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  1. 1. 958 Am J Psychiatry 165:8, August 2008 Treatment in Psychiatry ajp.psychiatryonline.org Treatment in Psychiatry begins with a hypothetical case illustrating a problem in current clinical practice. The authors review current data on prevalence, diagnosis, pathophysiology, and treatment. The article concludes with the authors' treatment recommendations for cases like the one presented. This article is featured in this month’s AJP Audio. Asperger’s Syndrome: Diagnosis and Treatment Karen Toth, Ph.D. Bryan H. King, M.D. “Marc” is a 15-year-old male who pre- sents with his parents for evaluation be- cause of significant symptoms of anxiety and depressed mood. Marc responds ver- bally when greeted in the waiting room but avoids eye contact. He has an above- average IQ, with significantly higher ver- bal than nonverbal abilities. Academic difficulties in elementary school led to a diagnosis at age 8 of nonverbal learning disability. Marc continues to struggle aca- demically and is falling further and fur- ther behind in school. He has strong in- terests in the Titanic and baseball that involve recitation of facts, dates, and numbers. He will talk at length on these topics, often using language that is more formal than expected for his age, but he is unable to sustain conversations on other topics. Although Marc prefers to in- teract with adults, he does describe him- self as having friends; later his parents re- veal that he does not interact with peers outside of school, and when asked, Marc is unable to describe what it means to be a friend. Marc’s parents are very con- cerned about the widening gap between Marc’s social development and that of his peers. Marc’s history includes perinatal problems, and his family history includes autism spectrum disorder. Asperger’s syndrome (AS) is considered to be a variant of autism rather than a distinct disorder, similar if not equiv- alent to high-functioning autism. The condition was first recognized and labeled “autistic psychopathy” by As- perger in 1944 (1). Asperger’s most famous cases were pa- tients described as having above-average intellectual and language abilities, with significant disturbances in social and affective communication. However, Asperger also de- scribed cases of patients with low intellectual and lan- guage abilities, similar to those Kanner (2) described as autistic in 1943. The similarities Asperger noted among these individuals with widely varying intellectual and lan- guage abilities presaged the current notion of a “spec- trum” of autistic disorders (3). Asperger’s contribution to the field went beyond merely identifying and describing this condition; he was concerned that affected children would be misunderstood and maltreated, so he sought to increase awareness of autism. He also advocated an ap- proach to education that involved individualized atten- tion, an emphasis on strengths rather than weaknesses, and engagement in learning by tapping into the child’s special interests. These approaches continue to be used today in the education of children with AS. Diagnosis Although Asperger first described cases in 1944, the term “Asperger’s syndrome” as a diagnostic label did not come into use until several decades later when Wing (4) argued that autism included not only children who were aloof but also those who were socially active but odd in their behavior. Wing proposed a spectrum of disorders with varying degrees of severity in each of the three symp- tom domains that together comprise the diagnostic crite- ria for autism, namely, impairment in social interaction, impairment in communication, and restricted, repetitive, and stereotyped patterns of interests and behaviors. At about the same time that AS became a widely used de- scriptive label, the term “high-functioning autism” was also being used to refer to children with autism who were relatively more able, in either verbal or nonverbal intelli- gence (5). Clinically, these two labels are sometimes used interchangeably, often describing children with autism who are atypical in their presentation and who frequently initiate social interactions (albeit lacking in reciprocity) as opposed to those who are more avoidant or aloof. DSM-IV-TR provides criteria for a differential diagnosis of AS based on intactcognitive ability (absence ofmental retar- dation or intellectual disability), no delays in early language milestones (i.e., use of single words by age 2 and phrases by age 3; see Table 1). However, this does not imply that lan- guage acquisition in AS is normal; for example, there may be deficits in pragmatic (i.e., social use of) language or use of overly formal or repetitive language. Hence, this distinction remains problematic. Results of research that has attempted to support a distinction between AS and high-functioning autism have thus far been mixed. The following section pre- sents a brief review of this research (see also reference 6).
