Parametros Practicos Evaluacion TGD

7/27/2019 Parametros Practicos Evaluacion TGD

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Practice parameter:

Evaluation of the child with

global developmental delay

Report of the Quality Standards Subcommittee of the AmericanAcademy of Neurology and

The Practice Committee of the Child Neurology Society

M. Shevell, MD; S. Ashwal, MD; D. Donley, MD; J. Flint, MD; M.Gingold, MD; D. Hirtz, MD; A. Majnemer, PhD;

M. Noetzel, MD; and R.D. Sheth, MD.

Published in Neurology2003; 60:367-380


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Objective of the guideline:

To make evidence-based recommendations

concerning the evaluation of the child with a non-

progressive global developmental delay.


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Methods of evidence review: Literature searches were conducted with the assistance of the

University of Minnesota Biomedical Information Services for

relevant articles published from 1980 to 2000. Databases

searched included MEDLINE, Healthstar, ERIC and CINAHL.

A bibliography of the 160 articles identified and reviewed forpreparation of this parameter is available at the American

Academy of Neurology Web site (http://www.aan.com/).

Each article was reviewed, abstracted, and classified by a

committee member. A four-tiered classification scheme for

diagnostic evidence recently approved by the Quality

Standards Subcommittee was utilized as part of this

assessment.


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AAN evidence classification

scheme for a diagnostic articleClass I:Evidence provided by a prospective study in a broad

spectrum of persons with the suspected condition, using a gold

standard for case definition, where the test is applied in a blinded

evaluation, and enabling the assessment of appropriate tests ofdiagnostic accuracy.

Class II:Evidence provided by a prospective study of a narrow

spectrum of persons with the suspected condition, or a well

designed retrospective study of a broad spectrum of persons withan established condition (by gold standard) compared to a broad

spectrum of controls, where test is applied in a blinded evaluation,

and enabling the assessment of appropriated tests of diagnostic

accuracy.


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AAN evidence classification

scheme for a diagnostic article

Class III:Evidence provided by a retrospective study where either

persons with the established condition or controls are of a narrow

spectrum, and where test is applied in a blinded evaluation.

Class IV:Any design where test is not applied in blinded evaluation

OR evidence provided by expert opinion alone or in descriptive

case series (without controls).


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AAN system for translation of

evidence to recommendations

Translation of evidence to

recommendations

Rating of recommendations

Level Arating requires at leastone convincing class I study or

at least two consistent,

convincing class II studies

A = Established asuseful/predictive or not

useful/predictive for the given

condition in the specified

population

Level Brating requires at leastone convincing class II study or

overwhelming class III evidence

B = Probably useful/predictive ornot useful/predictive for the

given condition in the specified

population


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AAN system for translation of

evidence to recommendations

Translation of evidence to

recommendations

Rating of recommendations

Level Crating requires at leasttwo convincing class III studies

C = Possibly useful/predictive ornot useful/predictive for the

given condition in the specified

population

U = Data inadequate or

conflicting. Given currentknowledge, test, predictor is

unproven


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Introduction

Developmental disabilities are a group of related chronicdisorders of early onset estimated to affect 5% to 10% ofchildren.

Global developmental delayis a subset of developmentaldisabilities defined as significant delay in two or more of thefollowing developmental domains:

gross/fine motor

speech/language, cognition

social/personal activities of daily living

Significant delay is defined as performance two standarddeviations or more below the mean on age-appropriate,standardized norm-referenced testing.


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IntroductionThe term global developmental delay is usually reserved foryounger children (i.e., typically less than 5 years of age),whereas the term mental retardation is usually applied to olderchildren when IQ testing is more valid and reliable.

Prevalence:

The precise prevalence of global developmental delay isunknown.

Estimates of 1% to 3% of children younger than 5 years of age

are reasonable given the prevalence of mental retardation in thegeneral population.

