AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

The autistic spectrum disorders are a neurobiologically diverse group of conditions whose precise relationship to each other is unclear, yet they present with a consistent, diffuse pattern of abnormality across several areas of behavior. Individuals with these disorders do not present merely with slow or limited development, but rather with development that is atypical in the pervasive but diffuse areas of functions affected.

Three main clusters of behaviors define autism, as follows: (1) social abnormalities, especially a lack of social reciprocity; (2) language abnormalities, with deviant communication features and limited development of language; and (3) rigid, stereotyped, repetitive patterns of unusual behavior.

Case reports consistent with autism exist from the 1890s, but Kanner first defined the syndrome in 1943, as did Asperger a year later.

The Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III), published in 1980, offered the first official definition and description of autism in the United States.

The prevailing public face of autism comes from the movie Rain Man in which actor Dustin Hoffman played an adult with autism with not only the behavioral rigidity, peculiar language, and social abnormality characteristic of the syndrome but also the savant abilities present in a quarter of individuals with autism who also have an intelligence quotient (IQ) of at least 35. Autistic spectrum disorders include autistic disorder, Asperger disorder, PDD not otherwise specified (PDD-NOS), Rett disorder, and childhood disintegrative disorder.

Pathophysiology

Despite extensive investigation, no consistent pattern of the cause of autism has emerged. In fact, more than 60 different disease entities have been shown to be likely causes of autism, including genetic, infectious, endocrine, toxic, and space-occupying etiologies. This suggests that autism is a final common clinical presentation of a variety of underlying neurobiological and genetic processes.

The rest of this section presents some of the many proposed mechanisms behind the development of autism.

Although abnormalities have been reported on every chromosome as associated with autism, some of the more common genes of interest are on the X chromosome. This makes intuitive sense, as the incidence of the disorder is much higher in males, and they have only one X chromosome. Genes of interest on the X chromosome include FMR1 (fragile X) and FMR2 (FRAXE syndrome), MECP2 (Rett syndrome), ARX, NGLN3, and NGLN4. The 22nd chromosome is also of particular interest, with sites at band 22q11 and 22q13 responsible for velocardiofacial syndrome, DiGeorge syndrome, and adenylosuccinate lyase deficiency. Interest in mitochondrial DNA is growing, as a recent unreplicated Portuguese study had estimated that more than 7% of children with autism have mitochondrial disease.

The first biochemical abnormality discovered in autism was found in 1961 in a group of 23 patients, one third of whom were reported to have high levels of whole blood serotonin. Subsequent studies have confirmed this observation, as well as noting that about 5% of autistic children instead have low levels of serotonin. The significance of this is still unclear, but one explanation is that these abnormalities may be secondary to still another etiology. When certain disorders associated with autism are treated, the associated serotonin abnormality disappears; this happens when treating hypothyroidism with thyroid hormone and when treating phenylketonuria (PKU) with a low phenylalanine diet.

Endogenous brain opioids are suggested to be increased in autism, but studies have shown both increased and decreased levels of opioids in different case series. Some open clinical trials suggest that naltrexone, an opioid antagonist, can affect the core symptoms, but these findings have not been replicated. A subsequent controlled trial of naltrexone showed no impact on core symptoms.

Vasopressin and oxytocin have been shown to play a role in social attachment, but no evidence exists as yet of such problems in autism. Studies of the dopaminergic, noradrenergic, and neuropeptide systems do not reveal evidence of consistent abnormalities.

Searches for structural abnormalities produce similar inconsistent results. Abnormalities of the ventricular system are reported, but these abnormalities are neither consistent nor specific. The frontal lobes, the insula, the limbic system, the corpus callosum, the thalamus, the brainstem, and the cerebellum have all had reported structural and/or functional abnormalities noted in autism, but again, no location has a consistent pattern of dysfunction. A current belief is that autism may more likely reflect abnormalities within a particular neural system or multiple neural systems, which are the connected networks of a variety brain regions.

Several immune dysfunctions were detected, including anomalies in cell-mediated immunity, with some measures inversely correlated with severity of autistic symptoms. Abnormally elevated interferon-alpha levels, antibodies against myelin basic protein, and antibodies in both subjects and first-degree relatives to neuron-axon filament proteins also have been found. Allergic reactions may play a role, as autistic children have increased eosinophil and basophil response to immunoglobulin E (IgE)–mediated reactions. Finally, enhanced immune response to viral infections, with autoimmune activation, is postulated. All together, these and other findings suggest depressed immune function, autoimmune mechanisms, or faulty immune regulation may be associated with the etiology of autism, but the causal connection between immune changes and autistic symptoms has yet to be made.

