Dtsch Arztebl Int. 2011 June; 108(25): 426431. Published online 2011 June 24. doi: 10.3238/arztebl.2011.

0426 Copyright notice Review Article

PMCID: PMC3139414

Early Detection of Hearing Impairment in Newborns and Infants

Martin Ptok, Prof. Dr. med. Dr. med. h. c.*1
Klinik und Poliklinik fr Phoniatrie und Pdaudiologie, Medizinische Hochschule Hannover *Klinik und Poliklinik fr Phoniatrie und Pdaudiologie Medizinische Hochschule Hannover Carl-Neuberg-Str. 1, 30625 Hannover, Germany ; Email: Ptok.Martin@MH-Hannover.de Received August 17, 2010; Accepted March 24, 2011. See "Hearingthe Gateway to Speech and Cognition" on page 425.
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Abstract
Background 12 out of 1000 newborns have markedly impaired hearing. Methods Review of the pertinent literature, which was retrieved with a selective search of the following databases: NHS EED (Economic Evaluation Database), HTA (Health Technology Assessment), DARE (Database of Abstracts of Reviews on Effectiveness), Clinical Trials, CDSR (Cochrane Database of Systematic Reviews), and PubMed. Results The current scientific evidence favors universal neonatal hearing screening (UNHS) for the early detection of hearing impairment. UNHS is best performed in two stages: first measurement of otoacoustic emissions and then automated assessment of the brainstem auditory evoked response. To be effective, UNHS programs must have a high coverage rate, high sensitivity and specificity, and proper tracking with a low rate of loss to follow-up. Children with positive screening tests for hearing impairment should undergo confirmatory testing as soon as possible and then receive the appropriate treatment. Early intervention is particularly critical for speech acquisition. Conclusion The early detection and treatment of hearing impairment in newborns and infants has a beneficial effect on language acquisition.
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Hearing plays a key part in learning to talk. Without speech and hearing it is difficult for interpersonal relationships to develop and thrive. In earlier times children who did not react to acoustic stimuli and were able neither to understand speech nor to acquire it spontaneously encountered severe discrimination, being dismissed as simple-minded or worse. As late as 1950, the standard policy was to wait until a hearing-impaired child had learned to speak proficiently before prescribing an individually designed hearing aid. The intention was to protect the hearing-impaired child from its own imperfect speech. Early detection of impaired hearing thus seemed superfluous, since in any case a hearing aid would not be prescribed until later (1). Growth in understanding of the functional and morphological maturation of the auditory system and of the complexities of emotional and social development in children, coupled with advances in hearing technology, have led to a fundamental change in attitude. Today, it is axiomatic that hearing impairment should be detected and treatment initiated as early as possible. Following a ruling by the Federal Joint Committee (Gemeinsamer Bundesausschuss) that came into effect on 1 January 2009, all newborn children in Germany are entitled to hearing screening (2). Universal newborn hearing screening (UNHS) is either recommended or already practiced and legally regulated (nationally or regionally) (4) in many other European nations, e.g., Austria (e1), Great Britain (e2), Italy (e3), and France (e4), as well as in various countries in Asia (e5) and in the whole of the USA (3). In deciding whether to establish a system for early detection of hearing impairment in newborns and infants, a range of questions had and have to be answered, for example:
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Will screening of newborn children always detect hearing impairment? How high are the sensitivity and specificity of UNHS? What proportion of newborns are screened? How high is the rate of children who have conspicuous findings but are lost to followup? Is it better to screen all newborns or only those with risk factors? What benefits does early detection of hearing impairment bring? Do children in whom hearing impairment is detected early by UNHS develop better than those who do not undergo UNHS and whose hearing problems are discovered later? What potential risks are involved in newborn hearing screening, e.g., by unnecessarily alarming parents whose children have a false-positive result? How soon and with what degree of certainty can confirmatory tests be carried out after a positive screening result? How quickly can treatment be initiated after confirmation of the diagnosis? Is it better to start treatment immediately or later?

Before these questions can be considered, however, two other issues have to be resolved:

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Quality: What type of hearing impairment is involved (e.g., middle ear impairment, inner ear impairment, unilateral or bilateral impairment)? Quantity: What is the degree of hearing impairment (e.g., expressed as hearing loss in decibels)?

This article describes how these questions can be answered or have already been answered.
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Methods
A selective search of the literature (checklist at www.prisma-statement.org) was carried out in the following databases:
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NHS EED (Economic Evaluation Database) HTA (Health Technology Assessment) or DARE (Database of Abstracts of Reviews on Effectiveness) (http://www.crd.york.ac.uk/crdweb; last accessed on 16 August 2010) Clinical Trials (http://clinicaltrials.gov/ct2/search; last accessed on 17 August 2010) CDSR (Cochrane Database of Systematic Reviews) (http://www2.cochrane.org/reviews; last accessed on 17 August 2010) PubMed/Medline (last accessed on 16 August 2010)

A search on the terms infant, newborn, child, pediatric, paediatric, hearing loss, hearing impairment, and deafness yielded 21 135 results. Restriction to the years 2007 to 2010 identified 3146 evaluable publications. The reason for excluding earlier studies was that those before 2007 were covered in an extremely thorough survey by the Institute for Quality and Efficiency in Health Care (Institut fr Qualitt und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) (5). Further restriction to publications including the terms clinical trial or comparative study narrowed the sample down to 379 studies. Screening of the abstracts of all 379 publications was followed by full-text analysis of the studies featuring empirical data.

Prevalence
Different studies broadly agree that one or two of every 1000 newborns have a hearing impairment that on current evidence warrants treatment or observation, i.e., permanent hearing loss with a lowering of the absolute threshold of hearing for speech perception by at

least 35 dB (e6 e8). To date, the UNHS study groups have concentrated on detecting such hearing impairments as early as possible (1).
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Classification of hearing disorders

The term hearing impairment is of little practical use without further qualification. It is advisable to classify disorders of hearing according to:
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Quality and location Cause Severity.

Quality and location

The hearing process can be divided into sound conduction, transformation of sound waves into bioelectrical signals, and neural processing. A hearing disorder may involve only one or a combination of these functions. Hearing impairments can thus be classified as follows:
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Impairments of conduction (defective transport of sound waves from the external environment to the inner ear) Sensory impairment (defective sensation and transformation of stimuli between the base of the stapes and the first neuron of the auditory nerves) Retrocochlear and central hearing impairment and auditory perception disorders (defective transmission, processing, and perception of stimuli) Combined hearing impairments.

Particularly important in the context of early detection of hearing disorders in newborns and infants are conductive and sensory impairments, together with auditory neuropathy, which is occasionally included among the central hearing impairments.

Causes
As with other sensory impairments, there are hereditary and non-hereditary or congenital and pre-, peri-, or postnatal causes of hearing disorders. While the cause of conductive hearing loss can usually be identified relatively simply (e.g., by means of otoscopy in the case of tympanic effusion or accumulation of earwax), even thorough diagnostic investigation fails to uncover the reason for around half of the cases of inner ear hearing impairment in childhood. Approximately 50% of severe hearing impairments arising in the inner ear are thought to be hereditary in origin. The precise causes of central auditory perception disorders cannot be established.

Severity
Classification of severity is usually based on the average hearing loss in the frequency range of normal speech. Thus the hearing impairment is described solely in terms of the absolute threshold of hearing. However, the principal function of hearing is to detect rapid changes of frequency and intensity in acoustic signals above the threshold, and thus to understand speech. The conventional adult classification according to speech comprehension (speech audiometric determination of whole-word comprehension and hearing loss for numbers) is not applicable to newborns and infants. Moreover, such a classification provides only a snapshot of hearing ability. Intermittent hearing impairments (e.g., in children with recurring tympanic effusions) must also be considered as significant disorders. In such cases it may be beneficial to record how often episodes of hearing impairment occur over an extended period of time, e.g., a year, and then to decide how best to proceed. Even precise classification according to the results of routine speech audiometric testing does not do justice to central hearing impairments and auditory perception disorders.
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Diagnosis of hearing disorders in early childhood

Diagnosis of hearing disorders in newborns and infants is generally a two-stage process. As described above, the current standard is UNHS, followed immediately by confirmatory diagnostic evaluation as appropriate.

