Intellectual Disability

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Practice Essentials

Intellectual disability (ID), is a descriptive term for subaverage intelligence and impaired adaptive functioning arising in the developmental period (< 18 years).

Signs and symptoms

Patients with ID and developmental delays may demonstrate the following:

Evaluation of patients for ID can include the following examinations:

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

Imaging studies

Additional tests

Detailed assessment by a licensed professional is necessary to confirm the diagnosis of ID. Some of the most commonly used tests in children include the following:

See Workup for more detail.

Management

The mainstay of ID treatment is the development of a comprehensive management plan for the condition. The complex habilitation plan for the individual requires input from care providers from multiple disciplines, including special educators, language therapists, behavioral therapists, occupational therapists, and community services that provide social support and respite care for families affected by ID.

Neuropathic pain due to dysautonomia or motor spasms may create chronic disturbances. Treatment should be prompt and include the following:

No specific pharmacologic treatment is available for cognitive impairment in the developing child or adult with ID.[6] Medications, when prescribed, are targeted to specific comorbid psychiatric disease or behavioral disturbances.

The psychostimulant class of drugs is commonly prescribed in individuals with ID, because of the diagnosis of attention deficit with or without hyperactivity disorder (ADHD/ADD) in 6-80% of these patients. However, few studies on stimulants in people with MR/ID are available. The studies that do exist indicate that benefits vary, and significant adverse events, such as severe social withdrawal, increased crying, drowsiness, and irritability, have been noted, especially at higher doses of methylphenidate (0.6 mg/kg).[7]

The neuroleptic drugs are the most frequently prescribed agents for targeting behaviors such as aggression, self-injury, and hyperactivity in people with MR/ID. These indications are generally off-label for ID and caution is advised.

See Treatment and Medication for more detail.

Background

Intellectual disability (ID) is a descriptive term for subaverage intelligence and impaired adaptive functioning arising in the developmental period (< 18 y). ID and other neurodevelopmental disabilities are seen often in a general pediatric practice.

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5), characterizes ID by deficits in general mental abilities, such as reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience. The deficits result in impairments to adaptive functioning, such that the individual fails to meet standards of personal independence and social responsibility in one or more aspects of daily life, including communication, social participation, academic or occupational functioning and personal independence at home or in community settings.[8]

Approximately 10% of children have some learning impairment, while as many as 3% manifest some degree of ID. The population prevalence of these combined disorders of learning rivals that of the common childhood disorder asthma.

ID originates during the developmental period (i.e., conception through age 18 years). ID is categorized as a neurodevelopmental disorder and is distinct from the neurocognitive disorders, which are characterized by a loss in cognitive functioning. Major neurocognitive disorder may occur with ID such as when an individual with Down syndrome develops Alzheimer's disease, for example. In a case like this, both ID and neurocognitive disorder would be diagnosed.

ID also can be categorized as syndromic, if associated with dysmorphic features, or nonsyndromic, if not associated with dysmorphisms or malformations. The understanding of specific ID syndromes is expanding with recent molecular genetic advances. More than 800 recognized syndromes listed in the Online Mendelian Inheritance in Man (OMIM) database are associated with ID, reflecting clinical diagnostic advances in the field. The most common associated chromosomal abnormality is trisomy 21, or Down syndrome. The most common X-linked abnormality associated with MR/ID is fragile X syndrome. However, for most cases of MR/ID, no specific genetic abnormalities are found.

Some forms of MR/ID are due to nongenetic factors and may be identifiable by their associated dysmorphisms and clinical presentation. Examples include prenatal exposure to teratogens (e.g., anticonvulsants, warfarin, alcohol) or prenatal thyroid dysfunction. Prenatal and postnatal exposure to lead and the associated decrement in IQ may increase an individual's chance of functioning in the MR/ID range. ID may result from an acquired infection or injury during the developmental period from, for example, a severe head injury or meningitis or encephalitis infection

Diagnostic criteria (DSM-5)

Intellectual disability (intellectual developmental disorder) is a disorder with onset during the developmental period that includes both intellectual and adaptive functioning deficits in conceptual, social and practical domains. According to the DSM-5, the following three criteria must be met[8] :

Severity is specified as mild, moderate, severe, or profound based on the level of impairment in adaptive functioning, and not IQ scores, because it is adaptive functioning that determines the level of support required. The three domains of adaptive functioning are conceptual, social, and practical.

