Autism Spectrum Disorder (Comprehensive Concise)

Autism Spectrum Disorder (ASD)

Overview

Characterized by persistent issues in social interaction, difficulties with change, and unusual responses to the environment.
DSM-5 uses the term "autism spectrum disorder (ASD)" to reflect the broader range of difficulties, corresponding to the DSM-IV diagnosis of autistic disorder but is somewhat narrower.
DSM-5 includes social communication disorder for problems in social (pragmatic language) communication.

Definition

ASD encompasses concepts previously recognized in DSM-IV as part of pervasive developmental disorder.
The triad of impairments (social interaction, communication, and repetitive/restricted interests/behaviors) is collapsed into two domains:
- Social communication (all four criteria must be met).
- Restricted and repetitive behaviors (at least two of four criteria must be met).
Sensory problems are included in the latter group.
Difficulties must be present from early childhood.
Individuals with established diagnoses of Asperger disorder or PDD-NOS can keep their label.
DSM-5 provides specifiers (e.g., etiologic factor, levels of support from levels 1-3, intellectual disability, language impairment, or catatonia).
DSM-IV had over 2,000 possible combinations of criteria for diagnosis, while DSM-5 has only 12.
DSM-5 takes a narrower view of autism, with higher cognitively functioning individuals and able younger children at risk of losing a diagnosis as $80\%$ of the higher cognitively functioning cases that previously would have had diagnoses of Asperger’s or PDD-NOS lose their diagnosis with DSM-5.
The new social communication disorder does not simply correspond to Asperger’s or PDD-NOS.

History

Leo Kanner (1943) first described autism, noting innate difficulties in affective contact and insistence on sameness.
He observed stereotyped motor mannerisms and communication deficits (echolalia, unusual voice, pronoun problems, pragmatic difficulties).
Hans Asperger reported on boys with social difficulties, good verbal abilities, circumscribed interests, and motor difficulties.
Asperger's work broadened the spectrum of autism and prefigured interest in genetic factors.

Diagnostic Criteria

A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history:
- 1. Deficits in social–emotional reciprocity.
- 2. Deficits in nonverbal communicative behaviors used for social interaction.
- 3. Deficits in developing, maintaining, and understanding relationships
B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history:
- 1. Stereotyped or repetitive motor movements, use of objects, or speech.
- 2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal–nonverbal behavior.
- 3. Highly restricted, fixated interests that are abnormal in intensity or focus.
- 4. Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment.
C. Symptoms must be present in the early developmental period.
D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.
E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay.

Severity Levels for Autism Spectrum Disorder

Level 3 “Requiring very substantial support”
- Severe deficits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others.
- Inflexibility of behavior, extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres. Great distress/difficulty changing focus or action.
Level 2 “Requiring substantial support”
- Marked deficits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or abnormal responses to social overtures from others.
- Inflexibility of behavior, difficulty coping with change, or other restricted/repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in a variety of contexts. Distress and/or difficulty changing focus or action.
Level 1 “Requiring support”
- Without supports in place, deficits in social communication cause noticeable impairments. Difficulty initiating social interactions, and clear examples of atypical or unsuccessful response to social overtures of others. May appear to have decreased interest in social interactions.
- Inflexibility of behavior causes significant interference with functioning in one or more contexts. Difficulty switching between activities. Problems of organization and planning hamper independence.

Comparative Nosology

Before DSM-III, autism was considered a form of childhood schizophrenia.
DSM-III (1980) officially recognized autism.
DSM-III-R proposed a more developmentally oriented definition.
DSM-IV included 12 criteria in three sets, Asperger disorder, Rett and childhood disintegrative disorder (CDD), and PDD-NOS.

Epidemiology

Early studies suggested autism was rare (1 per 2,000), but current estimates are about 69 per 10,000 (1 in 145 children).
Increased rates are associated with better services and public awareness.
Males are affected three to five times more often than females.
Observed gender rates and differences: Increased severity in females with classic autism and potential underdiagnosis in able females.
Autism is seen in all cultures and levels of ability.

Etiology

Psychosocial Theories

Early theories focused on “refrigerator” mothers, but structured teaching and behavioral methods proved superior.
More recent theories address atypical cognitive and behavioral profiles:
- Theory of mind deficits (inability to attribute mental states to others).
- Weak central coherence (diminished drive to integrate details into coherent wholes).
- Executive dysfunction (difficulties in attention shifting, working memory, inhibition, abstraction, and processing multiple cues).
These theories lack unequivocal support and are challenged by developmental changes and variable outcomes.

