1. Intellectual Disability
Jess P. Shatkin, MD, MPH
Vice Chair for Education
NYU Child Study Center
New York University School of Medicine

2. What’s in a Name? Idiot Moron Feeble Minded Mentally Retarded
Intellectual Disability
AAMR
American Assn on Intellectual and Developmental Disabilities (AAIDD)

3. Learning Objectives Participants will be able to:
Define 4 levels of severity of mental retardation.
Identify the primary comorbid Axis I disorders.
Describe 6 risk factors for mental retardation.
Identify the 3 most common causes of mental retardation.
Define behavioral phenotypes for 5 “common” mental retardation syndromes.

4. Definition Deficits in IQ and adaptive functioning IQ of 70 or below
Measured by standard scales
Wechsler, Stanford-Binet, Kaufman
Impairments in Adaptive Functioning
Effective coping with common life demands
Ability to meet standards of independence
Vineland, AAMR Adaptive Behavior Scale

5. Degrees of Severity Mild Mental Retardation
IQ: to approximately 70
Moderate Mental Retardation
IQ: to 50-55
Severe Mental Retardation
IQ: to 35-40
Profound Mental Retardation
IQ: Less than 20-25

6. AAIDD Proposed Classification
Based upon the intensity of supports needed, as opposed to IQ (the traditional system):
Intermittent Support
Limited Support
Extensive Support
Pervasive Support

7. Mild Mental Retardation
Previously referred to as “educable”
Largest segment of those with MR (85%)
Typically develop social/communication skills during preschool years, minimal impairment in sensorimotor areas, often indistinguishable from “typicals” until later age
By late teens acquire skills up to approximately the 6th grade level

8. Moderate Mental Retardation
Previously referred to as “trainable”
About 10% of those with MR
Most acquire communication skills during early childhood years
Generally benefit from social/vocational training and with moderate supervision can attend to personal care
Difficulties recognizing social conventions which interferes with peer relations in adolescence
Unlikely to progress beyond the 2nd grade academically
Often adapt well to life in the community in supervised settings (performing unskilled or semiskilled work)

9. Severe Mental Retardation
3 – 4% of those with MR
Acquire little or no communicative speech in childhood; may learn to talk by school age and be trained in elementary self-care skills
Can master sight reading “survival” words
Able to perform simple tasks as adults in closely supervised settings
Most adapt well to life in the community, living in group homes or with families

10. Profound Mental Retardation
1 – 2% of those with MR
Most have an identifiable neurological condition that accounts for their MR
Considerable impairments in sensorimotor functioning
Optimal development may occur in a highly structured environment with constant aid

11. Prevalence 1% (1 – 3% in developed countries)
The prevalence of MR due to biological factors is similar among children of all SES; however, certain etiological factors are linked to lower SES (e.g., lead poisoning & premature birth)
More common among males (1.5:1)
In cases without a specifically identified biological cause, the MR is usually milder; and individuals from lower SES are over-represented

12. Psychiatric Features No specific personality type
Lack of communication skills may predispose to disruptive/aggressive behaviors
Prevalence of comorbid Axis I disorders is 3-4 times that of the general population
The nature of Axis I disorders does not appear to be different between “typicals” and those w/MR
Patients with MR and comorbid Axis I disorders respond to medications much the same as those without MR

13. Most Commonly Associated Axis I Disorders
ADHD
Mood Disorders
Pervasive Developmental Disorders
Stereotypic Movement Disorders
Mental Disorders due to a GMC

14. Predisposing Factors
No clear etiology can be found in about 75% of those with Mild MR and 30 – 40% of those with severe impairment
Specific etiologies are most often found in those with Severe and Profound MR
No familial pattern (although certain illnesses resulting in MR may be heritable)

15. Predisposing Factors (2)
Heredity (5% of cases)
Autosomal recessive inborn errors of metabolism (e.g., Tay-Sachs, PKU)
Single-gene abnormalities with Mendelian inheritance and variable expression (e.g., tuberous sclerosis)
Chromosomal aberrations (e.g., Fragile X)
Early Alterations of Embryonic Development (30% of cases)
Chromosomal changes (e.g., Downs)
Prenatal damage due to toxins (e.g., maternal EtOH consumption, infections)