Universal newborn hearing screening

The various studies on UNHS have either measured otoacoustic emissions (OAE) (e9) or performed automated auditory brainstem response (AABR) audiometry, or both. In twostage screening, OAE measurement is followed by AABR audiometry. In one very thorough analysis, Wolff et al. found that the reported sensitivity of OAE measurement varied from 50% to 100% and the specificity from 49% to 97% (6). A weakness of OAE measurement is that it does not detect fluctuating hearing impairments or those due to auditory neuropathy (e9 e12). A controlled study carried out in the UK employed two-stage screening: The estimated sensitivity (no follow-up of screening-negative children, assumption of at least a few false negatives) was 91.7% (95% confidence interval [CI] 0.742 to 0.977), the specificity 98.5% (95% CI 0.983 to 0.987) ([7, 8], evaluated by [6]). From the practical clinical viewpoint, neither OAE measurement nor AABR audiometry is simple to perform. Although the equipment has become much easier to use (Figure), it is

advisable for the tests to be conducted by well-trained and experienced staff, and also to keep the referral rate reasonably low.
Figure 1 Hearing screening with a handheld touch-screen device capable of both measurement of transitory evoked otoacoustic emissions (TOAE) and automated auditory brainstem response (AABR) audiometry

Another criterion of the quality of UNHS is the coverage rate, i.e., the proportion of newborns screened. Varying figures are reported in the literature. Green, for example, found that 95% of newborns were screened in the states of the USA in which UNHS was compulsory by law, against only 26% in the remaining states (9). Whenever screening arouses suspicion of hearing impairment, the child concerned must undergo confirmatory diagnostic evaluation; the rate of loss to follow-up of a UNHS program should be kept as low as possible. To this end, functioning central registries must be set up (e13). These centers should ideally maintain registers of children who have not been screened and children with a conspicuous screening result. The screening center can then track these children and ensure that the required investigations are instigated. Despite the recommendations of the Federal Joint Committee, Germany is not yet completely covered by such tracking centers for UNHS. Selective screening of newborns with specific risk factors has been discussed as an alternative to UNHS (Box). These children have an up to 10 times higher risk of suffering an impairment of hearing that requires treatment (1% to 2% instead of 0.1% to 0.2%). However, around half of all hearing-impaired children exhibit no risk factors and would therefore not be among those screened. For this reason, selective screening is no longer recommended. BOX. Hearing impairment in early childhood: signs and risk factors (11)
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Concern on the part of parents/guardians regarding the hearing, speech development, or general development of their child Family history of permanent hearing impairment in childhood Stay of more than 5 days in the neonatal intensive care unit, possibly including the need for ventilation, extracorporeal membrane oxygenation, assisted breathing, administration of ototoxic drugs or loop diuretics, and hyperbilirubinemia requiring transfusion Intrauterine infections such as cytomegalovirus, herpes, rubella, syphilis, and toxoplasmosis

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Craniofacial anomalies, including malformation of the earlobe, auditory canal, or auricular appendages and anomalies of the auditory pit and petrosa External signs that may indicate a syndrome involving sensorineural hearing loss or permanent conductive hearing loss, e.g., a white forelock Syndromes involving immediate, progressive, or late-onset hearing loss, such as neurofibromatosis, osteopetrosis, and Usher syndrome; other complexes associated with hearing disorders are Waardenburg, Alport, Pendred, and Jervell-Lange-Nielsen syndromes Neurodegenerative diseases such as Hunter syndrome or sensorimotor neuropathies such as Friedreich ataxia and Charcot-Marie-Tooth syndrome Demonstration in culture of infections associated with sensory hearing loss, including bacterial or viral (especially herpes or varicella) meningitis Head injury, particularly fractures of the skull base or petrosa requiring inpatient treatment Chemotherapy Otitis media recurring frequently or persisting for more than 3 months

It is advisable for newborns with specific risk factors, e.g., those who have been treated for more than 5 days in a neonatal intensive care unit or required ventilation, to be referred for immediate AABR screening or go straight to (confirmatory) diagnostic evaluation. An American committee of experts recommends that children with risk factors (box) be monitored/examined regularly for 3 years (10, 11). UNHS is worthwhile only if (a) the diagnosis is confirmed and treatment instigated without delay and (b) these measures then have a positive impact on patient-relevant endpoints, i.e., if hearing-impaired children who are diagnosed early develop better with regard to speech acquisition than those whose hearing disorders are detected and treated later. No relevant prospective randomized trials have been conducted for ethical and moral reasons, but cohorts with and without UNHS have been compared. Sininger et al. found that final diagnosis and commencement of treatment were some 24 months earlier in hearingimpaired children who had undergone UNHS than in those who had not been screened (e14). The few studies on receptive speech skills (speech comprehension) show a significant benefit of UNHS; regarding expressive speech skills, there was at least a trend towards better development in UNHS children (for example [76, 12 14]). Wolff et al. are quite right to point out that the clinical significance of these advantages is unclear (6) (see also [e15]); however, the findings of the DECIBEL Collaborative Study Group indicate that newborn hearing screening is superior to distraction audiometry in the ninth month of life not only in terms of development of social behavior, gross motor skills, and both receptive and

expressive speech skills, but also with regard to quality of life as assessed by questionnaire (15). The potential drawbacks of UNHS include unnecessary alarming of the parents in the case of false-positive findings. However, studies have failed to confirm any such disadvantages. Since UNHS (as desired) leadsor is intended to leadto early detection and thus to prompt treatment, the risks and drawbacks of early treatment can be counted as (late) disadvantages of UNHS. Case studies and case reports have described an increased rate of meningitis in children who receive a cochlear implant (CI) at an early age. Reefhuis et al. reported incidence of 138.2 cases per 100 000 person-years, 30 times higher than in a comparative cohort (e16). It must be pointed out, however, that most reports describe the use of a CI electrode that is now no longer employed. Although the data do not permit definitive conclusions, it is currently not thought that UNHS entails any risks that might lead to it being discredited.
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Confirmatory diagnostic evaluation

If UNHS indicates that a child may have a hearing impairment, complementary investigations to confirm the diagnosis should be instigated as soon as possible. These examinations should be able to definitively confirm or exclude hearing impairment, and if a hearing disorder is present they should provide precise qualitative and quantitative characterization (e17). For the above-mentioned reasons this is practically impossible; however, confirmatory diagnostic procedures can describe hearing impairment, in the sense of permanent hearing loss of 35 dB or more, well enough for appropriate treatment to be instigated.

Pedaudiology
Hearing tests can fundamentally be divided into subjective and objective examinations. In subjective tests a sound stimulus is offered and the examiner observes and evaluates the childs reaction. Objective hearing tests are not truly objective, but are termed so because they do not require cooperation by the child. The auditory stimulus is presented (semi)automatically, and simultaneously specific neurobiological reactions are registered (16). Declau et al. (17) published data on confirmatory diagnostic evaluation after positive UNHS in a large group of children: Of 170 children with a positive UNHS result (corresponding to ca. 87 000 newborns screened), 5 had a tympanic effusion that regressed during the observation period. Permanent hearing impairment was confirmed in 116 children, bilateral in 68 cases and unilateral in the other 48 neonates. The average absolute threshold of

hearing was 70 to 80 dB nHL. The initial (screening) AABR result was confirmed in full in 60.4% of cases. Interestingly, 11.6% of the newborns thought to have a unilateral hearing impairment on UNHS were found to have a bilateral impairment when assessed in more detail. Objective hearing tests were used for confirmatory audiological diagnosis, but no subjective tests. This is regrettable, because even in young children subjective hearing tests yield results that help to decide how best to proceed.
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Conclusion and perspective

Overall, the studies that have been carried out to date indicate that properly conducted UNHS followed by a functioning program of observation for children affected by hearing impairments yields positive results with regard to speech and general development. The risks and drawbacks of UNHS seem slight. Nevertheless, the data on early detection of hearing impairment in newborns and infants are not very robust: Further research is clearly required. Besides the full-scale implementation of UNHS, the most important single measure for the practical realization of early detection of hearing impairments in newborns and infants in Germany seems to be the installation of a system of tracking centers covering the whole country. In the next few years we must on the one hand consider whether the rate of false-positive UNHS results can be reduced by improved assessment of the middle ear status (e18, e19). On the other hand, particularly thinking about future early interventions, we must investigate the potential utility of hybrid screening schemes, combining audiological testing with genetic screening (e.g., 35delG in GJB2/connexin mutation [e20, e21] or congenital cytomegalovirus infection [e22,e23]).

