Clinical manifestations

Presentation and course

Intellectual disability is not a disease, a syndrome, or a designation that encompasses a group of medical disorders. It is instead a construct embedded within that of disability and descriptions of human functioning (67; 82). In 2009, the American Association on Intellectual and Developmental Disabilities published their latest definition as follows (02):

Intellectual disability is characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social, and practical adaptive skills. This disability originates before age 18.

The Association states that 5 assumptions are essential to the application of the definition:

	(1) Limitations in present functioning must be considered within the context of community environments typical of the individual's age, peers, and culture.
	(2) Valid assessment considers cultural and linguistic diversity as well as differences in communication, sensory, motor, and behavioral factors.
	(3) Within an individual, limitations often coexist with strengths.
	(4) An important purpose of describing limitations is to develop a profile of needed supports.
	(5) With appropriate personalized supports over a sustained period, the life functioning of the person with intellectual disability generally will improve.

Intellectual disability is also defined by the American Psychiatric Association in its Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-5; 05) as:

	(A) Deficits in intellectual functions, such as reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience, confirmed by both clinical assessment and individualized, standardized intelligence testing.
	(B) Deficits in adaptive functioning that result in failure to meet developmental and sociocultural standards for personal independence and social responsibility. Without ongoing support, the adaptive deficits limit functioning in one or more activities of daily life, such as communication, social participation, and independent living, across multiple environments, such as home, school, work, and community.
	(C) Onset of intellectual and adaptive deficits during the developmental period.

Intellectual disability can be seen as a limitation in intellectual functioning resulting from various causative pathological processes. Intellectual functioning is often defined as an intelligence quotient (IQ) obtained by standardized tests or batteries of tests, eg, Wechsler Intelligence Scale for Children-Revised, of 70 or below. In most tests producing an IQ, the mean is 100 and the standard deviation is 15 points with a confidence interval of ±5. Thus, 70 is 2 standard deviations below the mean. One can diagnose intellectual disability with a score up to 75 if significant deficits exist under criterion B.

The American Association on Intellectual and Developmental Disabilities (AAIDD) definition uses multiple dimensions for further description of individuals, rather than subcategorizing by severity specifier as they had done in earlier definitions. These dimensions include intellectual ability, adaptive behavior, participation, interaction, social roles, physical and mental health, and environmental and cultural context. Previously, DSM-4 had assigned subcategories based upon IQ scores (03; 04). The categories had ranged from mild to moderate, severe, and profound. IQ in mild intellectual disability is 2 to 3 SD below the mean (50-55 to 70); in moderate intellectual disability, 3 to 4 SD below the mean (35-40 to 50-55); in severe intellectual disability, 4 to 5 SD below the mean (20-25 to 35-40); and in profound intellectual disability, IQ is more than 5 SD below the mean (below 20-25) (14; 83). However, in the new DSM-5, severity level (mild, moderate, severe, profound) is defined on the basis of adaptive functioning and not by IQ scores. Epidemiologic studies often subdivide it into mild (IQ 50 to 70) and severe (IQ below 50) alone (64). An older AAIDD classification still referred to at times categorized intellectual disability into educable (IQ 50 to 75), trainable (IQ 30 to 50), and severely or profoundly retarded (IQ below 30). For the medical clinician, the term intellectual disability should be used when the above criteria are met and they are not due principally to a dementing or psychiatric illness. This implies that there is neither a progressive neuropathological lesion such as might occur with an inborn error of a metabolism or a neurodegenerative disorder, nor that a psychiatric disorder such as schizophrenia or depression is the primary cause of the maladaptive functioning.

Assessment. The administration of age-appropriate, norm-based tests of intellectual function by skilled practitioners is the mainstay of formal evaluation and diagnosis of intellectual disability. Diagnosis requires standardized measurement of both intelligence and adaptive function, rather than a single IQ score, and should be periodically re-evaluated with repeat psychological, educational, and achievement assessment (42).

Although an IQ properly estimated at 1 point in time may change later, it generally remains within 1 standard deviation of the original score, particularly when it falls into an obviously abnormal range. The stability of the IQ score may be affected by the age at which the assessment is done. Early testing has limited predictability of future performance, with it being best in the more severely disabled. It may also be influenced by poor visual-motor functioning, as opposed to language and information processing deficits, which have an impact on results at a later age. For a review of the commonly used tests with their age ranges, the reader is referred to Mahone (43).

Intelligence test results should be integrated with the neurodevelopmental assessment, evaluation of adaptive functioning, and behavioral observation. The physician should emphasize the desirability of providing the least restrictive environment and assist parents and caregivers with appropriate opinions about diagnosis, prognosis, and options for treatment, management, and education.

