Focus on Autism and Related Conditions

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder presenting with varied severity in symptomatology and multifactorial etiology. As implied by the word spectrum, ASD is arguably not a single entity; rather, it is a collection of many different conditions that share common behavioral manifestations. Indeed, from the early days of its description, some authors questioned whether autism should even be recognized as a distinct entity, given the many and varied etiological pathways that seemed to be associated with it (1, 2). There are currently no reliable biomarkers to parse heterogeneity in ASD; even in the presence of shared genetic contributions (e.g., fragile X), the nature and severity of autism symptoms—or even whether the diagnosis can be made—is variable (3). The search for more specific medical interventions or treatments that effectively remediate the core symptoms of autism is ongoing. Even so, there have been tremendous gains in our knowledge of genetics and neurobiology, which are leading to a better understanding of the underlying pathophysiology of ASD.

Epidemiology

The Autism and Developmental Disabilities Monitoring Network tracks the prevalence of ASD among 8-year-olds in 14 states for the Centers for Disease Control and Prevention (CDC). The prevalence of autism was thought to be approximately 1 in 110 in 2006, 1 in 88 in 2008, and 1 in 68 in 2010 (4). There is significant variability in this number from state to state, which appears to be at least partially related to the number of data sources investigators are able to access for review. Although many have wondered whether the increase in prevalence may reflect changes in diagnostic criteria, the steady increase captured by the CDC is arguably independent of significant methodological changes. Other factors may certainly include an increased awareness and availability of services for ASD relative to other similar diagnoses (5, 6). However, there is no evidence that the growth in the numbers of cases of ASD is actually coming at the expense of any other diagnosis (i.e., there has been no equivalent reduction in frequency of intellectual disability or learning disabilities). If one assumes that at least some of the increase is real (i.e., more than what might be expected as a result of changes in ascertainment and help seeking) (7, 8), concerns for potential environmental factors are quite appropriate (9). In her review of environmental contributions to the higher prevalence rate of ASD, Herbert (9) argued that there is evidence to suggest that environment and its interaction with vulnerable physiology accounts for the actual increase in incidences of autism.

There is great variability in the global prevalence of ASD in epidemiologic reports, suggesting that autism is likely underrecognized in developing countries (10). In addition, and across all studies to date, boys with ASD outnumber girls with ASD by about 4:1; reasons for this difference are unknown, further accentuating the multifactorial etiology of ASD (11).

Definition

DSM-5 Classification

ASD is a neurodevelopmental disorder with two core symptom domains: deficits of social communication/interaction and fixed/repetitive behaviors. DSM-5 made two important changes in the classification of ASD. First, the previously separated core symptoms of communication deficit and abnormal social interactions were combined into a single symptom domain of deficits in social interaction and communication. Second, the DSM-5 criteria for ASD combined autism, pervasive developmental disorder, and Asperger’s syndrome into a single entity called autism spectrum disorder. This change in DSM-5 was supported by research demonstrating that pervasive developmental disorder, Asperger’s syndrome, and autism shared core symptoms that ranged in severity across dimensions rather than representing three distinct disorders.

Social communication deficit in ASD is often observed by age 2 years. There is an absence of joint attention, which involves participating in the shared experience of one person responding to another’s pointing. A child may not respond to his or her name being called or may not bring an object to another person to share in the child’s experience. A prominent developmental milestone that is missed is theory of mind, an ability to understand that the mindset of another exists and may be different from one’s own (12). Individuals with ASD lack this ability to attribute representational mental states, thereby losing the ability to interpret intentions and other nonverbal cues of the social world. They have difficulty seeing the world from another’s perspective.

At about this same time in development, a child with ASD may have less interest in playing with other children. Rather, the child may appear to be content in solitary play, showing limited ability for imaginative play, absence of spontaneous speech, or inability to read facial expressions. The child’s expressive communication may lack hand gestures, and there may be aprosodic speech and reduced or unusual eye contact or facial expression. During adolescence, there is an absence of sustained friendships.

Fixated and repetitive behaviors may manifest during early childhood as an intense interest in repeatedly playing with unusual items or repeating activities such as opening or closing doors and lining up toys. Repetitive movements may be motor stereotypies such as hand flapping, walking on toes, echolalia, and scripted speech (repeating a phrase heard on the radio, television, or film or by others). Fixated interests might take the form of a perseverative need to repeat the same show or activity, in which any interruption from this activity results in tantrums. The “obsessive insistence on the preservation of sameness,” as observed by Kanner (13) in his original cases, might include an inability to tolerate any change in routines or an intense need to observe the rules.