16. Predisposing Factors (3)
Environmental Influences (15-20% of cases)
Deprivation of nurturance, social/linguistic and other stimulation
Mental Disorders
Autism & other PDDs
Pregnancy & Perinatal Problems (10% of cases)
Fetal malnutrition, prematurity, hypoxia, viral and other infections, trauma
General Medical Conditions Acquired in Infancy or Childhood (5% of cases)
Infections, trauma, poisoning (e.g., lead)

17. Disability Low birth weight is the strongest predictor of disability
Male children and those born to black women and older women in the USA are at increased risk for ID
Lower level of maternal education is also independently associated with degree of disability

18. Etiology At least 500 causes now known
Over 150 MR syndromes have been related to the X-chromosome
Most common cause of MR:
Down’s Syndrome (most common genetic cause)
Fragile X Syndrome (accounts for 40% of all X-linked syndromes; most common inherited cause)
Fetal EtOH Syndrome (most common attributable cause)
together these 3 account for 30% of all identified cases of MR

19. Down’s Syndrome
Most common chromosomal abnormality leading to MR (1.2/1000 births)
Nondysjunction of chromosome 21
Relative strengths:
Visual (vs. auditory processing)
Social functioning
Relative weaknesses:
Language expression and pronunciation
Generally viewed to suffer less severe psychopathology than other developmentally delayed groups
After 40 years of age, affected individuals nearly always demonstrate postmortem neuronal defects indistinguishable from Alzheimer’s Disease

20. Behavior & Psychiatric Illness in Downs
Recent population based survey of social and healthcare records found:
Females had better cognitive abilities and speech production compared with males
Males had more behavioral troubles
ADHD symptoms were often seen in childhood across gender
Depression was diagnosed more often in adults with mild/moderate intellectual impairment
Autistic behavior was most common in those with profound intellectual disability
Elderly often showed a decline in adaptive behavior consistent with Alzheimer’s
Maatta et al, 2006

21. Down’s Syndrome

22. Fragile X Syndrome
FMR-1 gene (>200 trinucleotide CGG repeats, Xq27.3)
An example of a “dynamic mutation” where more mutations occur with successive generations
General problems: MR, mild CT dysplasia, & macro-orchidism
Only 50% of females with the full mutation demonstrate IQs in the borderline/mild MR range (vs. 100% of males)
Increases the risk for ADHD, autism (20-60%) & social phobia
Increasing deficits in adaptive and cognitive functioning with age
Relative strengths:
Verbal long-term memory
Relative weaknesses:
ST memory, VM integration, sequential processing, math & attn

23. Fragile X Syndrome

24. Fragile X Syndrome

25. Fetal EtOH Syndrome Incidence > 1:1000
Irritable as infants, hyperactive as children (ADHD)
Teratogen amount: 2 drinks/day (smaller birth size), 4-6 drinks/day (subtle clinical features), 8-10 drinks/day (full syndrome)
General problems: prenatal onset of growth deficiency, microcephaly, short palpebral fissures
Syndrome can include:
Facial deformities (ptosis of eyelid, microphthalmia, cleft lip [+/- palate], micrognathia, flattened nasal bridge and filtrum, & protruding ears)
CNS deformities (meningomyelocele, hydrocephalus)
Neck deformities (mild webbing, cervical vertebral & rib abmormalities)
Cardiac deformities (tetralogy of Fallot, coarctation of aorta)
Other abnormalities (hypoplastic labia majora, strawberry hemangiomata)