Early diagnosis also requires a sound knowledge of childhood development and the infant's neurologic examination. In infants, suspicion may be raised if there are signs of early neuromotor abnormalities, such as delayed motor development, persistence of primitive reflexes, abnormal oromotor responses, hemiparesis, spasticity, hypotonia, or other abnormalities of movement (49; 69). In toddlers and preschool children, delayed social or language development is a sensitive indicator of intellectual disability. Global developmental delay diagnosis can be given for individuals under the age of 5 years when the clinical severity level cannot be reliably assessed during early childhood (05). In all age categories, the presence of dysmorphic features, abnormal head size and growth, and the presence of major congenital malformations may assist in its early recognition and diagnosis.

Prognosis and complications

Most persons with intellectual disability should have a life expectancy reaching into adulthood. Those with IQ scores between 50 and 70 generally develop the ability to read and perform basic math functions whereas those with IQ below 50 are more dependent upon others for assistance with daily needs. Those between 35 and 50, previously referred to as trainable, typically develop independence in toileting, feeding, and dressing and participate in work environments. Those scoring below these levels are generally dependent upon others.

Persons with intellectual disability who have major malformations and related health problems, more common in those with more severe levels of disability, may have shorter life expectancy based upon these conditions. For example, individuals with Down syndrome may develop an early-onset Alzheimer dementia with pathological findings typical for that disease, with related morbidity and mortality.

Life expectancy for those with the more severe levels of intellectual disability is generally less than that for the general population (31; 76). The decrease is greatest for those who are immobile, have profound intellectual disability, and are unable to feed or care for themselves. For those who were mobile, but nonambulatory, about 50% would be expected to survive to at least 20 years of age. In children with severe or profound disability, those who were immobile, had not mastered toilet skills, and were tube fed usually died within 4 years. By 10 years of age, 80% had died, and even if survival lasted until age 15 years, life expectancy was still only about 4 years more. The most common cause of death was respiratory disease. Survival appears better for children treated in skilled nursing facilities. In 1 cohort of children with severe neurologic disabilities treated in such a facility with access to acute medical treatment, 10-year survival rates were at or greater than 73% for children ranging from less than 1 year of age through adolescence (60).

People with intellectual disabilities have higher rates of health problems and utilize more health care services than unaffected individuals. Those with intellectual disability experience significantly higher rates of problems in both physical health and mental health than the general population, with nearly all reporting physical problems and one third mental health problems in a survey in Wales (36). Similar results were found from a national survey sample of children in the United States. Prevalence of comorbid medical conditions were significantly higher, as well as health care utilization and unmet needs, in children with developmental disabilities compared to a group of children without developmental disabilities (68). In worldwide samples, those with intellectual disability have higher rates of epilepsy, other neurologic problems, sensory loss, mental health conditions, sleep problems, endocrinologic conditions, dermatologic conditions, and fracture risk (32). Another epidemiological sample also identified more problems with constipation and upper respiratory infections than controls (75). People with intellectual disability had 1.7 times more healthcare visits than controls as well as more prescriptions per year (4.3 prescriptions per year in those with intellectual disability vs. 3.1 in controls). In Taiwan, 12.4% required inpatient care in a 7-month time period, with an average of 1.43 visits and an average stay of 16.91 days (39). The main reasons for inpatient care were surgery, fever, gastroenterologic disorders, psychiatric disorders, and accidents.

Many individuals with intellectual disability have associated disabilities. Cerebral palsy is common, with a study of affected children in Iceland demonstrating 40% to have intellectual disability (73). Children with hemiplegia had the highest IQ scores, whereas those with dyskinetic cerebral palsy had the lowest. More severe motor impairments were associated with lower scores (72). About one third of persons with both intellectual disability and cerebral palsy also develop epilepsy, with the prevalence greatest in spastic quadriplegia and acquired hemiplegia and lowest in mild symmetric spastic diplegia and mainly athetoid cerebral palsy (49).

Autism spectrum disorders are also commonly seen in children with intellectual disability. In a sample from the Netherlands, prevalence ranged from 7.8% to 19.8%, with variation depending on the instrument and method chosen (19). Using the DSM-IV-TR criteria, felt by the researchers to be the most reliable and well-founded, 16.7% were affected. The cases were nearly equally divided between those with autism (8.8%) and those with pervasive developmental disorder-not otherwise specified (PDD-NOS) (7.9%). The overall frequency was lower in those with mild intellectual disability, at 9.3%, whereas 26.1% of those with moderate, severe, and profound levels were affected. In adults with intellectual disability sampled in a metropolitan area of England, a higher prevalence of 30% was reported, based upon service providers’ report on a screening questionnaire (52).

