practical Pediatrics 2008; 10(3) : 266 It includes alpha fetoprotein (AFP), human Pre-test and post test counseling chorionic gonadotropin(hCG) and unconjugated Preliminary genetic counseling of estriol(uE3)estimation in maternal serum. candidates who desire prenatal diagnosis usually Expressed in multiple of median (MoM) values, deals with the following: a) The risk that the fetus maternal serum AFP and uE3 are reduced by 25% is affected, (b) The nature and probable whereas hCG levels are doubled in pregnancies consequences of the specific problem, (c) The with Down syndrome. None of these parameters risks and limitations of the procedures to be used, alone gives absolute discrimination but taken (d) The time required before a report can be together they provide a means of modifying a issued, (e) The possible need for a repeat woman’s prior age related risk to give an overall procedure in the event of a failed attempt and probability that the unborn is unaffected.When (f) The limitation of a test (in view of lab error). this probability exceeds 1 in 250, invasive testing in the form of amniocentesis or placental biopsy Definition and aims of genetic or cordocentesis is offered. Disadvantages of counseling second trimester screening is that it creates more The American Society of Human Genetics anxiety and late intervention if fetus is affected (ASHG)1 defined genetic counseling as a posing risk to mother. First trimester screening communication process that deals with the human using β hCG and pregnancy associated plasma problems associated with the occurrence or the protein A (PAPP-A) has been advocated recently risk of recurrence of a genetic disorder in a with similar sensitivity and advantage of early family. The process involves an attempt by one detection. or more appropriately trained persons to help the Now a days the concept of one stop clinic individual or family to understand the problem, for assessment of risk for fetal anomaly (OSCAR) choose a course of action and adjust to the is prevalent in western countries. It means that situation. in one hour single visit both the biochemical (βhCG, Pregnancy associated plasne protein A Understand PAPP-A) and USG (Nuchal translucency (NT) a) The diagnosis, prognosis and available + crown rump length (CRL) + anomaly scan) is management carried out between 11-14 weeks. It has a predictive value of 86%. b) The genetic basis and chance of recurrence b) Ultrasound screening: Routine fetal anomaly c) The options available (including genetic scan is done at 16-18 weeks to look at the major testing) for dealing with the risk of malformations. Significant sonographic findings recurrence are seen in nearly all fetuses with trisomy 13, 77-100% of trisomy 18 and 33-50% of fetus with Choose Down syndrome. Presence of multiple The course of action appropriate to their abnormalities raises the risk of chromosomal personal and family situation and their ethical abnormality to 35%. and religious standards and act in accordance 3. Single gene disorders (Thalassemia, with the decision Cystic fibrosis,spinal muscular atrophy, etc) Most important in this group is thalassemia Adjust especially in North India. To the psychosocial impact of the genetic Screening protocol is shown in Fig. 1 condition in the family. 76 2008; 10(3) : 267

Non pregnant woman Pregnant woman MCV & MCH

MCV<80fl and/or MCH<27pg

HbA2 Estimation and Hb No Yes electrophoresis

HbA2 > 3.5% and/or abnormal Hb

No Yes

HbA2 and Hb electrophoresis of spouse

Spouse if β thalassemia carrier or abnormal Hb carrier

Reassurance No Yes No risk of child with Thalassemia major Counsel for risk of β thalassemia + prenatal diagnosis

Fig.1. Screening protocol for thalassemia.

77 Indian Journal of Practical Pediatrics 2008; 10(3) : 268 While genetic counseling is a compre- Table 2. Indications of genetic hensive activity, the particular focus will counseling depend upon the family situation. A pregnant • History of a previous child or family history couple at high genetic risk may need to make of unexplained mental retardation/ urgent decisions concerning prenatal dysmorphism/multiple malformations diagnosis; parents of a newly diagnosed child • History of a previous child or family history with a rare genetic disorder may be desperate of degenerative brain disease-regression of for further prognostic information, while still mile stones coming to terms with the diagnosis; a young adult at risk of a late onset degenerative • Acutely sick neonate or infant, failure to disorder may be well informed about the thrive, recurrent vomiting, acidosis, condition, but require ongoing discussions convulsions about whether to go ahead with a presympto- • Neuromuscular disorders matic test; and a teenage girl, whose brother • Childhood deafness has been affected with an X linked disorder, • Down syndrome and other chromosomal may be apprehensive to learn about the disorders implication for her future children. Being able • Relatives of a person with chromosomal to establish the individual’s and the family’s translocation particular agenda, to present information in a clear manner, and to address psychosocial • Exposure to teratogens issues are all crucial skills required in genetic • Unexplained still birth/s with or without counseling. Indications for genetic counseling congenital malformation are given in Table 2. • Skeletal dysplasia (Proportionate/ When to suspect a genetic disorder disproportionate short stature) • Ambiguous genitalia, primary amennorhea, Genetics in Primary Care (GPC) Faculty infertility Development Initiative have endorsed the concept of developing a simple set of red flags • Familial cancers and cancer prone disease that could alert clinicians to the possibility of • Single gene disorder like thalassemia, Spinal genetic condition. The working group defined muscular atrophy, hemophilia or family the red flag as any clinical finding discovered pedigree suggestive of a typical pattern of in history, physical examination, or laboratory inheritance(AR, AD, X linked) studies that suggests the presence of a • Multifactorial/polygenic-Hypertension, genetically influenced disease and that may diabetes, obesity, psychotic disorders require further action such as intervention, • Consanguineous marriage counseling, referral, screening or follow-up. • Advanced maternal age These are not 100% sensitive or specific, but • Positive maternal serum screen should raise a clinician’s sensitivity to genetic influences on their patients. One can memorize • Patient or family member with a known these genetic red flags by a mnemonic-”Family mendelian disorder GENES”. • Previous child with a chromosomal disorder ‘F’Family history to look for any other • Abnormal USG findings affected member in single or multiple generation • Recurrent pregnancy loss/still births

