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Developmental disorders are a group of conditions in which early brain
development is impaired. This very large group of disorders includes
diagnoses such as intellectual disability (ID) and autism spectrum
disorder (ASD). The core diagnostic features of ASD include
impairment in reciprocalsocial communication and social interaction,
and restricted, repetitive patterns of behavior, interests, or activities.
These symptoms must be present from early childhood and impair
everyday functioning. ASD is diagnosed clinically, though standardized
behavioral diagnostic instruments can assist this process. ASD is more
common in boys than girls, and the core diagnostic features can be
addressed through multiple different types of nonpharmacologic
interventions, including specialized education, physical therapy,
occupational therapy, speech and language therapy, and behavioral
therapy, such as applied behavior analysis (ABA).
Individuals with ID/ASD have high rates of comorbid ADHD.
Treatment of ADHD, especially hyperactivity, in individuals with
ID/ASD is similar to the treatment of ADHD in neurotypical individuals,
agonists, and atomoxetine. Compared to
their neurotypical peers though, individuals with ID/ASD and comorbid
ADHD experience lower effect sizes with ADHD treatment, lower
tolerated doses of ADHD medication, and more risk of adverse effects,
including increased rates of decreased appetite, insomnia, depressive
symptoms, irritability, and social withdrawal.
Some individuals with developmental disorders demonstrate symptoms of
irritability and aggression, which can sometimes be helped with a
pharmacologic intervention if nonpharmacologic interventions are
ineffective. The strongest evidence for the pharmacologic treatment of
irritability/aggression in individuals with developmental disorders exists
for the use of risperidone and aripiprazole to treat irritability in children
with ASD. Doses for this purpose are likely lower than those used to
treat schizophrenia or bipolar disorder, and adverse events are relatively
common and may include sedation, weight gain, and extrapyramidal
Individuals with developmental disorders are at high risk of having
comorbid anxiety and depression. Although no large prospective,
randomized, controlled trials (RCTs) exist to support the use of selective
serotonin reuptake inhibitors (SSRI) for this purpose, case studies and
open-labelstudies have shown possible benefits. RCTs of SSRIs for the
treatment of repetitive behavior in children with developmental disorders
have shown mixed results, although they have demonstrated that
individuals with developmental disorders may be at increased risk of
emotional and behavioral adverse events from SSRIs, and therefore,
target dosing should be lower than in individuals with typical
Individuals with developmental disorders have high rates of comorbid
medical and psychiatric disorders, and therefore may often be
prescribed multiple different concurrent medications. Precaution should
be taken to avoid any pharmacodynamic or pharmacokinetic drug–drug
interactions, and such interactions should always be considered to
Sleep disturbances are common in individuals with developmental
disorders. Melatonin has the strongest body of evidence for being a safe
and effective treatment of sleep disturbances in this population.
Developmental disorders are a group of conditions characterized by impaired early
brain development, resulting in deficits of cognitive, communicative, behavioral,
sensory, or motor functioning. This broad group of disorders includes diagnoses such
as intellectual disability, and autism spectrum disorder (ASD), which will be the
focus of this chapter, attention-deficit/hyperactivity disorder (ADHD) and tic
disorder, which are covered in another chapter, and communication disorders,
learning disorders, cerebral palsy, congenital hearing loss, and congenital blindness.
Intellectual disability (ID), previously labeled mental retardation, is a disorder with
deficits in intellectual and adaptive functioning. Although ID is typically reserved for
older children, for whom intellectual testing is more valid and reliable, global
developmental delay (GDD) is the diagnosis given to younger children in which
delays exist in two or more developmental domains. ASD, which includes prior
diagnoses of autistic disorder, Asperger disorder, and pervasive developmental
disorder (PDD) not otherwise specified, is a condition involving deficits in social
communication, as well as the presence of restricted and repetitive patterns of
behavior, interests, or activities.
EPIDEMIOLOGY, NATURAL COURSE OF THE
Developmental disorders are common in the community, affecting as many as 15% of
children in the U.S., based on parent report.