High rates of mental health problems have been reported amongst those with intellectual disability. Up to 50% of adolescents have problems with disruptive and antisocial behaviors. Common diagnoses reported include attention deficit hyperactivity disorder, pervasive developmental disorders, anxiety disorders, conduct disorders, and emotional disorders (34). Although these mental health problems are functionally impairing, they are frequently unidentified in adolescents with intellectual disability and hence untreated (28). In a British sample of children, 36% of those with intellectual disability had a psychiatric problem compared to 8% of controls, accounting for 14% of all children with such problems (23). Major challenging behaviors are estimated to occur in 10%, with high incidences of moderate to severe tantrums as well as verbal and physical aggression (07). Another study also found that individuals with intellectual disability who have more mental and physical health problems have higher odds of displaying aggressive behaviors than those with fewer and less severe physical health problems (17).

Clinical vignette

DM presented at 31 months of age with his parents due to concerns about development. He was born at 40 weeks gestation by spontaneous vaginal delivery after an uneventful pregnancy. Mild dysmorphic features were noted in the nursery, and a genetic evaluation was completed, including karyotype and FISH probes for suspected syndromes. Workup did not reveal an etiology. At 31 months, DM had a language age equivalent of 18 months (DQ=58) and a visual motor age equivalent of 21.5 months (DQ=68), and he was given a diagnosis of global developmental delay. An MRI of the brain was performed to further evaluate the etiology of DM’s constellation of findings and was unremarkable.

DM returned to clinic at age 7 with continued concerns about his learning and additional concerns about behavior. He had been appropriately placed in a special education setting but was having trouble with hyperactivity, for which he was treated successfully. The causes of DM’s delays were reconsidered, and a chromosomal microarray was requested. A 13q11 microdeletion was detected as the probable cause of DM’s intellectual disability and his dysmorphic features.

Biological basis

Etiology and pathogenesis

The causes of intellectual disability are diffuse, and the efforts to evaluate etiology require a thorough understanding of the types and timing of insults to the developing brain. Successful determination of etiology of developmental delay is variable and influenced by the severity of delay, the domains in which delays are found, and the presence of dysmorphisms or focal findings on examination. In general, the greater the severity of delay, the more likely the etiology will be uncovered. It is estimated that as many as 40% to 60% of children with developmental delay will have a cause identified when all modalities of etiologic determination are considered (history, physical examination, imaging studies, chromosomal or genetic evaluations, metabolic testing, etc). The majority of etiologies identified will be in the children with moderate to severe impairments or delay (24; 18).

The cause of intellectual disabilities may be best categorized as those of prenatal onset (eg, structural anomalies of the central nervous system, genetic disorders, intrauterine infections, toxic exposures), those of perinatal onset (perinatal hypoxic ischemic encephalopathy, prematurity), or those of neonatal or postnatal onset (neonatal infection, complications of prematurity, infection, toxins, trauma, or environmental exposures). However, nearly 75% of etiologic diagnoses are attributed to genetic syndromes, perinatal asphyxia, cerebral dysgenesis, severe psychosocial deprivation, and toxin exposure (70).

PRENATAL
	Developmental or cerebral dysgenesis
		• Anencephaly • Neural tube defects • Encephalocele • Holoprosencephaly • Lissencephaly • Micrencephaly • Megalencephaly • Hydranencephaly • Porencephaly • Schizencephaly
	Chromosomal or genetic
		• Trisomys/chromosomal abnormalities • X-linked syndromes • Multiple minor congenital anomaly syndromes • Contiguous gene syndromes • Single gene disorders • Microdeletion and duplication syndromes
	Prenatal Infection
		• Toxoplasmosis • Syphilis • Rubella • Cytomegalovirus • Herpes simplex virus • Streptococcus • Human Immunodeficiency virus
	Toxic exposures
		• Alcohol-related birth defects • Ionizing radiation • Drug embryopathies • Teratogens
PERINATAL
		• Peri- and postnatal hypoxic-ischemic encephalopathy • Undetected inborn errors of metabolism
	Prematurity
		• Intracranial hemorrhage • Hydrocephalus • Periventricular leukomalacia • Periventricular hemorrhagic infarction
POSTNATAL
	Nutritional
		• Severe pre- and postnatal protein malnutrition • Periconceptual folate deficiency • Vitamin and essential element deficiency
	Infection
		• Herpes simplex virus • Streptococcus • Human Immunodeficiency virus • Meningitis • Encephalitis
	Traumatic brain injury
		• Physical abuse (nonaccidental trauma) • Accidental trauma • Birth trauma
	Toxic exposures
		• Heavy metals (lead, mercury)

Structural abnormalities of the central nervous system are the result of a multitude of insults that are primarily prenatal in origin. Primary malformations such as neural tube defects (ranging from anencephaly to spina bifida occulta), cerebral dysgenesis (eg, lissencephaly, porencephaly, microcephaly, schizencephaly, agenesis), and congenital hydrocephaly, hydrencephaly, etc., can all be associated with significant intellectual disability. Some malformations have been found in association with autosomal deletions, including holoprosencephaly (2p23-22, 7q32-36, 18p11) and lissencephaly (17p13) (09). Nongenetic insults include vascular disruptions, amniotic bands, and unrecognized toxic exposures. There are numerous multiple minor congenital anomaly syndromes associated with intellectual disability and cerebral dysgenesis that appear to be nongenetic (49).