Abnormal electroencephalogram (EEG) results can be found in as many as 43% of individuals with autism, particularly in those with lower IQs. Seizures are estimated to occur in as many as 30% of children with autistic disorder. A few epileptic syndromes are clearly linked to the diagnosis of autism, including tuberous sclerosis, Lennox-Gastaut, West syndrome, Landau-Kleffner syndrome, and pyridoxine-dependent seizures. However, the authors' experience with seizures in autism has not generally led to better understanding of the origin of autistic symptoms.

The pathophysiology of childhood disintegrative disorder and Asperger disorder is unknown, although Asperger disorder appears to follow a familial transmission pattern. Associated disorders like seizures are less common in Asperger disorder than in autism.

Rett disorder is transmitted as a dominant X-linked illness with full or nearly full penetrance, with early death of most male fetuses through spontaneous abortion. Diffuse generalized atrophy of the cerebrum and cerebellum is present, with nonspecific, generalized EEG abnormalities present by age 2 years. Mutations in MECP2 gene (methyl-CPG-binding protein 2) are present in 80% of classic Rett disorder patients, with recent reports of CDKL5 gene mutations present in some of the MECP2 negative cases. Phenotypic variability in Rett syndrome is now thought to be related to X chromosome inactivation patterns and variations in the location of the mutation. Autism cases without Rett features have been shown to not have mutations in MECP2, further confirmation that Rett syndrome and autism are separate entities.

Frequency

United States

Current estimates are that slightly more than 0.1% of the general population has classic autism by DSM-IV criteria. When the full autism spectrum is viewed, the prevalence is higher, with 0.3-0.7% having the disorder: Asperger disorder is estimated to occur in 0.2-0.5% of school-aged children, Rett disorder occurs in 5-15 girls per 100,000, and childhood disintegrative disorder occurs with a frequency of 1-4 cases in 100,000. Prevalence rates of autistic disorder in more recent studies have been noted to be as much as 40 times higher than past studies, but this does not necessarily mean that the true prevalence of the disorder is increasing. This is because more recent studies are performed in an environment of higher awareness of the disorder and use more inclusive diagnostic criteria. Remember that as recent as the 1970s, autistic children were more commonly labeled as "psychotic," thus making comparisons with this era of data highly suspect.

International

Depending upon diagnostic criteria used, rates are similar to those in the United States.

Mortality/Morbidity

Increased mortality is seen in autism, with a risk that increases with age, and it is observed to be an even greater problem with females with the disorder. The increased mortality may be due to associations with severe mental retardation and other medical conditions, such as epilepsy. Mental retardation is present in 75% of affected individuals. Depending on the population studied, epilepsy develops in 4-42% of affected individuals, with some of the increased rates due to associated mental retardation. The course of illness is often unpredictable. A gradual clearing of some of the symptoms can occur in adulthood but with the persistence of residual deficits. An intellectual decline can occur during adolescence. Depending on severity, 2-17% of patients may achieve a nonretarded level of cognitive and adaptive functioning. Marriage is rare, but as they mature, adult patients may have greater success in achieving employment and developing the capacity for independent residence.

Studies have shown 3 consistent factors that relate to improved outcome: (1) higher IQ, (2) presence of speech, and (3) overall severity of disorder. Mentally retarded autistic individuals who have not gained useful verbal communication by age 5 years are unlikely to live independently as adults. Intensive early preschool intervention of 25 or more hours per week with either applied behavior analysis (ABA) or other therapies focused on improving functioning (language and social interactions) have been shown by a few well controlled and many more retrospective studies to improve outcomes.

Sex

• Male-to-female ratio for autism is 3:4. Female prevalence increases as disease severity increases.
• Asperger disorder and childhood disintegrative disorder show a similar male-to-female ratio of about 4:1.
• Rett disorder was previously believed to never occur in males, but case reports and improved genetic studies have now shown this is possible.

Age

In most cases, these disorders can be detected and distinguished from other forms of developmental delay before age 3 years. Parent interviews and videotapes have demonstrated manifestations as early as age 12 months. Parental concern develops at the mean child age of 19 months, and they first seek professional advice at a mean child age of 24 months.

• Childhood disintegrative disorder typically develops in children aged 3-4 years, while Rett disorder becomes apparent in children aged 18 months to 4 years. Individuals with Asperger disorder may have delayed detection because of the greater subtlety of presentation.
• According to some parents and investigators, a subset of children have social and verbal regression between age 2 and 5 years that heralds the onset of more typical autistic symptoms. These children, due to their atypical presentation, are among those labeled as PDD-NOS.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

Diagnosis of autism

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), from which the symptom list below is taken directly, requires the presence of at least 6 of the below symptoms and at least 1 item from each of the 3 symptom groupings. In addition, at least 2 symptoms must come from the social impairment group of symptoms. Delays or abnormal functioning as depicted in any one of the symptom groups must be present by age 3 years. This means that patients with autism have impairments in social interactions, in communication, and in patterns of behavior.