Based on approximately 4 million annual births in the UnitedStates and Canada, between 40,000 to 120,000 children borneach year in these two countries will manifest globaldevelopmental delay.


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Clinical Question

What is the diagnostic yield of metabolic and genetic

investigations in children with global developmental

delay?


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Analysis of the Evidence

Metabolic testing in children with globaldevelopmental delay

Reference Class N

Results

(% patients with abnormal screening)

33 II 151 26% for mild delay; 77% for severe

delay; genetic etiology in 28%, 5%

were metabolic disorders

34 III 1,087 0.6%.; standardized biochemicalscreening


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Reference Class N

Results


35 III 1,568 1.3%; standardized

biochemical screening

7 III 60 63% with all testing but less than 1%

for metabolic testing

36 III 281 5< 5%; nonstandardized evaluation;

etiologic yield of 72% for whole group


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Reference Class N

Results


28 III 99


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Conclusions

Routine screening for inborn errors of metabolism in children

with global developmental delay has a yield of about 1% that

can, in particular situations such as relatively homogeneous

and isolated populations or if there are clinical indicators,

increase up to 5%. When stepwise screening is performed the

yield may increase to about 14%.


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Cytogenetic studiesreporting cytogenetic andfragile X

Reference Class N Results

% of patients with abnormal results on

cytogenetic studies

41 III 2,757 2.93% (2.61% also had FraX)

42 III 256 3.9%

43 III 274 4.7% (9.1% also had FraX)

44 III 166 5.4%


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Cytogenetic studiesreporting cytogenetic andfragile X


% of patients with abnormal results on

cytogenetic studies

28 III 99 7.1 %

29 III 120 11.6% (2.3% also had FraX)

7 IV 60 10%

45 IV 170 3.5%


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Cytogenetic studiesreporting on fragile Xprevalence


% of patents with fragile X (FraX)

47 II 1,581 0.7% FraX overall with 1.0% in males,

0.3% in females, and 7.6% in males

with clinically pre-selected criteria

48 II 80 0% females with FraX

49 II 20 0% females with FraX

50 II 278 0.3% females with FraX


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55 III 103 3.9% FraX

56 IV 4,940 5.3% FraX


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Analysis of the EvidenceCytogenetic studiestesting for Rett syndrome

Patients with classic Rett syndrome appear to develop normally

until 6 to 18 months of age, then gradually lose speech and

purposeful hand use, and develop abnormal deceleration of

head growth that may lead to microcephaly.

Seizures, autistic-like behavior, ataxia, intermittent

hyperventilation, and stereotypic hand movements occur in

most patients.

Rett syndrome is believed to be one of the leading causes of

global developmental delay/mental retardation in females and

is caused by mutations in the X-linked gene encoding methyl-

CpG-binding protein 2 (MECP2). About 80% of patients with

Rett syndrome have MECP2mutations.


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Analysis of the EvidenceCytogenetic studiestesting for Rett syndrome

The prevalence of Rett syndrome in the general population is

approximately 1 to 3 individuals per 10,000 live births and it

has been estimated that there are approximately 10,000

individuals in the United States with this disorder.

Currently there are insufficient data to estimate the prevalence

of Rett syndrome variants in milder affected females or in

males.


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Cytogenetic studiesMolecular screening forsubtelomeric chromosomal rearrangements

Reference Class Level of mental

retardation

N N (% )of patients

with significant

rearrangements

68 I Controls

Mild

Moderate/Severe

75

182

284

0

1 (0.55)

21 (7.39)

69 I Controls

Unspecified

Mild

Moderate/Severe

150

61

82

46

0

0

0

0


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retardation

N N (% )of patients

with significant

rearrangements

70 II Unspecified 27 2 (7.4)

71 II Moderate/Severe 29 2 (8.89)


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retardation

N N (% )of patients

with significant

rearrangements

72 II IQ< 60 254 13* (5.12)



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retardation

N N (% )of

patients with

significantrearrangements

74 II Mild

Moderate/Severe

44

117

0

13 (11.11)

75 II Mild

Moderate/Severe

42

28

0

1 (3.57)


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retardation

N N (% )of patients

with significant

rearrangements


77 II Mild

Moderate/Severe

29

82

3 (10.3)

7 (8.5)



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Conclusions The accumulated data suggest that cytogenetic studies will be

abnormal in 3.7% of children with global developmental delay,

a yield that is likely to increase in the future as new techniques

are employed.