In addition to severity, the specifier “associated with a known medical or genetic condition or environmental factor” may be given. Examples include genetic disorders, such as fragile X syndrome, tuberous sclerosis, and Rett syndrome; and environmental factors including fetal alcohol exposure (even in the absence of fetal alcohol syndrome).

Pathophysiology

MR/ID is the end result of many disorders of CNS function. Most individuals with significant intellectual impairment have no discernible structural abnormalities of the brain. CNS malformations, a visual correlate of the disorders, are diagnosed in 10-15% of cases; dysfunction is localized primarily to the cortical structures, including the hippocampus and the medial temporal cortex. The most common malformations consist of neural tube defects, hydranencephaly, and microcephaly. Less commonly, CNS malformations include disorders of migration (the lissencephalies) and agenesis of the corpus callosum.

Multiple congenital anomaly syndromes with malformations confined to nonneurologic organ systems may be present in 5% of all patients with MR/ID. Between 3% and 7% of cases may be associated with a wide array of inborn errors of metabolism complicated by multiorgan system disease. Alcohol exposure in utero may account for as many as 8% of those with mild MR/ID.

Most individuals with mild MR/ID and other learning disorders do not have other neurologic complications, CNS malformations, or dysmorphisms. They are more likely, however, to be born into families of low socioeconomic status, low IQ, and little education. The etiologic contribution of poverty to their poor cognitive function remains unclear. Clearly, however, poor cognitive functioning and MR are correlated positively with a life of poverty.

Frequency

United States

The frequency of MR/ID of all degrees ranges from 1-3% of the population. ID has an overall general population prevalence of approximately 1% and prevalence rates vary by age. Prevalence for severe intellectual disability is approximately 6 per 1,000.[8]

International

A study with excellent ascertainment conducted in Aberdeen, Scotland, yielded a prevalence of 1 in 300 for severe MR and 1 in 77 for mild MR. Among those with severe MR were more boys than girls (male-to-female ratio 1.2:1), and among those with IQ >70, in the mild range of deficiency, boys exceeded girls by a ratio of 2.2:1.[9]

Although prevalence rates vary from country to country, the variance in prevalence may be attributed to ascertainment bias, the standardization methods employed from study to study, and a generalized upward drift in IQ scores over time. Even so, the greatest variance in statistics of prevalence is most likely to fall within the category of mild MR, a group for which the ascertainment bias is large.

Race-, sex-, and age-related differences in incidence

Consistent racial differences in prevalence of MR/ID and associated mortality rates are not known to exist.

The gender ratios for mortality and morbidity do not differ from the gender ratio noted in the severe/profound ranges of intellectual disability (ie, male-to-female ratio, 1.2:1).

MR/ID refers to intellectual impairment that develops prior to the age of 18 years.

Certain syndromes associated with MR/ID, such as Down syndrome, are associated with shorter life expectancy than the general population. In a comparison of those with MR/ID with and without Down syndrome from the California Department of Developmental Services cohort, excess mortality in the Down syndrome group tended to decrease with advancing age up to 35-39 years but increased thereafter. The increase in death rate from age 40 years was steeper in patients with Down syndrome than in those without Down syndrome.[10]

Mortality/Morbidity

MR/ID itself is not necessarily associated with an increased premature death rate. However, individuals with severe to profound MR/ID experience a decreased life expectancy related to the underlying etiology or additional complicating neurologic disorders, such as epilepsy. Neurologic dysfunction resulting in immobility, significant oral motor incoordination, dysphagia, and aspiration confers a greater risk of premature death than MR/ID itself. When significant neurologic dysfunction is associated with other organ system anomalies, an individual's life expectancy is shortened further.

Respiratory disease is the most prevalent cause of death among individuals with profound MR/ID. In particular, respiratory infections were the leading cause of death among a Finnish cohort of children with MR/ID.[11] For those affected by mild MR/ID, life expectancy does not differ from that of the general population.

