Developmental Disabilities

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Chapter 61 Developmental Disabilities

Cerebral Palsy

Clinical Features

Cerebral palsy (CP) is a disorder of the development of movement and posture that causes activity limitation; it is attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain (Bax et al., 2007; Rosenbaum et al., 2007). The motor disorders in CP are often accompanied by mental retardation (52%), epilepsy (45%), ophthalmological defects (e.g., vision impairment, motility problems, strabismus) (28%), hearing impairment (especially in those with very low birth weight, kernicterus, neonatal meningitis, or severe hypoxic-ischemic insults) (12%), and speech, oromotor impairments, and language disorders (38%) (Ashwal et al., 2004). Oral-motor problems including feeding difficulties, swallowing dysfunction, and drooling can affect nutrition and growth, oral health, respiration, and self-esteem (Ashwal et al., 2004). The disturbances of movement and posture include spasticity, hypotonia, ataxia, and dyskinesia. The likelihood and severity of the associated deficits generally parallel the severity of the motor impairment.

In birth cohorts from developed countries, the prevalence of CP is 1 to 2 per 100 live births and 100 in 1000 surviving infants less than 28 weeks gestational age (Paneth et al., 2006). This is comparable to figures from the ninth and most recent report from the western Swedish study on the prevalence and origin of CP in a population-based study of 88,371 live births occurring from 1995 to 1998 that reported a prevalence of 1.92 per 1000 live births. (Himmelmann et al., 2005). Gestational age-specific prevalence was 77 per 1000 for children born before 28 weeks. The prevalence of CP was 20% in those born at 24 to 26 weeks of gestation (Ancel et al., 2006), 40 per 1000 for children born at 28 to 31 weeks, 7 per 1000 for children born at 32 to 36 weeks, and 1.1 per 1000 for children born after 36 weeks. Spastic hemiplegic CP occurred in 38%, diplegic CP in 35%, quadriplegic CP in 6%, dyskinetic CP in 15%, and ataxic CP in 6%. For the first time in this series of long-term cohort studies, hemiplegia was the most common CP type, owing to the decline in preterm diplegia. There was also an increase in full-term dyskinetic CP compared with pre-1994 cohorts.

Studies of childhood cognitive and behavioral outcome in children with CP demonstrate an increased frequency of attention deficit hyperactivity disorder (ADHD) (20%) as well as other learning issues, particularly nonverbal learning disabilities (NVLDs), developmental coordination disorders (DCDs), and visuospatial problems. Those born at 23 to 25 weeks gestation have the highest frequency of CP and cognitive difficulties (Johnson et al., 2009; Vohr, 2010). During the 1990s, increased disability in very preterm infants was notable and probably due to increased survival rates (Wilson-Costello et al., 2005). However, since 2000, neurodevelopmental impairment has decreased. Improved outcomes reflect increased antenatal steroid use and cesarean section delivery, as well as decreases in sepsis, severe cerebral ultrasonographic abnormalities, and postnatal steroid use (Wilson-Costello et al., 2007). Preterm infants followed into adulthood show increased numbers of neurological signs in very preterm–born adults compared to term-born controls and are strongly associated with lower intelligence quotient (IQ) (Allin et al., 2006a). Furthermore, young adults who were born very preterm have different personality styles from their term-born peers; they are at an increased risk for psychiatric difficulties (Allin et al., 2006b). Even with these caveats, outcome has significantly improved over the past 2 decades.

Diagnosis and Etiology

A history of delayed motor milestones and the clinical examination are the basis for the diagnosis of CP. Both the Gross Motor Function Classification System (GMFCS), which defines five levels of motor function (Palisano et al., 1997), and a measure of upper-extremity function such as the ABILHAND-Kids or the Bimanual Fine Motor Function Classification are useful in diagnosing CP. The National Perinatal Collaborative Project, monitoring more than 50,000 pregnancies, documented that among the 200 children with CP, the most important predictors of CP were maternal intellectual impairment, birth weight less than 2000 g, a malformation of any organ system, and breech presentation or delivery (Croen et al., 2001). Commonly used indicators of perinatal hypoxia-ischemia such as abnormal fetal heart rate, presence of meconium, and low Apgar scores did not predict CP and were relatively common in healthy infants. Almost 95% of infants with 5-minute Apgar scores of 3 did not have CP. Even when the Apgar scores are low, the CP risk is minimal unless the infant continues to have neurological problems (e.g., lethargy, hypotonia, poor suck, seizures) in the newborn nursery. In addition to perinatal hypoxic ischemic encephalopathy, other documented causes of CP in the term infant include brain malformations, genetic and metabolic disorders, intrauterine (Nelson, 2009) and perinatal infection (congenital infections, maternal infection during pregnancy and labor, and neonatal meningitis), and stroke, generally resulting in hemiplegic CP (Nelson, 2007). Specific risk factors for stroke in both term and preterm infants includes history of infertility, oligohydramnios, preeclampsia, prolonged rupture of membranes, cord abnormality, chorioamnionitis, and primiparity. Twin gestation is an independent risk factor for CP in both preterm and term infants, as is a vanishing twin in the survivor (Blickstein, 2002; Bonellie et al., 2005). Among preterm infants, risk factors for CP (Hagberg et al., 2009) include long-term ritodrine tocolysis, severe respiratory distress syndrome, low umbilical cord pH (Malin et al., 2010), postnatal steroid therapy (per contra Kent et al., 2005), patent ductus arteriosus requiring surgical ligation, peri-intraventricular hemorrhage, moderate to severe ventricular dilatation, periventricular leukomalacia (PVL), and need for home oxygen (Locatelli et al., 2010; Takahashi et al., 2005; Tran et al., 2005; Vohr, 2010). In the Swedish cohort study (Himmelman et al., 2005), the origin of CP in children born at term was considered to be prenatal in 38%, peri/neonatal in 35%, and unclassifiable in 27%. Among preterm-born children, the etiology was prenatal 17%, peri/neonatal 49%, and unclassifiable 33%.