• (Group 1) Qualitative impairment in social interaction, as manifested by at least 2 of the following:
  • Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction
  • Failure to develop peer relationships appropriate to developmental level
  • A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (eg, by a lack of showing, bringing, or pointing out objects of interests)
  • Lack of social or emotional reciprocity
• (Group 2) Qualitative impairments in communication as manifested by at least 1 of the following:
  • Delay in, or total lack of, development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gestures or mime)
  • In individuals with adequate speech, marked impairment in the ability to initiate or sustain conversation with others
  • Stereotyped and repetitive use of language or idiosyncratic language
  • Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level
• (Group 3) Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least 1 of the following:
  • Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or in focus
  • Apparently inflexible adherence to specific, nonfunctional routines or rituals
  • Stereotyped and repetitive motor mannerisms (eg, hand or finger flapping or twisting, or complex whole body movements)
  • Persistent preoccupation with parts of objects

• Characteristic deviant communication features in autism include a lack of social chat, pragmatic deficits, pronoun reversal, delayed echolalia, neologisms, lack of emotion in speech, phrase repetitions, and idiosyncratic use of language. Behavioral manifestations frequently involve repetitive, self-stimulatory behavior, especially in more severely affected individuals. This behavior can be self-injurious in some, as with arm biting, head slapping, and skin picking.
• Childhood disintegrative disorder is characterized, in contrast, by normal development for at least 2 years, followed by loss of previously acquired skills in language, social skills, bowel or bladder control, play, and motor skills, while presenting with the autistic triad of abnormal communication and social interaction and repetitive, stereotyped behavior.
• Rett disorder is characterized by normal development for 7-18 months, followed by rapid deterioration of behavior and mental status, deceleration of previously normal head growth, loss of hand skills and social engagement (both of which were developing normally), the appearance of poorly coordinated gait or trunk movements, and the development of severe impairment of language and psychomotor retardation. Abnormal sleep patterns have been noted to develop as early as age 4 months, heralding the change in developmental trajectory.
• Individuals with Asperger disorder are often seen as having a milder version of autism. Similar to autism, patients with Asperger disorder have restricted and stereotyped behavior patterns and interests, plus significant social impairments. However, unlike autism, patients with Asperger disorder have much less impairment in cognitive development and have no significant general delay in language development.
• PDD-NOS is diagnosed when no other specific autistic spectrum disorder can be diagnosed, but a severe and pervasive impairment in relating to others still is present. In addition, to receive a PDD-NOS diagnosis, either (1) verbal or nonverbal communication difficulties or (2) stereotyped behaviors or interests should be present.
• Some controversy exists of the difference between PDD-NOS and Asperger disorder. DSM-IV-TR actually gives both diagnoses the same diagnostic code (299.80), though it states that the PDD-NOS label cannot be used if any of the more specific autistic disorders can be diagnosed. PDD-NOS has the broadest definition in the category: impairment in 2 of 3 autistic symptom clusters (difficulty relating to others, communication problems, and repetitive behaviors) makes the diagnosis.
• In addition to the specific disorders included in DSM-IV-TR, evidence from genetic studies (see Causes) suggests that many family members of autistic persons have a broader autistic phenotype with milder features and characterized by (1) less severe stereotyped repetitive behaviors, (2) more subtle social deficits, (3) normal intelligence, (4) the lack of abnormal language features (including pronoun reversal and echolalia), and (5) lack of association with epilepsy.
• Reading the DSM-IV-TR criteria carefully is advisable when making an autistic spectrum diagnosis.

Physical

Overall, relatively little is found on physical examination other than the characteristics of comorbid conditions, where present, such as fragile X syndrome or tuberous sclerosis.

• A neurological examination can screen for possible inborn metabolic and degenerative diseases.
• Head circumference is greater than the 97th percentile in 25% of individuals with autistic disorder; arrest of head circumference growth in Rett disorder can occur in children older than 5 months.
• Motor clumsiness may occur, especially with Asperger disorder.
• A slight increased risk of nonspecific minor congenital abnormalities exists.
• Mental status examination findings include poor eye-to-eye gaze, lack of social interaction, stereotypic and repetitive use of language, inability to carry a conversation, preoccupation with a few stereotyped patterns of interest, and stereotyped and repetitive motor mannerisms.