Key Messages.
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The current scientific evidence supports the demand for universal newborn hearing screening (UNHS) conducted by carefully trained personnel. A functioning system for registering and tracking both non-screened children and those with a conspicuous screening result is of crucial importance. Two-stage (or combined) screening yields better results than measurement of otoacoustic emissions alone; however, children exhibiting specific risk factors should immediately undergo AABR screening or (confirmatory/excluding) diagnostic evaluation.

Conspicuous findings on screening should be swiftly followed by confirmatory diagnostic assessment and, if indicated, treatment. On the available evidence, the risks and disadvantages of UNHS are slight.

Acknowledgments
Translated from the original German by David Roseveare.

Footnotes
The author declares that no conflict of interest exists.

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References
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11. American Academy of Pediatrics, Joint Committee on Infant Hearing Year 2007 position statement Principles and guidelines for early hearing detection and intervention programs.Pediatrics. 2007;120:898921. 12. Yoshinaga-Itano C, Coulter D, Thomson V. Developmental outcomes of children with hearing loss born in Colorado hospitals with and without universal newborn hearing screening programs.Semin Neonatol. 2001;6:521 529. [PubMed] 13. Vohr B, Jodoin-Krauzyk J, Tucker R, Topol D, Johnson MJ, Ahlgren M, et al. Expressive vocabulary of children with hearing loss in the first 2 years of life: Impact of early intervention. J Perinatol.2010;31:274280. [PubMed] 14. Moeller MP. Early intervention and language development in children who are deaf and hard of hearing. Pediatrics. 2000;106 15. Korver AM, Konings S, Dekker FW, Beers M, Wever CC, Frijns JH, et al. Newborn hearing screening vs later hearing screening and developmental outcomes in children with permanent childhood hearing impairment. JAMA. 2010;304:17011708. [PubMed] 16. Ptok M. Das schwerhrige Kind. Dtsch Arztebl. 1997;94(28-29):A 1932A 1937. 17. Declau F, Boudewyns A, Van den Ende J, Peeters A, van den Heyning P. Etiologic and audiologic evaluations after universal neonatal hearing screening: Analysis of 170 referred neonates. Pediatrics.2008;121:1119 1126. [PubMed] e1. Weichbold V, Nekahm-Heis D, Welzl-Muller K. Evaluation of the austrian newborn hearing screening program. Wien Klin Wochenschr. 2005;117:641646. [PubMed] e2. Kennedy C, McCann D, Campbell MJ, Kimm L, Thornton R. Universal newborn screening for permanent childhood hearing impairment: An 8-year follow-up of a controlled trial. Lancet.2005;366:660662. [PubMed] e3. Ciorba A, Hatzopoulos S, Camurri L, Negossi L, Rossi M, Cosso D, et al. Neonatal newborn hearing screening: Four years experience at Ferrara university hospital (CHEAP project): Part 1. Acta Otorhinolaryngol Ital. 2007;27:10 16. [PMC free article] [PubMed] e4. Leveque M, Schmidt P, Leroux B, Danvin JB, Langagne T, Labrousse M, et al. Universal newborn hearing screening: A 27-month experience in the french region of champagne-ardenne. Acta Paediatr. 2007;96:1150 1154. [PubMed] e5. Fukushima K, Mimaki N, Fukuda S, Nishizaki K. Pilot study of universal newborn hearing screening in japan: District-based screening program in okayama. Ann Otol Rhinol Laryngol.2008;117:166171. [PubMed] e6. Fortnum HM, Summerfield AQ, Marshall DH, Davis AC, Bamford JM. Prevalence of permanent childhood hearing impairment in the united kingdom and implications for universal neonatal hearing screening: Questionnaire based ascertainment study. BMJ. 2001;323:536540. [PMC free article][PubMed] e7. Kennedy CR. Controlled trial of universal neonatal screening for early identification of permanent childhood hearing impairment: Coverage, positive predictive value, effect on mothers and incremental yield. Wessex universal neonatal screening trial group. Acta Paediatr Suppl.1999;88:7375. [PubMed] e8. Parving A. The need for universal neonatal hearing screening some aspects of epidemiology and identification. Acta Paediatr Suppl. 1999;88:6972. [PubMed] e9. Ngo RY, Tan HK, Balakrishnan A, Lim SB, Lazaroo DT. Auditory neuropathy/auditory dys-synchrony detected by universal newborn hearing screening. Int J Pediatr Otorhinolaryngol.2006;70:12991306. [PubMed]

e10. Ptok M. Diagnostik und Therapie der auditorischen Neuropathie. Kinder- und Jugendmedizin.2007;7:321327. e11. Kumar UA, Jayaram MM. Prevalence and audiological characteristics in individuals with auditory neuropathy/auditory dys-synchrony. Int J Audiol. 2006;45:360366. [PubMed] e12. Kirkim G, Serbetcioglu B, Erdag TK, Ceryan K. The frequency of auditory neuropathy detected by universal newborn hearing screening program. Int J Pediatr Otorhinolaryngol. 2008;72:14611469.[PubMed] e13. www.neugeborenen-hoerscreening.de/zentralen/anschriften/index.html, last accessed on. 2011. Jun 1, e14. Sininger YS, Martinez A, Eisenberg L, Christensen E, Grimes A, Hu J. Newborn hearing screening speeds diagnosis and access to intervention by 20-25 months. J Am Acad Audiol.2009;20:4957. [PubMed] e15. Stevenson J, McCann DC, Law CM, Mullee M, Petrou S, Worsfold S, et al. The effect of early confirmation of hearing loss on the behaviour in middle childhood of children with bilateral hearing impairment. Dev Med Child Neurol. 2011;53:269274. [PubMed] e16. Reefhuis J, Honein MA, Whitney CG, Chamany S, Mann EA, Biernath KR, et al. Risk of bacterial meningitis in children with cochlear implants. N Engl J Med. 2003;349:435445. [PubMed] e17. Neumann K, Nawka T, Wiesner T, Hess M, Bottcher P, Gross M, et al. Quality assurance of a universal newborn hearing screening. recommendations of the german society of phoniatrics and pediatric audiology. HNO. 2009;57:17 20. [PubMed] e18. Hunter LL, Feeney MP, Lapsley Miller JA, Jeng PS, Bohning S. Wideband reflectance in newborns: Normative regions and relationship to hearing-screening results. Ear Hear. 2010;31:599610. [PubMed] e19. Sanford CA, Feeney MP. Effects of maturation on tympanometric wideband acoustic transfer functions in human infants. J Acoust Soc Am. 2008;124:21062122. [PMC free article] [PubMed] e20. Prasad S, Cucci RA, Green GE, Smith RJ. Genetic testing for hereditary hearing loss: Connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA)Hum Mutat. 2000;16:502 508. [PubMed] e21. Ahmad S, Tang W, Chang Q, Qu Y, Hibshman J, Li Y, et al. Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness. Proc Natl Acad Sci U S A. 2007;104:13371341. [PMC free article] [PubMed] e22. Ross SA, Novak Z, Fowler KB, Arora N, Britt WJ, Boppana SB. Cytomegalovirus blood viral load and hearing loss in young children with congenital infection. Pediatr Infect Dis J. 2009;28:588592.[PMC free article] [PubMed] e23. Hilgendorff A, Daiminger A, Dangel V, Kreuder J, Geidel C, Reiss I, et al. Oral valganciclovir treatment in a CMV congenital infected infant with sensorineural hearing loss (SNHL) first detected at 4 months of age. Klin Padiatr. 2009;221:448449. [PubMed]
Indian J Palliat Care. 2011 January; 17(Suppl): S70S73. doi: 10.4103/0973-1075.76247 Copyright Indian Journal of Palliative Care PMCID: PMC3140088