Genetic etiologies of intellectual disabilities may take the form of chromosomal aberrations, trisomies, X-linked syndromes, contiguous gene syndromes, single gene disorders, and microdeletion and duplication syndromes. The fragile X syndrome is the most common X-linked intellectual disability syndrome, with an estimated prevalence of 1 per 3500 individuals. It is, after trisomy 21, the second most common chromosomal disorder leading to intellectual disability. It accounts for 30% to 50% of mentally retarded males in families with X-linked intellectual disability (12). Fragile X syndrome is caused by a trinucleotide (CGG) repeat expansion in the FMR1 gene (Xq27.3). Individuals with full mutation have more than 200 repeats and typically demonstrate the physical, behavioral, and cognitive phenotype of fragile X syndrome. Individuals with premutation (55-200 CGG repeats) are far more common, and although premutation carriers were initially thought to be asymptomatic, there is growing awareness that these individuals may have mild manifestations of fragile X syndrome.

Other discoveries arising from advances in cytogenetics have been made on autosomal-linked syndromes with intellectual disability. The Williams syndrome involves vascular, connective tissue and the central nervous system. Features include supravalvular aortic stenosis, hypertension, prematurely aging skin, dysmorphic facial features, infantile hypercalcemia, and intellectual disability (53). Interestingly, patients with Williams syndrome tend to be very social and demonstrate a high degree of empathy (46). The syndrome is reported to be caused by submicroscopic deletions within chromosome 7q11.23, and it appears that the deletion of 1 elastin gene allele is the mechanism of the vascular and connective tissue pathology. Miller-Dieker syndrome is characterized by severe intellectual disability, generalized agyria or pachygyria, absent or hypoplastic corpus callosum, and microcephaly. Craniofacial features include a prominent forehead with bitemporal narrowing and furrowed brow, a small nose with anteverted nares, prominent upper lip, and micrognathia (20). Deletions of a gene in the 17 p13.3 region appear to be responsible for this disorder and for lissencephalic dysgeneses (22; 21).

Molecular genetics has revealed interesting gene variations that result in differing intellectual disability syndromes. We now understand how 2 distinct syndromes involving intellectual disability, Prader-Willi and Angelman syndromes, can result from the same deletion on chromosome 15 through genomic imprinting (Mascari et al 1992; 26). In Prader-Willi syndrome the deletion is of paternal origin, whereas in Angelman syndrome it is maternal. Heterodisomy (uniparental disomy) occurs when both undeleted chromosomes are inherited from the same parent. Genomic imprinting refers to differential expression of a gene depending on its parental derivation. It can be seen in embryonic development, neoplasia, microdeletion syndromes, and in some single-gene disorders that show phenotypic differences depending on the parental origin of the gene.

Proper regulation of thyroid hormone levels is critical to normal development. Thyroid hormone affects neuronal growth. Hypothyroidism can lead to cretinism, which can be caused either by defects in thyroid hormone synthesis and utilization (sporadic cretinism) or from iodine deficiency (endemic cretinism). Sporadic cretinism usually occurs secondary to thyroid dysgenesis. Hereditary forms are most commonly due to errors in thyroxin synthesis; however, mutations in the TSH receptor have also been reported (37). Although untreated hypothyroidism is rare in developed countries because of neonatal screening and iodized salt, it remains a problem in some developing areas of the world. Sporadic cretinism is associated with neonatal hypothyroidism, which includes prolonged jaundice, lethargy, hypotonia, poor feeding, and a hoarse cry. Early diagnosis is critical as these patients can improve with treatment. Evidence supports initiating aggressive treatment 2 weeks after birth (81). Endemic cretinism is associated with deaf mutism, poor growth, and neurologic signs such as spasticity, ataxia, and intellectual disability. They usually do not respond to thyroid hormone therapy.