Metabolic or genetic causes for CP occur infrequently (i.e., 0%-4%). In almost all such cases, there are atypical complaints such as features in the history of a progressive rather than a static encephalopathy, findings on neuroimaging representative of certain genetic or metabolic disorders, or a family history of childhood neurological disorder with associated “CP”. Metabolic and genetic studies are not routine in the evaluation of the child with CP. Consider metabolic and genetic testing when atypical features exist in the history or clinical examination. Evaluating CSF may be appropriate in children with dyskinetic CP of unknown etiology. Detection of a brain malformation in a child with CP warrants consideration of an underlying genetic or metabolic etiology. Of all CP types, the ataxic form most often has a genetic basis. Dopamine-responsive dystonia may mimic CP and is easily diagnosed and treated when suspected (Chaila et al., 2006). Other genetic or metabolic disorders that may mimic CP include: urea cycle disorders, sialidosis type 1, Sjögren-Larsson disease (fatty aldehyde dehydrogenase deficiency), metachromatic leukodystrophy, Krabbe disease (spastic CP), Lesch-Nyhan syndrome, glutaric aciduria 1 (dyskinetic CP), ataxia telangiectasia, Leigh syndrome and other mitochondrial disorders, and subacute sclerosing panencephalitis (ataxic CP) (García-Cazorla et al., 2009).

Brain imaging is useful in determining the cause and prognosis of CP (Krägeloh-Mann, 2007). Neonatal imaging predicts the localization and extent of PVL as well as the neurological outcome and extent of CP in later childhood (Ancel et al., 2006; Sie et al., 2005). Very low-birth-weight premature infants with either echolucency in the periventricular cerebrum or moderate to severe ventricular enlargement have a greater than 50% risk of developing CP. (Hintz and O’Shea, 2008). However, one-third of infants with CP have no ultrasound abnormalities (Ancel et al., 2006). Ultrasound abnormalities are present in preterms that develop disabling CP but not in preterms (usually male) who ultimately develop mild CP (Paneth, 2001). This suggests a different etiology for CP in these two groups. Hypothyroidism of prematurity is associated with twice the risk of echolucencies on ultrasound, and this group is at increased risk for CP (Leviton et al., 1999).

Based on available data, proposed practice parameters for the evaluation of children with CP include neuroimaging if an etiology is not already established. In a study of 273 children over 35 weeks gestation who underwent neuroimaging, one-third had normal scans; focal infarction was observed in 22% of the children with CP and 45% of those with hemiplegia, with the next most common finding being brain malformation (e.g., hydrocephalus, polymicrogyria, cerebellar abnormalities); 12% of the children had PVL and 5% a history of hypoxia-ischemia (Wu et al., 2006). Magnetic resonance imaging (MRI) demonstrates that brain malformations are relatively common in term infants with CP (10%). PVL is the most common finding in preterm infants with CP (Barkovich, 2006). Oxidative stress and excitotoxicity resulting from excessive stimulation of ionotropic glutamate receptors on immature oligodendrocytes are the most prominent molecular mechanisms for PVL (Fatemi et al., 2009). PVL in term-born children is often associated with neonatal resuscitation and respiratory distress (Tang-Wai et al., 2006), and the degree of disability is generally greater than in the preterm (Krageloh-Mann et al., 1999). Multiple cerebral infarctions are associated with perinatal hypoxic-ischemic encephalopathy, whereas most unilateral infarctions are prenatal in origin (Nelson, 2007; Nelson and Chang, 2008; Volpe, 2009) and warrant evaluation for an underlying coagulopathy (Ashwal et al., 2004). Severe injury to the cerebellum occurs as a complication of extreme prematurity. The clinical features include striking motor impairment and variable degrees of ataxia and athetosis or dystonia, which represent a distinct clinical type of CP. Most children are severely impaired with cognitive, language, and motor delays, and microcephaly is the rule (Bodensteiner et al., 2005). Larger corpus callosum size has been associated with better motor performance in preterms (Rademaker et al., 2004). Outcome studies of children and adolescents born preterm suggest a correlation between the presence of MRI abnormalities, CP, and greater cognitive difficulties (Mirmiran et al., 2004; Woodward et al., 2006). Reduced cortical and cerebellar volumes may result from enhanced apoptosis or excitotoxic damage to highly susceptible immature neurons (Bhutta and Anand, 2001). Experimental models of hypoxic-ischemic encephalopathy indicate that neurons in the neonatal brain are more likely to die by delayed apoptosis extending over days to weeks than those in the adult brain. Neurons die by glutamate-mediated excitotoxicity involving downstream caspase-dependent and caspase-independent cell death pathways (Fatemi et al., 2009).