Pain in Children: Neglected, Unaddressed and Mismanaged

Lulu Mathews
Institute of Palliative Medicine, Calicut, Kerala, India Address for correspondence: Dr. Lulu Mathews; E-mail: lulumathews@gmail.com This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Pain is one of the most misunderstood, under diagnosed, and under treated/untreated medical problems, particularly in children. One of the most challenging roles of medical providers serving children is to appropriately assess and treat their pain. New JCAHO regulations regard pain as the fifth vital sign and require caregivers to regularly assess and address pain. Pain being a personal experience, many different terms are used to describe different sensations. Assessment of pain in children is linked to their level of development. Children of the same age vary widely in their perception and tolerance of pain. Keywords: Pain in children, Neglected and unaddressed, Barriers to pain assessment and management
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INTRODUCTION
Every child will experience pain at one time or another, whether it is from everyday bumps and bruises, or due to more chronic conditions such as headaches, gastrointestinal problems, or diabetes. In fact, as many as 40% of children and adolescents complain of pain that occurs at least once weekly, and chronic pain affects at least 15%20% of children. Just as chronic pain is more prevalent in women than men, girls report more pain than boys.[1] Pediatric pain stems from a wide range of chronic conditions- usually muscle, bone, or joint pain, headaches, or abdominal pain-and require pain management. But the medical community has not placed the same emphasis on pain management for pediatric patients as it has for adults and seniors. Each year, 1.5 million children have surgery, and many receive inadequate pain relief and in 20% of cases, the pain becomes chronic. Of children aged 517 years, 20% suffer headaches.[2] . More than one-third of children complain of abdominal pain lasting two weeks or longer.[3] Juvenile arthritis, which causes joint inflammation and aches, affects nearly 250,000 people under the age of 16 years.[4] If left unaddressed, chronic pain can affect children in ways that will follow them throughout their lives. They can develop emotional and psychological scars from their pain that can taint future choices concerning their lives and health care. Untreated pain in childhood also can lead to chronic pain in adulthood and old age[5]
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BE AN ADVOCATE FOR YOUR CHILDS PAIN MANAGEMENT

Pain is truly both a physical and an emotional experience perceived and processed by the brain, it is a real health problem as well. Each child has different pain perception, and the meaning of pain is also different from child to child. The goal of treatment is to decrease the intensity of pain and make the child feel better. For acute pain, this goal is often met successfully. But chronic pain-pain lasting for at least three months or more-has a different effect on the nervous system and needs to be treated differently. Perhaps one of the most difficult challenges professionally. Perhaps one of the most difficult challenges professionally and emotionally is learning to handle pain in pediatric patients. It is sometimes a necessary part of our work to inflict pain during procedures, immunizations, and other treatments. In the past, there was a relative lack of accountability for providing pain relief. Culture has changed as evidenced by the New JCAHO (Joint Commission on Accreditation of Healthcare Organizations) regulations which regard pain as the fifth vital sign and require caregivers to regularly assess and address pain.[6] However, pain remains one of the most misunderstood, under diagnosed, and Under treated/untreated medical problems in children.

WHY IS PEDIATRIC PAIN NEGLECTED?

Pediatric pain is neglected and undertreated for several reasons: 1. Children and adults react differently when it comes to pain. 2. Doctors focus on the source rather than the symptom. Many physicians become so focused on determining what is causing a childs pain that they fail to perform pain management. 3. Some physicians do not understand pediatric pain management.
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TELLTALE SIGNS OF PAIN IN CHILDREN

Certain behaviors can alert you to your childs pain, even if the child can not properly express it himself. These include:
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Favoring one arm or leg over the other. A decrease in physical activity. Changes in appetite or sleep pattern. Avoiding contact with other children. Crankiness, irritability, or unruly behavior. Nonverbal expressions of pain such as gasping, wincing, or frowning. Physical cues like dull eyes, flushed skin, rapid breathing, or sweating.

Another way to help your children is to go over the lists of words with them that express pain, so they can use the words that best show what they feel, like sore, itchy, burning, and aching. Do not rely on just the verbal: Ask children to point to their bodies to show where they hurt and how the pain travels through them.

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PHYSIOLOGY OF PAIN
Pain sensation is a product of several interacting neural systems. Pain transmission can also be modulated by descending pathways that constitute the analgesia system. Neonates have the same number of pain nerve endings per square millimeter of skin as adults. They are present in fetus from the second trimester. The central nervous system tracts that subserve pain are completely myelinated by 30 weeks of intra uterine life. Cortical interconnections with the thalamus, those tracts that play a role in higher perception of pain, are complete by 24 weeks. The descending inhibitory controllers of pain, though, are deficient in the neonate controllers of pain, though, are deficient in the neonate. This leads to the likelihood that neonates, particularly preterm neonates, may be more sensitive to pain than older children and adults.[7]

THE HARM OF PAIN

Pain assists us in avoiding physical harm, but unrelieved pain may be inherently harmful both psychologically and physiologically. Failure to intervene early in childrens pain may lead to impairment in functioning and disruption in families. Unaddressed pain heightens anxiety and fear, which, in turn, increases perception of pain.[8]
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ATTITUDES ABOUT PAIN:BARRIERS TO ADEQUATE PAIN MANAGEMENT IN CHILDREN

We have made a number of advances in our approach to pain management in children, but misconceptions still exist.[9] 1. Many providers believe that children do not remember pain, that children experience less pain than adults, that children are too fragile to receive potent drugs, and that narcotics may induce addiction. 2. Medical caregivers may believe that if one is urgently trying to save a life, there is no time to worry about pain control. Concentration on intensive care may put the

neonate into the role of biologic machine rather than a human being capable of perceiving, responding to, and interacting with his or her environment. 3. Assumptions on the part of patients as well as caregivers affect pain assessment. Many children will deny pain because of fear of disappointing caregivers or fear of an injection. 4. Many health care providers also at least subconsciously believe that they, rather than the child, can accurately judge a childs pain experience. They may attribute a childs distractibility to absence of pain. This perception represents a misunderstanding of the powerful roles of distraction and comforting in the attenuation or relief of pain. 5. We still expect children to react to pain with some predictable, visible signs such as sweating, tachycardia, wincing, crying, jerking away, and muscle tension. The absence of these typical signs may be considered as adaptation on the part of the child.

CANT CHILDREN CATEGORIZE PAIN?

There are several categories of pain. One of the most common is that which is associated with a disease state (e.g., arthritis, sickle-cell disease) or that which is associated with an observable physical injury or trauma (e.g., burns, fractures). Some of the most challenging conditions involve pain that is not associated with a well-defined or specific disease state or physical injury (e.g., tension headaches, recurrent abdominal pain). Pain may also be caused by the medical provider (e.g., circumcisions, injections). Pain may be caused by habits and behaviors as well (e.g., abdominal pain related to intake of alcohol or spicy foods, and so on).
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A DEVELOPMENTAL APPROACH TO ASSESSMENTNEONATES, TODDLERS, AND SCHOOL GOING KIDS

To accurately assess pain in children, the medical care-giver must tailor assessment strategies to the childs developmental level. Several factors modify pain perceptions including age, cognition, sex, previous pain experience, temperament, cultural and family factors, and situational factors. There are three widely used categories of behavioral indicators of pain: global rating scales (GRS) behavioral observation scales (BOS). and indirect measures, GRS rely on the assessment of predictable behavioral indicators of pain such as crying, wincing, or screaming. Indirect measures of pain may be assessed by requests for medication, or well behavior such as playing. We know, however, that requests for pain medication are not reliably linked to pain intensity. BOS focus on the

documentation of specific behaviors indicative of pain. Physiologic measures (e.g., heart rate and blood pressure) are helpful as adjuncts to behavioral observation, but are neither sensitive nor specific pain indicators.

Neonates
There is no easy or scientific way to tell how much pain an infant is having. BOS and physiologic measures can be difficult to interpret. Neonates may manifest pain by crying or being silent, wiggling, or being still. The infant may make faces or not. The cry of pain in the neonate is quite distinctive. Primary caregivers easily distinguish and interpret cries.