Many different forms of infection occurring in the pre-, peri-, and postnatal periods are major causes of intellectual disability worldwide. Prenatal infections such as toxoplasmosis, syphilis, rubella, cytomegalovirus, herpes, or varicella, are associated with rashes, hepatosplenomegaly, jaundice, microcephaly, growth retardation, cataracts, visual and hearing loss, intracranial calcifications, and seizures. These are usually obvious at birth if infection occurred during the first or second trimester. Acute and chronic bacterial and fungal meningitis and various forms of encephalitis, in particular neonatal and childhood herpes simplex encephalitis, contribute to the causes of intellectual disability.

A population-based, case-control study attempted to identify prenatal and perinatal risk factors associated with intellectual disability, and Bilder and colleagues identified the following risk factors: poly/oligohydramnios, advanced paternal/maternal age, prematurity, fetal distress, premature rupture of membranes, primary/repeat cesarean sections, low birth weight, assisted ventilation greater than 30 minutes, small-for-gestational age, low Apgar scores, and congenital infection. When cases of known or suspected genetic disorders were excluded from the analysis, advanced parental age and primary cesarean section lost their significance (08).

It is now well established that exposures to alcohol, chemicals, some medications and heavy metals may adversely affect the fetal developing brain and lead to later intellectual disability. Criteria for the diagnosis of fetal alcohol syndrome include a history of alcohol abuse during pregnancy, prenatal and postnatal growth retardation, neurodevelopmental abnormalities, and dysmorphic features including at least 2 or 3 signs: microcephaly, short palpebral fissures, poorly developed philtrum, thin upper lip, and flattening of the maxillary area. Alcohol-related birth defects may occur in offspring who do not fulfill all the criteria for the diagnosis of fetal alcohol syndrome.

There are no specific neuropathologic correlates of intellectual disability. Changes may be minimal or grossly obvious, depending on the type or timing of the etiologic insult. These changes include brain malformation syndromes that result from failure of induction of mesoderm and neuroectoderm; disorders of cell migration, proliferation, and differentiation; defects in gyral sulcation, axon growth, synapse formation, dendritic arborization, and process elimination; and postnatal destructive changes secondary to metabolic insult, vascular compromise, infection, or trauma. Major cerebral insults during the first trimester result in either fetal death or severe malformation. Because markers of repair such as macrophages, hypertrophic astrocytes, or glial fibrils are not present during the first half of pregnancy, it is difficult to distinguish between atrophy, malformation, or failure of central nervous system components to grow. Furthermore, these abnormalities may coexist, and acute central nervous system injury may occur in brains already damaged by an earlier insult.

Marked intellectual disability often accompanies obvious malformations such as micrencephaly, lissencephaly, holoprosencephaly, schizencephaly, and major midline defects (20). Here, and in cases where many neurons are lost as a result of toxicity or trauma, the size and connectivity of the neuronal networks is impaired to such a degree that its capacity to process information is severely limited (62). However, in many affected individuals there is no gross morphological abnormality.

Evidence is mounting that defects in synaptogenesis and synaptic plasticity are crucial processes underlying intellectual disability. Postmortem analysis of brain tissue from individuals with intellectual disability often shows dendritic spines with altered shapes, densities, and branching (33). Dendritic spines receive the large majority of all excitatory glutaminergic synaptic transmission and are focal points of synaptic plasticity. Thus, it is likely that abnormalities in these structures will impair information processing at the cellular and network level (62). In addition, it is emerging that defects in the regulation of synaptic activity and morphogenesis of dendritic spines are apparently common features associated with mutations in several genes implicated in intellectual disability (30; 06; 77). Characterized intellectual disability-related genes encode diverse proteins that fall into distinct functional subclasses including transmembrane proteins, microtubule- and actin-associated proteins, regulators and/or effectors of RhoGTPase pathways, and transcription and chromatin-remodeling factors (13). Over the past decade, epigenetic mechanisms such as DNA methylation, histone modification, and chromatin remodeling have emerged as mechanisms that play a pivotal role in complex brain functions and may be implicated in the etiology of intellectual disability (27; 66). Despite this apparent diversity, unifying biological networks and pathways underlying potential pathophysiological mechanisms for intellectual disability are emerging, and readers can refer to the review by van Bokhoven for genetic and epigenetic networks associated with intellectual disability (78).

Epidemiology

The prevalence of intellectual disability has been found to range widely. This variation is thought to be related to such factors as differences in case definitions, study design, and case ascertainment methods. Assuming a normal distribution for intelligence with a mean of 100, 2.3% of children would be expected to have an IQ score greater than 2 standard deviations below the mean on an intelligence test, for an estimated prevalence of 23 per 1000. However, prevalence as ascertained from community samples has been shown to be closer to 10 per 1000 (84).