26. Fetal EtOH Syndrome

27. Prader-Willi Syndrome
Deletion in chromosome 15 (15q11-13); freq 1:15000
60-80% w/microscopic deletion on paternal 15; remaining PWS have 2 copies of maternal chromosome w/no paternal chromosome (“uniparental disomy”)
Infantile hypotonia, hyperphagia/food seeking, morbid obesity, small hands/feet, mild to moderate MR
Relative stability in adaptive functioning during adolescence and early adulthood
Relative strengths:
Expressive vocabulary, LT memory, visual/spatial integration and visual memory (unusual interest in jigsaw puzzles)
Relative weaknesses:
Temper tantrums, emotional lability, mood symptoms (dx?), anxiety, skin picking, OCD symptoms (>50% OCD)

28. Prader-Willi Syndrome

29. Prader-Willi Syndrome

30. Angelman Syndrome
Severe MR, seizures, ataxia & jerky arm movements (puppet-like gait), absence of speech, and bouts of laughter (aka “happy puppet”)
Deletion in chromosome 15 (15q11-13)
In contrast to PWS, all identified cases of deletion traced to maternal chromosome 15
Illustrating “genomic imprinting,” (the fact that the parent of origin of the deletion at the same locus impacts the phenotype; that is, deletion of paternal 15q11-13 results in Prader-Willi but deletion of maternal 15q11-13 results in Angelman.)

31. Angelman Syndrome

32. Williams Syndrome
MR, supravalvular aortic stenosis, “elfin-like” facies, infantile hypercalcemia, and growth deficiency
Deletion of elastin gene (7q11.23)
Relative strengths:
Remarkable facility for recognizing facial features
Loquacious, pseudo-mature “cocktail party speech”
Relative weaknesses:
Increased risk for ADHD, Anxiety D/O

33. Williams Syndrome

34. Psychotropic Medications
No medications identified to treat MR nor to address specific symptoms
No medications are FDA approved
Rates of medication use vary from 12 – 40% in institutions vs. 19 – 29% in community settings amongst current studies (excl anticonvulsants)
Singh et al, 1997
More recent review found that 22.8% of MR persons in group homes in the Netherlands were prescribed psychotropic medications
Stolker et al, 2002

35. Stimulants
ADHD is the most widely diagnosed psychiatric disorder amongst children and adolescents with MR
Prevalence rates estimated to be 8.7 – 16% (Emerson, 2003; Stromme & Diseth, 2000)
At least 20 RDBPC trials published involving MTP with persons with MR; positive results range from 45 – 66%; lower than the rates found with non-MR population
Positive predictors of response include IQ>50 and higher baseline scores on parent/teacher ratings of inattention and activity level
Limited data on other treatments for ADHD symptoms
Handen et al, 2006

36. Antidepressants: Sertraline/Zoloft ®
No DBPC studies w/Sertraline in patients w/MR
One open label study of children with PDD noted improvements in anxiety and agitation (Steingard et al, 1997)
Luiselli et al (2001) noted a case of one adult w/severe MR who showed improvement in SIB with Sertraline
In the adult MR/PDD population, Sertraline has been found to result in clinically significant improvement of SIB and aggression (Hellings et al, 1996; McDougle et al, 1998)

37. Antidepressants: Fluoxetine/Prozac®
Among 15 published case reports and 4 prospective open label trials involving children and adults with MR and/or PDD, decreases in SIB, irritability, or depressive symptoms were noted (with the exception of two studies) for the majority of subjects treated with fluoxetine (Aman et al, 1999)
Among the negative studies, some individuals discontinued fluoxetine due to increased aggression, agitation, and hypomanic behavior
One open label study of fluoxetine in 128 children with MR/PDD, 3-8 y/o, reported an excellent response in 17%, a good response in 52%, and a fair/poor response in 31% (DeLong et al, 2002)

38. Antidepressants: Fluvoxamine/Luvox®
One open label study of 60 adults w/MR ( mg/d) reported a significant reduction in ratings of aggression after 3 weeks of treatment (La Malfa et al, 2001)
McDougle et al (1996) conducted a DBPC study of fluvoxamine in 30 adults w/PDD and found significantly reducted aggression and repetitive thoughts/behavior
McDougle (1998) also reported significant side effects and minimal clinical improvement in a DBPC study of children with PDD and symptoms of ritualistic and repetitive movements
Fukuda et al (2001) conducted a DBPC trial in 18 children w/PDD where clinical global ratings improved for half of the subjects and significant gains were noted in eye contact and language use