In mixed populations (both males and females), a yield of

between 0.3% and 5.3% (average yield of 2.6%) has been

demonstrated for fragile X testing. The higher range of this

yield exists for testing amongst males.

There is a suggestion that clinical preselection for the fragile X

syndrome amongst males may improve diagnostic testing

beyond routine screening.


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Conclusions After Down syndrome, Rett syndrome is believed to be the

most common cause of developmental delay in females.

Although milder variants in females and more severe

phenotypes in males recently have been recognized, estimates

of their prevalence are not currently available.

Subtelomeric chromosomal rearrangements have been found

in 6.6% (0-11.1%) of patients with idiopathic moderate to

severe developmental delay.


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Recommendations1. Given the low yield of about 1%, routine metabolic screening

for inborn errors of metabolism is not indicated in the initialevaluation of a child with global developmental delay providedthat universal newborn screening was performed and the

results are available for review. Metabolic testing may bepursued in the context of historical (parental consanguinity,family history, developmental regression, episodicdecompensation) or physical examination findings that aresuggestive of a specific etiology (or in the context of relativelyhomogeneous population groups) in which the yieldapproaches 5% (Level B; class II and III evidence). If newbornscreening was not performed, if it is uncertain whether a patienthad testing, or if the results are unavailable, metabolicscreening should be obtained in a child with globaldevelopmental delay.


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Recommendations2. Routine cytogenetic testing (yield of 3.7%) is indicated in the

evaluation of the child with developmental delay even in theabsence of dysmorphic features or clinical features suggestive of aspecific syndrome (Level B; class II and III evidence).

3. Testing for the fragile X mutation (yield of 2.6%) particularly in thepresence of a family history of developmental delay, may beconsidered in the evaluation of the child with global developmentaldelay. Clinical preselection may narrow the focus of who should betested without sacrificing diagnostic yield. Although screening for

fragile X is more commonly done in males because of the higherincidence and greater severity, females are frequently affected andmay also be considered for testing. Because siblings of fragile Xpatients are at greater risk to be symptomatic or asymptomaticcarriers, they can also be screened (Level B; class II and class IIIevidence).


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Recommendations4. The diagnosis of Rett syndrome should be considered in females

with unexplained moderate to severe mental retardation. If

clinically indicated, testing for the MECP2gene deletion may be

obtained. Insufficient evidence exists to recommend testing of

females with milder clinical phenotypes or males with moderate orsevere developmental delay (Level B; class II and class III

evidence).

5. In children with unexplained moderate or severe developmental

delay, additional testing using newer molecular techniques (e.g.FISH, microsatellite markers) to assess for subtelomeric

chromosomal rearrangements (6.6%) may be considered (Level

B; class II and class III evidence).


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Clinical Question

What is the role of lead and thyroid screening in

children with global developmental delay?


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Analysis of the EvidenceLead Screening

Lead is the most common environmental neurotoxin. Studies

over several decades have shown a relation between marked

elevations in serum lead levels, clinical symptoms and cognitivedeficits (but not definitively mental retardation).

Average blood lead levels in the United States have fallen

dramatically from 15g/dL in the 1970s to 2.7g/dL in 1991

through 1994.

It is estimated that there are still about 900,000 children in the

United States between the ages of 1 and 5 years who have blood

lead levels equal to or greater than 10 g/dL.


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Analysis of the EvidenceLead Screening

It is unlikely at the present time for a child to have symptomatichigh-level lead exposure that would cause moderate to severeglobal developmental delay.