In prevalence studies, a categorization of severity of intellectual disability by IQ is often used, with an IQ lower than 50 being considered severe intellectual disability and an IQ of 50 to 70 considered mild intellectual disability. Most of the variation in prevalence figures has been found in the mild range. Based on their review, Roeleveld and colleagues calculated a “true” average prevalence rate for mild intellectual disability in school-aged children of 29.8 per 1000 (64). The prevalence of severe intellectual disability has been found to be more stable across populations at 2 to 4 per 1000, with Roeleveld calculating an average prevalence of 3.8 per 1000 (64). The addition of more recent data does not appear to significantly alter these averages (38).

A higher prevalence of intellectual disability has been found among male versus female children, approximately 1:5.1 (38). This has been attributed to biological factors, such as X-linked genetic conditions, as well as possible societal factors that may increase the likelihood of boys being referred for services and, therefore, identified (38). There is a greater prevalence of intellectual disability among African-American children as compared with children of other racial groups in the United States, and low socioeconomic status is strongly and inversely related to the prevalence of intellectual disability, particularly mild intellectual disability (54).

Prevention

As there is yet no treatment to cure intellectual disability; therefore, efforts have been focused on the reduction of preventable causes of the disorder. President Kennedy formed a commission on Mental Retardation in the early 1960s with an audacious goal of reducing intellectual disabilities in the United States by 50% by the year 2000. Although efforts have fallen short of the 50% goal, tremendous strides have been made over the last half century to identify preventable causes of intellectual disability, to educate the medical community and public about these findings, and to implement strategies to eliminate preventable causes of this burden for individuals, families, and society.

Some of the important contributions to reduction of intellectual disability in the last 5 decades include understanding prenatal risks, including the effects of maternal alcohol consumption, teratogenic medications, and folate deficiency on the fetal nervous system, Rh disease and maternal immunotherapy, and the profound benefit of newborn screening for children with metabolic disorders such as PKU and congenital hypothyroidism. The contribution of immunizations is seen in the reduction of congenital measles and rubella, complications of Haemophilus Influenza type B, and varicella. Brosco and colleagues estimated that 7 condition-specific causes of intellectual disability (congenital syphilis, Rh disease, measles, Hib meningitis, congenital hypothyroidism, PKU, and congenital rubella) collectively accounted for about 16.5% of intellectual disability cases in 1950 and only 0.005% of cases in 2000 (10). Brosco and colleagues explored the question of whether medical interventions such as advances in surgical techniques and in critical care medicine during the past half century increased the number of children with intellectual disability, and they found that no other new medical therapies introduced during this period were associated with a clinically significant increase in intellectual disability prevalence (11).

Differential diagnosis

Although the etiologic possibilities for global developmental delay or intellectual disabilities are tremendous, the differential diagnosis of intellectual disability is somewhat limited. As children often present in the preschool years with a chief complaint of delay, particularly in language, the differential diagnoses should include: hearing impairment, specific language impairments, and autism spectrum disorders (ASD). All of these diagnoses may present as delay or may be associated findings in a child with delay or intellectual disability.

In an older child of school age, the presenting complaint may be academic underachievement. In this scenario, a child may have a mild or borderline form of intellectual disability that did not come to attention in the preschool years. The differential diagnosis at this age should, however, include higher forms of language disorders and learning disabilities as well as attentional deficits.

At any age, a child who presents with delays that are acquired (regression of skills), a multitude of neurodegenerational considerations should be entertained including: infectious etiologies, neuromuscular disorders, metabolic disorders, toxic exposures, and psychiatric illnesses.

Diagnostic workup

There have been a number of guidelines published to guide the diagnostic workup of individuals with intellectual disability or global developmental delay (18; 71; 51). These guidelines have relatively similar recommendations for the diagnostic evaluation process.

The diagnostic workup of intellectual disability starts with a thorough clinical history, including prenatal and birth history. A 3-generation family history should be obtained, with particular attention to family members with intellectual disability, developmental delays, psychiatric diagnosis, congenital malformations, miscarriages, stillbirths, and early childhood deaths (51). Evaluation should continue with a complete physical examination, with special focus on assessment of growth parameters including: head size, minor congenital anomalies (dysmorphologic examination), neurocutaneous findings, and neurologic examination. Hearing and vision should be assessed, and full ophthalmologic examination can also provide important diagnostic clues.