Comorbid psychiatric conditions are diagnosed more frequently in those with intellectual disabilities than in the general population. Even so, psychiatric disorders probably are underappreciated in this population.

History

Presenting signs/symptoms

The presenting symptoms and signs of MR/ID typically include cognitive skills delays, language delay, and delays in adaptive skills. Developmental delays vary depending on the level of MR/ID and the etiology. For example, in mild nonsyndromic MR/ID, delays may not be notable until the preschool years, whereas with severe or profound MR associated with syndromes or extreme prematurity, for example, significant delays in milestones may be noted from birth.

Diagnoses of MR/ID and autism frequently overlap. Approximately 50-75% of those with autism (autistic disorder) also have MR/ID.[13] Some literature has suggested diagnostic shifts from MR to autism for unknown reasons.[14]

Family history

Guidelines from the American Academy of Pediatrics recommend that the evaluation of a child with MR/ID includes an extensive family history, with particular attention to family members with MR, developmental delays, consanguinity, psychiatric diagnoses, congenital malformations, miscarriages, stillbirths, and early childhood deaths. The clinician should construct a pedigree of 3 generations or more.[15]

Physical

Developmental assessment

See the list below:

Physical examination

See the list below:

Causes

Prenatal conditions (genetic)

Trisomy 21 or Down syndrome

Fragile X syndrome

See the list below:

Contiguous gene deletion syndromes

Although less common, some of these syndromes can be readily identified clinically. The following syndromes often can be confirmed by utilizing a fluorescence in situ hybridization (FISH) probe to the deleted region in question.

Prader-Willi syndrome

Angelman syndrome

Smith-Magenis syndrome

CATCH 22 syndrome

Williams syndrome

Wolf-Hirschhorn syndrome

Langer-Giedion syndrome

Miller-Dieker syndrome

Single gene mutation syndromes

Tuberous sclerosis

Rubinstein-Taybi syndrome

Coffin-Lowry syndrome

Rett syndrome

Smith-Lemli-Opitz syndrome

Costello syndrome

Many other single-gene disorders are associated with MR with additional phenotypic and behavioral features including such problems as microcephaly, seizures, or short stature, with or without dysmorphic facies.

Recent advances in genetic linkage analysis techniques in families with multiple affected members have revealed more than 50 candidate genes along the X chromosome. In some kindreds with a pattern of X-linked nonsyndromic mild MR (XLMR), linkage analysis has identified candidate genes that code for interleukin receptors, G protein signaling factors, transcription factors, and transcriptional repressors.

Environmental causes

Fetal alcohol syndrome and fetal alcohol effect

Alcohol results in a wide range of teratogenic effects.[25] The most severely affected individuals meet criteria for fetal alcohol syndrome (FAS) by demonstrating short palpebral fissures, dental crowding, camptodactyly flattened philtrum, thin vermillion border, flattening of the maxillary area, microphthalmia, prenatal and postnatal growth deficiency, microcephaly, and developmental delay.

Fetal alcohol effect (FAE) can be diagnosed only in the context of (1) maternal history of alcohol use and (2) a child with developmental and behavioral abnormalities that also manifests growth deficiency or the characteristic facial dysmorphisms.

The prevalence of FAS may be as high as 1.9 in 1000 live births and is the leading cause of MR in the western world. The impact of the milder FAE remains unknown. The teratogenic effects of alcohol may be responsible for as many as 8% of cases of mild MR. Alcohol's deleterious effects on cortical plasticity contribute to cognitive impairment.

Congenital hypothyroidism

Congenital hypothyroidism (known as cretinism in the past) is a neurologic syndrome that results from severe thyroid hormone deficiency during the fetal period. In the infant, the syndrome comprises deaf mutism, moderate to severe MR, spasticity, and strabismus.

Normal fetal brain development requires sufficient production of both maternal and fetal thyroid hormones. Normal glandular production of T4 and T3 requires sufficient dietary intake of iodine.