78 2008; 10(3) : 269 to establish a particular pattern of inheritance like a genetic diagnosis especially because early AR, AD, etc. However, lack of family history diagnosis may enable effective surveillance and does not rule out genetic cause. prevent complications. ‘G’ Group of congenital anomalies. ‘S’Surprising lab values in healthy patients A patient with three or more minor congenital may precede the onset of clinical symptoms of a anomalies warrants additional evaluation to look disorder. Two important examples are high for a major anomaly like structural heart, kidney cholesterol in familial hypercholesterolemia and or cerebral defect. Single minor anomalies occur high serum transferrin saturation or ferritin level in approximately 15% all newborns. Presence in hereditary hemochromatosis. In such cases of 3 or more anomalies is unusual and present in early diagnosis of a hereditary condition can lead 1% of all newborns. to prevention of the serious, irreversible consequences of untreated disease. ‘E’ Extreme or exceptional presentation of common conditions. Early onset of disease or Steps in evaluation of a child with unusual severe reaction to infective or metabolic genetic disorder disease. 1. History with particular emphasis on ‘N’ Neuro-developmental delay or pedigree construction and analysis (see Box 1&2) regression in children, or early onset neurologic deterioration in adults. Increasing severity of 2. Detailed clinical examination neurologic disease, association with other 3. Diagnosis unusual findings like facial dysmorphism and early onset increase the likelihood of an 4. Management with strong emphasis on underlying genetic cause for any given neurologic genetic counseling regarding recurrence risk and abnormality. Recent evidence suggests that at prenatal diagnosis if possible. least 15-20% of mental retardation (MR) is 1. History and pedigree analysis caused by identifiable genetic problem. Chromosomal abnormalities are seen in 4-28% • Draw at least 3 generation pedigree using of children with MR. However, many standard set of symbols (Box 1&2 ) neurogenetic conditions are associated with few or no non-neurologic findings like spinal • Male lines are placed on left muscular atrophy and spinocerebellar ataxias. • All the members of same generation are ‘E’ Extreme and unusual pathologic placed on same horizontal levels findings. Bilaterality of pathologic findings in • Roman numerals indicate generations and paired organs or structure is considered an Arabic numerals indicate each individual extreme presentation and is suggestive of a strong within a generation role for genetic factors e.g. bilateral breast cancer correlate strongly with autosomal dominant • Write name and age of each member of mutations in BRCAI and BRCA2 genes. pedigree Likewise the appearance of multiple primary • History suggestive of maternal infections or neoplasms in the same person is a red flag. antenatal drug exposure Physician in practice and training should recognize these unusual findings for pursuing • Developmental milestones 79 Indian Journal of Practical Pediatrics 2008; 10(3) : 270 • Identify consanguineous marriages, presence of dysmorphism, confirmation or miscarriages, infertility, congenital exclusion of the diagnosis of known malformations, and similarly affected chromosomal syndromes, for example Down individuals in a family Syndrome, unexplained mental retardation with • Identify pattern of inheritance depending or without dysmorphism, multiple malformation upon the detailed history syndrome, X-linked recessive syndrome manifesting in a female, two or more than two 2. Clinical examination monogenic disorders in a patient, pregnancy at a • Complete anthropometric measurements risk of aneuploidy because of previous along with percentile depending upon the chromosomally abnormal child, abnormal suspected disorder maternal serum screening, advanced maternal age, or abnormality detected on fetal ultrasound • Head to toe examination for facial scanning, abnormalities of sexual differentiation dysmorphism, any skin abnormalities, any and development, infertility, recurrent malformation or deformities miscarriages or still births. • Any dysmorphic facial features with relevant iii. Single gene disorder(Thalassemia, SMA, facial measurements DMD, Neurometabolic disorder, etc) • Presence of any minor or major malformation or neurocutaneous stigmata B) Laboratory • Complete general and systemic examination a. Cytogenetic (Conventional/High Resolution banding HRB) and /or fluorescence insitu • Clinical photograph of the patient hybridization (FISH) if a specific microdeletion • Examination of parents syndrome is suspected. 2 ml blood in heparin is required and should be sent to lab within 24 3. Diagnosis hours. A) Clinical b. Molecular studies for a specific suspected i. Syndromic diagnosis is based on identification single gene disorders DNA diagnostic tests are of known syndromes based on the clinical extremely important for prenatal diagnosis and phenotype. There are excellent texts available for carrier detection. Presently DNA diagnosis for understanding this interesting field of clinical thalassemia, hemoglobinopathies, hemophilia, genetics. In addition, there are computer Duchenne muscular dystrophy, fragile-X-mental databases available for syndrome search such as retardation, cystic fibrosis, megalencephalic London Dysmorphology Database and Pictures leucodystrophy and spinal muscular atrophy are of Standard Syndromes and Undiagnosed available in India. For providing prenatal Malformations (POSSUM). Referring to the diagnosis, the DNA diagnosis of the affected books giving detailed descriptions of syndromes child in the family needs to be done beforehand. and diagnostic approaches is also of great Sample for molecular tests should be saved in help4-8. EDTA vials. Unless the type of mutations in the proband or carrier parents is identified, prenatal ii. Chromosomal (to be confirmed by diagnosis is not feasible. It is limited by high cost, cytogenetic analysis)- Important indicators of a genetic heterogeneity, and ethnic difference of chromosomal abnormality are failure to thrive, disease prevalence. 80 2008; 10(3) : 271 c. Enzyme studies for lysosomal storage Psychosocial issues disorders like Gaucher disease, mucopoly- The psychosocial impact of a genetic saccharidosis diagnosis for affected individuals and their Nondirectiveness in genetic families cannot be over emphasized. The counseling diagnosis of any significant medical condition in a child or adult may have psychological, The main principle of genetic counseling is financial and social implications, but if the nondirectiveness which is the art of presenting condition has a genetic basis a number of facts without influencing decision. It promotes additional issues arise. These include guilt and the autonomy or self determination and personal blame, the impact on future reproductive control for the client. To maintain the sense of decisions and the genetic implications to the psychological well being amongst the clients, extended family. genetic counseling has also been defined as a Guilt and blame: Feelings of guilt arise in dynamic psycho educational process centered on relation to a genetic diagnosis in the family in genetic information. With a therapeutic many different situations. Parents very often relationship established between providers and express guilt at having transmitted a genetic clients, clients are helped to personalize technical disorder to their children, even when they had and probabilistic genetic information, to promote no previous knowledge of the risk. On the other self determination and to enhance their ability to hand, parents may also feel guilty for having adapt over time. The goal is to facilitate client’s taken the decision to terminate an affected ability to use genetic information in a personally pregnancy. Healthy members of a family may feel meaningful way that minimizes psychological guilty that they have been more fortunate than distress and increases personal control. It their affected relatives and at-risk individuals promotes understanding, decision making, may feel guilty about imposing a burden onto personal control, adaptation to stress inducing their partner and partner’s family. Although in events and reduces psychological distress. most situations the person expressing guilt will As it is evident genetic counseling is a have played no objective causal role, it is complex process and ideally requires the important to allow him or her to express these following: (a) Correct diagnosis, (b) Trained concerns and for the counselor to reinforce that counselor with good knowledge of genetics this is a normal human reaction to the and excellent communication skills and predicament. Blame can sometimes occur in (c) Psychosocial support to the family in coping families where only one member carries the up with the disorder and making decision with genetic risk (“It wasn’t our side”), but again this non directive counseling. is less likely to occur when the genetic situation has been explained and is understood. The person who seeks genetic counseling is called the consultand or counselee and the one Reproductive decision making: Couples aware who gives it is the counselor. In addition to of an increased genetic risk to their offspring must medical specialists, trained persons with various decide whether this knowledge will affect their backgrounds like nursing, social work education plans for a family. Some couples may be faced and psychology can function as genetic with a perplexing range of options including counselors. different methods of prenatal diagnosis and the