  2. 2. Am J Psychiatry 165:8, August 2008 959 TREATMENT IN PSYCHIATRY ajp.psychiatryonline.org Asperger’s Syndrome vs. High-Functioning Autism Over the past two decades, a growing body of research has attempted to address the diagnostic and phenotypic ambiguity between AS and high-functioning autism. Some authors believe that the neuropsychological and be- havioral profiles of AS and high-functioning autism differ (e.g., reference 7), while others have argued that there is little empirical evidence for a distinction between these two disorders (e.g., references 8, 9). Ozonoff and col- leagues (10) conducted a comprehensive study that exam- ined differences based on external criteria (cognitive/ intellectual profiles, executive func- tion, language, current symptoms, early history, and course of illness) as opposed to criteria involving the def- inition of the two syndromes. They found few group differences in cur- rent symptom presentation and cog- nitive function but many differences in early history. Individuals with AS outperformed those with high-func- tioning autism on the comprehen- sion subtest of the WISC-III and in expressive language ability, but there were no differences on measures of executive function (flexibility and plan- ning). Individuals with AS also had better imaginative and creative abilities and more circumscribed interests, whereas those with high-functioning autism showed a greater insistence on sameness. Early history variables were best able to differentiate the two disorders. Com- pared with children with AS, those with high-functioning autism were more impaired in early language develop- ment and behavior over the preschool period, had more severe lifetime symptoms, and had a greater need for spe- cialized education services. Ozonoff et al. concluded that AS and high-functioning autism appear to be on the same spectrum but differ primarily in severity of developmental course. However, in terms of prognosis, the preschool-age differences they identified had largely disappeared by ad- olescence, indicating that the prognosis for individuals with high-functioning autism may be better than previous studies have reported. A more recent study (11) examined the core symptom domain of social interaction and used the Wing and Gould (12) classification system (aloof, passive, and active but odd) to evaluate potential differences in quality of social interaction between individuals with AS and those with autism. Results showed that individuals with AS tended to be active but odd in presentation as compared with the more aloof and passive profile of those with autism, sup- porting the view that these two groups may differ both in symptom severity (i.e., quantitatively) and in the quality of their social impairment. There continues to be much debate regarding the over- lap and differentiation of these two disorders. It is fueled in part by a tautological dilemma wherein the disorders are defined on the basis of severity of impairment, so stud- ies that appear to confirm differences relating to severity of impairment are to be expected. More systematic studies of both quantitative and qualitative aspects of functioning are needed. Epidemiology and Pathophysiology Current estimates indicate that AS occurs at a rate of about 2.5/10,000, as compared to 60/10,000 for all autism spectrum disorders (that is, autistic disorder, pervasive de- velopmental disorder not otherwise specified, and AS). These rates represent an upward trend over time, due at least in part to changes in case definition and improved awareness (13). The rates for AS have not been well established because of the paucity of research with carefully diag- nosed samples. Likewise, relatively few studies of genetic and environmental factors in the pathophysiology of AS have involved large and well-character- ized samples. One such study examined in detail the family, prenatal, and perin- atal histories of 100 male children with AS who were followed into late adoles- cent and early adulthood (14). Results indicated a paternal family history of autism spectrum disorder in about 50% of the sample, and pre- and perinatal risk factors in about 25% of cases. Pre- and perinatal factors included prenatal exposure to alcohol, severe postnatal asphyxia, neonatal seizures, and prematurity. Even fewer studies have examined risk factors by diag- nostic subgroup. One such study examined obstetric risk factors and found fewer pregnancy and labor complica- tions in patients with AS than in those with autism, perva- sive developmental disorder not otherwise specified, and comparison subjects; those with AS were more likely to have a forceps or vacuum delivery than those with autism, but they did not differ from comparison subjects on a number of other pre- and perinatal variables (15). Most studies of pre- and perinatal risk factors conclude that these factors do not operate independently in autism but may be related to extant fetal abnormalities or to genetic or environmental factors. This has led many re- searchers to speculate whether children with similar genetic risk factors vary in phenotypic expression (i.e., symptom severity) due to exposure to different levels of en- vironmental risk. Regarding genetic factors, a genome-wide scan for susceptibility loci was performed on a sample of in- dividuals with AS, identifying two loci (on chromosomes 1 and 3) that have similarly been implicated in the genetics of autistic disorder (16). Studies such as these support the pre- vailing view that AS is not a separate disorder from autism but a variant on the milder end of the spectrum (5). Evidence-Based Assessment In spite of the continuing debate regarding diagnostic issues, an evidence-based, best-practice assessment ap- “A primary focus of most intervention programs for individuals with AS is on enhancing social competence.”