2 Collectively, developmental disorders
are nearly twice as likely in boys and children insured by Medicaid, relative to girls
and those insured by private insurance, respectively.
prevalence of developmental disorders is reported by families with incomes below
the federal poverty level and with lower maternal education (any educational
attainment less than a college degree).
For ID and GDD, the overall prevalence is estimated to be between 1% and 3% of
the population, though with considerable variability depending on how the diagnosis
is defined and reported in the literature.
Intellectual disability is more prevalent in
males versus females, and in low- and middle-income countries relative to highincome countries.
ASD is increasing in prevalence, with the Centers for Disease Control and
Prevention reporting about 1 in 68 children (1.47%) being identified with the
5 Although around one-third of children with ASD may also qualify for
intellectual disability, the proportion of children with average or above average
intelligence being diagnosed with ASD has been steadily increasing over the years
and may explain some of the increase in overall ASD prevalence.
children with ASD who are boys has consistently been 4 to 5 times that of girls.
the United States, around 30% of children with ASD have some level of ID.
The course and prognosis of both ID and ASD vary considerably depending on the
severity of the deficits, the impact of comorbid medical and psychiatric conditions,
and the access to services and treatments. Many individuals will go on to live rich
and fulfilling lives, with minimal required assistance in daily life functioning, though
some will require constant supervision in supportive group housing, and assistance
for basic tasks of daily living.
PATHOPHYSIOLOGY: DISEASE ETIOLOGY,
Many different known and unknown genetic and environmental factors can lead to the
impairment in early brain development associated with developmental disorders.
For both ID and ASD, risk factors include preterm birth, low birth weight, small
for gestational age, and low Apgar scores, though all of these are associated more
6 For ID specifically, risk factors may differ depending on the
severity of ID. Studies have shown risk factors for mild ID to include mothers under
the age of 20 years or older than 30 years, paternal age greater than 40 years,
increasing birth order, increasing social disadvantage, maternal education less than
high school, being part of a multiple birth, and being second or later in the birth
7,8 The risk of severe ID was consistently increased with increasing maternal
age and decreasing level of maternal education.
7 For ASD without ID, additional risk
factors include mothers aged 35 years or older, first-born infants, male infants, and
increasing socioeconomic advantage.
In only about half of all cases of ID can a specific etiology be identified and may
include genetic anomalies, intrapartum asphyxia, cerebral dysgenesis, and
In only about 30% of children with ASD can an identifiable
genetic etiology be determined.
10 Although inherited genetic forms of ID likely
represent a minority of identified cases, ASD on the other hand is widely considered
to be one of the most heritable neuropsychiatric conditions with heritability estimates
11 For parents with one child with ASD, the recurrence rate in future
siblings is thought to be 5% to 20%, with higher rates if the original child with ASD
12 This recurrence rate increases to about 33% if a family already has two
For inherited genetic anomalies, X-linked gene defects account for 10% to 12% of
all ID cases in males, with fragile X syndrome being the most common.
syndrome, marked by a CGG triplet repeat expansion in the FMR1 gene on the X
chromosome, is also the most common single-gene cause of ID, accounting for about
0.5% to 3% of individuals with ID,
14 and ASD, accounting for around 1% to 3% of
10,15 Single-gene disorders, some heritable like fragile X syndrome, account for
about 5% to 7% of ASD cases and include PTEN macrocephaly syndrome (~1%),
tuberous sclerosis complex (~1%), and Rett syndrome (~1%).
causes of ID and ASD include inherited metabolic disorders, such as
phenylketonuria, adenylosuccinate lyase deficiency, and Smith–Lemli–Opitz
15 Although inherited metabolic disorders are relatively rare, accounting
for only 1% to 5% of cases of ID, the potential for positive prognosis with treatment
Other genetic anomalies that can lead to ID and ASD include noninherited, or de
novo, single-gene mutations, chromosomal aberrations, and imprinting/epigenetic
14 Chromosomal aberrations may account for up to 25% of individuals with
ID, about 8% or 9% of which is due to trisomy 21, or Down syndrome, the most
14,16 Prader–Willi and Angelman syndromes, both
associated with developmental delays, are two examples of disorders involving
Environmental causes of ID range in the literature from 2% to 13% and include
antenatal toxin exposure (e.g., fetal alcohol spectrum disorders), antenatal infection
(e.g., TORCH infections), and early severe psychosocial deprivation.