Toddlers
Reports of caregivers can be invaluable in pain assessment in the toddler age group. The fear factor is a large contributor to experience of pain in this and the school-age group. Toddlers may become very quiet and inactive while in pain or may become very active. Parents report that they arent acting like they normally do. Interpreting toddlers behavior may be difficult due to exacerbating factors such as separation anxiety, memory of previous painful experiences, and physical restraint. Sometimes toddlers manifest their pain and fear by aggressive outbursts.[10]

School-age children
School-age children are more accurate in communicating about their pain. By age 8 years, children can very reliably describe location of pain. Symptom scales and self-report tools are appropriate for most children 4 years of age and older. Children older than 8 years who understand the concept of order or number can use a Numeric Rating Scale or a Horizontal Word Graphic Rating Scale. Pain diaries may be helpful in the school age group. Schoolage children also exhibit self-control when they are experiencing pain. They may not report pain in an attempt to show bravery.[11]
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DISCUSSION
If pain is not addressed and treated early on, it can greatly impact a childs quality of life by interfering with mood, sleep, appetite, school attendance, academic performance, and participation in sports and other extracurricular activities. Further, if unrelieved, childhood pain can enhance a childs vulnerability to pain later in life. Early experiences such as pain are associated with multiple alterations in the adult brain in a number of animal models. Repeated exposure to pain may cause altered pain sensitivity, anxiety, stress disorders, hyperactivity, and attention deficit disorder, impaired social skills, and patterns of selfdestructive behavior.[8] It is essential that healthcare providers begin to recognize pediatric

pain so that appropriate strategies can be devised to target and reduce childrens distress and pain-related disability. Unaddressed pain can also result in significant financial stress for families who not only have to cover healthcare expenses, but who may also have to miss work to care for a sick child. Inadequate prevention and relief of pediatric pain are still widespread. Many obstacles exist to providing appropriate pain care to children and adolescents.
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CONCLUSION
Children are particularly responsive to pain-controlling strategies that involve their imaginations and senses of play. Sensory and procedural information coupled with behavioral techniques can be used to distract children away from painful procedures and to decrease fear and anxiety. All patients in pain can benefit from well-chosen use of psychologic techniques. This approach in children must take into account the developmental level of the child. Approaches as simple as covering the wound or as involved as play therapy may be used. It is wise to keep children with their caregivers if at all possible. With proper guidance, parents assist with distracting the child and reinforcing the suggestions of the medical team. Developing a calm, patient, understanding approach to the needs of the child and his or her caregivers can markedly enhance the encounter. In spite of so much understanding about pediatric pain management, the sad reality is that pediatric pain management research has not been effectively translated into routine clinical practice.

Footnotes
Source of Support: Nil Conflict of Interest: None declared Other Sections

REFERENCES
1. Goodman JE, McGrath PJ. The epidemiology of pain in children and adolescents: A review. Pain.1991;46:247 64. [PubMed] 2. Zeltzer LK, Schlank CB. New York NY: HarperCollins; 2005. Conquering Your Childs Chronic Pain: A Pediatricians Guide for Reclaiming a Normal Childhood.

3. Chronic Abdominal Pain in Childhood: Diagnosis and Management. Retrieved from American Academy of Family Physicians. Available from: http://www.aafp.org/afp/990401ap/1823.html. 4. Juvenile Arthritis. from American Academy of Orthopaedic Surgeons. Website: Available from:http://orthoinfo.aaos.org/topic.cfm?topic=A00075. 5. Zeltzer LK, Anderson CT, Schechter NL. Pediatric Pain: Current status and new directions. Curr Probl Pediatr. 1990;20:41586. 6. McCaffery M. Pain relief for the child: Problem areas and selected non-pharmacologic methods.Pediatric Nurs. 1977;3:116. 7. Scanlon JW. Appreciating neonatal pain. Adv Pedi. 1991;38:31731. 8. Anand KJ, Scalzo FM. Can adverse neonatal experiences alter brain development and subsequent behavior? Biol Neonate. 2000;77:6982. [PubMed] 9. Paris P. Pain management in the child. 1987;5:699-707. Emerg Med Clin North Am. 1987;5:699707. [PubMed] 10. Kuttner L. Management of young childrens acute pain and anxiety during invasive medical procedures. Pediatrician. 1989;16:3944. [PubMed] 11. Rivera WB. Practical points in the management of postoperative pediatric pain. J Post Anesth Nurs. 1991;6:40 2. [PubMed]

Ischemic Stroke in Infants and Children: Practical Management in Emergency

Sara Ciccone,* Michela Cappella, and Caterina Borgna-Pignatti
Department of Clinical and Experimental Medicine-Pediatrics, University of Ferrara, 44121 Ferrara, Italy *Sara Ciccone: Email: saraciccone.unife@gmail.com Academic Editor: Halvor Naess Received September 23, 2010; Revised April 27, 2011; Accepted May 2, 2011.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. y
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Abstract
Stroke is a rare disease in children, with an estimated incidence 13/100000 and a significant impact on morbidity and mortality. Clinical presentation and risk factors, present in almost half of pediatric patients, are not the same as in adults. The diagnosis of stroke in children is often delayed because signs and symptoms can be subtle and nonspecific. History and clinical examination should exclude underlying diseases or predisposing factors. Neuroimaging is crucial in defining diagnosis. Other tests might be necessary, according to the clinical picture. We present here the most recent practical directions on how to diagnose and manage arterial stroke in children, according to different international guidelines on the subject.

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1. Introduction
The World Health Organization (WHO) defines stroke as a clinical syndrome of rapidly developing focal or global disturbance of brain function lasting >24 hours or leading to death with no obvious nonvascular cause [1]. This definition should be integrated by a reference to neuroimaging, at present considered essential to define the neurovascular origin of symptoms. A modern definition could be a clinical syndrome characterized by (1) a neurological deficit related to the perfusion territory of a cerebral artery and (2) neuroradiological evidence of an ischemic lesion [2, 3]. Transient ischemic attacks (TIAs) are defined as a sudden, focal neurologic deficit that lasts for less than 24 hours, of presumed vascular origin, confined to an area of the brain or eye perfused by a specific artery [4]. In childhood, on the contrary, even in the presence of transient symptoms, imaging often shows a cerebral infarction [5]. Strokes are classically divided in primarily ischemic or hemorrhagic. While adult strokes are prevalently ischemic (80%) and due to atherosclerosis, in childhood up to 45% of strokes are hemorrhagic and are associated with a wide spectrum of risk factors [6]. The estimated incidence of ischemic stroke in children older than 28 days of life is variable [79] but, according to a large prospective, population study, it averages 13/100.000 for all strokes, 7.9/100.000 for ischemic strokes, and 5.1 for hemorrhagic strokes [8]. Approximately 20% of children die after an ischemic stroke while more than 50% of those surviving present neurological sequelae, most commonly hemiparesis [7, 9]. The cumulative stroke recurrence rate has been reported to be 15% at 1 year, and 19% at 5 years [10], and up to 41% at 5 years [11]. A risk factor is present in almost half of the children at the time of stroke [12] (Table 1). Common risk factors in childhood are congenital heart disease, sickle cell disease, infections, and various prothrombotic conditions [1315]. The most common cause of stroke in children is probably heart disease, detected in 19% of children with arterial thrombosis (Canadian Pediatric Ischemic Stroke Registry) [16]. Recent studies underline the importance of infection: it seems that at least a third of cases of childhood stroke occur in such a context. A fifth of the children with ischemic infarction of unknown origin has a history of prior chickenpox [1618].

Table 1 Risk factors for pediatric stroke.

In about 80% of children with arterial stroke, arterial imaging is abnormal [12]. The purpose of this paper is to provide practical up-to-date directions on how to diagnose and manage arterial stroke in children (1 month18 years), in an emergency department. Neonatal stroke is not included because of its peculiar characteristics. In preparing this work we followed the most recent guidelines on arterial stroke in childhood (Pediatric Stroke Working Group, 2004; American College of Chest Physicians, 2004; Italian Society of Pediatrics, 2007; American Stroke Association, 2008). Additionally, a literature review was made, analyzing relevant articles on the subject, up to August, 2010 by searching Pubmed, EMBASE, Cochrane Library and in bibliographies of relevant articles. Search terms were stroke, emergency, child, childhood, management.
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2. Diagnosis 2.1. Clinical Presentation

The clinical presentation of stroke differs depending on age, involved artery, and cause [19, 20]. While in infancy symptoms are usually aspecific, in older children, the most frequent presenting symptoms are focal neurologic deficits such as hemiplegia or a gross, focal motor deficit [21]. Symptoms according to the involved artery are listed in Table 2. The vascular territory of the middle cerebral artery is the most frequently affected.