Prevention and Management

Prevention of CP has focused on prevention of prematurity, optimal treatment during the perinatal period, and the development of neuroprotective agents (Nelson and Chang, 2008). Magnesium sulfate may prevent CP in the very low-birth-weight preterm infant by altering oxygen free radicals, excitatory amino acids, and even cytokines (American College of Obstetricians and Gynecologists Committee on Obstetric Practice, 2010). Indomethacin may prevent intraventricular hemorrhage. Treating transitory hypothyroidism in the preterm may improve outcome, although those preterms with transient hypothyroidism do less well than those who are euthyroid (van Wassenaer et al., 2005). The effectiveness of inhaled nitric oxide is debated, with some studies showing efficacy and others not (Mestan et al., 2005; Nelson and Chang, 2008). A recent study (Takahashi et al., 2005) suggested that long-term ritodrine tocolysis, prolonged hypocarbia, and postnatal steroid therapy (per contra Kent et al., 2005) are associated with an increased risk for CP in the preterm infant, raising the possibility of the need for further changes in pre- and perinatal care. Infections during pregnancy, as well as chorioamnionitis at delivery, are risk factors for CP (Nelson, 2009); the resultant elevated cytokines are the presumed brain toxic agent (Gilstrap and Ramin, 2000; Girard et al., 2009). Improved management aimed at diminishing cytokine production may eventually prevent some cases of CP (Dammann and Leviton, 2004; Girard et al., 2009). The mode of delivery of early preterm infants may affect outcome. Some studies suggest that a policy of elective cesarean section in cases of premature rupture of membranes and breech presentations of fetuses weighing less than 1000 to 1500 g may be beneficial (Gabriel et al., 2004), but others do not (Nelson and Chang, 2008). Intraventricular hemorrhage, which usually occurs within 6 hours after birth and possibly during labor and delivery, may be preventable. Hypothermia treatment of hypoxic-ischemic encephalopathy, generally using a “cool cap,” appears to be improving outcome (Fatemi et al., 2009).

Data from several studies involving children with CP (n = 1918) found that about half (range 35% to 62%) of these children develop epilepsy. However, no evidence exists that electroencephalography (EEG) is useful in determining the etiology of CP (Ashwal et al., 2004) and plays no role in workup or management unless seizures occur. By contrast, since the frequency of associated cognitive and sensory deficits is high in the child with CP, appropriate screening should be undertaken.

Rehabilitative therapy influences outcome. The main goals of treatment are to improve the child’s motor function and modify the environment to improve mobility. Orthopedic surgery is sometimes required (Steinbok, 2006). Dorsal rhizotomy has been used to decrease spasticity and improve gait or make children who are wheelchair bound more comfortable. Botulinum toxin and baclofen also have a role in the treatment of spasticity (Gough et al., 2005; Lundy et al., 2009). Because of the high frequency of oromotor dysfunction, nutrition, growth, and other aspects of swallowing dysfunction should be monitored (Ashwal et al., 2004).

Assessing long-term outcome, Mesterman et al. (2010) accessed by phone 163 of all 204 patients diagnosed with CP (at age 0 to 5 years) between 1975 and 1994 in Tel Aviv. Of the 95 patients between 18 and 30 years at the time of the survey, one-third to one-half required help with activities of daily living like eating, toileting, and dressing, one-third did not walk independently, but 80% had 12 years of schooling or more in either regular or special education. Only five were married, most lived at home, but notably, the majority reported being quite satisfied with their lives (Miller, 2007; Shikako-Thomas et al., 2009). The factors that decrease life expectancy in CP are immobility, profound retardation, and the need for special feeding (Strauss et al., 2007). Mobile children with CP may live well into adulthood.

Intellectual Disability

Clinical Features

The definition of a significant intellectual disability (ID) is a performance two standard deviations or more below the mean on age-appropriate standardized norm-referenced tests. The term global developmental delay (GDD) is usually reserved for young children (typically < 5 years of age), while the term intellectual disability (which will replace mental retardation in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders [DSM 5]) is usually applied to older children, in whom IQ testing results are more reliable (Shevell et al., 2003). The American Association of Intellectual and Developmental Disabilities (formerly known as the American Association of Mental Retardation) defines ID not as an absolute condition but as a construct that assists in educational planning and determines needs in terms of activities of daily living. The diagnosis therefore requires both low IQ (<70) and difficulties in adaptive behavior as expressed in conceptual, social, and practical adaptive skills (www.aaidd.org). This definition links the severity of ID to the degree of community support required to achieve optimal independence (Katz and Lazcano-Ponce, 2008). Mild ID indicates the need for intermittent support; moderate ID for limited support; severe ID for extensive support, and profound ID for pervasive support. The IQ definition of ID uses 100 as the mean and 15 as the standard deviation. Children with mild ID have an IQ of 55 to 69, those with moderate ID have an IQ of 40 to 54, those with severe ID have an IQ of 25 to 39, and those with profound ID have an IQ under 25. The level of functioning of children with an IQ around 60 to 70 varies significantly. About half require special education, and half attend regular school. Those in special schools are more likely to have a personal or family history of language delay. Similarly, IQ scores are only one factor in the differentiation between borderline intellectual function (BIF; IQ 70-84) and mild ID. An individual’s overall IQ score can be misleading because he or she may have strengths or weaknesses that markedly affect functioning, or there may have been even minor measurement errors on the test administration. An individual’s adaptive behaviors and functioning are of great importance when making this determination; an IQ of 70 is not necessarily a reliable cutoff between mild ID and BIF. Someone with an IQ of 69 may potentially function better overall than someone with a borderline range IQ of 71. An assessment of adaptive behaviors is crucial to the diagnostic process here too. Clinical interview with the individual and a collateral contact who knows them well can help assess adaptive functioning, as can standardized measures of adaptive behaviors (e.g., Vineland Adaptive Behavior Scales).