Biologic Theories

Children with ASD are at high risk for seizures.
They may exhibit neurobiologic soft signs and biochemical abnormalities (e.g., delayed hand dominance, persistent primitive reflexes, high serotonin levels).

Genetic Factors

Twin and family studies demonstrate a central role of genetics.
Monozygotic twin concordance rate for autism is about $60\%$ , and for BAPs is $80\%$ to $90\%$ .
Rare mutations with significant biologic effects, CNVs, and common genetic variants that confer small effects contribute to risk.
Associated variants overlap with those in schizophrenia and major depression.
Discovered genes converge on chromatin modification, synaptic and signaling proteins, and targets of FMRP and underscore the importance of midfetal human cortical development.
Rare, de novo variations in non-protein-coding regions carry risk.
Identical genetic variations may increase liability for a broad range of neurodevelopmental disorders.
Epigenetic mechanisms and environmental factors may also be important.

Other Medical Conditions and ASD

Associated with conditions like Fragile X syndrome (FXS).
A triplet repeat of cytosine–guanine–guanine in the regulatory domain of the gene FMR1is founded in most cases.
Novel conditions are being identified through a genotype-first approach (e.g., mutations in CHD8).
The success of identifying novel conditions for ASD using this “genotype-first” approach will help refine the autism spectrum and allow development of more targeted treatments or interventions for ASD.

Pre-, Peri-, and Neonatal Factors

Increased rates of complications are observed.
Genetic predisposition may interact with perinatal factors.

Other Etiologies

The precise mechanisms remain to be specified, and this is an area of active work although there is clearly a very strong role for genetic factors in the pathogenesis of autism, there is at least some potential role for environmental factors.

Postmortem and Neuroimaging Studies

Neuroimaging and Brain Development

MRI studies have contributed greatly to understanding brain structure and function in ASD.
Case-control designs compare individuals with ASD to typically developing controls (TDCs).
ASD is heterogeneous, with varying severity and co-occurring conditions.
Studies may not replicate due to heterogeneity and inadequate sample size.
Individuals with ASD tend to have enlarged heads.
MRI studies find total tissue volume $6\%$ larger in individuals in the ASD group than the control group.
Total tissue volume size increase includes both gray and white matter.
IBIS shows axonal fibers development is blunted in ASD between 6 and 24 months in ASD.
Beginning of development of ASD before the end of the first year of life.
White matter microstructural abnormalities appear at 7 months.
Frontal and temporal regions are often the most enlarged.
White matter is disproportionately enlarged, supporting disrupted connectivity.
There is decreased cross-sectional width of the corpus callosum.
Frontotemporal and frontoparietal regions contribute the most to increased brain volume.
Brain overgrowth begins in the first few years of life, normalizing by adolescence.
Synaptic pruning is deficient in individuals with ASD, with hyperactive mTOR impairing the ability to prune synapses.
Cortical thinning accelerates with age in frontal and temporal lobe regions.