Environmental causes of ASD include first trimester intrauterine exposure to
valproic acid, thalidomide, misoprostol, the organophosphate insecticide
chlorpyrifos, and phthalates, in addition to first trimester rubella infection.
receiving much scrutiny, multiple studies have shown no support linking vaccines to
Developmental disorders are typically recognized clinically once it becomes clear
that a child is delayed in meeting one or more developmental milestones. Primary
tasked by the American Academy of Pediatrics (AAP) to assess development at
every routine preventative visit throughout childhood.
encourages pediatricians to use standardized developmental screening tools (e.g.,
Ages and Stages Questionnaires—ASQ and Parents’ Evaluation of Developmental
Status—PEDS) at the 9-, 18-, and 24- or 30-month visit, and an autism-specific
screening tool at the 18- and 24-month visits (e.g., Modified Checklist for Autism in
21,22 Once concerns are raised by routine surveillance or
screening measures, children should be referred to early intervention and early
childhood programs, as well as to developmental specialists, when indicated.
Early recognition of developmental disorders depends on children having access
to preventative medical care, and almost 25% of children with special health care
needs might not have that access.
23 The nature and severity of the developmental
deficits also contribute to the age at recognition. The sensitivity of developmental
and autism screening measures rarely reaches 0.9,
developmental deficits may go undetected. For children with ASD, the mean age of
diagnosis has been around 53 months,
though children with intellectual disability
and those diagnosed with autistic disorder are typically diagnosed earlier; children
with higher IQ scores and those eventually diagnosed with Asperger disorder, whose
limitations do not include communication delays, are typically diagnosed later.
Some individuals with particularly subtle deficits may not be diagnosed until
adulthood. Individual symptoms that may lead to an earlier diagnosis of ASD may
include severe language deficits, hand flapping, toe walking, and sustained odd
ID is defined by both the American Psychiatric Association and the American
Association on Intellectual and Developmental Disability (AAIDD) as a disorder
with deficits in intellectual and adaptive functioning in conceptual, social, and
1,25 The Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-V) requires that the disability has onset “during the
developmental period,” whereas the AAIDD requires the disability to start before
age 18 years. Intellectual functioning is assessed clinically and by standardized tests
of intelligence, like IQ testing (e.g., Wechsler Intelligence Scale for Children and the
Stanford–Binet Intelligence Scale), with a cutoff being two standard deviations
below the mean for the general population, or a score of around 65 to 75, for
1 Older references focused diagnosis primarily around IQ scores, and
subcategories of intellectual disability (then called mental retardation) were set to
1 Current methods of diagnosis focus more on measures of
adaptive functioning, because this is more relevant to planning treatment and
supports. Adaptive functioning is also assessed clinically or with standardized tests
of adaptive functioning (e.g., Vineland Adaptive Behavior Scales). Subcategories for
intellectual disability in the DSM-V are now based on levels of adaptive functioning,
mild, moderate, severe, and profound. As standardized testing for intellectual and
adaptive functioning is typically valid for children above the age of 5 years, for
children younger than 5 years, the diagnosis of GDD is used and describes significant
delays in two or more developmental domains, including gross/fine motor,
speech/language, cognition, social/personal, and activities of daily living.
ASD is defined by the DSM-V as the presence of persistent impairment in
reciprocal social communication and social interaction, and restricted, repetitive
patterns of behavior, interests, or activities, present from early childhood, and
impairing everyday functioning (Table 88-1).