The prevalence of ID in industrialized countries is 0.3% to 3%. Mild ID represents the majority (85%), but roughly 0.4% of the general population is severely intellectually disabled. As a rule, those with severe ID are more likely to have a definable biological cause, whereas those with mild ID tend to come from socially disadvantaged backgrounds and often have a family history of BIF or mild ID (Online Mendelian Inheritance in Man [OMIM] website; Opitz, 2000; Stromme and Magnus, 2000). Environmental factors also play a role. For example, smoking during pregnancy is associated with more than a 50% increase in the prevalence of ID. Other environmental factors may include maternal alcohol use during pregnancy (fetal alcohol syndrome), lead toxicity, and iron deficiency. The risk for recurrence of severe ID is 3% to 10%, and of mild ID, 5% to 40%, suggesting there are many routes to mild ID. The ratio of boys to girls with ID, especially mild ID, is 1.4 : 1. Male excess is present in autism, syndromic X-linked ID (S-XLID) (associated with a specific phenotype), and nonsyndromic X-linked ID (NS-XLID). About 15% of males with ID have X-linked intellectual disability (XLID) (Stevenson and Schwartz, 2009). About 25% of all males with severe ID have XLID, and almost 50% of all cases of mild ID are due to XLID (Partington et al., 2000; Ropers and Hamel, 2005). The recurrence of ID in families with one previous child with severe ID is reported to be between 3% and 9% (Centers for Disease Control and Prevention [CDC], 2009).

Diagnosis and Etiology

Children with ID often have neurological and psychiatric comorbidities. Epidemiological studies suggest that as many as one-fifth of them have epilepsy by the age of 10 years (Airaksinen et al., 2000). The probability of developing epilepsy is fivefold greater for children with severe ID (35%) than for those with mild ID (7%). CP coexists in 6% to 8% of the mildly ID and as many as 30% of the severely ID. Microcephaly occurs in one-fifth of XLID syndromes. Macrocephaly also occurs secondary to increased brain volume or hydrocephalus. Syndromes without hydrocephaly include fragile X, Opitz FG, and Lujan. Syndromes with hydrocephalus include X-linked hydrocephaly-MASA spectrum and hydrocephaly-basal ganglia calcifications syndrome. Children with GDD and ID are at risk for physical disabilities. Impaired vision occurs in 15% to 50% and impaired hearing in about 20%. Thus a formal ophthalmological examination is appropriate. Audiometric assessment can be done by behavioral audiometry or brainstem auditory evoked response (BAER) testing (Shevell et al., 2003). Notably, cutaneous findings are fairly common in XLID, but cardiac anomalies are uncommon (Stevenson and Schwartz, 2009).

An increased prevalence of psychopathology and maladaptive behavior occurs in children with ID. In one epidemiological study, almost 40% of those with ID also had a psychiatric diagnosis, 42% with severe ID and 33% with mild ID (Stromme and Diseth, 2000). The most common comorbid psychiatric diagnoses were ADHD and autistic spectrum disorder (ASD). Overall, autistic features are reported in 9% to 15% of the mildly ID and 12% to 20% of the severely ID. Table 61.1 details specific cognitive and behavioral problems in several common genetically defined ID syndromes, along with the possible neuropathological basis of these disorders.

Etiology is ultimately determined in anywhere from 10% to 81% of children with GDD/ID. Evaluation of ID should be sequential; key elements include the medical, family, and developmental histories, dysmorphology and neurological examinations, and appropriate laboratory and neuroimaging tests (Moeschler and Shevell, 2006; Shevell et al., 2003). The latter can include careful metabolic evaluation together with neuroimaging studies, EEG, cytogenetic studies, and genetic and ophthalmological consultations as appropriate (Mao and Pevsner, 2005; Shevell et al., 2003). Auditory and visual function must be determined, since these are common comorbidities. If a child was born in a locale without universal newborn screening, consider a screening metabolic evaluation that includes a capillary blood gas, serum lactate and ammonia levels, serum amino acids and urine organic acids, and thyroid function studies. An EEG is appropriate when the history suggests possible seizures, paroxysmal behaviors, or an underlying epilepsy syndrome.