39. Antidepressants: Paroextine/Paxil®
Davanzo et al (1998) demonstrated reductions in aggression (but not SIB) in 15 adults with MR in an open label study, but effects did not last beyond a one month period
A retrospective chart review of 12 adults with MR found only 1/3 of subjects were “minimally” or “much” improved in domains of aggression, property destruction, or SIB (Branford et al, 1998)
Masi et al (1997) treated 7 adolescents with MR and MDD; after 9 weeks of treatment, 4 subjects no longer met DSM-IV criteria for MDD

40. Antidepressants: Citalopram/Celexa®
Verhoeven et al (2001) found citalopram effective in an open label trial of 20 adults with MR and MDD, demonstrating a moderate to marked improvement in 12 of 20 patients on CGI after 6 months

41. Antipsychotics in the Treatment of MR
The typical antipsychotics have long been prescribed for disorders other than psychosis in patients with MR, including aggression, hyperactivity, antisocial behavior, sterotypies, and SIB
The atypical antipsychotics are now being increasingly used b/c of the belief that they carry a decreased side effect profile

42. Antipsychotic: Clozapine/Clozaril®
Found effective in treating resistant psychosis in adults with MR (Antochi et al, 2003)

43. Antipsychotic: Risperidone/Risperdal®
Efficacious in both children and adults with MR in controlling hyperactivity, irritability, aggressive behavior, SIB, and repetitive behaviors (Aman & Madrid, 1999; Hellings, 1999; Turgay et al, 2002; Van Bellinghen & DeTroch, 2001)
A DBPC trial in 118 children w/MR, 5-12 y/o, found 53.8% were responders vs. 7.9% w/placebo (Aman et al, 2002)
Similarly, McCracken et al (2002) reported a 69% response rate (vs. 12% w/placebo) among 101 children w/PDD, most of whom had comorbid MR

44. Antipsychotic: Olanzapine/Zyprexa®
McDonough et al’s (2000) open label study of 7 adults w/MR documented improvement in SIB in 57% of subjects and worsening effects in 14%
Similarly, a chart review of 20 adults w/MR found significant decreases in global challening behaviors and specific target behaviors, such as aggression, SIB, and destructive behaviors (Barnhill & Davis, 2003)
Handen & Hardan (2006) conducted a prospective open label trial in 16 adolescents w/MR and found 12 of 15 experienced a 50% or greater decrease on behavior ratings assessing irritability
Robust clinical effects noted in Friedlander et al’s chart review of adolescents and young adults w/MR (2001)

45. Antipsychotic: Quetiapine/Seroquel®
Hardan et al (2005) reported efficacy in the treatment of hyperactivity, inattention, and conduct problems in 10 children and adolescents w/MR
Martin et al (1999) found quetiapine poorly tolerated in a study of boys with autism

46. Antipsychotic: Ziprasidone/Geodone®
A case series of children and adolescents w/PDD reported decreased aggression and irritability (McDougle et al, 2002)
Cohen et al (2003) switched 40 adults w/MR to ziprasidone from other antipsychotics and noted an improved side effect profile w/either no change or improvement in maladaptive behavior in 72% of subjects

47. Antipsychotic: Aripiprazole/Abilify®
Stigler et al (2004) found aripiprazole beneficial in treating aggression, agitation, and SIB in five children w/PDD
Staller (2003) reported decreased irritability, anxiety, and preoccupations in an adult w/Asperger’s D/O

48. Alpha-2 Agonists: Guanfacine/Tenex® & Clonidine/Catapres®
Frankhauser et al (1992) demonstrated the efficacy of clonidine in the treatment of hyperactivity in children w/PDD
Posey et al (2004) conducted a chart review of 80 children w/PDD who had been treated with guanfacine; 24% of the sample evidenced decreased hyperactivity, inattention, and tics