Causes

• Genetics: An estimated 3-9% of those with autistic traits have chromosome aberrations, and the location of these abnormalities have been reported on every chromosome. The most frequently observed associated chromosomal anomaly is fragile X, which is reported to be present in 2-4% of individuals with autism. Tuberous sclerosis seems to be the next most common chromosomal anomaly in autism, with estimates from 1-4% of cases.
• The rate of autism in siblings of autistic individuals is 2-6%. This means that the risk or occurrence among siblings is 6 times the risk in the general population, which, though suggesting a genetic cause, is a rate much lower than that found in single gene diseases. The concordance rate for monozygotic twins is 60-90%; for dizygotic twins, it is less than 5%. The rate for dizygotic twins rises to 10% when broad-spectrum diagnostic criteria are used. Possible increased risk for anxiety and depressive disorders is seen in family members, which may present even before the patient with autism shows signs of illness. Six to twenty-four percent of siblings have some form of cognitive disorder, including learning disabilities.
• Most studies indicate that relatives of individuals who are autistic have an increased rate of social deficits that are qualitatively similar to those found in autism. Two studies show that the pattern and the severity of autism in one family member or between monozygotic twins is of little or no predictive value in determining the severity or pattern of illness in the other affected family member. This indicates that even when the genetic liability is identical, the variations in clinical manifestation are wide.
• Autoimmune mechanisms have been postulated, but thus far, little consistent evidence exists beyond that outlined in Pathophysiology to support these hypotheses. Major epidemiologic studies have failed to find evidence that measles, mumps, and rubella (MMR) vaccine use or thimerosal (mercury vaccine preservative) exposure is associated with autism. Birth season of March or August was once proposed to be a risk for autism, with the implication that seasonal viral exposures trigger autoimmune responses, but this has not been a consistent finding.
• No specific cause has been detected for childhood disintegrative disorder.
• Genetic abnormalities are the likely cause of Rett disorder, as a small group of monozygotic twins showed 100% concordance, while dizygotic twins showed no concordance. A dominant X-linked inheritance with full or nearly full penetrance and with early death of affected males through spontaneous abortion is probable. Genetics have determined that 80% of classic Rett syndrome cases have mutations in one gene, methyl-CPG-binding protein 2 (MECP2). Two studies looking for this mutation in autism cases without Rett features were negative, further arguing that autism and Rett syndrome are distinct entities.
• Early data in Asperger disorder are strongly suggestive of a genetic component. Although specific genetic mutations have been found in a few patients (Xp22.13, Xp22.3, Xq13, Xp22.1), the vast majority of Asperger disorder cases have no specific explanation yet.
• Research had suggested that environment and season of birth predicted the development of an autistic disorder, but subsequent investigators have not confirmed these associations. In particular, the observation of an increased incidence of autistic disorder among children of immigrant parents now appears to point to genetics rather than environment as the culprit.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Fragile X
Phenylketonuria
Other mental retardation
Schizotypal personality disorder
Schizoid personality disorder
Selective mutism
Expressive language disorder
Mixed receptive-expressive language disorder
Stereotypic movement disorder
Congenital deafness
Congenital blindness
Attachment disturbance/psychosocial deprivation
Epilepsy
Landau-Kleffner syndrome
Obsessive compulsive disorder
Tuberous sclerosis
Tourette disorder

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Screen for phenylketonuria.
• Chromosomal analysis can be used to look for fragile X (present in 2-4% of cases) and other chromosomal abnormalities. This is indicated for males with autism spectrum disorder due to the fragile X association.

Imaging Studies

• MRI may be helpful as part of a neurological investigation in the presence of focal neurological findings or severe developmental delay, but it cannot be used for diagnosis of autism.

Other Tests

• EEG is useful in the presence of symptoms consistent with seizures because of the high prevalence of seizure disorder in individuals with autism. Importantly, Landau-Kleffner syndrome (a rare acquired epileptic aphasia) may make someone appear autistic, but treatment is uniquely centered on seizure control.
• An audiological examination is appropriate for possible hearing impairment if a lack of response to auditory stimulation is a concern.
• Psychological and neuropsychological testing for mental retardation and other language disorders can be difficult in the face of severe language difficulties, but specific tests are available. Cognitive and linguistic assessments are crucial so that individualized treatment can be developed, with programs aimed at the appropriate level. Some amount of prognostic prediction can be made based on the degree of cognitive disabilities.
• Neuropsychological testing can be helpful in autistic spectrum disorders, especially Asperger disorder, to determine the specific areas of deficit and strength. Savant skills (cognitive skills that are both 1 standard deviation above the general population mean and 2 standard deviations above the patient's own cognitive level) are present in 25% of individuals with autism whose IQ is over 35.
• Psychiatric assessment is necessary and can help rule out comorbid attention deficit disorder (ADD), mood disorder, obsessive-compulsive disorder, anxiety disorders, and tic disorders. However, the reliable diagnosis of other psychiatric disorders is increasingly difficult with increasing severity of autistic symptoms.
• Home environment and emotional supportiveness of family should be evaluated.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Treatments should be individualized and should focus on behaviors, communication, and social deficits.