Genetic defects are important causes of ID, and recent years have seen important progress in identifying the genes involved in ID. As of June 2010, the entry mental retardation results in 1647 hits on OMIM. If a family history of consanguinity exists or a close family member (sibling, aunt/uncle, or first cousin) is known to have GDD, testing specific to the known disorder should be performed. When there is a family history of unexplained GDD, cytogenetic testing (e.g., high-resolution chromosome studies, testing for subtelomeric deletions, fluorescent in situ hybridization (FISH) and even microarray-based cytogenetics) is appropriate. In the absence of a familial history of GDD, specific historical or physical findings are useful to direct testing (Van Esch et al., 2005). Observed dysmorphic features may prompt specific testing for such entities as Down syndrome, fragile X syndrome (FXS), Rett syndrome, Prader-Willi/Angelman (by FISH), or congenital hypothyroidism (Jones, 2006). Parental consanguinity, documentation of loss or regression of developmental milestones, or unexplained prior parental loss of a child are likely to be caused by a definable disease process, and thus a comprehensive genetic evaluation should be considered (Shevell et al., 2003). Epigenetic factors (e.g., chromatin remodeling) also play a role (Tsankova et al., 2007).

Increasingly sophisticated genetic testing is becoming available. Reviewing the literature on diagnostic studies in ID, Van Karnebeek et al. (2005) found that chromosome abnormalities detectable by classical cytogenetics were diagnostic in about 10% of patients. The median additional benefit of subtelomeric studies was 4.4%, although the rate of subtelomeric abnormalities in ID may be as high as 10% (Lamm et al., 2006; Shao et al., 2008). The yield for FXS screening is higher in those with more severe ID (4%) versus those in the borderline–mild ID group (1.0%) (Mastergeorge et al., 2010). Overall, the etiology of ID can be detected by classical molecular karyotyping and molecular testing for specific disorders in about 20%. Multiplex ligation-dependent probe amplification may be a rapid, accurate, reliable, and cost-effective alternative to FISH for the screening of subtelomeric rearrangements in patients with idiopathic ID (Palomares et al., 2006). Genomic microarrays, also called array comparative genomic hybridization, may also represent one of several novel technologies that allow rapid detection of chromosomal abnormalities such as microdeletions and microduplications from genomic DNA samples (Engels et al., 2007). More than 5000 chromosome copy number variations (CNVs) are now in a Toronto database (Li and Andersson, 2009).

Progress in the clinical and molecular characterization of XLID has outpaced progress in the delineation of ID due to genes on the other 22 chromosomes. Almost half of the estimated 200 XLID genes are identified, and another 20% have been regionally mapped (Stevenson and Schwartz, 2009). The combination of clinical delineation with gene identification and the development of gene panels for screening nonsyndromic XLID minimizes unproductive laboratory testing (Stevenson and Schwartz, 2009). To date, 87 genes have been associated with nonsyndromic or syndromic XLID or both, including FXS, Duchene muscular dystrophy, and Coffin-Lowry syndrome (Stevenson and Schwartz, 2009). Using imaging technologies and more careful scrutiny, some nonsyndromic XLID families were found to have syndromic findings with time. Eighteen genes have been associated with both nonsyndromic XLID and syndromic XLID. This apparent conundrum may be explained by the type of mutation, the location of the alteration in different domains of a gene, or observer inconsistencies (Stevenson and Schwartz, 2009).

Inherited metabolic diseases are responsible for 1% to 5% of unspecified ID, but the mean yield of metabolic investigations is only about 1% (Van Karnebeek et al., 2005). ID is rarely a unique symptom in inborn errors of metabolism. However, some exceptions should be kept in mind, including creatine transporter defect, some patients with adenylosuccinate lyase deficiency, 4-hydroxybutyric aciduria, and Sanfilippo disease type B (García-Cazorla et al., 2009). Table 61.2 lists some of the metabolic disorders that cause isolated ID. Some are potentially treatable.

The identification of ID-associated genes has provided insights into brain function. Two major types of ID genes exist: those leading to dysfunctional neurodevelopmental programs and brain malformations, and those that lead to alterations in molecular synaptic organization and plasticity mechanisms (Vaillend et al., 2008). Some metabolic disorders appear to influence the expression of one or the other group of genes (Stephen et al., 2003). Affected genes have roles in processes such as neuronal outgrowth, synaptic structure and function, and synaptic plasticity and learning and memory. Polymorphisms that predispose to ID but are insufficient to cause symptoms on their own might be present within the protein-coding regions of genes, within their regulatory regions, or in genes that encode small, regulatory ribonucleic acids (RNAs). Allelic variants of genes that are involved in XLID might be candidates for such polymorphisms (Ropers and Hamel, 2005).

Management

Available evidence demonstrates the benefits of early intervention through a variety of programs, at least with respect to short-term outcomes, and suggests that early diagnosis of a child with global delay may improve long-term outcome (Shevell et al., 2003). The management of children with ID focuses on finding the appropriate educational setting for children with mild ID, vocational training for those with moderate ID, and determining home or institutional placement for those with severe and profound ID.

