Autism spectrum disorder (ASD) is a behaviorally defined neurologically-based developmental disorder with an onset before 3 years of age. ASD encompasses three diagnoses: autism, Asperger disorder (AD), and pervasive developmental disorders not otherwise specified (PDD-NOS). Autism is defined by abnormal development and/or regression in social interaction and communication along with repetitive and stereotyped interests and behaviors.1 Although the DSM-IV-TR also lists disintegrative and Rett disorder as subtypes of ASD, the former is rarely diagnosed and the latter is recognized as a distinct neurodegenerative disorder. Diagnosis of autism is usually made around the age of 18 to 24 months, although, upon reflection, parents typically report concerns in the first year of life. This gap between parents’ early concerns and the relatively late diagnosis, along with the importance of early intervention, highlights the necessity to find reliable tools for early diagnosis. Recent studies have suggested that symptoms of autism may be detectable as early as 14 months of age using standardized assessments.2 ASD associated with developmental regression accounts for approximately one-third of the cases and usually occurs between the first and second years of life. Late-onset developmental regression, particularly after 3 years of age, highly suggests an underlying neurological disorder.

The prognosis of ASD is variable. It has been estimated that 40% to 70% of children with ASD will manifest subnormal intellectual function with higher early levels of intellectual, adaptive, language, and social function predictive of later autism symptoms and acquisition of cognitive skills.3-5 Data collected through the Autism and Developmental Disabilities Monitoring Network from 14 surveillance areas in the United States suggest that the average prevalence of ASD as 6.6 per 1000 children (approximately 1:150), with this prevalence ranging from 3.3 to 10.6 per 1000 children.6 These data also suggested that the previously noted increase in the prevalence of ASD has recently stabilized and confirmed previous reports that ASD is more prevalent in males than females with a ratio ranging from 3.4:1 to 6.5:1.6

The etiology of ASD is unknown, but it is becoming clear that ASD probably results from a genetically vulnerable individual being exposed to an environmental agent or endogenous stressor during a critical period in development. This so-called triple hit hypothesis attempts to account for both the complex nature of this disorder and lack of simple associations found between ASD and genetic markers.7 Investigation of environmental pollutants has been facilitated by modern information technology. Studies have linked clinical databases coordinated by the Centers for Disease Control and Prevention with monitoring databases from the Environmental Protection Agency.8,9 Such studies have suggested that environmental toxins, particularly mercury, may be related to an increased risk of ASD.8-10 The role of immunizations containing thimerosal, a mercury-containing preservative, is still unclear. While recent large-scale studies have demonstrated little influence of thimerosal on neuropsychological outcomes in childhood,11 meta-analysis of epidemiologic studies and a comparison of outcomes of children receiving vaccines containing different amounts of thimerosal have indicated the possibility of a link between thimerosol and ASD.12,13 Regardless of the safety of thimerosal-containing vaccines, it is clear that the public perception of vaccine safety could significantly affect the health of children.14-16

Known genetic syndromes associated with ASD are discussed later in this chapter, but these probably account for less than 10% of individuals diagnosed with ASD.17 Twin studies suggest a strong genetic component, but genetic studies that have evaluated candidate genes or whole genome screens have failed to find one genetic cause. Researchers have focused on several schemes to increase the sensitivity of their analysis, including examining the genetic basis of endophenotypes,18,19 using large samples derived from the Autism Genetic Resource Exchange,20 and examining the shared genetic pathways between known genetic syndromes associated with ASD.21 Most researchers have concluded that multiple genes interact to predispose an individual to developing ASD.17

Table 27-1 lists the reported anatomic brain abnormalities found in ASD. Abnormalities in cortical white22-25 and gray24,26,27 matter, the limbic system,28-31 particularly the hippocampus and amygdala,32,33 as well as in the cerebellum,24,26,28,34 have been reported. The functional and developmental significance of these neuropathologic abnormalities has led to speculation regarding pathogenic mechanisms underlying ASD. The reduced number of Purkinje cells in the cerebellum with few significant changes in the inferior olive may point to a prenatal onset.28 The abnormally increased white matter volume has been proposed to be the result of an increase in the short association fibers in the frontal and temporal lobes due to an increased number of microcolumns.22 This, in turn, has been proposed to result in too much intracortical communication, an imbalance between local and distant cortical communication, and a deficit in large-scale cortical integration that is required for high-order cognitive processes such as language, behavioral regulation, and context-based social interactions. Abnormalities of the amygdala have been linked to abnormal fear conditioning in animal models.35 Clearly ASD is associated with widespread abnormalities of brain development, but the timing, localization, and links between these abnormalities are still not known. In addition, the connection between these neuropathologic findings and the derailment of cognitive development is a matter of intense debate. As discussed next, these abnormalities may be related to abnormal brain growth, maturation, and/or immune system dysregulation.