81 Indian Journal of Practical Pediatrics 2008; 10(3) : 272 use of assisted reproductive technologies. For imagined healthy child in addition to their others the only available option will be to choose sadness about their child’s disabilities, and this between taking the risk of having an affected chronic sorrow may be ongoing throughout the child or remaining childless. Couples may need affected child’s life. to reconsider these choices on repeated occasions Long-term support and follow up: Most during their reproductive years. Decision making families will require ongoing information and may be more difficult in particular circumstances, support following the initial genetic counseling including marital disagreement, religious or session, whether for coping with an actual cultural conflict, and situations where the diagnosis or the continued risk of a genetic prognosis for an affected child is uncertain. For disorder.Follow up sessions may be needed to many genetic disorders with variable severity, reinforce the informations (usually forgotten or although prenatal diagnosis can be offered, the wrongly remembered by the consultands), to clinical prognosis for the fetus cannot be answer new queries, to provide latest information predicted. When considering reproductive and to provide psychological support to the decisions, it can also be difficult for a couple to family during the process of coping up, till the reconcile their love for an affected child or family acceptance and adjustments take place. member, with a desire to prevent the birth of a further affected child. Counseling before genetic testing Impact on the extended family: The Genetic counseling is an integral part of the implications of a genetic diagnosis usually genetic testing process and is required because reverberate well beyond the affected individual of the potential impact of a test result on an and his or her nuclear family. For example, the individual and family, as well as to ensure parents of a boy just diagnosed with Duchenne informed choice about undergoing genetic muscular dystrophy will not only be coming to testing. The extent of the counseling and the terms with his anticipated physical deterioration, issues to be addressed will depend upon the type but may have concerns that a younger son could of test being offered, which may be diagnostic, be affected and that daughters could be carriers. presymptomatic, carrier or prenatal testing. They also face the need to discuss the possible Though many genetic disorders can be family implications with the mother’s sisters and suspected and finally diagnosed by molecular/ female cousins who may already be having their cytogenetic or enzyme estimation tests, most of own children. them are without any treatment or the treatment is expensive. As a result carrier detection, Bereavement: Bereavement issues arise antenatal screening, prenatal diagnosis followed frequently in genetic counseling sessions. These by termination of pregnancy in case of affected may pertain to losses that have occurred recently child remains the only option. Management and or in the past. A genetic disorder may lead to counseling depending upon the type of genetic reproductive loss or death of a close family disorders is given below. member. The grief experienced after termination of pregnancy following diagnosis of abnormality 1) Mendelian disorders: For most of the is like that of other bereavement reactions and common genetic single gene disorders either may be made more intense by parents’ feelings enzyme based or molecular diagnosis is available of guilt. After the birth of a baby with congenital though facilities for diagnosis of all disorders are malformations, parents mourn the loss of the not available in our country.

