Chapter 27. Autism

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

The relationship between epilepsy and autism is complicated. Children with ASD associated with a known genetic syndrome have a particularly high rate of clinical motor seizures. However, epileptic aphasia with subclinical seizures may also be particularly prevalent in ASD.102 The prevalence of EEG abnormalities was found to range from 30%103 to 60%104 using 24-hour EEG monitoring, while a prevalence of epileptiform abnormalities was approximately 82% using MEG.105 The significance and prevalence of subclinical epileptiform activity in ASD is unknown. Language regression and autistic-like behavior can be observed in epileptiform aphasias, such as Landau–Kleffner syndrome (LKS) and electrical status-epilepticus during slow-wave sleep (ESES).106 Brain lesions and migrational anomalies have also been associated with ASD.51,53,73,107

Behavioral Evaluation

Few reliable tools are available for screening children younger than 18 months, but the AAP recommends the Communication and Symbolic Behavior Scales Developmental Profile Infant/Toddler Checklist.108 Screening tools for toddlers and children older than 18 months fall into two categories: level 1, shorter questionnaires used to screen for children at-risk for ASD; and level 2, longer questionnaires combined with clinical examination that require more experienced clinical acumen. Level 2 helps differentiate ASD from global developmental delay and specific language impairment.109-113 The more reliable tools are outlined in Table 27-7. Verification of the diagnosis of ASD should involve more in-depth examination and caretaker interview. The Autism Diagnostic Observation Schedule (ADOS) combined with the Autism Diagnostic Interview (ADI) have become a standard, at least for research studies. These instruments require specialized training and their accuracy may be improved by an extended developmental examination that includes an evaluation of language and adaptive functioning.114-117 If the neurologist believes that the child has any other developmental or behavioral disorders regardless of signs and symptoms of ASD, the patient should be referred to a psychologist, neuropsychologist, or physical or occupational therapist if appropriate.

Neurological Studies

The particularly high prevalence of epileptiform abnormalities in ASD children without clinical seizures suggests a screening EEG study should be conducted.102 Although a routine EEG that includes sleep can be used, it is often difficult to obtain an adequate study, usually because the child needs to be sedated for lead placement. Thus, it is preferable to obtain a 24-hour overnight EEG in order to collect an adequate sample of sleep without medication effect and to determine the frequency and severity of epileptiform abnormalities.103,104,106

The location of the epilepsy focus may be related to ASD symptoms in children with epileptic aphasia. For example, although both LKS and ESES have manifestations of language regression, autistic type behavior is more common in ESES. The cortical distribution of epileptic discharges is different in these two groups.106 MEG provides a superior ability to localize the focus of discharges and has been used to show a correspondence between behavior and location of epileptiform discharges. Indeed, MEG has demonstrated that the primary epileptiform activity may be limited to the left perisylvian region in children with LKS, while autistic children may manifest epileptiform abnormalities similar to the children with LKS plus independent epileptiform activity outside of the left perisylvian region, particularly in the right perisylvian and/or frontal regions.105 Taken together, EEG and MEG studies appear to suggest that autistic symptoms are associated with more widespread epileptiform disturbance, with a possible implication of disturbances within the frontal cortex being related to autistic-type behavior, and suggest a pivotal role of neurophysiological studies in ASD.

Anatomic neuroimaging has uncovered lesions and migrational anomalies in children with ASD.51,53,73,107 Lesions such as Chiari I malformation could explain unexplainable discomfort in ASD.118 Magnetic resonance spectroscopy is essential for diagnosing a creatine deficiency.88 One study suggests that PET may be useful after an initially unremarkable MRI scan since subtle neuronal migrational anomalies may be more obvious after knowledge of a regional metabolic abnormality.107 PET may be particularly useful when EEG or MEG abnormalities are found and the anatomic MRI is normal. Other more advanced imaging methods may be well suited for diagnosing ASD, especially as these tools undergo rapid development and application to the clinical arena. For example, diffusion-weighted and tensor imaging demonstrates abnormalities in corpus callosum and cortical white matter anisotropy and diffusivity as well as white matter maturation,119-121 and cortical volumetric changes have been associated with social and intellectual function in ASD.122,123