Table 2 Clinical presentation of stroke depending on the involved artery.

2.2. Differential Diagnosis

Diagnosis of stroke in children is often delayed because signs and symptoms can be subtle and nonspecific, such as mild single limb weakness, incoordination, and sensory disturbances, initially attributed to causes other than stroke [22]. In a child presenting with an acute neurologic deficit, before a diagnosis of ischemic stroke is made, other cerebrovascular diseases (hemorrhagic stroke, cerebral venous sinus thrombosis) need to be considered. Frequent causes of acute hemiplegia are Todd's palsy, where focal seizures usually precede monoparesis or hemiplegia, and hemiplegic migraine, in which hemiplegia is preceded by visual or sensitive disorders and followed by headache. It is also necessary to exclude meningoencephalitis, generally associated with fever, headache and altered consciousness. Acute neurologic deficits may be caused by tumors, central nervous system disorders including acute disseminated leukoencephalitis, cerebellitis, reversible posterior leukoencephalopathy, alternating hemiplegia, metabolic disorders, epilepsy, and psychogenic diseases [23].

2.3. Early Investigations (on Presentation)

The first step to detect a stroke is including this option in the differential diagnosis of an acutely ill child. Early diagnosis allows prompt starting of appropriate therapy.

2.3.1. History
Clinical history should include ethnic origin, the presence of sickle cell disease or congenital heart disease, head or neck trauma (associated with intracranial hemorrhage and dissection), recent infection (especially chickenpox), vasculitis and blood disorders [19], as well as cerebrovascular diseases, coagulopathies, or immunologic disorders among firstdegree relatives. How and how rapidly symptoms develop is of major importance. Up to a third of children who have had a stroke have a history of recent events consistent with TIAs [24].

2.3.2. Physical Examination

A complete physical and neurologic examination, including monitoring of vital parameters, will identify neurologic damages and allow presumptive diagnosis of the brain vessel involved. Signs of systemic diseases that increase the risk of stroke should be looked for.

2.3.3. Imaging Studies

Non-contrast computed tomography (CT) can be performed promptly and quickly in emergency. It can adequately exclude hemorrhagic stroke or parenchymal abnormalities that produces a mass effect, and it may reveal a low-density lesion in arterial ischemic stroke and cerebral venous sinus thrombosis. However, CT is usually normal within the first 12 hours after the onset of symptoms [6]. It should be requested whenever magnetic resonance (MR) is not available [19]. MR, in fact, is the gold standard imaging modality for the investigation of arterial ischemic stroke in infants and children [25] due to its greater sensitivity and specificity. MR is useful to differentiate stroke from stroke mimics but it is rarely available in emergency [26]. The diagnostic efficiency of MR can be further improved by perfusion techniques, that quantify relative cerebral blood flow, volume, and transit time by the use of bolus administration of gadolinium-based contrast material [5, 27,28]. MR with diffusion weighting is very useful in accurately identifying regions of early ischemia and infarction [26]. MR angiography is a noninvasive procedure that detects large vascular abnormalities [29], and it is as effective as cerebral angiography in identifying large ischemic lesions [30]. MR angiography is a reasonable alternative to conventional arteriography in most patients [31, 32]. If the pattern of brain injury could be consistent with venous infarction, emergency vascular imaging should include MR venography. In fact, 10% of hemorrhagic strokes in children are secondary to cerebral venous sinus thrombosis [6]. Vascular imaging of the extracranial circulation, such as cervical MRA or Doppler ultrasound, should also be performed, particularly if the history is suggestive of a cervical arterial dissection.

2.3.4. Other Investigations

Complete blood cell count, iron studies, prothrombin time, partial thromboplastin time, sedimentation rate, and antinuclear antibodies could be useful [19].

2.4. Second-Line Investigations (after 48 Hours as Indicated)

Once stroke has been diagnosed, several studies may be helpful for the ongoing evaluation and management of the patient.

Electrocardiogram and transthoracic or transesophageal echocardiogram are always necessary in all children with known or suspected congenital heart disease who have had a stroke [20, 33]. Echocardiography may be helpful to diagnose patent foramen ovale; this abnormality can be up to four times greater in children with stroke with undetermined etiology than in the general population [34]. The diagnosis of some conditions, including extracranial arterial dissection, particularly involving the posterior circulation, and small-vessel vasculitis, is difficult using MR angiography alone. In these circumstances, catheter cerebral angiography is sometimes required. However, catheter cerebral angiography is an invasive procedure, not commonly performed in children, and it has similar diagnostic yield as MR combined with MR venography and MR arteriography [6]. Conventional angiography can be necessary in order to identify moyamoya syndrome [19]. Hemoglobin electrophoresis and urine drug screening, particularly for sympathomimetics may be indicated. A full evaluation for thrombophilia is reasonable in all children with stroke. It should include evaluation of protein C and protein S deficiency, antithrombin III, heparin cofactor II, plasminogen, von Willebrand's antigen, factor VIII, factor XII, factor V Leiden, activated protein C resistance, prothrombin 20210 gene, serum homocysteine, methylenetetra-hydro-folate-reductase, lipoprotein (a), and antiphospholipid antibodies [3537]. When indicated on the basis of clinical suspicion, more extensive diagnostic testing, such as cerebrospinal fluid analysis, lipid profile, Varicella-Zoster and human immunodeficiency virus, and screening for metabolic disorders might be performed. However, in the majority of cases, the results of these studies will not have an impact on emergency care [19]. We suggest a flow chart for diagnosis of ischemic stroke in emergency (see Figure 1).
Figure 1 Flowchart: diagnosis of ischemic stroke in emergency.

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3. Management in Emergency
Guidelines based on strong evidence for the acute care of childhood stroke do not exist, with the exception of sickle cell disease. Therefore, treatment recommendations for ischemic stroke in children are extrapolated from adult guidelines. Children with early acute ischemic cerebral stroke need to be admitted to a clinical unit where continuous monitoring is possible. Only in selected cases treatment in intensive care units is needed [38, 39].

3.1. Supportive Care

The general approach in emergency includes simple measures such as maintenance of respiratory and cardiovascular functions, aggressive treatment of infection, seizures and fever, maintenance of normoglycemia and normovolemia [20,40], and oxygen supplementation to keep SaO2 > 95% during the first 24 hours after stroke [41]. Medical or surgical treatment of intracranial hypertension, when present, is important, because children have higher risk of tonsillar herniation due to cerebral edema. Hyperventilation is a short term solution that should be used for imminent herniation until a definitive therapy, such as decompressive neurosurgery, can be offered [40, 42, 43].