Functional Neuroimaging

fMRI studies paint a complex picture of brain functioning differences in ASD.
Signals come from blood oxygen level changes accompanying neural activity.
Task-based fMRI studies test hypotheses about hypo- or hyperactivity in specific brain regions (e.g., amygdala).
Theories suggest disturbances in various neural systems are underlying mechanisms of ASD that have significant effects of brain functioning.
Replicated studies indicate the role of specific brain areas whose functions are atypical in ASD.
Face perception and the fusiform gyrus (FFG) are often underactive in ASD.
The amygdala and reward system may be hypoactive with functional synchronization with the limbic system.
The orbital prefrontal cortex plays a key role in emotional learning.
There is increased attention given to task-free fMRI studies, most notably what has been termed resting state (rs-) fMRI (rs-fMRI).
There is underconnectivity in the brains of individuals with ASD.
The Human Connectome Project will allow connectivity matrices derived from graph theory on resting state and diffusion data from individuals with ASD to be compared to several other groups, including, for example, typical development, Alzheimer, and ADHD.
rs- fMRI is an important component of a major NIH initiative—the Human Connectome Project, which contains various compotents:
- The Human Connectome and related endeavors will allow connectivity matrices derived from graph theory on resting state and diffusion data from individuals with ASD to be compared to several other groups, including, for example, typical development, Alzheimer, and ADHD.
- One of the most relevant components of the Human Connectome Project for understanding ASD involves exploring, in unprecedented detail, how the brain typically grows and connects during childhood and the transition through puberty to adolescence and young adulthood. The Lifespan Human Connectome Project Development (HCP-D) Study is currently enrolling 1,300+ healthy children, adolescents, and young adults (ages 5 to 21) to discover how different parts of a child’s brain are connected and how these connections (the “connectome”) change as the brain develops. Characterizing brain development in healthy children will also allow us to better understand differences that can occur in children with ASD.
- Similarly, data collection is now ongoing for a large- scale, two-site longitudinal baby connectome project. The study includes 500 participants who will be studied with brain imaging and behavioral phenotyping at four to six visits from birth to age 5 years. These longitudinal, developmental studies are providing the basis for a developmental perspective (i.e., early and longitudinal study of brain and behavioral development) on the cognitive neuroscience of ASD.
- The developmental connectome studies will document the changes in brain functional connectivity as a function of the infant/child’s age and sex and also detect changes in connectome during critical periods of childhood before, during, and after major developmental transitions.
- Finally, fMRI might actually provide a means to better quantify treatment effectiveness and reveal whether behavioral improvements correspond to compensatory changes in brain function or normalization of developmental pathways.

Connectome-Based, Individual Differences and Prediction

The human brain is a complex dynamic system, and it is notoriously difficult to build comprehensive theoretical models for even simple neurobiologic and cognitive processes.
With these challenges in mind, the advent of technologies in machine learning from computational sciences and graph theory from mathematics have sparked new modeling approaches in cognitive neuroscience.
One particularly influential modeling approach is the connectome- based predictive model (CPM).
Irrespective of nuisance artifacts such as head motion or anatomical differences. This will allow the field of ASD neuroimaging research to move beyond case-control studies to fully explore the heterogeneity of ASD.

Understudied Groups in ASD Neuroimaging

The majority of ASD research has focused on individuals with relatively intact language and cognitive functioning, resulting in expressions of more severe phenotypes being understudied. ASD + MV may display abnormalities in preattentive auditory perceptual processing and structural deficits in brain structures that support expressive language function.
Recent developments in imaging genetics of variants linked to ASD + ID (e.g., FMR1, NRXN1, CNTNAP2) suggest that these variants may shape brain structure in predictable but often opposing ways, indicating the need to take genotype into account in future ASD + ID work.

Neurochemistry

Approximately one-third of children with ASD have increased peripheral levels of serotonin.
Hyperdopaminergic functioning might explain overactivity and stereotyped movements.
Opioid antagonists like naltrexone have shown disappointing results overall.
Work has centered on agents like oxytocin that may impact attachment and social brain systems.

Immune Theories of ASD

There is no evidence that vaccines cause autism.
Maternal immune activation (MIA) models suggest maternal immune dysregulation contributes to ASD.

Diagnosis and Clinical Features

DSM-5 requires three social communicative features and at least two restricted/repetitive features.
Symptoms must be present from early childhood and cause clinically significant impairment that have various additional codes that can be used to denote specific features such as intellectual delay or catatonia that cannot be better explained by any intellectual difficulty.
Individuals with previously “well-established” DSM-IV diagnoses can retain a diagnosis in DSM-5.
For cases in which there are major problems in social communication but who do not meet criteria for autism, the new category of social communication disorder can be considered.
Misdiagnosis is possible, particularly at extremes of age and cognitive functioning.
Evaluation includes detailed history, medical/genetic examination, developmental assessment, and psychological testing.
Age of onset is early, with parental concern around 12–18 months or parents may report that the infant is “too good”.
A developmental regression/stagnation may be reported in $20\%$ or so of cases or DSM-IV type Asperger’s may not be picked up until the child enters preschool and social difficulties with peers become striking.

Impairments in Social Communication

Infants with ASD show less interest in social interaction.
Language may fail to develop, or difficulties such as echolalia, pronoun problems, and pragmatic deficits may emerge.

Restricted Activities and Interests

Children with ASD have problems with change and routine.
Areas of interest remain highly restricted.
Repetitive and stereotyped movements are frequent.