Advances in genetic diagnosis have had immediate benefits for families, allowing for carrier testing, genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis. Some of the gene discoveries have also pointed to potential strategies for treatment. For example, newborn screening suggests that FXS occurs in 1 in 5000 males (Coffee et al., 2009). The mGluR5 hypothesis for FXS has led to the use of mGluR5 antagonists for the treatment of FXS. For example, R-baclofen, a GABA agonist that downregulates mGluR5 activity, has been anecdotally helpful in FXS; controlled trials are in progress. Minocycline lowers matrix metalloproteinase 9 (MMP9) levels at the synapse, which are upregulated in FXS. Minocycline treatment in patients with FXS and a recent survey of 50 patients treated with minocycline revealed improvements in behavior and language based on parent questionnaire in approximately 70% (Schneider et al., 2009).

Autistic Spectrum Disorders

Clinical Features

The diagnosis of an autistic spectrum disorder (ASD) currently requires the early onset of a triad of deficits: impaired sociability, impaired verbal and nonverbal communication, and restricted activities and interests (Rapin and Tuchman, 2006). The range of disabilities seen among children on the spectrum cannot be overemphasized. Indeed, the DSM-5 will emphasize the dimensional nature of the disorder, quantifying each feature as mild, moderate, or severe. ASD will become a dyadic disorder (social/communication deficits and fixated interests and repetitive behaviors) (Box 61.1) and will be diagnosed as with or without a language disorder, since not all ASD children have language disorders. Pragmatic language skills, however, will be incorporated into the social domain. The changes are based on research results which thus far have failed to document either pervasive developmental disorder–not otherwise specified (PDD-NOS) or Asperger disorder as separate biological entities. In addition, removing the age criteria allows for inclusion of children, generally those functioning at a higher intellectual level, who present outside of the current age cutoff.

The reported frequency of ASD has increased significantly in the past 2 decades. In the 1990s, the estimated frequency was about 1 per 1000, but the current estimate is about 1 per 100 or even higher. ASDs are 4 times higher in males. The reported increase is attributed to changes in diagnostic practices, with emphasis on the spectrum aspect of the disorder, different referral patterns (more evaluations of language delayed male toddlers), greater availability of services prompting increased utility of diagnosis, loosening of age at diagnosis requirement, and increased public awareness (Frombonne, 2005; Hertz-Picciotto and Delwiche, 2009; Newschaffer et al., 2007). In addition, some children who would have been previously and perhaps correctly diagnosed with a developmental language disorder are receiving ASD diagnoses (Bishop et al., 2008). However, these variables may not completely explain the increase. Environmental factors cannot be discounted (Szpir, 2006), although the theory that the measles, mumps, rubella (MMR) vaccine plays any role in the increase has been completely discredited (Observations, 2010). Both advanced maternal and paternal age may play a role in increasing the frequency of autism (Durkin et al., 2008). The high concordance in monozygotic twins, the increased risk for recurrence in siblings (≈5%-10%), a broader autistic phenotype in families with an autistic proband, which includes anxiety and mood as well as social style and obsessive characteristics (Daniels et al., 2008), and the association with a number of genetic disorders (Box 61.2) support a hereditary basis in many cases (Gillberg, 2010).

The symptoms of ASD, like other developmental disorders, often change with age. Sibship studies provide the basis for investigations of the behavioral manifestation of autism during the first year of life (Elsabbagh and Johnson, 2009). Atypical eye contact, decreased response to name, poor imitation, absent social smile, passive temperament, and delayed language are early markers of the disorder (Zwaigenbaum et al., 2005). Sibling studies suggest there are both early-onset (clear by 12 months) and late-onset (clear by 18 months) forms of autism (Elsabbagh and Johnson, 2009; Zwaigenbaum et al., 2009). Approximately a third of autistic children regress between ages 1 and 3 years, with a peak at 2 years (Lord et al., 2004). Conversely, some toddlers and preschoolers with typical symptoms of autism may no longer appear autistic by school age. They may seem a bit odd and have peculiarities of language prosody and pragmatics. Social skills may be tenuous. NVLDs or ADHD may become the school-age diagnosis (Helt et al., 2008; Lord et al., 2006). Most, however, retain the typical features of autism, particularly those who are intellectually impaired. The natural history of Asperger disorder is less well documented. Often the diagnosis is delayed until late childhood, adolescence, or even adulthood because language is not delayed. NVLDs or ADHD may be the apparent presenting complaint (Martin and Klin, 2004). The characteristic overfocus in a particular or sometimes peculiar interest area may escalate over time, but it may also be the key to a special form of adult success. Outcome studies of children diagnosed with ASD suggest that although 40% show overall improvement during adolescence, as many as a third may deteriorate (Howlin, 2005; Rapin and Tuchman, 2006). The onset of seizures can cause the deterioration. Psychiatric comorbidities commonly develop: depression, bipolar disorder, anxiety, schizophrenia, and even catatonia (Billstedt et al., 2005; Hutton et al., 2008). A minority of patients, usually the higher-functioning group, improve significantly during adolescence. Approximately two-thirds of adults with autism show poor social adjustment (limited independence in social relations), and half require institutionalization. Autistic adults who are not intellectually impaired tend to improve more than those who are intellectually impaired. Prior to the broadening of the diagnostic category, even though higher-functioning individuals with autism and Asperger disorder had the best outcome, only 15% to 30% had fair to good outcomes, and only 5% to 15% became competitively employed, led independent lives, married, and raised families. Psychiatric problems were common in this group. Probably, some “odd” adults go undiagnosed in childhood and adolescence, thus increasing the proportion of those with ASD who ultimately function in the mainstream. Some are highly productive and original in their work (Billstedt et al., 2007; Seltzer et al., 2003). A recent report that assessed outcome in a cohort with normal IQ documented better adult functioning. Half of the participants were rated as “very good” or “good” on a global outcome measure. However, there was considerable variability in measured cognitive ability over time. Over half the sample had large gains or losses in cognitive ability of greater than one standard deviation (Farley et al., 2009).