Iodine deficiency may affect an estimated 800 million people worldwide. It can result in endemic goiter, fetal wastage, milder degrees of developmental delay, and endemic congenital hypothyroidism.

Perinatal/postnatal conditions: These conditions are responsible for fewer than 10% of all MR cases.

Congenital cytomegalovirus (CMV)

Congenital rubella - No longer an important etiology in countries with high vaccination rates

Intraventricular hemorrhage related to extreme prematurity - An important cause only in societies with advanced neonatal care and survival of the premature

Hypoxic-ischemic encephalopathy - Always results in combined CP/MR

Traumatic brain injury - Shaken baby syndrome, closed head injury sustained in motor vehicle accidents

Meningitis - Decreasing in importance as the incidence of Haemophilus influenzae type B decreases in vaccinated populations

Trichomoniasis during pregnancy[26]

Neurodegenerative disorders

Laboratory Studies

The examiner must determine the nature and extent of the laboratory investigation following a history and physical examination. Recommendations have been made by both the American Academy of Pediatrics[27] and the American Academy of Neurology[5] .

Availability of genetic testing, and thus recommendations for work-up, are changing rapidly. Chromosomal microarray and new sequencing techniques have revolutionized genetic testing.[28]

Array-based comparative genetic hybridization (CGH) or "microarray" is increasingly used in the evaluation of MR/ID and should be considered in the work-up of all children with MR/ID either after or as first-line instead of high-resolution karyotype and fragile-X testing (see below). The yield may be as high as 20%; however, a high false-positive rate can also confound interpretation.[29, 30, 31, 28]

High-resolution karyotype (at the 650 band level of resolution at least) should be completed in all children with MR/ID.[27] Chromosomal abnormalities (trisomy 21 and others) may account for as many as 50% of those affected by severe to profound MR/ID.

Fragile X testing (ie, DNA analysis of the FraX promoter region) should be ordered in all children with MR/ID.[5] In the postpubertal period, the clinical manifestations of Fragile X syndrome are likely to be readily apparent, such that DNA analysis can be ordered with more selectivity in this population. Sex chromosome aneuploidy is seen in as many as 5% of children with mild MR/ID or learning disabilities.

FISH probes are ordered as clinically indicated, as follows:

Given their low yield, metabolic labs are not routinely ordered unless clinically indicated or newborn metabolic screen was not done or results are not available.[5]

Consider lead testing in children with risk factors.

Imaging Studies

See the list below:

Other Tests

Detailed assessment by a licensed professional is necessary to confirm the diagnosis of MR/ID. Some of the most commonly used tests in children include the following:

Electrophysiologic studies

Histologic Findings

Pathologic analysis of cortical tissue by the Golgi method in the 1970s suggested that in cases of profound, unclassified MR, dendritic spines were decreased and/or had immature morphology. These findings have been confirmed in cortical autopsy material from individuals with Down syndrome and FraX. Dendritic spine morphology is related directly to the intradendritic microtubular components and their organization.

Microtubules in dendrites of cortical neurons often are fragmented or in disarray in cases of developmental failure. In contrast, in some neuronal storage diseases associated with impaired cognition, dendritic spines are sprouted exuberantly beyond the developmental period and in ectopic locations. A relationship is implied, then, between dendritic spine morphology and number and cognitive development in the human.

Medical Care

See the list below:

Other concerns

See the list below:

Consultations

See the list below:

Diet

Nutritional supplements are of no proven benefit.

Activity

Because obesity is more prevalent in those with MR/ID, regular physical activity should be included in the management plan[35] . Adaptive exercise programs for those with concomitant physical disabilities should be recommended as needed.[32]

Medication Summary

No specific pharmacologic treatment is available for cognitive impairment in the developing child or adult with MR/ID.[6] Medications, when prescribed, are targeted to specific comorbid psychiatric disease or behavioral disturbances.

Development of nootropic drugs that may alter cognitive processes positively has been of interest to researchers. Medications currently prescribed for dementia, such as acetylcholinesterase inhibitors, are not accepted treatments for MR/ID, and clinical trials have not been conducted in children. Phosphodiesterase inhibitors enhance cortical plasticity in an animal model of fetal alcohol syndrome.