Noncore Symptoms Commonly Observed

There are many behaviors that are commonly seen among individuals with ASD that do not fall into either of the two domains that define the disorder. These behaviors are thus referred to as “noncore” symptoms. Intellectual disability and language delay or limited verbal ability are common in autism. Even in the absence of intellectual disability, adaptive functioning is markedly impaired. Challenging behaviors, such as self-injury, may be more likely to occur in the presence of language impairment and may be an important treatment focus (14).

Comorbid Psychiatric Disorders

Individuals with ASD are often diagnosed as having comorbid disorders. It is estimated that approximately 20%−53% of individuals with ASD have an intellectual disability, with an IQ of ≤70 (15). Approximately 70% receive diagnoses of additional psychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), anxiety disorders, obsessive-compulsive disorder (OCD), depression, and schizophrenia. Nearly 40% are diagnosed as having two or more psychiatric disorders (16). Anxiety spectrum disorders may be the most common psychiatric conditions comorbid with ASD. Simonoff et al. (16) reported that 29% of their study participants met criteria for DSM-IV social anxiety. Leyfer et al. (17) found that 44% and 12% of individuals with ASD met DSM criteria for OCD and separation anxiety, respectively. Ghaziuddin et al. (18) observed that up to 30% of individuals with ASD met criteria for depression, especially those with higher IQ. There is some speculation that the anxiety and mood problems observed among individuals with ASD are the byproduct of their core symptoms rather than being truly comorbid disorders. Individuals with ASD are also prone to freezing behavior, with the highest risk period for comorbid catatonia in the adolescent years (19).

Comorbid Medical Disorders

Seizure disorder is the most common comorbid medical illness, with a range of 11%–39% among individuals with ASD (20, 21). Among individuals with ASD, there appears to be a bimodal distribution of epilepsy onset before age 5 years and during adolescence (22). Gastrointestinal problems are also commonly observed among individuals with ASD and have been reported for approximately 46%−85% of cases (23), with constipation or diarrhea being the most common symptoms. A cross-sectional study by Valicenti-McDermott et al. (24) showed that a lifetime history of gastrointestinal symptoms, which included abnormal stooling and frequent constipation, vomiting, and abdominal pain, was observed in 70% of children with ASD compared with 42% of children with other developmental disabilities and 28% of children without developmental disabilities. Sleep disturbances are also common among individuals with ASD and occur across all levels of intellectual functioning (25). At times, there may be a known underlying etiology such as obstructive sleep apnea or gastroesophageal reflux; however, it is also possible that sleep disturbance in ASD is secondary to psychiatric illnesses as in ADHD or anxiety disorder, or sleep disturbance may even be associated with whatever process is underlying ASD itself.

Etiology

Genetics

There is strong heterogeneity in the genetic architecture of ASD. It appears that a known or potentially causal genetic abnormality can be identified in approximately 10%−30% of individuals with ASD. These abnormalities include mutations, genetic syndromes, and de novo copy number variations (26–28). The importance of genetic factors is also clearly supported by family and twin studies. Concordance rates of monozygotic twins in studies of autism are 88% (29). Although there is strong heritability in the genetic architecture, much of the research suggests that genomic variation occurs de novo with chromosomal deletions and duplications (27, 28). These are distinct, individually rare genetic causes of ASD, indicating that ASD may be a syndrome associated with hundreds of genetic/genomic disorders, each accounting for a very small fraction of cases (30). Many of these genetic events, including CNTNAP2, SHANK, and NRXN, have roles in synaptic function. Of note, abnormalities in these genes are also implicated in the development of intellectual disability and do not always result specifically in ASD (31–33).

Among the most common of the genetic disorders associated with ASD are fragile X syndrome (1%), tuberous sclerosis complex (1%), and Rett syndrome (0.5%) (14). ASD may commonly be seen in the setting of Smith-Magenis syndrome and Timothy syndrome (34, 35), among many others.

Neuropathology and Neuroimaging

Postmortem studies of brain tissue acquired from individuals with ASD have shown increased brain weights but reduced numbers of neurons in the amygdala, cerebellum, and fusiform gyrus of the temporal lobe (36, 37). In addition, alterations in the basic columnar organization of the frontal and temporal lobes with diffuse ongoing inflammation throughout the brain have been observed in some brains (37, 38). However, relatively few brains are available for study, and organizations such as the Autism Science Foundation are supporting campaigns to expand and support neuroanatomical studies in ASD. Emerging technologies in brain imaging have shown some correlation of pathology with these initial postmortem studies.