1 The diagnosis is made clinically,
though standardized behavioral diagnostic instruments, including caregiver
interviews, questionnaires, and clinician observation measures (e.g., Autism
Diagnostic Interview and Autism Diagnostic Observation Schedule), are available to
potentially assist in diagnosis.
by all of the following, currently or by history (examples below):
initiate or respond to social interactions.
poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body
language or deficits in understanding and use of gestures; to a total lack of facial expressions and
friends; to absence of interest in peers.
following, currently or by history (examples below):
lining up toys or flipping objects, echolalia, idiosyncratic phrases).
Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal
greeting rituals, need to take same route or eat food every day).
preoccupation with unusual objects, excessively circumscribed or perseverative interest).
smelling or touching of objects, visual fascination with lights or movement).
Severity is based on social communication impairments and restricted, repetitive patterns of
Symptoms must be present in the early developmental period (but may not become fully manifest until
social demands exceed limited capacities, or may be masked by learned strategies in later life).
should be below that expected for general developmental level.
After a child is identified to have a developmental disorder, further diagnostic
workup is warranted to identify an etiologic cause, because some causes may be
treatable (e.g., metabolic disorder), some may inform of other potential comorbid
medical problems (e.g., cardiac conditions in Down syndrome and fragile X
syndrome), and some may help inform parents of risks for future children. This
further etiologic workup should include a thorough medical history (including
prenatal and birth history), a family history going back three or more generations, and
a physical and neurologic examination focused on findings consistent with
If children with ID or GDD still do not have a known etiologic cause after this
workup, they should be referred for chromosomal microarray and possibly screening
for inborn errors of metabolism given the treatable nature of some metabolic
4 The American College of Medical Genetics and Genomics proposes that
in the event of a diagnosis of ASD without a known cause despite the above workup,
all children should undergo chromosomal microarray, those children with clinical
indicators should undergo metabolic or mitochondrial testing, fragile X testing should
be performed for all boys, MECP2 (Rett syndrome) testing should be performed in
all girls, PTEN testing in children with macrocephaly, and neuroimaging only if
specific clinical indicators (e.g., seizures, regression, history of stupor/coma,
behavior analysis (ABA) services.
What signs and symptoms of autism spectrum disorder does L.B. demonstrate?
Based on the DSM-5 criteria for ASD, L.B. is showing persistent deficits in social
communication and social interaction in multiple settings, as demonstrated by his
deficits in nonverbal communication (poor facial expressions), lack of relationship
building with children, and poor social–emotional reciprocity (lack of shared
enjoyment). L.B. also demonstrates restricted, repetitive patterns of behavior with his
stereotyped “woop”-ing noises and his inflexible insistence on sameness, with
aggression associated with transitions.
Therapy and Psychosocial Interventions
Individuals with ID or ASD can benefit from many different services to help with
issues of communication, social skills, sensory integration, behavior modification,
gross and fine motor, executive functioning, and adaptive functioning. Most of these
services are provided to children through the public education system, at no cost to
the families, as ensured by the Individuals with Disabilities Education Act (IDEA).
The IDEA provides all states with grants to provide early intervention services for
children with developmental delays under the age of 3. Services vary between states,
though each child and family are evaluated and given an Individualized Family
Service Plan (IFSP), which spells out the services to be provided, which may
include, but are not limited to, physical therapy, occupational therapy, speech and
language therapy, and behavioral therapy. For children reaching the age of 3 years,
and still eligible for specialized education, an Individualized Education Plan (IEP) is
drafted, which outlines the services to be provided in the school setting, starting in
preschool. IEP services could include all of the same types of services as above, as
well academic support, social skills groups, social pragmatics counseling,
vocational training, and emotional counseling. IEPs are required to be reevaluated
every 3 years, with updated testing and evaluation. Families must consent to both
IFSPs and IEPs, and if they disagree with the supports proposed, there is a process
by which they can appeal to have changes made.
Despite the services assured by the IDEA, children and families with
developmental disabilities also often receive psychosocial services in their
communities. In fact, in the 2011 Survey of Pathways to Diagnosis and Services,
almost two-thirds of children with ASD and/or ID were receiving a communitybased service.