Based on the history and physical examination, if an etiology is suspected, specific tests to confirm the diagnosis should be ordered (eg, fluorescent in-situ hybridization for elastin gene deletion in suspected Williams syndrome). If no specific etiology is suspected, it is recommended that the clinician should obtain high resolution karyotype (more than 650 bands) and molecular genetic testing for fragile X syndrome for all patients. However, with advances in technology and advent of chromosomal microarray (CMA) testing, CMA is increasingly becoming the most commonly ordered initial genetic diagnostic test in patients with unexplained global developmental delay or intellectual disability (25). CMA permits genome-wide detection of copy number variants (CNVs) at a significantly higher resolution than G-banded karyotyping. The International Standard Cytogenetic Array (ISCA) Consortium stated in its consensus statement that CMA should be the first line diagnostic test for individuals with global developmental delay or intellectual disability, autism spectrum disorder, or multiple congenital anomalies (48). Additionally, a systemic review by the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society found that microarray was the genetic test with the highest diagnostic yield in children with unexplained global developmental delay/intellectual disability, with average diagnostic yield of 7.8% (47). DNA testing for fragile X syndrome is still considered a first-tier test for the diagnostic evaluation of an individual with unexplained global developmental delay or intellectual disability after a normal CMA, or concurrently, and is appropriate testing for both males and females, especially if there are concomitant autistic features or a family history supportive of X-linked inheritance (25). The diagnosis of Rett syndrome with testing for the methyl-CpG-binding protein 2 (MECP2) gene mutation should be considered in females with unexplained moderate to severe intellectual disability (71).

Van Karnebeek and colleagues found that the yield of neuroimaging studies for abnormalities in individuals with intellectual disability or global developmental delay was 30%, with MRI more sensitive than CT scan; however, the yield for finding a diagnosis based on these studies was only 1.3%, ranging from 0% to 3.9% of patients studied (80). The value of a negative MRI result has not been studied. If neuroimaging is performed in selected cases with physical findings such as microcephaly or focal neurologic findings, the rate of abnormalities detected is increased. Although there is not complete agreement in the various guidelines about the standard use of neuroimaging in evaluating all individuals with intellectual disability, there is general consensus that MRI is more useful than CT scan and that MRI is indicated when there are physical findings such as microcephaly or focal neurologic findings on physical examination.

The yield of routine metabolic testing (eg, urine organic acids, plasma amino acids, plasma lactate, thyroid studies) in individuals with intellectual disability or global developmental delay is low. Van Karnebeek and colleagues found the mean diagnostic yield from metabolic studies to be 1% (range 0.2% to 8.4%), with the higher rates in selected populations (80). In addition, it is unusual for metabolic disorders to present without findings in the history or physical examination such as growth delay or coarse facial features. Given these considerations, it is recommended that metabolic testing be targeted only to those individuals who have signs and symptoms suggestive of a possible metabolic disorder. The reader is referred to Curry and colleagues for a list of selected clinical findings/laboratory abnormalities that may indicate the need for further metabolic investigation (18). Metabolic testing should also be considered in the absence of newborn screening test results.

EEG is not recommended as a routine part of the etiologic evaluation in individuals with intellectual disability/global developmental delay. An EEG can be obtained when an individual with intellectual disability/global developmental delay has a history or examination features suggesting the presence of epilepsy or a specific epileptic syndrome (71).

Management

Management includes early genetic counseling, family support and education, and referral for early intervention developmental treatment services for young children, ages birth to 3 years (15). Beginning at 3 years of age, additional special educational services are indicated for the intellectual disability (16). Those with associated behavior disorders and autism spectrum disorders may also benefit from behavior management programs focused on principles of applied behavioral analysis, employing task analysis, and operant principles of learning (56).

Medication management of the core intellectual problems in intellectual disability is centered primarily on attention and executive functioning through use of the stimulant medications (40). Efficacy has been demonstrated with both the amphetamines and methylphenidate, where dopaminergic and noradrenergic systems in the frontal cortex are affected. Treatment results in improved attention, alertness, vigilance, and arousal. Enhanced functioning has been demonstrated in sustained attention, attentional allocation, motor response speed and organization, and motor inhibition. Specific improvements have also been reported in short-term recall, long-term memory tasks, working memory, and academic performance. A randomized, controlled, double-blind trial also supported the effectiveness of methylphenidate in reducing attention deficit hyperactivity disorder symptoms in children with intellectual disability (74).

Piracetam, described as a nootropic agent for promotion of learning, is a derivative of gamma-aminobutyric acid (GABA) with an affinity for the AMPA glutamate receptor and is approved for use in Europe (40). Based upon effects seen in rodent models, it has been tried in a population of children with Down syndrome, but improvements have not been seen (41). Cholinesterase inhibitors, such as donepezil, used widely in the treatment of Alzheimer disease, and rivastigmine, have also been tried in persons with intellectual disability (40). Reductions in cognitive and adaptive deterioration and a reduction in behavioral symptoms were reported in a trial of donepezil in adults with Down syndrome with early dementia, but problems with adverse effects were seen (61). It has also been used in those without dementia, with improvements seen in language function but not cognition or behavior (29; 35). Rivastigmine also resulted in improved language, attention, memory, and adaptive function in adolescents with Down syndrome (61).