• Behavioral interventions
• • Traditional applied behavior analysis (often called ABA) evaluates the ABC's of behavior (antecedents, behaviors, consequences) and aims to mold a patient's behavior into more socially and functionally useful patterns. Although helpful, the treatment may be insufficient, in that, the meaning of the behavior to the child must be understood as much as possible. The difficult behaviors of individuals with autism frequently serve a communicative purpose as the means by which these individuals attempt to influence their environment. In many school districts, this is considered the standard of care for young autistic children.
  • Aggressive, self-injurious, or stereotyped behaviors can indicate a need for help, or they can be used to escape from stressful situations, obtain desired objects or stimulation, or protest against unwanted events and activities.
  • Useful principles for dealing with troublesome behaviors include (1) the establishment of clear and consistent rules, (2) introduction of changes one step at a time, (3) exploration of underlying factors, (4) consideration of environmental modifications, and, possibly, (5) the use of obsessions as reinforcers for positive behaviors.
  • Individuals who are autistic find it difficult to attend to more than one stimulus at a time, so cues must be kept simple. Reinforcement of desired behaviors, with punishment of behavioral excesses (eg, through time outs), can be effective.
• Increasing communication skills
• • Children aged 6-7 years who do not develop useful speech remain highly impaired in the use of verbal communication and require an alternative system, such as signs or pictorially based systems.
  • Facilitated communication, where a therapist guides the patient's hand to utilize nonverbal language systems, is not effective.
  • For those with some speech, programs may help improve comprehension, enhance speech complexity, or correct problems of intonation and articulation. However, to be effective, they must be more than isolated 1-hour speech therapy sessions, as they need to involve the active participation of all those working with the patient.
  • Echolalia or stereotyped speech needs to be understood in terms of its role in communication, particularly of feelings and for stress relief, with efforts made to deal with the underlying cause, as well as consistent behavioral interventions to extinguish the troublesome aspects of the behavior.
• Modifying social difficulties
• • In severely disturbed individuals, highly inappropriate behaviors, such as screaming or masturbating in public, should be the focus of treatment using behavioral techniques.
  • Social skills training in every situation to which a person is exposed is useful. Education of peers about the effects of autism can improve interaction and enhance integration. The inability of people with autism to understand the thoughts, ideas, or feelings of others (the "theory of mind" deficit of autism) can be targeted and improved through appropriate educational programs.
  • Combined, structured education programs have been designed that are effective for improving functioning and increasing the capacity for children with autism to be integrated into normal schools. Programs in general are most effective when begun early (age 2-4 y) and involve intensive full spectrum interventions.
  • Adults with autism continue to need treatment and, depending on severity, are likely to continue to require high levels of supervision and structure, with specialized daycare, group settings, and, at times, residential care. Individuals with Asperger syndrome require similar intervention. The relative preservation of function may create unrealistic expectations and an underestimation of needs. Specific testing of a complexity to sufficiently document the subtle abnormalities is essential in treatment planning.
  • A large array of alternative treatments exist for autism, most with only anecdotal evidence of their utility. Before committing to an alternative treatment, families and professionals need to look carefully at the supporting evidence for it, the cost, and ensure its administration will be safe for their child.
  • Hospitalization is rarely indicated and only when self-injurious or aggressive behavior is so severe it can no longer be managed at home. Hospitalization, when required, is often difficult to obtain as most communities do not have an acute care psychiatric hospital equipped for the type of behavior management treatment required for these patients. Residential treatment or long-term hospitalization is occasionally necessary.

Consultations

• Neurologist if seizure disorders are present
• Speech and language therapist
• Behavioral psychologist with experience with autistic spectrum disorders in devising behavioral plans
• Neuropsychologist may be helpful, especially with developing educational plans

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medications do not treat the disorder itself, although core symptoms in some individuals may be affected by medications. Most research to date has been conducted on children, contrary to the usual methodology in medicine. In general, medications are used to target symptoms, symptom complexes, or comorbid disorders, such as ADD, obsessive-compulsive disorder, depression, dysthymia, and tic disorders. Use of medications has become more common, with the prevalence of autistic children taking medications (psychotropics, antiseizure medications, megavitamins) rising from 42% in 1995 to 65% in 2003 (Coleman, 2005). Less evidence of efficacy exists in the other PDDs, so treatment decisions in those cases are often based on the evidence that exists in autism. As a general rule, autistic children seem to be more sensitive to psychoactive medications, so the adage of "start low and go slow" with every drug trial is particularly applicable to this population.