Associated Features

Up to $33\%$ of children with ASD meet criteria for intellectual disability that reflects an uneven cognitive profile, with peaks and valleys at the subtest level.
Adaptive functioning skills lag behind mental age.
Savant or “splinter” skills may be present.
Reduced social engagement and motivation may contribute to difficulties in understanding and relating to the social world that might constrain engagement in social experiences, thus altering the developmental trajectories of neural specialization and behavioral expertise in the social domain.

Motor and Sensory Abnormalities

Motor abnormalities include delayed walking, gait abnormalities, and motor stereotypies.
Atypical perception of and response to sensory information involving hypo- and hypersensitivity.

Physical Characteristics

Higher rates of minor physical anomalies are observed.
Toddlers with autism may develop macrocephaly.

Pathology and Laboratory Examination

EEG abnormalities are observed, particularly with intellectual deficiency.
Seizures can have their onset at any time in the developmental period.
Laboratory tests may be relevant, with screening for associated genetic conditions (identifying factors in 10–20% of cases).

Differential Diagnosis

Includes other neurodevelopmental disorders, intellectual deficiency, language-communication disorders, and primary intellectual deficiency.
Visual and hearing difficulties should be evaluated.

Course and Prognosis

ASD is typically a lifelong disability, but outcomes are improving with earlier intervention.
There are cases of “optimal outcome” and those with severe intellectual disability can still make gains to maximize self-sufficiency to the degree possible.
Vocational challenges and mental health issues can be a source of difficulty.
Factors associated with better long-term outcome include presence of communicative speech by the age of 5 or and nonverbal IQ above 70
.

Treatment

No treatment reverses core symptoms, but interventions can improve language, communication, cognitive, social, and adaptive functioning.
Effective approaches use behavioral, developmental, and special education principles applied in a comprehensive and individualized manner.
Intervention goals must be updated periodically based on progress and consideration of evolving age- and context- specific needs and challenges.
Intensity and timing of intervention are important factors in shaping outcomes, with children receiving intervention at a younger age and more intensively (i.e., 15+ hours per week), showing better intervention response.
Many evidence-based practices use principles and procedures derived from applied behavior analysis (ABA).
Visual and/or augmentative approaches may facilitate communication like using visual cues
(e.g., giving a partner a picture of an item in exchange for the actual item) or electronically generated sounds that are designed to address difficulties in understanding language or using speech.
These include (1) timeliness (the earlier, the better), (2) intensity, (3) use of manualized and clearly operationalized instructional strategies, (4) focus on the core features of ASD, including sensory issues, as well as functional/adaptive skills, (5) assessment procedures to generate and update individualized sets of goals, (6) collection systems to monitor progress and implementation fidelity, (7) involvement of caregivers in establishing treatment goals and delivering intervention, (8) developmental appropriateness and developmental sequencing of goals (i.e., teaching age-appropriate skills and their developmental prerequisites), (9) promoting the individual’s active engagement and communicative intent, (10) incorporating intervention strategies and opportunities in everyday routines,
(11) thoughtful environmental arrangements (including minimizing distractions/maximizing focus toward salient stimuli), (12) creating predictable and consistent routines and experiences, with a balance between structure and novelty to support flexibility, (13) incorporating the individual’s special interests when possible, and provision of reinforcements that are meaningful to the individual, (14) use of task analysis to break down complex functional skills into teachable steps, (15) use of scripts, visual supports, and practice opportunities to remind the individual about the steps involved in the targeted skill (e.g., rehearsing the steps involved in buying groceries through visual scripts and supported role-playing), (16) focus on generalization skills (e.g., using the skills acquired in a therapy sessions at home and school), (17) addressing challenging behaviors through the systematic analysis of their function, and teaching more desirable behavioral alternatives, (18) using prompts to facilitate the individual’s response to the instruction, while also fading supports over time to promote autonomy.
Psychopharmacology can be used for medication to be of significant benefit for other features such as irritability, overactivity, aggression, and self-injury.
Antipsychotics may produce decreased irritability and agitation. More recently atypical neuroleptics have been utilized that can reduce agitation and other problematic behaviors.
Selective Serotonin Reuptake Inhibitors several studies using placebo control methods have shown benefits for repetitive behaviors and impulsive aggression.
Stimulants can be applied to many school-aged children exhibit significant problems with attention and overactivity, side effects may be higher than in the general pediatric population.
Complementary and Alternative Treatments These are frequently used by parents although, by definition, they lack a strong evidence base.