82 2008; 10(3) : 273 a) Neurogenetic disorders (Single gene): In an autosomal recessive disorder risk of recurrence is 25% for the sibling. In autosomal There are a multitude of neurogenetic dominant disorder the risk of recurrence for the disorders (NGD) and the number is increasing sib is 50% if one of the parents is affected. If it due to identification of new genes. Counseling is a sporadic case (new mutation) risk of is easier if the inheritance is known but becomes recurrence in sib is very low but gonadal complex if the etiology is multifactorial/ mosaicism cannot be ruled out. In X-linked polygenic. In the latter situation most of the times recessive disorders, risk of recurrence for boys one has to resort to empiric risk figures for is 50% where as females usually do not manifest. counseling. There are some well known neurogenetic b) Hemoglobinopathies disorders with classical Mendelian inheritance. If a confirmed diagnosis of any of these disorders In most of the common haemoglobinopathies like is possible then counseling and prenatal diagnosis alpha, beta thalassemias and sickle cell anemia is straight forward. Problems arise due to a the mode of inheritance is autosomal recessive. phenotypic overlap of many of these disorders, Autosomal recessive disorders manifest if both non availability of diagnostic modalities and the parents are carrier of the mutant gene. The genetic heterogeneity. Hereditary ataxias are disease usually occurs in one generation only. important example : more than 50 syndromes The risk of occurrence and recurrence is 25% in have been described with almost all types of such cases (Fig.2). Identification of mutation in inheritance patterns. Following are some such couples or proband is a prerequisite for common single gene neurogenetic disorders. prenatal diagnosis. So, to have an affected child both parents need to be carriers and prenatal i) Autosomal recessive: Majority of diagnosis is also indicated in this situation. neurometabolic disorders (eg. phenyl ketonuria, maple syrup urine disease, biotinidase deficiency, There is no risk of having an affected child methyl melonic aciduria, etc), lysosomal storage if only one partner is a carrier or is affected disorders (MPS other than Hunter syndrome, (Figs.3 and 4). If only one partner is a carrier Gaucher’s type2&3, Niemann Picks disease, etc), there is a 50% chance of the baby being a carrier neuromuscular disorders like SMA etc. and all babies will be carriers if one partner is affected with an autosomal recessive ii) Autosomal dominant disorders : hemoglobinopathy. Identification of carrier Huntingtons disease, Myotonic dystrophy, status is easy and is possible by measurement of Tuberous sclerosis, Neurofobromatosis, etc. HbA2 which is almost always high in carriers iii) X-linked disorders: Duchenne muscular except in a rare situation of silent carrier status dystrophy, Fragile X syndrome, Menke’s Kinky when HbA2 may be normal and carrier status can hair disease, Pelizaeus Merzbacher disease , only be confirmed by molecular studies. Ornithine transcarbamylase deficiency, Rett syndrome, etc. In X-linked recessive disorders, risk of recurrence for boys is 50% where as females iv) Mitochondrial Disorders: MERRF, usually do not manifest. Majority of genetic MELAS, KSS, etc. diseases exhibit genetic heterogeneity where In single gene disorders, the risk of different gene mutations lead to identical recurrence will depend on the type of inheritance. phenotype.

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Fig.2. 25% Risk of affected child if both parents are carrier

Affected

Carrier

Normal

Fig.3. No risk of affected child if only one parent is carrier

Fig.4. No risk of affected child if one parent is affected 84 2008; 10(3) : 275 For most of the common single gene on empiric risk figures available in literature. disorders either enzyme based or molecular Prenatal diagnosis is possible in some defects diagnosis is available though facilities for using fetal ultrasonography. Table 3 shows risk diagnosis of all disorders are not available in our of recurrence of some common malformations. country. Prenatal diagnosis is possible by using the same techniques on fetal tissues – Chorionic Points to Remember villus biopsy or amniotic fluid. • Genetic counseling has an integral role in 2. Chromosomal disorders: Majority of the management of genetic disorders. chromosomal disorders have associated mental Counseling should be nondirective, psycho retardation. eg Down Syndrome, Edward educational and involves good syndrome (Trisomy18), Patau Syndrome communication with latest information, (Trisomy 13). All de novo numerical and confidentiality, and truthfulness. Besides structural chromosomal abnormalities have a low treating the patients, physicians should risk of recurrence (< 1%). Risk is higher if either make the parents or couple aware of the of the parents is carrying a balanced translocation. genetic disorder, risk of recurrence, Prenatal screening for common chromosomal prognosis and prenatal diagnosis. disorders has good sensitivity using maternal serum biochemical markers and ultrasonography. • Because of the increased requirement for Definitive diagnosis can be provided by genetic counseling an expansion of chromosomal studies on amniotic fluid, chorionic genetics training for residents and villus biopsy or cord blood sample. clinicians and the development of 3. Multifactorial disorders: Counseling computer-based interactive video programs and risk of recurrence in these disorders is based for genetic counseling is recommended.

Table 3. Empiric risk of recurrence of isolated malformation

Malformation Frequency per Recurrence for normal 1000 births parents of one affected child Anencephaly/Spina bifida 4 – 5 5 % Cardiac malformation 6 – 8 3 – 4 % Cleft lip and cleft palate 2 4 – 5 % Cleft palate alone 0.5 2 – 6 % Pyloric stenosis 2 – 3 3 % Talipes equinovarus 3 – 4 2 – 8 % Dislocation of hip 3 – 4 3 – 4 % Hischsprung disease 0.1 6 %

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Box 1. Common pedigree symbols, definitions and abbreviations Instructions • Key should contain all information relevant to interpretation of pedigree (e.g. define shading) • For clinical (non-published) pedigrees include: a) family names/initials, when appropriate b) name and title of person recording pedigree c) historian (person relaying family history information) d) date of intake/update • Recommended order of information placed below symbol (below to lower right, if necessary): a) age/date of birth or age at death b) evaluation c) pedigree number (e.g. I-1, I-2, I-3)

Male Female Sex Comments unknown Individual Assign gender by phenotype. Square represents male; circle represents a female; a diamond represents whose sex b. 1925 30 y 4 mo in not known. Age/date of birth can be given at the bottom right hand corner.

Affected Fillings can be shading, hatches, Individual dots, lines, etc

Multiple For ≥ 2 conditions the symbols are traits in an partitioned correspondingly, each individual quadrant with different fillings/patterns representing different features.

Multiple Number of the siblings is written individuals;6 6 6 inside the symbols; affected number individuals should not be grouped. known Multiple “n” is used in the place of “?” individuals; n number n n unknown

Deceased If known, write “d” with age at death individual below symbol. d. 35 y d.4 mo Stillbirth Birth of a dead child with gestational (SB) age noted. SB28 wk SB30 wk SB34 wk

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Pregnancy Gestational age and karyotype (if known) (P) below symbol. Light shading can be used P P P for affected and defined in key/legend. LMP: 7/1/94 Or 20 wk Proband First affected family member coming to P medical attention PPP Consultand Individual(s) seeking genetic counseling/testing.