The newer generation antipsychotics have developed a frontline position in the treatment of autism. This is due to several well-designed studies with one of these agents, risperidone (Risperdal), showing broad effects on several of the core symptoms of autism. Dosages in these studies were low, usually in the 1-2 mg/d range, although doses as high as 4.5 mg were used in larger children. Other second-generation antipsychotics have not received as much study with autism, but many practitioners try them out with individual patients when risperidone is not effective or not tolerated. The relative lack of long-term adverse effects of the second-generation antipsychotics when compared with traditional antipsychotics makes them a more attractive option.

Antidepressants play several roles in the treatment of individuals with autism and PDDs. They are used to treat comorbid depressive disorders, obsessive-compulsive disorder, or other comorbid anxiety disorders, but they also may play a role in symptom management because of the effect they have on serotonin dysfunction, which is an issue for at least some individuals with autism. Any of the antidepressants may play a role in the treatment of depressive disorders, but the only evidence for efficacy in either anxiety symptoms or obsessive-compulsive symptoms is for the selective serotonin reuptake inhibitors (SSRIs), including clomipramine. These drugs may decrease obsessive stereotyped behaviors and also may enhance overall communication and improve social reciprocity, to minor degrees.

Stimulants have been shown to be helpful in treating ADD symptoms in the autistic spectrum disorders, but with lower efficacy (~50% vs 80-90% in nonautistic patients) and have a notably higher rate of side effects. Beta-blockers play a more limited role in the treatment of autism, and the PDDs and are used solely for the treatment of aggression and self-injurious behavior, where they can reduce the intensity and frequency of the behavior. Patients whose symptoms are characterized by overactivity, overarousal, poor frustration tolerance, and self-injurious behavior may be the most likely to benefit.

With regard to opioid antagonists, at one point, it was felt that increased opiate activity might cause the social and behavioral abnormalities in autism. Some evidence of abnormalities in this system has been found, but control of symptoms shows no effect on core symptoms of autism. Studies have shown a decrease in hyperactivity. No effect on self-injurious behavior has been shown. One study of Rett disorder showed a more rapid deterioration in the illness of those receiving naltrexone. Much hope was recently placed on the use of secretin injections; however, careful evaluation of treatment with this hormone in autism failed to find significant treatment benefits. Some small-scale studies showed positive responses to use of stimulants in autism; however, the use of stimulants is uncommon in this condition. This is because side effects are particularly frequent, with worsened irritability, aggression, and insomnia. Stimulant use is best reserved for higher functioning patients with comorbid symptoms

consistent with ADHD.

No evidence exists as to whether it is better to use SSRIs, antipsychotics, alpha agonists, or stimulants as the first line of treatment for autism, so the decision must be left to the clinician's judgment and the primary behavioral target. Multiple medications may be necessary for optimal medication management. If drugs from one category are not effective, it would suggest that a trial of drugs from another category should be considered. As with any medication used in the treatment of autism, dosages used generally should be lower than those used for comparably aged healthy individuals, with more gradual dosage adjustments.

Drug Category: Antidepressants

Have central and peripheral anticholinergic effects, as well as sedative effects, and block the active reuptake of norepinephrine and serotonin. Fluvoxamine and fluoxetine have the most research support for use in autism, though the body of literature is far from extensive.

Drug Name	Fluoxetine (Prozac)
Description	Best studied of the SSRIs, consider as a first-line agent, like fluvoxamine. In 2002, Delong et al studied 129 autistic children aged 2-8 years and found positive benefits in 52%. Studies have shown improvement in irritability, lethargy, stereotypies, and inappropriate speech, although some may develop worsening of hyperactivity, irritability, and agitation. Long half-life of this drug can cause problems if such adverse reactions are noted, so some consider it a second-line drug. Selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine.
Adult Dose	10-60 mg PO qd
Pediatric Dose	2-7 years: 0.15-0.5 mg/kg/d (Delong, 2002) 7-17 years: 10-60 mg PO qd, may increase by 10 mg q14d; consider limit of 30 mg/d in lower weight patients
Contraindications	Documented hypersensitivity; concurrently taking MAOIs or took them in last 2 wk; coadministration with ergotamines and phenothiazines
Interactions	Lithium, tryptophan may increase the risk of adverse effects, including serotonin syndrome; inhibits the metabolism of cytochrome P450 2D6 isoenzyme increasing plasma concentrations of tricyclic antidepressants, phenothiazine neuroleptics, and type 1C antiarrhythmics; cimetidine may decrease clearance of drug; causes increase in phenytoin plasma levels; increases toxicity of diazepam, trazodone by decreasing clearance; also increases toxicity of MAOIs, highly protein-bound drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic impairment and history of seizures; MAOIs should be discontinued at least 14 d before initiating fluoxetine therapy; monitor for suicidality/agitation qwk x4, then q2wk x2, then q4wk x1, then as indicated