28 The odds of using any school- or community-based service were
almost 8 times more likely for children with ASD, and over 9 times more likely for
children with ID, compared to children without those respective diagnoses.
To address the core symptoms of ASD, which include social communication
deficits and repetitive, restricted behaviors and interest, the most prevalent treatment
modality has been applied behavior analysis (ABA). ABA is a behavioral therapy
rooted in the concepts of operant conditioning, in which an antecedent leads to a
behavior, which results in a consequence. In ABA, preferred behavior, such as an
appropriate social response, is reinforced with an incentive. Classic ABA employs
the use of discrete trial training (DTT), in which specific skills are broken down into
discrete components and systematically taught in highly structured settings, often
using incentives like food and stickers. Critics of this form of ABA worry that
children with ASD are unlikely to apply the learned skills outside of the trial setting.
As a result, multiple different therapy approaches have been created, such as Pivotal
Response Therapy and the Early Start Denver Model, both derivations of ABA, and
the Developmental, Individual-differences, Relationship-based (DIR) Floortime
approach, which all operate in more naturalistic settings, focus more on building
child initiation and motivation, and employ natural incentives like positive affect and
affection. The research evidence to support such interventions for children and young
adults with ASD varies widely, as is explored in Wong et al.’s
recent review. Operant conditioning though, and the principles of manipulating
antecedents, behavior, and reinforcements, remains the mainstay for the treatment of
aggressive behaviors in individuals with developmental disabilities.
Individuals with ID often require the same types of interventions as individuals
with ASD, though perhaps with a stronger emphasis on adaptive functioning training,
and building skills of independent living. Likewise, for individuals with ID, the
evidence base for psychological interventions is varied. One recent review and
meta-analysis of psychological therapies for individuals with ID showed that in the
literature, individual therapy seems to be superior to group interventions, and
sizes exist for therapy for depression and anger, though there is no evidence that
therapy has an effect on interpersonal functioning.
The evidence supporting psychopharmacologic interventions in individuals with
ID/ASD is relatively limited. There are only a few large double-blind, randomized,
placebo-controlled trials (RCTs), many of which were funded by, or affiliated with,
the manufacturers of the particular study medications. Most of the existing RCTs are
for individuals with ASD and are of children and adolescents, likely, in part, because
of the complications involved in consenting adults with ID/ASD to participate in
research. Additionally, the targets for medication intervention with the strongest
research evidence are behaviors, which relay little about any possible underlying
emotional etiology for the individual.
Despite the limitations of the evidence, clinicians working with individuals with
ID/ASD know that medications can often serve a very important role as part of a
comprehensive treatment plan. Although much of the literature is of studies of
children with ASD, it should be noted that a large percentage of these studies
contained many individuals with comorbid ID (76%,
). However, the literature confirms that individuals with ID/ASD are more
sensitive to adverse events from medications compared to their neurotypical peers,
and therefore, pharmacologic interventions should be performed with caution.
At the time of this writing, there are no medications approved by the U.S. Food
and Drug Administration (FDA) to treat any of the core diagnostic elements of
ID/ASD. The target symptom behaviors with the most research evidence include
hyperactivity, irritability, repetitive behaviors, and self-injurious behavior. As
anxiety disorders are the most common comorbid psychiatric conditions in
individuals with ID/ASD, anxiety/depression is another frequent target for
psychopharmacologic intervention, though with considerably less research support.
Sleep disturbances are also remarkably common in individuals with developmental
disabilities and often are a target for medication intervention.
Individuals with ID/ASD have high rates of comorbid ADHD, with literature in
children with ASD showing prevalence rates of about 30% for children derived from
community, nonclinical, populations (28%37 and 31%38
children evaluated in the clinical setting.
39 The mainstay of treatment for symptoms of
ADHD in individuals with ID/ASD, like their neurotypical peers, includes
stimulants, α2 agonists, and atomoxetine.