With increasing understanding of genetic and cellular mechanisms of specific genetic syndromes associated with intellectual disability, targeted therapeutic options are being explored to treat underlying genetic defects. The best example would be clinical trials with gamma-aminobutyric acid (GABA) agonist and metabotropic glutamate receptor 5 (mGluR5)-specific antagonist for fragile X syndrome. Similar efforts are being made for tuberous sclerosis, Down syndrome, and Rett syndrome as well (59).

Persons with intellectual disability may present with challenging behaviors such as aggression, self-injury, stereotypy, and hyperactivity. Various medications have been useful for treating these behaviors (40; 55). The stimulant medications (described above) have been particularly useful in treatment of hyperactivity, impulsivity, and inattention. The atypical or second-generation antipsychotics have been efficacious in children with psychosis, bipolar disorder, conduct disorder, and severe ADHD (55). They include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Risperidone has specifically been shown to have short-term efficacy in the treatment of disruptive behaviors and aggression in children and adolescents with intellectual disability and those with autism spectrum disorders.

Other pharmacologic agents have also been used in very limited trials in managing the behavior problems seen in those with intellectual disability (55). The selective serotonin reuptake inhibitors and tricyclic antidepressants have been used for depression, repetitive behaviors, aggression, and self-injury. The alpha-adrenergic agonists clonidine and guanfacine have been used for hyperactivity and impulsivity in children with intellectual disability. Beta-adrenergic antagonists also have been used for aggression and self-injury. Mood stabilizers and lithium have been tried for management of the symptoms of mania.

A pharmacological approach to controlling unwanted behavior should always be performed in conjunction with behavior counseling programs, with regular monitoring by the physician.

Special considerations

Pregnancy

A cohort study of a group of pregnant women in South Western Sydney found an unusually high rate of preeclampsia in pregnant women with intellectual disability and/or self-reported learning difficulties and found that their children more often had low birth weights and that they were more frequently admitted to neonatal intensive care or special care nursery (45). Although the reasons for these findings were not clear, pregnant women with intellectual disabilities typically have multiple risk factors for adverse pregnancy and poor birth outcomes, including low literacy, low income, and poor health (45).

Certain disorders associated with intellectual disability are known to carry an increased risk of adverse pregnancy and birth outcomes. For instance, women with Down syndrome may be at high risk during pregnancy due to associated health conditions such as cardiac disease, thyroid disease, and epilepsy. Women with Down syndrome have been documented to deliver infants both with and without Down syndrome. Infants born to mothers with Down syndrome are at increased risk for prematurity and low birth weight, and those infants without Down syndrome have a greater than average number of congenital anomalies (79).

The children of women with phenylketonuria (PKU) are at risk for growth retardation, microcephaly, significant developmental delays, and birth defects if maternal phenylalanine levels are elevated during pregnancy. Women with PKU who have their blood phenylalanine concentration in good control before conception have an excellent chance for normal pregnancies and neonatal outcome; the best outcomes occur when strict control of maternal phenylalanine concentration is achieved before conception and continued throughout pregnancy (01). Guidelines exist regarding the optimal management of PKU in women of childbearing years and during pregnancy (57). Tuberous sclerosis in pregnancy may present with serious maternal and fetal complications that include acute intra-abdominal bleeding due to a ruptured renal tumor, renal failure, bleeding into a renal cyst, severe pre-eclampsia with pathologically enlarged kidneys, severe intrauterine growth retardation, premature rupture of the membranes, and preterm labor (58).

Anesthesia

Induction of anesthesia may be difficult in a person with intellectual disability who is frightened and combative in an unfamiliar and threatening environment. Agents that have been used with success include ketamine, which can be taken orally. This can be given with diazepam and glycopyrrolate to counteract some of the possible side effects of ketamine alone (50). The rate of postoperative complications in institutionalized persons with severe intellectual disability is far higher than in the general population. These include atelectasis and pneumonia, particularly following intra-abdominal operations. Possible reasons include an impaired ability to communicate, alterations in response to pain, failure to suspect an unusual diagnosis, pulmonary insufficiency, and a high incidence of gastroesophageal reflux.

Particular precautions are required for those with certain types of neuromuscular disorders and intellectual handicaps. Hypersomnolence and alveolar hypoventilation are common features of myotonic dystrophy, and appear to be related to central nervous system dysfunction, as well as respiratory muscle weakness and poor diaphragmatic relaxation. Even mildly affected cases are susceptible to the anesthetic risks imposed by hypoventilation. There is an association between nonprogressive intellectual handicap and dystrophinopathy. About 20% of boys with Duchenne muscular dystrophy have intellectual disability. Along with the difficulties arising from generalized muscle weakness, there is also a significant risk of malignant hyperthermia.