3.2. Anticoagulant Therapy and Antiplatelet Agents

The choice between anticoagulant and antiplatelet agents is controversial and there are few data to guide this decision in children [44]. As anticoagulation therapy, both unfractionated heparin and low molecular weight heparin (LMWH) have been used in children with AIS. Current guidelines recommend anticoagulation in children with proven arterial dissection or cardioembolic stroke or during the diagnostic evaluation period, until a cardiac source or an arterial dissection has been excluded [42]. Heparin should be used in children thought to have a high risk of recurrence and a low risk of secondary hemorrhage [5, 45]. According to the international literature, LMWH at the dose of 1 mg/kg every 12 hours represents a safe initial therapy for ischemic stroke in infants and children. Hemorrhagic stroke needs to be excluded before starting treatment [4649]. Low molecular weight heparin offers several advantages over standard unfractionated heparin and oral anticoagulants: lower risk of heparin-induced thrombocytopenia, fewer drug interactions, fewer adverse effects on bone when given long term, and lower cost. Furthermore, LMWH is administered subcutaneously, and it demonstrates predictable age-dependent pharmacokinetics and less need for monitoring, thus reducing the need for multiple venipunctures [46]. Enoxaparin (1 mg/kg subcutaneously for children more than 2 months of age, or 1.5 mg/kg for infant less than 2 months of age) is the most frequently used LMWH in

children [47]. In children with cardiac embolism or vascular dissection, LMWH is administered for 3 to 6 months [50]. Concerning antiplatelets, even in absence of randomized clinical trials for the use of aspirin in the acute treatment of AIS in children, most experts agree that this drug use is reasonable for secondary stroke prevention. Standard dosage of 1 to 5 mg/kg/day for a minimum of 3 to 5 years from the acute event is recommended as secondary prevention [50]. The increased risk of Reye's syndrome should be considered. Clopidogrel has been used at dosages of about 1 mg/kg per day in children unable to take aspirin [42, 51]. Thrombolysis with tissue plasminogen activator (tPA) is not currently used and the Royal College of Physicians, AHA Stroke Council, and ACCP guidelines do not recommend it. In fact, the diagnosis of stroke in children is usually made after the time interval required for intravenous or intraarterial tPA thrombolysis (3 hours and 6 hours after stroke onset, resp.) [3, 5254]. The International Paediatric Stroke Study group recommends that thrombolysis should not be used unless it is part of randomised control trial [55, 56].
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4. Hemorrhagic Stroke
Hemorrhagic stroke is as common as arterial ischemic stroke with an estimated incidence of 1.52.9 per 100.000 children per year [41]. It includes spontaneous intraparenchymal hemorrhage and nontraumatic subarachnoid hemorrhage. Structural lesions are the most common causes of intraparenchymal hemorrhages in a population-based cohort [57]. Brain tumors (27%) and arteriovenous malformations (17%) are the most frequent. Medical etiologies are less common. Coagulopathies (13%) include various causes of thrombocytopenia, hemophilia and von Willebrand's disease, sickle cell anemia (6%), hypertension (10%), and infections (6%). Intraparenchymal hemorrhages of idiopathic origin are also frequent (23%). Non-traumatic subarachnoid hemorrhages are most often caused by intracranial aneurysms. Ruptured aneurysms account for 10% of intracranial hemorrhages in children. The incidence of subarachnoid hemorrhage is increased in various congenital and hereditary conditions such as cerebral artero-venous malformations, cardiac disorders (coarctation of the aorta, bacterial endocarditis, and atrial myxoma), autosomal dominant polycystic kidney disease, connective tissue abnormalities (Marfan's syndrome, fibromuscular dysplasia, and Ehlers-Danlos type IV), hematological disorders (sickle cell

disease, G6PD deficiency, and thalassemia), phakomatoses (neurofibromatosis type 1, especially following radiation therapy and tuberous sclerosis) [58]. Headache or vomiting due to raised intracranial pressure, seizures and focal neurologic deficits are the presenting symptoms in children [41]. During evaluation of pediatric stroke it is mandatory to exclude an acute intraparenchymal bleeding. To this end non-contrast TC should be performed. Treatment of hemorrhagic stroke requires a multidisciplinary team management with neurological and neurosurgical care. Management options in hemorrhagic stroke fall into two categories: general efforts to stabilize the patient and measures to reduce the risk of rebleeding [5]. Surgical management is controversial, and there is no evidence that surgical evacuation of a supratentorial intraparenchymal hematoma is beneficial at any age [59, 60]. However, evacuation of a rapidly expanding hematoma causing cerebral herniation may be of benefit [6]. Surgical or endovascular obliteration of aneurysms and artero-venous malformations is effective for many individuals, but stereotactic radiotherapy is being used increasingly in children with artero-venous malformations that are small or difficult to approach surgically. Several large retrospective studies have shown that stereotactic radiotherapy is safe and effective for the treatment of children with an artero-venous malformation [61, 62]. Treatment of coagulation defects and hematologic disorders should reduce the risk of subsequent hemorrhage. Emergency splenectomy is indicated for intraparenchymal bleeding associated with idiopathic thrombocytopenic purpura. Other important complications of non-traumatic subarachnoid hemorrhage that require treatment are hydrocephalus, vasospasm, and hyponatremia [5].
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5. Stroke in Sickle Cell Disease

The most common hematologic risk factor for stroke is sickle cell disease (SCD). Eight percent of patients younger than 19 years will develop a stroke. In this group the highest rate of first ischemic stroke is in children between 2 and 5 years of age while hemorrhagic stroke affects adults aged 20 to 30 years. Both familial and environmental factors seem to be involved in the occurrence of stroke [19]. In the absence of therapy recurrence of stroke is as high as 40% [63]. Small infarctions have been found on MR in 20 to 35% of children with SCD in the absence of symptoms [64, 65]. These so-called silent infarcts, predominantly located in frontal and

parietal cortical, subcortical, and border-zone areas are associated with deterioration in cognitive function and with an increased risk of clinically symptomatic stroke [66, 67]. Stroke may also be due to large vessel vasculopathy that generally involves the middle cerebral artery territory. Some individuals develop progressive vasculopathy of the intracranial internal carotid artery and of its distal collateral vessels, a picture called moyamoya syndrome. Small infarctions typically involve the basal ganglia and the deep white matter within the anterior circulation. Risk factors for stroke in SCD are summarized in Table 3.
Table 3 Risk factors for stroke in sickle cell disease.

5.1. Prevention
The presence of high cerebral blood flow velocity as measured by transcranial Doppler (TD) identifies patients at high risk of primary prevention. In healthy children, the velocity in the middle cerebral artery is around 90 cm/s while in SCD children it is 130140 cm/s. Stroke risk is high when velocity is >200 cm/s. A randomized trial (Stroke Prevention Trial in Sickle Cell Anemia: STOP) compared periodic blood transfusion with standard care in 130 children with SCD who were selected for high stroke risk on the basis of TD results. The trial was halted because of the high number of strokes in the standard-care arm compared with the transfusion-treated group (11 versus 1), in whom the risk of stroke was reduced from 10% to <1% per year [68]. The current National Heart, Lung, and Blood Institute of the National Institutes of Health (NHLBI) recommendation is to evaluate children between 2 and 16 years with SCD using TD at 6 month intervals. If velocity is >200 cm/s, confirmed after a control performed few weeks later, chronic transfusion therapy should be started [63] and should not be discontinued even if TD normalizes (as demonstrated by the randomized controlled trial STOP II [5]).

5.2. Therapy
The treatment of acute ischemic infarction resulting from SCD includes intravenous hydration and exchange transfusion to keep HbS <30% and Hb between 1012.5 g/dL [69]. Exchange transfusion avoids the theoretical risk of increasing blood viscosity that could accompany a rapid increase of the hematocrit [5].

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6. Conclusions
Stroke is relatively rare in children, except, as mentioned, in sickle cell disease. It represents, however, one of the ten top causes of childhood death. Its relatively rarity causes a lack of awareness that cerebrovascular disease occurs in children. Furthermore, risk factors and clinical presentation are distinctive compared to adults. For these reasons diagnosis is often delayed. It has been estimated that 4872 hours frequently elapse between the onset of symptoms and diagnosis [70]. When evaluating a child with stroke, several tests, including imaging studies, are helpful to confirm the diagnosis, to differentiate hemorrhagic from ischemic stroke, and to guide the emergency management. No uniform approach exists for the treatment of childhood stroke. Until data based on randomized pediatric clinical trials will be available, treatment recommendations for the acute care of children with stroke will continue to be extrapolated from adult guidelines.
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Int J Otolaryngol. 2011; 2011: 487532. Published online 2011 June 28. doi: 10.1155/2011/487532 Copyright 2011 Dimitrios G. Balatsouras et al.