Low-level lead exposure remains possible, and it has beenestimated that each 10 g/dL increase in blood lead level maylower a child's IQ by about 1 to 3 points.

The relation and clinical significance of mildly elevated butnontoxic levels (i.e., those that do not require medicalintervention) to developmental status remains controversial.

In a cohort of children (age 12 to 36 months) identified onroutine screening at a urban public hospital, elevated leadlevels (10 to 25 g/dL) resulted in a 6.2- point decline in scoreson the Mental Developmental Index when compared to childrenwith lead levels below 10 g/dL (class II study).


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Lead Screening

In a study of data drawn from the NHANES III, an inverserelation between blood lead concentration at subtoxic levelsand scores on four measures of cognitive functioning was

demonstrated (class III study). Of 72 children referred to a child developmental center with

developmental and/or behavioral problems compared tocontrols, a significantly higher distribution of leadconcentrations was demonstrated, with 12% of the samplepossessing a concentration greater than 10 g/dL (class II

study).

In a study of children drawn from a population at low risk forlead exposure, 43 children with either developmental delay orattention deficit hyperactivity disorder did not demonstrateelevated lead levels compared to controls (class II study).


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Lead Screening

The recently published guidelines of the American Academy of

Pediatrics, candidates for targeted screening include children 1 to

2 years of age living in housing built before 1950 situated in an

area not designated for universal screening, children of ethnic orracial minority groups who may be exposed to lead-containing

folk remedies, children who have emigrated (or been adopted)

from countries where lead poisoning is prevalent, children with

iron deficiency, children exposed to contaminated dust or soil,

children with developmental delay whose oral behaviors placethem at significant risk for lead exposure, victims of abuse or

neglect, children whose parents are exposed to lead

(vocationally, avocationally, or during home renovation), and

children of low-income families.


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Thyroid Screening

Unrecognized congenital hypothyroidism is a potentially treatable

cause of later developmental delay. Delay in diagnosis and

treatment beyond the newborn period and early infancy has been

clearly linked to later often substantial, neurodevelopmentalsequelae.

Implementation of newborn screening programs has been

extremely successful in eliminating such sequelae.

In some countries, where comprehensive newborn screening

programs are not yet in place, congenital hypothyroidism hasbeen found to be responsible for 17/560 (3.8%) cases of cognitive

delay evaluated in a pediatric neurology clinic (class II Study).

Many of these children also had prominent systemic symptoms.


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Conclusions

Low-level lead poisoning is associated with mild cognitive

impairments but not with global developmental delay.

Approximately 10% of children with developmental delay and

identifiable risk factors for excessive environmental leadexposure may have an elevated lead level. In the absence of

systematic newborn screening, congenital hypothyroidism may

be responsible for approximately 4% of cases of cognitive

delay.


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Recommendations

1. Screening of children with developmental delay for lead toxicity

may be targeted to those with known identifiable risk factors for

excessive environmental lead exposure as per established

current guidelines (Level B; class II evidence).

2. In the setting of existing newborn screening programs for

congenital hypothyroidism, screening of children with

developmental delay with thyroid function studies is not

indicated unless there are systemic features suggestive of

thyroid dysfunction (Level B; class II evidence).


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Clinical Question

What is the diagnostic yield of EEG in children with

global developmental delay?


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EEG

The vast majority of articles on EEG and global developmentaldelay are class IV studies on small cohorts of children with analready established diagnosis (e.g., sub-acute sclerosing

panencephalitis or progressive myoclonic epilepsy

) that isoften a progressive encephalopathy rather than a staticencephalopathy such as global developmental delay.

Two class III studies (n=200 children with global developmentaldelay) who had EEG have been reported.

In one study, the EEG did not contribute to determining theetiology of developmental delay.

In the second study, 10 of 120 children were found to haveepileptic syndromes. It is likely that all of these children alreadyhad overt seizures and a recognized epilepsy for which anabnormal EEG result is expected.