Specific Clinical Features

Intelligence and Cognition

IQ is not one of the defining criteria for an ASD diagnosis (Matson and Shoemaker, 2009). Although most children with ASDs are intellectually disabled (70%-85%), some have average or even superior intellectual ability. If Asperger disorder is included as an ASD, the rate of ID drops considerably. IQ, however, is a key predictor of long-term outcome in autism, especially for those with an IQ of less than 50, who generally fare poorly. Munson et al. (2008), however, have recently suggested that distinct subtypes of autism exist that differ in severity of intellectual ability, patterns of cognitive strengths and weaknesses, and severity of autism symptoms. Normal IQ is a positive prognostic sign.

Communication

Verbal and nonverbal communication disturbances are a cardinal feature of ASD. Tager-Flusberg et al. (2009) have suggested using expressive language developmental benchmarks assessed with particular parent report and standardized measurement tools as a way of quantifying language capacity in preschool autistic children (e.g., preverbal communication, first words, word combinations, sentences, complex language). Different types of linguistic problems are seen (Rapin and Tuchman, 2006), and the severity of the language deficit generally parallels IQ. In lower-functioning ASD children, language, if present at all, is echolalic; repetitive stereotyped phrases are common. Some script from videos they watch over and over. Some children fail to process language and despite normal hearing, appear deaf (verbal auditory agnosia) (Deonna et al., 2009). Higher-functioning children sometimes talk too much—they talk to talk (semantic and pragmatic deficits) but do not use language to communicate (pragmatics). These children are often extremely literal and concrete. Prosody is frequently impaired, as evidenced by mechanical, excessively rapid, monotonic, high-pitched, and/or poorly modulated speech.

Long-term prognosis correlates with language skills at age 5 to 6 years. Those with conversational language do significantly better than children with little or no language. Nonverbal cognitive ability at age 2 was generally the strongest predictor of age 5 language, while at age 3 communication scores were a stronger predictor of age 5 language for children with autism. Early joint attention as well as vocal and motor imitation skills were more impaired in children who did not develop language by age 5 (but had relatively strong nonverbal cognitive skills) than in children who did develop language by 5 (Thurm et al., 2007).

Abnormalities of play are part of the autistic child’s communication disorder. Play ranges from repetitive stereotypic and indiscriminate sensory use of objects (mouthing, rubbing, etc.), to functional object use and imitation, to mechanical play with puzzles, to interactive play with adults like running, catching, and tickling games, to activities involving their circumscribed areas of interest (e.g., board games, computers, electronic games, high-level word and number tasks). Often, engaging in these activities is pleasurable. Pretend play is often rudimentary, even in higher-functioning young children, involving, for example, simple role taking (Waterhouse et al., 1996). Dress-up for itself alone without additional pretending is common.

Diagnosis and Etiology

Evaluation

The clinical history and observations of the child are the basis for the diagnosis of an ASD. Several questionnaires for parents are available for quantifying the diagnostic criteria. For very young children, the Modified Checklist for Autism in Toddlers (M-CHAT) has been used (Robins et al., 2001). The Social Responsiveness Scale (Constantino, 2005), the Guilliam Autism Rating Scale (GARS) (Guilliam, 2006a), and the Guilliam Asperger Disorder Scale (GADS) (Guilliam, 2006b) are all quick standardized diagnostic measures, as are the Current and Lifetime Social Communication Questionnaires (SCQs) (Rutter et al., 2005), which are excellent screens. The Childhood Autism Rating Scale (CARS) (Schopler et al., 2000) can be used to quantify office observations. The Autism Diagnostic Observation Scale (ADOS) (Lord et al., 1999) and the Autism Diagnostic Interview–Revised (ADI–R) (Rutter et al., 2003) are the gold-standard diagnostic measures but are time consuming and require special training to administer. Neither is probably necessary in the typical clinical setting. Studies comparing ADOS and ADI diagnoses to that of an experienced clinician show excellent concordance.