PMCID: PMC3133014

Study of Allergic Rhinitis in Childhood

Dimitrios G. Balatsouras, 1 * George Koukoutsis, 1 Panayotis Ganelis, 1Alexandros Fassolis, 1 George S. Korres, 2 and Antonis Kaberos 1
ENT Department, Tzanion General Hospital of Piraeus, Afentouli 1 & Zanni, 18536 Piraeus, Greece ENT Department, Atticon University Hospital of Athens, 1 Rimini Str., Haidari, 12462 Athens, Greece *Dimitrios G. Balatsouras: Email: dbalats@hotmail.com Academic Editor: R. L. Doty Received February 13, 2011; Accepted April 28, 2011.
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Abstract
Allergic rhinitis is common among children and quite often represents a stage of the atopic march. Although sensitization to food and airborne allergens may appear in infancy and early childhood, symptoms of the disease are usually present after age 3. The aim of this

study was to determine the most frequent food and indoor and outdoor respiratory allergens involved in allergic rhinitis in children in the region of Piraeus. The study was performed in the outpatient clinic of otolaryngologic allergy of a general hospital. Fifty children (ranged 6 14 ) with symptoms of allergic rhinitis and positive radioallergosorbent test (RAST) for IgE antibodies or skin prick tests were included in the study. Thirty six (72%) of the subjects of the study had intermittent allergic rhinitis. The most common aeroallergens determined were grass pollens and Parietaria, whereas egg and milk were the food allergens identified. The detection of indoor and outdoor allergens in the region of Piraeus, based on skin prick tests and RAST tests, showed high incidence of grasses and food allergens, which is similar to other Mediterranean countries.
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1. Introduction
Allergic rhinitis is one of the most common disorders, which affects 540% of population, according to various reports [1, 2]. It may be classified as persistent and intermittent allergic rhinitis, depending on the frequency of symptoms. It presents a high morbidity because it affects social life, professional activities, and, especially in children, school performance [3]. Allergic rhinitis is common among children and quite often represents a stage of the atopic march [4]. Although sensitization to food and airborne allergens may appear in infancy and early childhood, symptoms of the disease are usually present after age 3. The aim of this study was to determine the most frequent respiratory and food allergens as a cause of allergic rhinitis in children in the region of Piraeus.
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2. Materials and Methods

We examined 50 children who presented with allergic rhinitis in the outpatient clinic of otolaryngologic allergy, belonging to the ENT department of our hospital. The age of the patients ranged from 6 to 14 years (mean 10.7 2.1), and they were all living in the region of Piraeus. Diagnosis was on the basis of a history of allergic rhinitis, either seasonal or perennial, on the findings of clinical examination and on the presence of positive radioallergosorbent (RAST) test for IgE antibodies (RAST-CAP-FEIA, Pharmacia, Uppsala, Sweden). All children were tested in a series of allergens, including grasses, cereales, parietaria, urtica, tree allergens (Olea europea,Cypressus sempervirens, Pinus pinea, and Populus alba), dust mites, animal dander and food allergens. The RAST results were classified, as Class 1 (low level of specific IgE), Class 2 (moderate level), Class 3 (high level), and Class 4 (very high level) [5]. In a group of 12 older children, skin-prick tests were

also performed. Details of this procedure are reported elsewhere [6]. The skin prick tests were considered positive if the mean wheal diameter was 3 mm or larger.
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3. Results and Discussion

The main clinical and demographic features of our patients are shown in Table 1. Twentynine patients were females and 21 males. Severity of rhinitis was mild in 19 patients (38%) and moderate/severe in the remaining 31 (62%), according to the criteria of ARIA [7]. Thirtyseven (74%) of the children suffered from other allergic diseases as well, including childhood asthma, allergic conjunctivitis, and atopic dermatitis.
Table 1 Clinical and demographic features of our patients.

Thirty six (72%) of the subjects of the study had intermittent allergic rhinitis, owed to pollen aeroallergens, with a mean of 2 allergens per patient (Tables (Tables22 and and3).3). Nine patients (18%) were sensitized to one allergen, 17 patients (34%) were sensitized to two and 10 patients (20%) to three allergens. The remaining 14 (28%) children suffered from persistent rhinitis, owed mainly to nonpollen aeroallergens and to food allergens. A mean of 1.5 allergens per patient was found in this group (Tables (Tables22 and and4).4). Seven (14%) of them were sensitized to one allergen, and another 7 patients (14%) were sensitized to two allergens. The mean values of total serum IgE were 449.7 ( 336.9) kU/L in the first group (patients with intermittent disease) and 934.2 ( 765.8) kU/L in the second group (patients with persistent disease), presenting significant variability (Table 1). The rate of agreement between the results of the skin prick tests when performed and the results of RAST was high (Table 2). There was no consistent correlation between severity of allergic rhinitis and RAST classes, suggesting that probably antibody levels are only one of the factors that determine symptom severity [8].
Table 2 Types of allergens, RAST classes, and skin reaction.

Table 3 Positive RAST (and skin prick test when performed) to various allergens in intermittent allergic rhinitis.

Table 4 Positive RAST (and skin prick test when performed) to various aeroallergens and food allergens in persistent allergic rhinitis.

Allergic rhinitis is a significant clinical problem in children. In the Mediterranean region there are characteristic climatic conditions, such as mildness of winter and poor rainfall during the summer, that facilitate the growing of a typical vegetation with production of allergenic pollen [1]. Rich and long pollinic seasons are, thus, favored, and the pollen grains of various plants can reach high atmospheric concentrations, causing severe clinical symptoms of rhinoconjunctivitis and asthma. The prevalence of allergic rhinitis in children in the Mediterranean countries has been reported to range from 9.4% to 16.8% [2, 9]. However, more than 40% of the children reported allergic rhinoconjunctivitis symptoms in the past [2, 10]. Most prevalent allergic plants with known clinical significance are grasses, Parietaria and Olea europaea. Parietaria was the most important allergenic pollen in the children of our study. This is an Urticacea plant characteristic of Mediterranean flora, which has been found to be the most common cause of allergy in the Mediterranean countries, either in adults or in children [11]. D'Amato and Lobefalo [12] in a study conducted in Naples, foundParietaria as the most common allergen in adults, and Kontothanasi et al. [6], in a study of allergens in adult patients in western Athens, which is a neighbouring region to ours, reported this allergen as the second most common after Graminae, and especially Dactilis glomerata. Other species of Urticaea and Cereales were less commonly determined allergens in the subjects of our study. From the trees, we found Olea europeae to be the most common aeroallergen, whereas Cypressus sempervirens, Pinus pinea, and Populus alba were less frequently identified. Olive trees are, only occasionally, found in the surroundings, but air currents carry their pollen from suburban areas. Olea europeae is a major tree producing allergenic pollen in the Mediterranean area [12, 13], and the same has been reported for cypress [14] and the other implicated trees [15].

In our study, most pollen aeroallergens were associated with intermittent rhinitis, whereas hypersensitivity in nonpollen allergens was associated with persistent rhinitis. We found house dust and mites (Dermatophagoides pteronyssinus andDermatophagoides farinae) the most common allergens and this agrees to previous reports in Mediterranean countries. According to Verini et al. [13] a high incidence of positive reactions to Dermatophagoides pt and fa was found, exceeding 70%. Furthermore, Ramadan et al. [16] found a high incidence of mites in Lebanon. Lower rates were reported in other studies, as in the investigation by Erel et al. [17] in which an incidence of 20% was found in Turkey. Positivity to dog and cat allergens is of lower incidence, especially in countries where keeping house pets is not a common practice [16]. Food allergy as a potentially important factor in the pathogenesis of allergic rhinitis should, also, be noticed [18]. We found only two cases with allergy owed to egg and milk, but further investigation of a large number of children for food allergy is warranted. Finally, we should mention that we found a mean of 2 allergens per patient in intermittent rhinitis and a mean of 1.5 allergens per patient in persistent rhinitis. Polysensitization has been also reported elsewhere, as in the study of Verini et al. [13], in which only 12% of children in a central Italian area were monosensitized, whereas the remaining were sensitized to 2-3 (56%) or even more allergens.

4. Conclusions
In conclusion, the detection of indoor and outdoor allergens in the region of Piraeus, based on skin prick tests and RAST tests, showed high incidence of grasses and food allergens, which is similar to other Mediterranean countries. Our results reflect the special characteristics of the region of Piraeus, which has a high population density and is polluted from industries, the port, and the heavy traffic. However, our subjects originated also from the country of the surrounding region, two nearby islands, and the rural area of Trizinia, resulting in the variety of allergens identified from our investigation.
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References
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