Brain growth appears to be dysregulated in ASD. Several lines of evidence point to an acceleration in brain growth during the first years of life followed by premature cessation of further brain growth by early childhood.36,37 A retrospective examination of head circumference (HC) measurements during the first 2 years of life demonstrated that HC growth was greater in every child with autism as compared to children with PDD-NOS and typically developing children.26 More recent prospective studies suggest that the accelerated growth is not isolated to the cranium, but may be a part of a more general dysregulation in growth38 related to higher levels of growth-related hormones.39 While reports have linked an early acceleration in HC to brain volume23,40 other studies suggest that the increase in HC is better correlated with increases in non-neural tissue volume.41

Several lines of evidence point to abnormalities of the immune system. Investigators have identified autoantibodies to neural tissue, including neuron-axon filament proteins, cerebellar neurofilaments, myelin basic protein, caudate, serotonin receptors and endothelial cells, abnormal cytokine levels in the CSF and blood, and alterations in the number and activity of T cells, monocytes, and natural killer cells.42 The important role of the immune system in nervous system development is being increasingly realized. For example, major histocompatibility complex-deficient mouse models demonstrate abnormal synaptic pruning43 and an absence of long-term depression.44 A link between immune system dysfunction and autism would help explain the association of autism with prenatal and postnatal infections, familial autoimmunity, gastrointestinal inflammation, animal models, and findings of immune system dysregulation.42

Medical History

Gestational and Neonatal

In utero exposure to several agents is associated with an increased incidence of ASD (Table 27-2). Fetal anticonvulsant syndrome associated autistic disorder was described in 4.6% of children exposed to either sodium valproate or carbamazepine in utero.45 In utero phenytoin and diazepam exposure in combination with sodium valproate or carbamazepine has also been associated with ASD.46 Older studies have documented the link between thalidomide and maternal alcohol and cocaine intake, and in utero viral infections to an increased risk of ASD.47-50 Nonfocal and focal brain damage early in life has also been associated with ASD.51-53

Medical

The prevalence of sleep disorders in children with autism ranges between 44% and 83%.54 Behavioral sleep problems appear to be the most common, but circadian sleep–wake problems are also common. Many children manifest multiple sleep problems.55 Sleep problems are important to address since sleep disturbance has been associated with impaired daytime function, appetite, and growth.54,56

Children with ASD have been documented to have a higher prevalence of ileo-colonic lymphoid nodular hyperplasia,57 although the risk of gastrointestinal disorders in general may not be elevated.58 It is important to recognize gastrointestinal symptoms, since such symptoms can result in behavioral instability, and improvement of such symptoms may improve functional outcome.

Development

Children with ASD typically have a history of developmental delay or regression in early language and social development. Fine-motor milestones are also typically affected but gross motor milestones are usually intact.

Family

Monozygous twins have a very high concordance rate (approximately 80%) of ASD symptoms while dizygous twins demonstrate a much lower concordance rate (approximately 10%), suggesting a clear genetic component in the development of ASD.59 Recurrence risk of idiopathic ASD in siblings is estimated to be approximately 5% to 10%.59 A family history of psychiatric, but not neurological, disease has been associated with ASD.60-62 While several studies have found increases in specific autoimmune diseases in family relatives of individuals with ASD (Table 27-2), others have not.63-66 Interestingly, while one study did not find a major association between ASD and a specific autoimmune diseases, it did find that the risk of ASD increased as the numbers of family members with autoimmune disease increased, supporting the idea of an interaction between a general immune defect and the environment.67

Social

Both advanced maternal and paternal age are independently associated with an increase risk of ASD.68,69 As described in the previous section, environmental pollutants, particularly mercury, appear to be associated with a higher risk of ASD.8-10

Symptoms

Delay or regression of early language and social development constitute the core symptoms of ASD (Table 27-3). Regression of skills may be subtle, especially if early, representing a minor loss in attained skills with a static developmental course. Some children will also present with fluctuations in language development, with parents noting both gain and loss of language skill. Some children lose or never attain typical early language, such as “mama” or “dada,” and instead gain rather idiosyncratic words or phrases. When ASD children start to speak in more than one word, the phrases used are atypical, usually being very stereotypical “scripted” phrases without pronouns. In addition, once recognizable speech develops, the intonation and volume is rather inconsistent and odd and may even have a sing-song type quality.