Presymptomatic carriers who may manifest disease later

Carrier of autosomal or X-linked recessive trait who will not become affected

Two parents are joined by a horizontal line

Consanguineous mating is indicated by a double line

Two parents joined by a horizontal line from which falls an inverted T to which their offspring are attached by short vertical lines

A single child is attached by a long vertical line directly to the parents’ horizontal mating line

Twins attach at the same spot along the inverted T if nonidentical; if identical they branch from a short vertical line and connected by a line.

87 Indian Journal of Practical Pediatrics 2008; 10(3) : 278 Box-2. Pedigree symbols and abbrevations for pregnancies not carried to term Male Female Sex Comments unknown Spontaneous If ectopic pregnancy, write abortion (SAB) ECT below symbol male female ECT Affected SAB If gestational age known, write below symbol. Key / legend male female 16 week used to define shading Termination Other abbreviations (eg. TAB, of pregnancy VTOP, Ab) not used for sake (TOP) of consistency male female Affected Key/legend used to define TOP shading

male female

Instructions • Symbols are smaller than standard ones and individual’s line is shorter (even if sex is known, triangles are preferred to a small square / circle; symbols may be mistaken for the ones given in the previous table box 1, especially in hand drawn pedigrees) • If gender and gestational age known, write below symbol in that order. • Parents who are unaffected and unrelated may be omitted from the pedigree. • To save space, huge pedigrees are sometimes drawn in circular or spiral form rather than in a rectangular form.

Bibliography 5. Jones KL, Smith WS. Smith’s Recognizable 1. Fraser FC. Genetic Counseling. Am J Human Patterns Of Human Malformation Sixth Edition. Genet 1974:26; 636-661. 6. Gardner RJM, Day TC, Sutherland GR. 2. Harper PS. Practical Genetic Counseling, 5th Chromosomal Abnormality and Genetic rd edn. USA Butterworth Heinemann. Oxford Counseling. 3 edition Oxford University University Press, 2004. Press,USA 2003. 3. Biesecker BB. Goals of Genetic Counseling. 7. Shprintzen RJ. Robin sequence. In: Cassidy SB, Clinical Genet 2001; 60:323-330. Allanson JE. Management of genetic st 4. Aase JM. Diagnostic Dysmorphology. New syndromes. 1 edn. Wiley-Liss, New York, York, Plenum Medical Book Company, 1990. 2001;pp323-336.

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RADIOLOGIST TALKS TO YOU

INTRACRANIAL HEMORRHAGE the brain should immediately be carried out. Most AND HYPOXIC ISCHEMIC of the germinal matrix hemorrhage occurs within ENCEPHALOPATHY IN THE 24 to 72 hours of birth. The second scan is done NEONATE at the end of a week. Subsequently, scans may be repeated at various times to study progress of * Vijayalakshmi G the lesion. Fig.1 is a parasagittal view. The ** Elavarasu E normal choroid plexus is a regular, white, C- *** Vijayalakshmi M shaped structure. In the figure there is a bulbous *** Venkatesan MD thickening of the choroid plexus in the floor of the lateral ventricle. This is GMH or Intracranial bleed is a common event in the subependymal hemorrhage. It is sometimes fragile neonatal brain. It can occur in the difficult to decide whether GMH is localized to germinal matrix, choroid plexus, brain the subependymal area or has extended into the parenchyma and in the subdural and ventricle as intraventricular hemorrhage (IVH). subarachnoid compartments. In the preterm, This has led to it being referred to as GMH-IVH. germinal matrix hemorrhage (GMH) is common. The focus of hemorrhage undergoes liquefaction The germinal matrix consists of thin walled in 2 to 4 weeks leaving behind a cyst (Fig.2). vessels that are likely to rupture easily with These cysts can be of varying sizes. If large, they sudden changes in pressure. This delicate can cause obstructive hydrocephalus. vasculature is found in the area between the caudate nucleus and the thalamus on both sides. Sometimes large hemorrhages extend into It is prominent between 24 and 34 weeks and and distend the ventricle. almost completely regresses by term. In the In Fig.3 you can see blood distending the newborn period autoregulation of cerebral blood left lateral ventricle and spreading into and flow is easily upset leaving the brain open to distending the third ventricle. The black right sudden rushes of blood and rupture of blood lateral ventricle is dilated due to obstruction of vessels. Therefore there is a high risk of the foramen of Munroe with blood and the intracranial hemorrhage. pressure of the hematoma. Dilatation of ventricles For all preterm babies less than 34 weeks or does not indicate a good prognosis. when there is a suspicion of bleed, ultrasound of As we try to localize hemorrhage let us * Associate Professor identify some helpful landmarks on certain ** Asst. Professor standard sections of the cranium. Fig.4 is a *** Professor midcoronal section. The choroid plexus in the Department of Radiology, floor of the lateral ventricles and the roof of the Chenglepet Medical College Hospital, third ventricle are seen as three white dots (V). Chenglepet, Tamilnadu. “S” is the Sylvian fissure. So normal ventricles

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Fig.1. Subependymal or GMH. The Fig.2 GMH which has evolved into a bulbous thickening is seen anteriorly. cyst. Note the dilated ventricles.

Fig.3. Intraventricular hemorrhage Fig.4 Normal midcoronal section. (IVH). Hypoechoic clot in LLV and 3V.

Fig.5. Intraparenchymal hemorrhage. Fig.6. Normal posterior coronal section.