  3. 3. 960 Am J Psychiatry 165:8, August 2008 TREATMENT IN PSYCHIATRY ajp.psychiatryonline.org proach for autism spectrum disorders, including AS, in- cludes a core diagnostic assessment as well as additional assessment for treatment planning, as described below. The instruments mentioned here are tools only and should not be used, in and of themselves, to make a diag- nosis (17). Core Diagnostic Assessment A comprehensive assessment for AS should include, at minimum, a detailed developmental history and review of social, communication, and behavioral development. Most centers use a tool such as the Autism Diagnostic In- terview—Revised (18, 19) for this purpose. Direct observa- tion of the patient, using the Autism Diagnostic Observa- tion Schedule (20, 21), is also essential to gather the kind of information (i.e., observations of social behavior) neces- sary for a diagnosis. The Autism Diagnostic Observation Schedule is a semistructured interview that requires es- tablished reliability and therefore is often conducted by practitioners specifically trained in autism spectrum dis- orders. Diagnostic tools specific to AS have been devel- oped, but in general they have not been standardized with participants with confirmed diagnoses of AS, and psycho- metric properties have not been well studied. These in- clude the Autism Spectrum Screening Questionnaire (22), the Gilliam Asperger Disorder Scale (23), the Asperger Syn- drome Diagnostic Scale (24), and the Adult Asperger As- sessment (25). Additional Assessment for Treatment Planning A comprehensive evaluation should also include screening for medical and psychiatric issues, including seizures, sleep difficulties, significant sensory issues dis- rupting daily function, anxiety and depression, and other psychiatric and behavioral issues. In addition, a review of school records and previous testing and interventions, as well as consultation with the child’s teachers for their ob- servations, particularly of peer interactions, is important to inform diagnosis and treatment planning. Assessment of intellectual, language, adaptive, and neuropsychologi- cal functioning may be conducted to further inform edu- cational planning and treatment. Finally, an occupational therapy evaluation, with assessment of strategies to miti- gate sensory issues, may be warranted, along with assess- ment of the family system (e.g., stress, depression, access to community resources), to improve outcomes for chil- dren with AS (26). Comorbid Psychiatric Disorders The most common comorbid diagnosis in individuals with AS and high-functioning autism is depression, occur- TABLE 1. DSM-IV-TR Criteria for Autistic Disorder and Asperger’s Disorder Domain of Functioning and Symptom Checklist Criteria for Autistic Disorder Criteria for Asperger’s Disorder Social interaction 2 or more symptoms 2 or more symptoms 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 (e.g., by a lack of showing, bringing, or pointing out objects of interest) Lack of social or emotional reciprocity Communication 1 or more symptoms No clinically significant delay in cognitive or adaptive abilities; early language milestones met on time (single words by age 2, phrases by age 3); other communication impairments may be present Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime) In individuals with adequate speech, marked impairment in the ability to initiate or sustain a 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 Restricted, repetitive, stereotyped interests and behaviors 1 or more symptoms 1 or more symptoms Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus Apparently inflexible adherence to specific, nonfunctional routines or rituals Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements) Persistent preoccupation with parts of objects
  4. 4. Am J Psychiatry 165:8, August 2008 961 TREATMENT IN PSYCHIATRY ajp.psychiatryonline.org ring in as many as 41% of patients (27). Other psychiatric disorders or symptoms that have been reported include anxiety (8%), bipolar disorder (9%), schizophrenia (9%), attempted suicide (7%), hallucinations (6%), mania (5%), psychotic disorder not otherwise specified (3%), schizoid personality disorder (3%), and obsessive-compulsive dis- order (OCD) (1%). To compare these rates to those in chil- dren with autism, in a recent study of 109 children with autism (28), the most prevalent diagnoses were specific phobia (44%), OCD (37%), attention deficit hyperactivity disorder (ADHD) (31%), and depression (10%). The rela- tively high rate of ADHD in Leyfer and colleagues’ sample (28) is of interest in light of the fact that the current DSM specifically excludes comorbidity with autism. Whether such a trumping rule is appropriate is the subject of cur- rent debate. Care must be taken when diagnosing certain other disorders, such as schizophrenia and psychosis, be- cause the intense preoccupations and interests seen in in- dividuals with AS can resemble delusions and disorders of thinking (29). In these cases, a detailed history must be ob- tained to determine the presence of such idiosyncratic in- terests prior to the onset of a presumed psychosis. It could also be argued that personality traits, for example schizoid or obsessive-compulsive, are much more common than currently reported in individuals with high-functioning autism or AS and that the differential diagnosis in this do- main is potentially very complicated. Treatment The average age at diagnosis of AS is about 11 years, compared with 5.5 years for autism (30). This is problem- atic, as prognosis is related not only to cognitive and lan- guage abilities but also to the provision of early, appropri- ate, structured education programs (31) and interventions aimed at improving social competence (32, 33). A limited number of studies have examined the efficacy of treat- ment approaches specific to AS or high-functioning au- tism. No single methodology or intervention strategy has been identified as the most effective or shown to be suc- cessful for all participants, nor is there a single compre- hensive treatment program for individuals with these dis- orders. Common approaches to treatment include adult- directed behavioral programs, such as those using princi- ples of applied behavior analysis, naturalistic child-cen- tered approaches, or a combination approach drawing on behavioral, developmental, and social-pragmatic princi- ples (34). The National Research Council and the Commit- tee on Educational Interventions for Children With Autism have identified critical variables for treatment planning, including prioritizing goals based on core challenges in social communication, establishing proactive approaches to problem