MRI studies have supported Kanner’s initial clinical description of large head size in autism, showing increased head circumference in 20%−30% of children with ASD, defined as 2 SD above the mean (39). However, children who later develop ASD have been observed with average to below-average head circumference at birth, with acceleration in brain growth during the first year of life, perhaps leading to above-average head circumference (40). Research studies using diffusion tensor imaging have started to delineate white matter abnormalities at a microstructural level in ASD (41).

Functional magnetic resonance imaging (fMRI) research has shown that individuals with ASD use different brain areas to process certain types of information during cognitive tasks. For example, during the task of facial recognition, hypoactivation of the fusiform gyrus and abnormal amygdala activation have been consistently reported (42). In addition, research from fMRI studies suggests impaired “connectivity” between various cortical regions among individuals with ASD (43). Mirror neuron systems that are located in several areas of the brain have been implicated in the activity of empathy, imitation, and language use by firing during the activity of observing another person’s actions. During a controlled fMRI study, researchers observing the task of imitation and emotional facial expressions have consistently found reduced activation of mirror neuron systems among children with ASD versus children in a control group (44). Although consistent, none of these findings are unique to ASD and thus would not appear to serve diagnostic utility.

Environment

Established environmental associations with ASD include advanced parental age, low birth weight, and gestational diabetes. Birth complications and fetal exposure to valproate also increase the risk for ASD. There is a growing interest in research exploring environmental factors that might interact with pathways that appear to be important in the development or expression of ASD. For example, Pessah and Lein (45) explored ways in which environmental agents may interfere with GABA, acetylcholine, and calcium signaling pathways. Pessah and Lein postulated that the genetically vulnerable pathways observed in ASD may lower the threshold for which environmental factors may be tolerated, leading to a variability of severity in symptoms across populations based on the particular genetic predisposition.

Diagnosis

The typical path to an ASD diagnosis starts with “red flags” raised by parents, teachers, early educators, and pediatricians. For early detection of ASD, two measures have good psychometric profiles for screening and are often used by clinicians: the Modified Checklist for Autism in Toddlers (sensitivity=0.77–0.97 and specificity=0.38–0.99) and the Infant-Toddler Checklist (sensitivity=0.86–0.89 and specificity=0.38–0.99) (46, 47). A positive result would warrant further testing; therefore, these instruments were intended to generate more false-positive results, with the understanding that a negative test result would necessitate further evaluation. Because of the strong variability of ASD symptomatology, various instruments that facilitated structured observation have been recognized as particularly helpful. The most commonly used of these instruments is the Autism Diagnostic Observation Schedule (specificity=0.72–1.0 and sensitivity=0.72–0.98, depending on age and severity). The Childhood Autism Rating Scale–Second Edition also shows good validity and reliability ratings, with sensitivity and specificity each at 0.82–0.95 (depending on age and severity) (48, 49).

ASD is and has always been a clinical diagnosis. It is important to take into account all available data. Although rating scales are extremely helpful in gathering and standardizing data, the diagnosis ultimately rests with the well-trained clinician and is not defined by a single test or symptom.

Treatment

There is no known medical agent that directly treats the core symptoms of ASD. Rather, current treatments target the frequent psychiatric and medical comorbidities and the interfering behavioral symptoms associated with ASD. To mitigate the effect of core symptoms of ASD, best practice aims to facilitate the acquisition of skills, remove barriers to learning, and improve adaptive functioning through a multidisciplinary approach of behavioral interventions and psychopharmacology.

Behavioral Interventions

The most formative management of autism has been early intervention and education. In 1987, Ivar Lovaas was among the first to elaborate on the concept of applied behavioral analysis (ABA) in autism. ABA is a method of empirically deriving learning principles to produce meaningful changes in behavior (50). The implementation of ABA techniques has produced language, cognitive, and adaptive skills when applied in a variety of settings, including home, school, and clinical environments. Meta-analyses support significantly improved outcomes associated with early intensive ABA-based treatment, with effect sizes of 0.30–1. These gains are generally not in core autism symptom domains and instead appear to be greatest in verbal IQ and language communication, with the strongest gains observed with early intervention (51, 52). Overall, studies are generally few and had small sample sizes. Models vary by how ABA principles are implemented and generalized. Different approaches focused more on discreet targets known to be important in ASD (e.g., joint attention and engagement) are showing clear promise (53). Parent behavioral intervention training for challenging behaviors has also been demonstrated to be helpful in ASD (54). In general, there remains a great need for research on psychosocial treatments as well as treatment programs for older children, adolescents, and adults with ASD.