90 2008; 10(3) : 281 are hardly seen. It is the white choroid plexus watershed area between the vascular territories that indicates their location in the midcoronal of the middle cerebral, anterior and posterior section.The curved white lines are the sulci and cerebral arteries. MRI also shows changes in in between them are the gyri. Posteriorly, the the same areas. One important abnormality in triangular part is the posterior fossa with the MRI which is a very good predictor of a poor tentorium and the cerebellum. Fig.5 shows a outcome is abnormal signals in the posterior limb round white area corresponding to a large of the internal capsule. Later, delayed parenchymal hemorrhage in a term neonate. myelination and cortical atrophy are seen. Note that there are no sulci and gyri in that area. In the preterm, the immature neurons or The opposite lateral ventricle is dilated because oligodendrocytes which are metabolically very of obstruction due to pressure from the hematoma active between the 23 and 32 weeks are more while the ipsilateral ventricle is compressed. susceptible to ischemic injury. This tissue is Hemorrhage can also occur within the around the ventricles which is the location of choroid plexus especially in the term infant. Fig.6 periventricular leukomalacia (PVL). It is an is a posterior coronal section. The normal choroid ischemia-reperfusion brain injury that occurs in plexus is seen as thin, symmetrical white the periventricular region. This is seen as divergent lines. In Fig.7. hemorrhage has made unilateral or bilateral white areas around the the choroid on the right appear thicker. So watch lateral ventricles (Fig.8). They assume a wedge for asymmetries between the two sides. shape with the apex towards the lateral ventricle. Most of these babies develop cerebral palsy and Hypoxia and ischemia in the newborn cause therefore this is an indicator of poor prognosis. injury to the brain. In 24 to 48 hours there is In 2 to 3 weeks the infarcted area will evolve swelling of brain tissue. This manifests as into small cysts. The cystic lesions may compressed slit –like ventricles and a diffuse loss eventually disappear leaving behind dilated of sulcal-gyral echodistinction in ultrasound. ventricles with scalloped edges. Mild After 48 hours, signs of ischemic injury in the periventicular halos can disappear without signs term infant are bright areas in the basal ganglia, of ischemic neuronal loss. Follow-up scans will thalami and the parasagittal, subcortical determine if damage is permanent.

Fig.7. Choroid plexus hemorrhage. Fig.8. Periventricular leukomalacia.

91 Indian Journal of Practical Pediatrics 2008; 10(3) : 282 Hydrocephalus is a complication of GMH Cranial ultrasound is a valuable tool in the and IVH. The cause is either an obliterative study of the newborn brain. It is reliable and arachnoiditis that causes a communicative portable and can be used repeatedly to study the hydrocephalus or obstruction of interventricular evolution of lesions.It can easily identify CSF pathways due to clot. Post hemorrhagic germinal matrix and parenchymal hemorrhage ventricular dilatation can be transient till CSF and can be used in follow-up that will enable the pathways clear. Sometimes it may persist or pediatrician to predict long term outcome. progress. Serial scans are necessary to evaluate for the need for surgical intervention. CT is more effective for parenchymal Atrophy of the brain due to ischemia is also lesions but the ease of obtaining ultrasound is its seen as passive dilatation of ventricles. Therefore advantage. MRI is superior to ultrasound but PVL has to be followed with repeat scans. impractical for repeated usage.

NEWS AND NOTES

NATIONAL CONFERENCE ON CEREBRAL PALSY (IIIrd NATIONAL CONFERENCE OF IACP) 21st – 23rd November 2008-08 Organised by NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Nagpur.

Organising Secretariat Dr.Vithalrao Dandge Prof. and Head, Dept. of Paediatrics V-42, Narendra Nagar, Nagpur-440015 Tel:0712-2744951, Fax: 0712-2747937, Mob.9422106774 E-mail: [email protected]

NATIONAL WORKSHOP ON MOLECULAR CYTOGENETICS: RAPID PRENATAL DIAGNOSIS BY FISH New Delhi. November 3-8, 2008 Contact Dr.Ashutosh Halder Associate Professor, Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi-110 029.India Tel: 011-26593304 ext 4211 (O) or 3694® Mobile: 09313309579 Email: [email protected]

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PICTURE QUIZ

A term neonate with facial asymmetry (mouth deviated to right on crying) with no evidence of facial palsy had deformed pinna, and preauricular tags. Echo cardiogram revealed atrial septal defect. Can you spot the diagnosis? Compiled by Dr.Ramesh Bhat Y. Associate Professor, Department of Pediatrics Kasturba Medical College, Manipal, Udupi District, Karnataka – 576 104.

Answer on Page: 288

93 Indian Journal of Practical Pediatrics 2008; 10(3) : 284

DERMATOLOGY

ALOPECIA AREATA IN CHILDREN Aetiology * Madhu R Cause of alopecia areata is unknown, but it is believed to be a T cell mediated autoimmune Abstract : Alopecia areata is an autoimmune disorder occurring in genetically predisposed non-scarring disorder of hair growth affecting individuals. Emotional stress has been considered genetically predisposed individuals. It is as a precipitating factor. characterised by the sudden appearance of one or more round or oval well circumscribed patches Genetic : Familial occurrence is reported in of hair loss. Different patterns such as oophiasis, 10% to 20% of affected persons.4,5 Mode of alopecia totalis, alopecia universalis may occur. inheritance is thought to be autosomal dominant It is associated with autoimmune disorders such with variable penetrance. Simultaneous as Hashimoto’s thyroiditis and vitiligo. Increased occurrence in identical twins has been reported.3 incidence is seen in patients with Down’s Presence of HLADR5 and DR4 has been shown syndrome. Its severity, course and prognosis are to correlate with the disease severity. Chronic unpredictable. Prognosis is good in children with form of alopecia areata is associated with DQ3. limited involvement. Treatment only controls the Long standing alopecia totalis or universalis have condition, but does not cure or prevent further additional associations with DR4, DR5, DR11 spread. and DQ7.4,6 IL 1 receptor antagonist gene is said to correlate with disease severity.4 Key Words: Alopecia areata, Children, Hair loss, Autoimmune. An increased incidence has been noted in patients with Down’s syndrome,7,8,9,10 This high Alopecia areata (AA), is characterised by frequency suggests that a genetic linkage for AA the sudden appearance of one or more round or may exist on chromosome 21. The Down oval well circumscribed patches of hair loss. It syndrome region of chromosome 21 has the is a non scarring, non inflammatory type of MX1 gene that encodes interferon-induced p78 alopecia, that occurs in 0.1% to 0.2% of the protein MXA. This protein is strongly expressed 1 population. Though this disorder occurs in all in lesional anagen hair bulbs from patients with ages, 24- 50% present in childhood with the first alopecia areata. In a case-control study, the 2 episode before 16 years of age. It has been MX1 (+9959) polymorphism was significantly 3 described in neonates and infants. Alopecia associated with alopecia areata, with an increased areata can cause tremendous emotional and risk for early onset disease.6 Atopy is found in psychosocial stress in affected patients and their 10% to 22% of patients.11 families. Autoimmunity: Hypothesis that alopecia areata * Asst Professor, is an autoimmune disease is well supported by Dept of Dermatology & Leprosy, the statistically significant association with other Govt. Stanley Hospital, Chennai. autoimmune disorders such as vitiligo, 94 2008; 10(3) : 285