Although vitamin and mineral therapies have gained popularity, their efficacy has not been established in clinical trials. A randomized controlled study of antioxidants and/or folinic acid for 18 months in 156 infants with Down syndrome found no evidence to support the use of these supplements in this population.[36]

Methylphenidate hydrochloride (Ritalin, Metadate ER)

Clinical Context:  Stimulates cerebral cortex and subcortical structures.

Dextroamphetamine sulfate (Dexedrine) and racemic amphetamine (Adderall)

Clinical Context:  Increase amount of circulating dopamine and norepinephrine in cerebral cortex by blocking reuptake of norepinephrine or dopamine from synapse.

Class Summary

The most common class of drugs prescribed in this population is the psychostimulants because of the diagnosis of attention deficit with or without hyperactivity disorder (ADHD/ADD) in 6-80%. Few studies are available on stimulants in people with MR/ID and, in many studies, those with MR/ID have been specifically excluded. Available studies indicate that benefits vary and significant adverse events, such as severe social withdrawal, increased crying, drowsiness, and irritability have been noted, especially at higher doses of methylphenidate (0.6 mg/kg).[7]

Clonidine hydrochloride (Catapres)

Clinical Context:  Agonist at presynaptic alpha2-adrenergic receptors within brain stem. Clonidine reduces norepinephrine release at these sites, reducing sympathetic outflow and enhancing parasympathetic outflow. May reduce aggression by increasing release of GABA in frontal cortex and other brain regions.

Guanfacine (Tenex)

Clinical Context:  Presynaptic alpha2-adrenergic receptor agonist that stimulates alpha2-adrenergic receptors in brain stem, activating an inhibitory neuron, which in turn decreases vasomotor tone and heart rate. Similar reduction in potentially negative impact on academic performance and cognitive function.

Class Summary

These agents are used commonly to modulate hyperactivity, aggression, tics, and dyssomnias. None of these drugs has an FDA-approved indication for MR/ID.

Risperidone (Risperdal)

Clinical Context:  Atypical antipsychotic with fewer adverse neurologic effects and less propensity for extrapyramidal movements (eg, pseudoparkinsonism, akathisia, acute dystonias, tardive dyskinesia).

Aripiprazole (Abilify)

Clinical Context:  A newer atypical antipsychotic, aripiprazole is indicated in acute bipolar mania and schizophrenia.

Class Summary

The neuroleptic drugs are the most frequently prescribed agents for targeting behaviors such as aggression, self-injury, and hyperactivity in people with MR/ID. These indications are generally off-label for MR/ID and caution is advised. Increasingly, they are more likely to be reserved for the older child or adult in whom intensive behavioral intervention has failed. Likewise, the prevalence of comorbid psychiatric disorders in MR/ID increases with age. Neuroleptics interact with receptors for a variety of brain neurotransmitters, including dopamine, serotonin, acetylcholine, histamine, and norepinephrine. Their ability to antagonize dopamine receptors appears to correlate with the efficacy of these drugs and imparts their antipsychotic properties. Likewise, antidopaminergic activity evokes extrapyramidal symptoms. Rarely, neuroleptic malignant syndrome may occur.

Further Outpatient Care

See the list below:

Prognosis

Individuals with MR/ID fare better today than at any other recorded time in world history.

Patient Education

Family support and education around the issues of MR can be obtained from the following:

Author

Ari S Zeldin, MD, FAAP, FAAN, Staff Pediatric Neurologist, Naval Medical Center San Diego

Disclosure: Nothing to disclose.

Coauthor(s)

Alicia T F Bazzano, MD, PhD, MPH, Clinical Faculty, Division of Pediatric Emergency Medicine, Harbor/UCLA Medical Center; Chief Physician, Westside Regional Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kenneth J Mack, MD, PhD, Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Attending Neurologist, Children's National Medical Center

Disclosure: Have stock (managed by a financial services company) in healthcare companies including Allergan, Cellectar Biosciences, CVS Health, Danaher Corp, Johnson & Johnson.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Karen H Harum, MD to the development and writing of this article.

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