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EEG

Another class III prospective study of 32 children withsignificant developmental dysphasia with or without associatedglobal developmental delay revealed nonspecific epileptic

abnormalities in 13 of 32 children (40.6%), a finding of unclearetiologic significance.

A retrospective class IV study of 60 children with globaldevelopmental delay, 83% of whom had EEG, yielded anetiologic diagnosis based on the EEG results in 2.0% of thecohort (specifically one child with ESESelectrographic status

epilepticus during slow wave sleep). Although the yield on routine testing is negligible, if there is a

suspected epileptic syndrome that is already apparent from thehistory and physical examination (e.g., Lennox- Gastautsyndrome, myoclonic epilepsy, Rett syndrome), the EEG hasconfirmatory value.


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Conclusions

Available data from two class III and one class IV study

determined an epilepsy-related diagnosis in 11 of 250 children

(4.4%). However, the actual yield for a specific etiologic

diagnosis occurred in only 1 patient (0.4%).


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Recommendations

1. An EEG can be obtained when a child with global

developmental delay has a history or examination features

suggesting the presence of epilepsy or a specific epileptic

syndrome (Level C; class III and IV evidence).

2. Data are insufficient to permit making a recommendation

regarding the role of EEG in a child with global developmental

delay in whom there is no clinical evidence of epilepsy (Level

U; class III and IV evidence).


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Clinical Question

What is the diagnostic yield of neuroimaging in

children with global developmental delay?


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Neuroimaging


(% patients with abnormal studies)

7 III 60 31.4% (CT, a few had MRI)

28 III 99 27% (CT); 41.2% when done on an

indicated basis vs 13.9% when on a

screening basis

100 III 23 4.3% (CT)

101 III 76 27.6% (CT) with 71.4% of these with

nonspecific atrophy

102 III 37 81% (CT)


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Neuroimaging



103 III 79 63% (CT)

45 IV 170 30% (CT); 65.5% (MRI); 19/29

patients who had MRI showed an

abnormality

104 III 224 48.6% ( MRI)

105 III 40 92.5% (MRI)

106 IV 3 100% (MRI) but small number of

patients


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Neuroimaging



107 III 13 100% (MRI) but small number ofpatients

108 III 21 Amount of abnormal cerebral white

matter on MRI correlated with degree

of mental impairment.


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Conclusions

Available data primarily from class III studies show that CT

contributes to the etiologic diagnosis of global developmental

delay in approximately 30% of children, with the yield

increasing if physical examination findings are present. MRI is more sensitive than CT, with abnormalities found in

48.6% to 65.5% of children with global delay with the chance of

detecting an abnormality increasing if physical abnormalities,

particularly cerebral palsy, are present.


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Recommendations

1. As the presence of physical findings (e.g., microcephaly, focal

motor findings) increases the yield of making a specific

neuroimaging diagnosis, physicians can more readily consider

obtaining a scan in this population (Level C; class III evidence).

2. If available, MRI should be obtained in preference to CT

scanning when a clinical decision has been made that

neuroimaging is indicated (Level C; class III evidence).

Neuroimaging is recommended as part of the diagnostic

evaluation of the child with global developmental delay (Level

B; class III evidence).


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Clinical Question

Are vision and hearing disorders common in children

with global developmental delay?


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Vision and hearing disorders In two class III studies totaling 365 children with global

developmental delay, abnormalities on vision screening werefound in 13%to 25% of children.

Refractive errors (24%), strabismus (8%), and a number oforganic ocular diseases (8%) were also detected in one ofthese reports.

Supporting these findings is a class IV retrospective review thatestimated the frequency of primary visual sensory impairmentin children with global developmental delay to range between

20% and 50%. Appears to be an increased prevalence of additional visual

developmental disability among individuals with syndromesfeaturing significant sensory impairment.