Fig.1. Single patch of alopecia Fig.2. Multiple patches of hair loss

Hashimoto’s thyroiditis, Addison’s disease, Pathogenesis myasthenia gravis, pernicious anemia, rheumatoid arthritis and Candida endocrinopathy Studies have shown that the injury is most syndrome where candidal infections tends to severe in the centre of the patch leading to begin by 5 years of age, but endocrinological premature and sudden precipitation of a group dysfunction may not be apparent until of follicles into telogen, the resting phase, with adolescence or even adult years.4,5,12,13 Increased resultant hair shedding. In the periphery, incidence of organ specific antibodies against impaired keratinisation and shaft breakage occurs thyroid, gastric parietal cells, etc has been in anagen follicles, followed by precipitation into reported. High titres of antibodies to hair telogen which results in the formation of the 3 follicular components have been observed in characteristic “Exclamation Point” hairs. Short, affected patients.4 loose hairs, in the margins of the patch that gradually thin towards the scalp are called With regard to cell mediated immunity, it “Exclamation Point” hairs, which are has been found that there is altered T-cell pathognomic of alopecia areata. The hairbulb regulation of the immune response. Lymphocytic represents the dot of the exclamation point. When infiltration around the hair follicles support the seen under a low-power microscope , free ends autoimmune theory. Neuropeptides such as are splayed giving a “frayed rope” appearance. Calcitonin gene-related peptide (CGRP) and substance-P play a significant role. CGRP which Clinical features has potent anti-inflammatory action is found to Alopecia areata, usually occurs over the be decreased in alopecia areata. There is a scalp, but may involve eyebrows and beard area. decreased expression of substance-P , which is The classical picture is that of a sudden capable of inducing hair growth, in the scalp of appearance of one or more oval or round well patients with alopecia areata.11 circumscribed smooth patches of hair loss that is Psychological : Role of stress has been asymptomatic. Skin is smooth and soft. Rarely frequently cited.4,14 erythema or mild edema may be present in early

95 Indian Journal of Practical Pediatrics 2008; 10(3) : 286 stages. Increased hair shedding has been reported. Differential Diagnosis Thin depigmented hair shafts may be seen before hair loss or with early hair regrowth. These grey Diagnosis is mainly clinical. However, the hairs may repigment later. Exclamation mark following conditions should run through one’s hairs may be found in the margins. Positive pull mind : test at the periphery of a plaque usually indicates 1. Naevus sebaceous, present since birth , that the disease is active, and further hair loss presents as a patch of congenital alopecia can be expected. In alopecia areata, when a tuft of hair is forced inward or bent, hairs kink at 2. Physiological hair cycle changes in early 5-10 mm above the surface. Shuster described infancy. this as the “ Coudability sign”.15 3. Frictional alopecia due to tight braided Various clinical patterns are as follows: hairstyle. Single or multiple patches. 4. Trichotillomania – patches of alopecia Ophiasis (Gk–serpent) pattern - Hair loss begins with twisted and broken hairs of different lengths as a bald spot on the posterior occiput and seen extends anteriorly and bilaterally in a 1 to 2 inch wide band, above the ears, occasionally extending 5. Tinea capitis – signs of inflammation, to the anterior aspect of the scalp. This pattern scaling and lymphadenopathy mostly seen in children, occurs in less than 5% of the patients and often progresses to alopecia 6. Scarring alopecia, post inflammatory totalis or universalis. atrophy - absence of follicular ostia or some degree of atrophy. Sisaipho (Converse-ophiasis spelled backwards) pattern occurs when hair loss spares the sides 7. Rarely lichen planopilaris, morphea,. and the occiput. 8. Diffuse alopecia areata resembling Alopecia totalis: 100% hair loss on the scalp telogen effluvium may be difficult to diagnose, wherein a punch biopsy will help confirm Alopecia universalis: Complete loss of hair on diagnosis. Characteristic histopathologic feature all hair-bearing areas. is the presence of a peribulbar lymphocytic Reticular or the diffuse pattern occurs when hair infiltrate (swarm of bees). loss is more extensive and the patches coalesce. Prognosis Nail involvement : Nail changes are seen in 10-44% of patients, with severe involvement The course of alopecia areata is variable and being observed in alopecia totalis or universalis. unpredictable. Spontaneous regrowth occurs The most characteristic pattern is the presence within a few months, with or without treatment. of superficial, uniform , minute pits arranged When there is limited involvement of few regularly in horizontal and or vertical rows. patches, prognosis is good , with complete Trachyonychia (rough sandpaper nails), proximal regrowth occurring within one year in 95% of shedding, opacity, punctate leukonychia may children. The severe, chronic form is seen in occur.16,17 about 7% to 10% of patients.1

96 2008; 10(3) : 287 Poor prognostic signs3, 18 7. Topical immunotherapy in chronic, severe alopecia areata - Dinitrochlorobenzene (DNCB) Early age of onset, ( less than 10 years at first SADBE (Squaric acid dibutyl ester), episode), family history diphenylcyclopropenone. Multiple patches with rapid progression 8. Cryotherapy, oral cyclosporin, Oophiasis, Sisaiphoo phototherapy, aromatherapy. Alopecia totalis, alopecia universalis Points to Remember • Alopecia areata is a clinical diagnosis. Associations – atopy, autoimmune conditions, Various modalities of therapy that are nail dystrophy, Down’s syndrome available, only control and not cure or Poor response to previous treatment. prevent further progression of the disease.