Drug Name	Clomipramine (Anafranil)
Description	Second-line treatment after the SSRIs due to higher incidence of adverse effects. More effective than placebo and desipramine, and benefits obsessive-compulsive symptoms, social interactions, stereotypies, and self-injury. Affects serotonin uptake while it affects norepinephrine uptake when converted into its metabolite, desmethylclomipramine.
Adult Dose	25 mg PO qd, increase by 10-25 mg q7-14d to 200 mg
Pediatric Dose	>10 years: 25 mg PO qd, increase by of 10-25 mg q7-14d to 200 mg; not to exceed 3 mg/kg/d or 200 mg/d, whichever is smaller; consider using divided doses during initial titration
Contraindications	Documented hypersensitivity; recent myocardial infarction; MAOI use within previous 2 wk; concurrent use with pimozide, linezolid, flumazenil, cisapride, class 1a antiarrhythmics
Interactions	Barbiturates, phenytoin, and carbamazepine decrease effects of clomipramine; clomipramine increases effects of anticholinergics, sympathomimetics, alcohol, and CNS depressants; toxicity of MAOIs increases with clomipramine; avoid use with cimetidine or erythromycin or other drugs that effect QT interval; caution in presence of 2D6 inhibitors (increase levels)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt withdrawal may cause discontinuation syndrome with agitation, gastrointestinal upset, headache, dizziness, lethargy, and irritability May be fatal in overdose, so caution should be used in individuals at risk for overdose or suicide attempts Caution in severe cardiopulmonary or renal impairment and those unable to metabolize sorbitol; monitor for suicidality/agitation qwk x4, then q2wk x2, then q4wk x1, then as indicated

Drug Category: Antipsychotics

Have shown benefit in behavior modification.

Drug Name	Olanzapine (Zyprexa)
Description	A small open study of children and adults with autism has demonstrated improvement in overall symptoms of autism, as well as in hyperactivity, social relatedness, affective responses, sensory responses, language, self-injurious behavior, aggression, irritability, anxiety, and depression. Of similar value as risperidone. May inhibit serotonin, muscarinic, and dopamine effects. Use is limited by frequent weight gain side effect, and it can cause sedation.
Adult Dose	2.5-20 mg PO qd
Pediatric Dose	Not established for autistic children, most administer similar to adults
Contraindications	Documented hypersensitivity
Interactions	Fluvoxamine may increase effects of olanzapine; antihypertensives may increase risk of hypotension and orthostatic hypotension; levodopa, pergolide, bromocriptine, charcoal, carbamazepine, omeprazole, rifampin, and cigarette smoking may decrease the effects of olanzapine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in narrow-angle glaucoma, cardiovascular disease, cerebrovascular disease, prostatic hypertrophy, seizure disorders, hypovolemia, and dehydration; risk of neuroleptic malignant syndrome, tardive dyskinesia, diabetes mellitus; monitor for involuntary movements at baseline and q6mo at minimum

Drug Name	Haloperidol (Haldol)
Description	Hyperactive or normoactive children with autism have been found to experience decreased hyperactivity, aggressiveness, temper tantrums, withdrawal, and stereotypies. Hypoactive children have not experienced any benefit. Because of adverse effects, it is recommended that olanzapine and risperidone be used preferentially if this class of drug is required.
Adult Dose	0.5-5 mg PO bid/tid
Pediatric Dose	0.5-4 mg PO qd
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; bone marrow suppression; severe cardiac or liver disease; severe hypotension; subcortical brain damage
Interactions	May increase tricyclic antidepressant serum concentrations and hypotensive action of antihypertensive agents; phenobarbital or carbamazepine may decrease effects of haloperidol; haloperidol coadministration with anticholinergics may increase intraocular pressure; encephalopathylike syndrome associated with concurrent administration of lithium and haloperidol
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Severe neurotoxicity manifesting as rigidity or inability to walk or talk may occur in patients with thyrotoxicosis also receiving antipsychotics; if IV/IM, watch for hypotension; caution in CNS depression or cardiac disease; if history of seizures, benefits must outweigh risks; significant increase in body temperature may indicate intolerance to antipsychotics (discontinue if occurs); significant risk of tardive dyskinesia, rare risk of neuroleptic malignant syndrome; monitor for involuntary movements at baseline and q6mo at minimum

Drug Category: Stimulants

Increase release of dopamine and norepinephrine, and block their reuptake.