Children with ASD lack well-modulated social interactions. It is important to differentiate between a child who does not interact because of a severe speech delay from one who truly has an underlying abnormality in social development. It is not the quantity of eye contact per se that suggests ASD, but the ability of the child to use eye contact to initiate, terminate, and regulate social interactions. Children with ASD are usually aloof and alone, choosing to play by themselves rather than seeking social interactions. They do not indicate their wants by pointing and may lead their parent by the hand to the item they want. Attention is dysregulated rather than purely increased or decreased. For example, sometimes children will be hyperfocused whereas other times attention will appear absent, sometimes accompanied by hyperactivity. While alone and hyperfocused, a child with ASD may line up small cars or other objects. As the ASD child becomes older and enters school, he or she has difficulties both initiating and maintaining friendships and typically requires significant assistance with social interactions.

Behavior is typically tenuous in children with ASD and can change very easily. Behavioral outbursts and tantrums are not unusual and can be a daily occurrence even in the high-functioning school-aged ASD child. Children with ASD can become very upset by change in routine or even on a daily basis due to the change from one classroom to another. One of the core components of ASD is stereotypical repetitive movements or interests. Motor stereotypies may arise during times of excitement or frustration and may be manifested by typical hand-flapping or spinning or, sometimes, more idiosyncratic complex movements.

Physical and Neurological Examination

There are limited, but key, examination findings in children with ASD (Table 27-4). Children should be monitored for unusual growth patterns and the physical examination should concentrate on dysmorphology and neurocutaneous stigmata in order to identify underlying genetic syndromes (Table 27-5) or tuberous sclerosis complex (TSC). Neurological examination should initially concentrate on cognitive factors, looking for symptoms described earlier and listed in Table 27-3. It is very difficult to perform a formal examination on many patients, but those who will cooperate may demonstrate “frontal’ signs such as motor impersistence and may even imitate and mirror the examiner’s movements. Hypotonia is not an uncommon finding on motor examination, and reflexes are sometimes generally depressed. Findings of hypertonia, dystonia, weakness, spasticity, or brisk reflexes would suggest a primary underlying neurological disease. Complex stereotyped mannerisms are not uncommon, but dyskinesia or choreoathetoid movements are abnormal for ASD. Gait tends to be asymmetric, with the child leading with one side of the body, particularly during running.

Genetic Disorders

Genetic disorders commonly associated with ASD and the prevalence of ASD in these disorders are given in Table 27-5.70-77

Metabolic Disorders

Although mitochondrial dysfunction has been associated with ASD (Table 27-6), it remains unclear whether such dysfunction is secondary to other underlying conditions or the primary biochemical abnormality leading to ASD.78-89 Mitochondrial abnormalities underlie hypotonia, epilepsy, autism, and developmental delay (HEADD) syndrome.82 Association and linkage studies have associated ASD with aspartate-glutamate carrier SLC25A12 gene single-nucleotide polymorphisms,83,84 although some have not been able to confirm this finding90 and such polymorphisms are not associated with biochemical abnormalities.91 Several isolated cases of other metabolic disorders have also been associated with ASD.92-96 Most of these reported cases manifested abnormal EEGs and seizures. CSF organic acids may have abnormal levels of ethanolamine.97

Neurological Disorders

ASD is found in 25% to 50% of individuals with TSC, but this only represents between 1% and 4% of patients with ASD.98 The total number of TSC lesions appears to be associated with autistic features, and studies have suggested that lesions in the right frontal and temporal lobes are more common in ASD patients who also have TSC.87,99,100 Rett syndrome should be considered in any female with language regression, characteristic hand-wringing, and acquired microcephaly. Such girls should undergo genetic testing for the MeCP2 mutation.101