Treatment1,11,19 • Psychological support and counseling is mandatory. Therapy of alopecia areata,at best controls • Any mode of treatment is considered to rather than cure or prevent the further spread of have failed only after a minimum period the disease. First and foremost step is to offer of 3-6 months because of the long period psychological support and counseling to the child for regrowth of hair. and the parents. • Thyroid screening should be routinely 1. Topical corticosteroid – Mid to high performed in all children with potent, applied twice daily longstanding AA. 2. 5% topical minoxidil solution applied References twice daily. Efficacy is enhanced when used in 1. Paller AS, Mancini AJ, eds. Hurwitz Clinical combination with anthralin or betamethasone rd dipropionate. Anthralin is applied two hours after Pediatric dermatology. 3 ed. Elsevier Saunders, 2006;pp157- 160. the second minoxidil application, whereas 2. Sharma VK, Dawn G, Kumar B. Profile of betamethasone is applied twice daily 30 minutes alopecia areata in Northern India. Int J Dermatol after use of minoxidil. 1996;35:22-27. 3. Short contact anthralin- 0.2 to 1% for 3. Wadhwa SL, Khopkar U, Mhaske V. Hair and 30 minutes. Scalp disorders, Alopecia areata. In: Valia RG and Valia AR. Eds, IADVL Textbook and atlas nd 4. Topical tacrolimus 0.1% twice daily.20,21 of dermatology.Vol I, 2 Edn, Bhalani, Mumbai 2001;pp733-738. 5. Intralesional triamcinolone acetonide in 4. Dawber RPR, Berker D,Wojnarowska F. children over 10 years. Disorders of hair, Alopecia areata. In: Champion RH, Burton JL, Burns DA, 6. Systemic corticosteroids in severe Breathnach SM, Eds. Textbook of dermatology. th and rapid progression- oral prednisolone 6 Edn., Blackwell Science publications, 1998; 0.5-1mg/kg/d for 4 wks and then tapered to pp2919- 2927. alternate day therapy for few months, during 5. Ahmed I,Nasreen S, Bhatti R. Alopecia areata which period the child should be monitored for in children. J Coll Physicians Surg Pak side effects of steroids. 2007;17:587-590. 97 Indian Journal of Practical Pediatrics 2008; 10(3) : 288

6. McDonagh AJ, Tazi-Ahnini R. Epidemiology impact of personal and family history of stress and genetics of alopecia areata. Clin Exp and autoimmunity. J Eur Acad Dermatol Dermatol 2002;27:405-409. Venereol. 2007;21:356-359. 7. Du Vivier A, Munro DD. Alopecia areata, 15. Shelley WB, Shelley ED. Alopecia areata. In: autoimmunity and Down syndrome. Br Med J Advanced dermatologic diagnosis. 1975;1:191-192. W.B.Saunders, Philadelphia 1992;pp224- 227. 8. Tan E, Tay YK, Giam YC. A clinical study of 16. Tosti A, Morelli R, Bardazzi F, et al. Prevalence childhood alopecia areata in Singapore. Pediatr of nail abnormalities in children with alopecia Dermatol 2002;19:298-301. areata. Pediatr Dermatol 1994; 112-115. 9. Tan E, Tay YK, Goh CL, Giam YC. The pattern 17. Tosti A, Fanti PA, Morelli R, et al. and profile of alopecia areata in Singapore: A Trachyonychia associated with alopecia areata: study of 219 Asians. Int J Dermatol A clinical and pathological study. J Am Acead 2002;41:748-753. Dermatol 1991;25:266-270. 10. Sharma VK, Kumar B, Dawn G. A clinical study of childhood alopecia areata in Chandigarh, 18. Sinclair R, Scarff CE. Alopecia areata. In: India. Pediatr Dermatol 1996;13:372-377. Williams H, Bigby M et al, Eds. Evidence- based Dermatology. Prism books pvt ltd, 2003; 11. Rogers M, Tay YK. Hair disorders, Alopecia pp577- 588. areata. In : Schachner LA , Hansen RC, Eds. rd Pediatric dermatology. 3 Edn . Mosby, London 19. Shelley WB, Shelley ED. Alopecia areata. 2003; pp546- 549. Eds. Advanced dermatologic therapy II. 12. Kurtev A, Iliev E. Thyroid autoimmunity in WB Saunders, Philadelphia 2001; pp68- 79. children and adolescents with alopecia 20. Rallies E, Korfitis C, Gregoriou S, Rigopoulos areata.Int J Dermatol.2005;44:457-461. D. Assigning new roles to topical tacrolimus. 13. Nanda A, Alsaleh QA, Al-Hasawi F, Al- Expert Opin Investig Drugs. 2007;16:1267- Muzairai I. Thyroid function, autoantibodies, 1276. and HLA tissue typing in children with alopecia 21. Yamamoto S, Kato R. Hair growth- stimulating areata. Pediatr Dermatol.2002;19:486-491 effects of cyclosporine A and FK506, potent 14. Kakourou T,Karachristou K, Chrousos G. immunosuppressants. J Dermatol Sci. 1994; A case series of alopecia areata in children: 7 suppl: S47- 54. Picture Quiz Answer: Cayler cardio-facial syndrome (Characterised by underdevelopment or absence of depressor anguli oris muscle on one side associated with major congenital anomalies, most commonly in cardiovascular system). NEWS AND NOTES

XINCPID – 2008 XI NATIONAL CONFERENCE OF PEDIATRIC INFECTIOUS DISEASES Organized by: Indian Academy of Pediatrics, Varanasi Date: 22nd & 23rd November 2008 Venue: Hotel Ramada, Varanasi Registration Fee: Rs.2000/- till 31st July 2008 Address of correspondence Dr.Ashok Rai, Organizing Secretary, XI NCPID-2008 C-29/61-A, KH-1, Raghubir, Maldahiya, Varanasi-221 002. Mobile: 94152-01567 / 98390-56960, Email: [email protected]

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