Metabolic Studies

Biochemical markers of mitochondrial dysfunction can be subtle. A combination of subtle abnormalities should raise the clinician's index of suspicion for a mitochondrial disorder. Some have suggested that mitochondrial disorders may be reflected by slight abnormalities in carnitine and lactate accompanied by more significant elevations in alanine and ammonia,124 while others have suggested that slight elevations in creatine kinase and aspartate aminotransferase78 can be associated with mitochondrial disorders. Case reports of creatine and cerebral folic acid deficiency suggest specific testing for these disorders. It should be noted that the child reported with cerebral folic acid deficiency demonstrated normal folic acid metabolite levels in non-nervous system tissues. The possibility of antibodies to the folate transporter was not investigated in this reported case. Such a possibility could be ruled out with a serum test if lumbar puncture is contraindicated or difficult.125

Genetic Studies

Karyotype testing has been useful in identifying chromosomal abnormalities.73,74 Dysmorphology, neurocutaneous stigmata, or a neurological course associated with Rett syndrome should suggest specific genetic testing. The PTEN tumor suppressor gene has been identified in significantly macrocephalic ASD patients.74,126-130 A high frequency of cryptic chromosomal rearrangements has been identified by noncommercial chromosomal microarray in ASD patients.131 Commercial chromosomal microarray products have not been evaluated in ASD, but the ability of these techniques to detect mutations associated with genetic syndromes associated with ASD as well as cryptic mutations make the cost-effectiveness of such products outstanding.

Workup

Although individually the various underlying abnormalities reported to underlie ASD may not seem to account for a substantial percentage of the ASD population, when added together, underlying medical abnormalities could account for a substantial percentage of the children with ASD. Most children with ASD do not receive a medical workup. With the large number of children diagnosed each year with ASD, identifying and treating an underlying etiology in even a small percentage of the population of children with ASD can have an incredible impact.

While Figures 27-1 and 27-2 outline the stepwise work up for the diagnosis of ASD and the investigation of underlying genetic abnormalities, Figure 27-3 provides an overview of the neurological workup. Any child with unexplained ASD should obtain a comprehensive workup including a 24-hour EEG, MRI, MRS, and complete metabolic testing as outlined in Table 27-7 (Figure 27-3). Further workup to determine the location of the focal abnormality using MEG or PET should be considered in children with focal or multifocal findings on EEG. Confirmed abnormal metabolic laboratory values, especially those that may represent mitochondrial dysfunction, should be investigated with pathologic and/or biochemical functional studies of the muscle, leukocytes, or skin.

Treatment options are summarized in Tables 27-8 and 27-9 and Figure 27-2.

Behavior

Stimulant medication such as methylphenidate, the selective norepinephrine reuptake inhibitor atomoxetine, alpha-adenergics such as clonidine, and antipsychotics such as risperidone, are useful for controlling behaviors such as hyperactivity, impulsivity, inattention, aggression, and explosive outbursts in children with ASD.132-137 Several controlled trials have demonstrated the efficacy of selective serotonin reuptake inhibitors in improving anxiety, repetitive behaviors, and global functioning.138-144

Epilepsy

Common clinical epilepsy in ASD should be treated similarly to epilepsy in non-ASD patients, keeping in mind that side effects from anti-epileptic medications may manifest as severe behavioral dysregulation.102 Many children with LKS or ESES respond to more specific anti-epileptic medications (high-dose sodium valproate with or without ethosuximide, benzodiazepines) and/or immunomodulatory treatment (steroids and intravenous immunoglobulin) in various treatment protocols.145-148 Multiple subpial transections have been used in refractory cases with success.146-148

Metabolic Disorders

Children with underlying mitochondrial disorders should be provided with the standard mitochondrial cocktail of the clinician's institution. This cocktail should be modified if a specific mitochondrial disorder is identified. Cerebral folic acid deficiency improves with folinic acid supplementation.96 A trial of folinic acid may be appropriate while awaiting the results of metabolic and antibody testing. However, the clinician should be aware that the CSF levels of 5-methyltetrahydrofolate may normalize with folinic acid supplementation, making measurement of 5-methyltetrahydrofolate in the CSF prior to supplementation preferable. The development of two patients with X-linked creatine transporter disorder was not helped by creatine supplementation.88 This is not unusual for this form of the disorder.149 However, other forms of creatine deficiency have been reported to respond to supplementation.150

Sleep Disorders

The lack of treatment guidelines for sleep problems in ASD has been recognized by the American Academy of Pediatrics.151 As with typically developing children, children with ASD who have restless sleep and low ferritin also respond to iron supplementation.152 For insomnia, melatonin and the new melatonin agonist Ramelteon have both been shown to be successful,153-155 as has behavioral management.156 In practice, many children with ASD do not respond to behavioral treatment or melatonin and require medication such as clonidine for initiation of sleep.