Pharmacologic Interventions

Although clearly of interest, there are currently no medical agents demonstrating effectiveness for addressing core symptoms of ASD. Some clinical trials have addressed the efficacy and safety of the major classes of psychotropic agents, including antipsychotics, selective serotonin reuptake inhibitors (SSRIs), α₂ adrenergic agonists, stimulants, and sleep agents. Studies of novel treatment strategies based on mechanism are in the pipeline. For example, several animal models of genetic disorders associated with ASD, including fragile X syndrome, tuberous sclerosis complex, and Rett syndrome, suggest that an imbalance may exist between excitatory and inhibitory brain systems in these conditions. Pharmacologic interventions targeting glutamate receptors, both agonists and antagonists, are being explored. Oxytocin is a hormone that has been shown in animal models to have a significant role in affiliative behavior; preliminary evidence in ASD showing that oxytocin may improve social communication is also prompting exploratory clinical trials.

Antipsychotics.

Risperidone and aripiprazole are the only agents with U.S. Food and Drug Administration–approved indications for treating irritability in the ASD population (55). Using the Aberrant Behavior Checklist Irritability subscale as a primary outcome, several studies have shown that there is clinically meaningful improvement and superiority for risperidone and aripiprazole relative to placebo (56, 57).

SSRIs.

The evidence for efficacy of SSRIs in the treatment of repetitive behavior is inconclusive to absent. The largest clinical trial for repetitive behaviors in ASD found no effect of citalopram and its use was associated with adverse effects, including increased energy level, impulsivity, hyperactivity, and insomnia (58). A secondary analysis suggested that a small signal might be present for individuals with higher symptom burden (59). Smaller double-blind, placebo-controlled trials have suggested the efficacy of fluoxetine and fluvoxamine (adults) in the treatment of repetitive and other maladaptive behaviors among patients with ASD (60, 61); however, results of a large, unpublished trial of fluoxetine for children and adolescents were negative. There is sparse literature supporting the use of SSRIs to treat anxiety and depression among individuals with ASD, yet these drugs remain among the most widely prescribed of all of the classes of psychotropic medications in this population (62).

Stimulants, α₂ adrenergic agonists, and atomoxetine.

There are randomized controlled trials of methylphenidate that support its use in the ASD population with ADHD comorbidity. Relative to the general population with ADHD, however, the effect size is smaller for stimulants in ASD, and there is a significantly increased likelihood of side effects (63). Results of a recent study of extended-release guanfacine for children with ADHD and ASD were positive (64). Atomoxetine use for hyperactivity in ASD is also supported by controlled trials (65, 66).

Sleep agents.

There is good evidence to support the use of melatonin for initial insomnia. A meta-analysis noted positive effects on initial insomnia compared with placebo among patients with ASD, showing an improvement of 73 minutes in overall sleep and 66 minutes in sleep onset (67).

Prognosis

There is a paucity of literature elucidating the prognosis of the ASD population into adulthood. Studies of outcomes among adults with ASD consistently show low to modest levels of independence or social inclusion among both higher- and lower-functioning individuals. The core symptoms of ASD—as well as the challenging, associated behaviors—have largely been observed to persist into adulthood. The most recent surveys approximate that 45%−75% of adults with ASD are treated with psychotropic medication (68,69). Greater age, lower adaptive skills, and higher levels of challenging behavior are associated with the likelihood of medication use. There have been some studies to substantiate increased mortality risk for individuals with ASD. A 2008 Danish study showed that the mortality risk for individuals with ASD was twice that of the general population (70). A 2010 longitudinal prospective study showed that this elevated mortality risk was closer to 6% in the United States (71). A 2011 study investigating the death of persons with ASD with and without seizure disorder showed that there was a higher-than- expected risk of mortality associated with seizure disorder than with ASD alone (72).

Future Outcomes

The field is moving forward with attempts to better understand ASD as well has how best to treat the disorder and its associated symptoms. Growing knowledge of specific genetic risk factors has revealed new therapeutic targets, and there are already novel drugs in development. There are also increasingly targeted behavioral and psychosocial interventions that are being developed and studied. Access to timely care remains a significant problem for many families, but changes in insurance coverage are enabling the provider pool to expand. In the future, as we come to understand the many pathways that lead to the diagnosis of ASD, we will most certainly come to a similar understanding of the pathways out.