The standard neurological examination is generally normal, although children with ASDs are often clumsy. Macrocephaly occurs in about a third of children with autism and generally becomes apparent around the age of 1 to 3 years. The fact that macrocephaly is not present at birth suggests there is an increased rate of brain growth in the first years of life that diminishes and may become subnormal in later childhood; macrocephaly in adults with autism is less common than in autistic children (Sacco et al., 2007). Tuberous sclerosis is probably the most common definable cause of autism; skin examination requires careful attention (Gillberg, 2010). Examination for dysmorphisms may be helpful in making genetic diagnoses like FXS, velocardiofacial syndrome, and Smith-Magenis syndrome (see Box 61.2). Hearing impairment may be excluded by a formal audiology assessment. EEG, including a sleep record or overnight video-EEG monitoring, is appropriate to exclude subclinical seizures when language comprehension is impaired or developmental regression has occurred (Kagan-Kushnir et al., 2005). Mild to severe epilepsy and partial and generalized seizures occur in up to one-third of patients with autism by early adulthood. Infancy (infantile spasms) and the peripubertal period are particularly vulnerable periods. The onset of seizures may play a role in adolescent deterioration. Children who are intellectually impaired have a higher risk for epilepsy, but seizures occur in high-functioning children as well. Epileptiform abnormalities on EEG and early epilepsy occur more frequently in children who undergo an early regression (Canitano et al., 2005). The relationship between epilepsy and autism is a subject of considerable disagreement (Tuchman, 2009), and the efficacy of treating epileptiform EEG activity in ASD is hotly debated (Lagae, 2009).

The extent of the evaluation for an underlying metabolic disorder depends on clinical suspicions and the relevance to family counseling. Box 61.2 lists some disorders that can be associated with an ASD phenotype. ASDs occur in approximately 20% of children presenting with intellectual disability and 10% of children with cerebral palsy.

Etiology

Neuropsychological

Three main neurocognitive phenotypes have been advanced to explain autism: underdeveloped theory of mind (TOM), weak central coherence, and executive dysfunction (Frith, 2003). Problems with TOM allude to the inability of those on the autistic spectrum to put themselves in another’s place and to understand that others might have different thoughts than they do. Complementing the TOM explanation of autism is an actively evolving view that mirror neurons are abnormal in the ASDs and underlie the inability to understand others’ emotions (Dapretto et al., 2006). One problem with the TOM hypothesis is that high-functioning autistics can often solve TOM paradigms. Executive dysfunction refers to difficulties with problem solving, planning, and organizing (Hill, 2004; Kenworthy et al., 2008), which are common in, but not specific to, autism. Weak coherence refers to difficulty integrating information into a meaningful whole. Although a detail-oriented, piecemeal-oriented style is common in autism, weak coherence does not clearly explain social difficulties. An inability to see the big picture may interfere with the ability to read emotional facial expressions. Baron-Cohen (2002) has suggested that autism represents the extreme male brain with empathizing weaknesses and systematizing strengths.

Genetics

ASDs are quite heterogeneous with respect to etiology. An identifiable genetic or metabolic disorder is found in 10% to 15% (see Box 61.2). Although over 15 autistic-susceptible gene loci have been extensively studied, the molecular pathogenesis of ASD is still not well understood (Battaglia and Carey, 2006; Schaefer and Mendelsohn, 2008; Sebat et al., 2007). Epigenetic factors affect the relationship between these genes and ASD pathogenesis (Tsankova et al., 2007.). Family members with the same mutation may not manifest autistic symptoms that could be, for example, due to gender effects or environmental factors. In most people with ASDs, extensive genetic testing does not reveal a cause, suggesting that inheritance is multifactorial. Mutations in genes encoding synaptic adhesion molecules like neuroligin, neurexin, CNTNAP (contactin-associated protein), and CADM1 (cell-adhesion molecule 1) suggest that impaired synaptic function underlies ASDs (Miller et al., 2005). However, knockout mouse models of these mutations do not show the full range of autistic symptoms. This could mean that gain of function as well as loss of function arising from these mutations are required for the full ASD picture. Endoplasmic reticulum (ER) stress due to these mutations may cause a trafficking disorder of synaptic receptors like GABAB receptors, resulting in impaired synaptic function and signal transduction. This theory provides for epigenetic factors playing a role as well (Momoi et al., 2010).

Neuropathology

Based on the core symptoms of autism, neuropathological abnormalities would be anticipated and are found in regions important to social function (frontal lobe, superior temporal cortex, parietal cortex and amygdale, language function (language cortex), and repetitive behaviors and stereotypies (orbital frontal cortex and caudate) (Amaral et al., 2008; Bauman and Kemper, 2005; Casanova and Trippe, 2009; Casanova et al., 2006; Herbert et al., 2002, 2005; Pardo and Eberhart, 2007; Schumann et al., 2010; Vargas et al., 2005). Functional imaging studies demonstrate that neural systems related to social functioning, like emotional face recognition and TOM, are abnormal (Corbett et al., 2009). Abnormalities of mirror neurons are also seen when subjects imitate and observe emotions (Rizzolatti and Fabbri-Destro, 2010).

Increased total brain volume, primarily due to increased white matter, is the most frequently replicated imaging finding (Verhoeven et al., 2010). Very young children with autism (18 months to 4 years) have a 5% to10% increase in brain volume, especially in the frontal lobe compared to controls, which parallels the increasing head circumference during this period. In contrast to other white-matter structures, both volume and density of the corpus callosum are reduced (Hardan et al., 2008; Minshew, 2009), perhaps resulting in decreased interhemispheric communication (Williams and Minshew, 2007

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