Stimulants are a group of medications derived either from methylphenidate or
amphetamine that act by increasing the amount of dopamine and norepinephrine in the
neuronal synaptic cleft. This increase in dopamine and norepinephrine is the result of
blocking the reuptake of dopamine and norepinephrine (methylphenidate and
amphetamine) and increasing the release of dopamine and norepinephrine
in their recent meta-analysis of pharmacologic treatments of
symptoms of ADHD in children with PDD, found four RCTs of stimulant
medications. All four RCTs studied methylphenidate and found it to be superior to
placebo for the treatment of global ADHD symptomatology and specifically
hyperactivity. In the largest of the four RCTs (n = 66),
41 effect sizes for hyperactivity
and impulsivity symptoms were greater than for inattention symptoms (0.77 vs. 0.60
for parent rating; 0.48 vs. 0.35 for teacher rating).
The effect size for the treatment of ADHD symptoms in children with PDD (0.67
40 however, was lower than estimates in a meta-analysis of
stimulant treatment of typically developing children with ADHD (0.77 for
methylphenidate and 1.03 for amphetamine).
In the study conducted by the Research
Unit on Pediatric Psychopharmacology (RUPP) group,
41 49% of children experienced
a therapeutic response, compared to 69% in the Multimodal Treatment Study of
Children with ADHD (MTA), which studied mostly neurotypical children (ID was an
exclusion criteria, and ASD was not mentioned as a comorbid diagnosis in any
Adverse events were more common in children with PDD treated with
methylphenidate versus placebo, with increased rates of decreased appetite,
insomnia, depressive symptoms, irritability, and social withdrawal.
adverse events with methylphenidate were also larger in children with PDD
compared to typically developing children, as evidenced by 18% of RUPP study
41 discontinuing the medication due to adverse events (primarily
irritability), compared to 1.4% in the MTA study.
Mean dosage in the four RCTs ranged from 0.29 to 0.45 mg/kg/dose.
analysis of the RUPP study data showed that methylphenidate doses of 0.25 and 0.5
mg/kg/dose were more consistently effective for treating ADHD symptoms than the
35 The highest dose used in the RUPP study was 0.625
mg/kg/dose, compared to the MTA study, in which the highest dose used was 0.8
Daily methylphenidate doses may be titrated weekly, until an optimal dose is
obtained. Improvement in symptoms should be noted within the first week.
Overall, the research literature shows that methylphenidate can be used to improve
ADHD symptoms, especially hyperactivity, in children with PDD, though with lower
effect sizes, lower tolerated doses, and more risk of adverse effects than children
without developmental disabilities.
guidelines suggest that amphetamine salts can be an option for children demonstrating
insufficient benefit or dose-limiting adverse events from methylphenidate.
Although the exact mechanism in ADHD is unknown, α2 agonists are thought to work
by stimulating the α2 adrenoceptors on norepinephrine-containing neuron cell bodies
in the locus coeruleus which modulates the tonic and phasic firing to the prefrontal
cortex. This allows the person to have increased attention on the desired task.
α2 Agonists include clonidine, a nonselective α2 adrenergic receptor agonist, and
guanfacine, a selective α2A adrenergic receptor agonist. α2 Agonists were initially
marketed for the treatment of hypertension, though have been shown to also improve
For clonidine, one small study (n = 8)
47 was identified by Reichow et al.
at clonidine versus placebo for the treatment of ADHD in children with PDD.
Although the original study found no statistically significant results, the effect size
for improvement in ADHD symptoms and irritability
was in the medium range (γ = 0.51 and 0.64, respectively) and smaller for
improvements in hyperactivity (γ = 0.30) and stereotypic behavior (0.24). The
report increased rates of hypotension and drowsiness
in some children who took clonidine. Mean dosage ranged from 0.15 to 0.20 mg/day.
One small pilot RCT (n = 11) looking at guanfacine treatment in children with
developmental disabilities showed statistically
significant reductions in hyperactivity subscales and global rating of improvement,
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