Drug Name	Dextroamphetamine and amphetamine mixtures (Adderall, Adderall XR)
Description	Drug not studied in autism, but most consider this the next alternative to methylphenidate when that is not tolerated. Use like methylphenidate for symptom-specific treatment of hyperactivity, irritability, and inattention when ADD is a comorbidity. Core symptoms of autism are not expected to improve with this medication. Anticipate a higher rate of side effects and need for lower dosages than in the nonautistic ADD patient.
Adult Dose	5-40 mg PO every am bid
Pediatric Dose	2.5 mg PO every am bid to start, increase by 2.5-5 mg/d/wk Many consider 1 mg/kg/d to be maximum dosage
Contraindications	Documented hypersensitivity; symptomatic cardiac disease; structural cardiac anomalies; hypertension; hyperthyroidism; glaucoma; drug abuse; MAO inhibitor use within 14 d
Interactions	May reduce effect of phenothiazines; frequent antacid use may increase levels; increases effect of meperidine; caution in combining with alpha2-agonists; do not combine with MAO inhibitors; may increase SSRI and tricyclic antidepressant levels; may lower seizure threshold with bupropion; additive effects with caffeine, modafinil; lithium may lessen effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Controlled substance with abuse potential; higher rate of side effects of all types in autistic patients; important to start with low dosage, and only increase slowly with monitoring; may increase tics, if present

Drug Category: Alpha2-agonist

Stimulate central (brain) alpha2-adrenergic receptors.

Drug Category: Beta-blockers

Inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation.

Drug Category: Opioid antagonist

Mostly experimental for this indication.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Outpatient Care

• Monitor for adverse effects to medication. Autistic individuals tend to have a higher incidence of adverse effects from medications, so use extra caution. No research guidance exists for the long-term use of medications. Risk of long-term adverse effects with these medications, apart from tardive dyskinesia with neuroleptics, is very low; therefore, clinical impressions must be used in determining long-term use.
• Monitor for other causes of deterioration of behavior and functioning, including concurrent illness, change in psychosocial environment, and other external stressors.

Transfer

• When self-injurious behavior escalates to the point of severe self-harm, transfer to a specialized facility may be necessary in order to review medication and behavioral treatments, enhance physical protection, and reassess needs for placement or housing.

Deterrence/Prevention

• No evidence of any effective deterrence or prevention strategies exists.
• Early intensive intervention may decrease ultimate functional impairment.
• Federal Early Intervention Program (up to age 3) is often the first source of treatment for these children. After age 3, local school districts have the legal mandate to take over and place these children on an individualized educational plan (IEP).

Complications

• Detection of Asperger disorder often is delayed until well into adulthood. Failure to detect this illness and implement appropriate social, educational, and vocational interventions may result in exacerbation of the disability through an accumulation of academic, social, and vocational failures. These, in turn, can increase the risk of secondary major depression or other adjustment reactions.

Prognosis

• Most children with autistic spectrum disorders have difficulties throughout life.
• Intensive, individualized behavior and treatment programming beginning early in childhood can result in significant improvement in functioning.
• Improvement in early adolescence is frequent.
• Individuals without mental retardation who are found to have Asperger syndrome frequently improve enough to live independent adult lives, and they may marry.
• Depending on the population studied, 2-15% of patients achieve a nonretarded level of cognitive and adaptive function.
• IQ below 50 at school age and lack of communicative speech by age 5-6 years is correlated with poor long-term outcome.
• The presence of epilepsy and other comorbid disorders is predictive of poorer outcome.

Patient Education

• Patient and family education about the causes, impact, treatments, symptoms, and prognosis is an essential part of ongoing treatment. Involvement of family as participants in the treatment is essential.
• Family-to-family support can greatly decrease the adverse impact of autistic spectrum disorder on youth and family functioning. Other families of children with autism, who have learned many things about how to work best with local care providers, can be excellent local resources.
• Families have strong reactions to the diagnosis of autism and often need time to grieve the loss of their ideal image for their child.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education articles Autism and Asperger Syndrome.
• A good book for family education is The Autism Sourcebook by Karen Siff Exhorn (2005).

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• All children aged 3-21 years who are diagnosed with autism or PDD must by law receive an appropriate education within the public educational system. Services for children aged younger than 3 years must be provided, but they may be provided by an agency with individualized education programs and individualized family service plans, generally through early intervention programs.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Paul Dagg, MD to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Apr 25, 2006