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Vision and hearing disorders In one class III study (n=260) with severe global developmental

delay in whom vision and audiologic screening were

performed, 18% of children were found to be deaf.

Another class III study (n=96) clinically suspected hearing lossfound that 91% had hearing loss as detected by behavioral

audiometry or brainstem auditory evoked response testing.

Retrospective analysis of legally mandated universal newborn

screening program (53,121 newborns over 4 years)

demonstrated the utility of a two-stage otoacoustic emissionevaluation process in accurately detecting early hearing loss in

a population not amenable to audiometric testing (class II

study).


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Conclusions

Several class III studies have shown that children with global

developmental delay are at risk to have primary sensory

impairments of vision and hearing. Estimates of vision

impairment or other visual disorders range from 13% up to 50%whereas significant audiologic impairments occur in about 18%

of children based on data in one series of patients.


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Recommendations1. Children with global developmental delay may undergo

appropriate vision and audiometric assessment at the time oftheir diagnosis (Level C; class III evidence).

2. Vision assessment can include vision screening and a fullophthalmologic examination (visual acuity, extra-oculo-movements, fundoscopic) (Level C; class III evidence).

3. Audiometric assessment can include behavioral audiometry orbrainstem auditory evoked response testing when feasible(Level C; class III evidence). Early evidence from screeningstudies suggest that transient evoked otoacoustic emissionsshould offer an alternative when audiometry is not feasible(Level A; class I & II evidence).


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Future Research

Recommendations1. Further prospective studies on the etiologic yields of various

diagnostic tests need to be undertaken on large numbers ofyoung children with global developmental delay including controlsubjects. These should include newer molecular genetic and

MRI technologies. With this information, prospective testing ofspecific evaluation paradigms would be possible.

2. Features (i.e., markers) present on the history and physicalexamination at intake need to be identified that will improvespecific evaluation strategies and enhance etiologic yield.

3. The timing of actual testing in children with global developmentaldelay needs to be addressed. Specifically, it should bedetermined at what age and on what basis one can be certainthat a child has a global developmental delay sufficient to justifytesting as well as at what age the yield from testing will beoptimal.


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Future Research

Recommendations4. Alternative strategies of conducting testing simultaneously or

sequentially need to be critically assessed. This should help

reduce unnecessary testing and provide cost-effective evaluations

and more accurate diagnostic yields.

5. Additional studies are needed to evaluate the role of EEG in a child

with global developmental delay in whom there is no clinical

evidence of epilepsy.

6. Additional studies are needed to better characterize visual and

auditory deficits in children with global developmental delay.

Further investigation of the sensorimotor impairments of children

with global delay are also needed to better determine how early

intervention therapies might improve the overall function of children

who are likely to have multiple needs.


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Future Research

Recommendations7. Issues related to quality of life and social support of families who

have children with developmental delay need further study.

Included in this should be the benefits that medical testing confer

by reducing parental concerns related to determining a specific

etiology and by providing important information regardingprognosis, genetic counseling, alleviation of parental anxiety, and

planning future educational and treatment needs.


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Acknowledgements

The committee thanks the following individuals for their

willingness to review early versions of this manuscript: David

Coulter MD, Child Neurology Society and the American

Association of Mental Retardation; Nancy Dodge MD, AmericanAcademy of Pediatrics, Chair Section on Children with

Disabilities; William Lord Coleman, MD, American Academy of

Pediatrics, Chair Section on Developmental and Behavioral

Pediatrics; Thomas B. Newman, MD, MPH, American Academy

of Pediatrics; Committee on Quality Improvement; RichardQuint, MD, MPH, Clinical Professor in Pediatrics, UCSF; Carl

Cooley, MD; Constance Sandlin, MD; Clinical Medical Director,

Genzyme Genetics.


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To view the entire guideline and additional AAN

guidelines visit:

www.aan.com/professionals/practice/index.cfm

Published in Neurology2003; 60:367-380

Parametros Practicos Evaluacion TGD

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