behaviors, individualizing modes of instruc- tion, implementing supports across contexts, planning for transitions, addressing psychiatric comorbidity, and pro- viding family support and education (35). Interventions to Improve Social Competence A primary focus of most intervention programs for indi- viduals with AS is on enhancing social competence; here we describe both general and newer, targeted approaches. Social skills are typically taught using a variety of meth- ods and in different settings, such as friendship groups at school, classroom activities, privately taught social skills group therapy programs, buddy or mentoring programs, and through individual and dyadic (i.e., pairing the child with AS with a peer) therapy. Methods or strategies for teaching social skills include direct instruction, role play- ing, modeling, social stories, in vivo practice with peers, and constructive feedback. The social stories technique refers to stories that can be written and illustrated to fit any scenario, with the goal of providing information on what people in a given situation are doing, thinking, and feeling. Social stories indicate the sequence of events, identify significant social cues and their meaning, and script for the child what he or she should do or say. Social stories are especially helpful in new situations, which of- ten cause anxiety because they are unknown and unpre- dictable, but they are useful in any situation to enhance the child’s understanding of what is likely to occur and to explain what is expected of the child. The perspective of all participants in a given social story is carefully delineated, as theory of mind skills (i.e., the ability to take another’s point of view) are often impaired in people with AS and must be directly taught (36). Other general techniques for teaching social skills in- clude first breaking skills down into smaller subskills and then teaching each skill through modeling and role plays. For example, conversation skills can be broken down into a number of subskills, such as greeting others, initiating topics, staying on topic, maintaining reciprocity, using nonverbal communication (eye contact, facial expres- sions, gestures) appropriately, checking in to see if the lis- tener is still interested, and appropriately ending conver- sations (i.e., saying goodbye). Higher-level skills can include accepting suggestions, handling criticism, resolv- ing conflicts, and showing empathy. Understanding the child’s cognitive profile is essential in tailoring a social skills program to an individual child’s needs and strengths. For example, verbal strategies should be utilized with chil- dren with better-developed verbal abilities, while visual strategies (e.g., social stories) should be emphasized with children with higher visual problem-solving skills. Targeted Intervention Strategies In recent years, a number of intervention studies have focused on teaching discrete aspects of social compe- tence, such as joint attention, emotion recognition, and theory of mind abilities. In general, these studies have in- dicated positive results, but they have been limited by small sample sizes (many are best characterized as pilot studies) and lack of long-term follow-up. Nevertheless, they point to the utility of focused and individualized treatment strategies to augment more broad-based edu- cational and social skills interventions for children with
  5. 5. 962 Am J Psychiatry 165:8, August 2008 TREATMENT IN PSYCHIATRY ajp.psychiatryonline.org autism and AS. In a training study of theory of mind and executive function, Fisher and Happé (37) found that in a relatively short period (i.e., 5–10 days of training), children with autism spectrum disorders could improve their per- formance on theory of mind tasks but not on executive function tasks. In a study that examined the use of assis- tive technology to teach emotion recognition to students with AS, LaCava and colleagues (38) found improved per- formance not only on basic and complex emotions that were directly taught via a computer software program but also on complex voice emotion recognition for emotions not specifically included in the training software. Finally, Turner-Brown and colleagues (39) demonstrated the util- ity of a group-based cognitive behavioral intervention to teach theory of mind and other social communication skills to adults with high-functioning autism. In sum, a comprehensive treatment plan for a child or adolescent with AS should capitalize on strengths, target specific areas of impairment (social, academic, adaptive) as well as comorbid medical or psychiatric disorders, and be implemented across settings to ensure success and generalization of skills. Additionally, there is emerging evidence to support the use of interventions targeting discrete aspects of social functioning to augment more broad-based intervention approaches. Summary and Recommendations AS, although first identified in 1944, is a relatively new diagnostic label referring to a set of behavioral character- istics shared by children with autism. Children and adults with AS typically have higher intellectual and linguistic abilities than those with autism but are quite impaired in their social communication skills. Individuals with AS are also at higher risk for certain psychiatric and medical dis- orders, such as depression, anxiety, and seizures. Diagnos- ing AS can be tricky, as the diagnostic criteria are not clearly differentiated from those defining autistic disorder. The prevailing view in the literature is that AS is not a dis- tinct disorder but a milder variant of autism. Whether or not this is so, children with AS are typically diagnosed at much older ages than those with autism, and thus appro- priate and targeted interventions are often not initiated at early ages, when they may have the greatest impact. Nev- ertheless, a number of strategies, including those promot- ing social competence, are widely used with children with AS and have been shown to have a positive impact on out- comes. Pharmacotherapy for associated conditions in AS has not been systematically studied and is currently in- formed by research in the general population. After careful review of developmental history, school records, and past medical records as well as time spent directly ob- serving and interacting with Marc, he was diagnosed as having Asperger’s syn- drome, anxiety disorder not otherwise specified, and depression not otherwise specified. Marc’s anxiety was determined to be related to both school and social in- teractions. His depression, which did not meet full criteria, was based on a history of social failure and rejection and his re- port of lessened interest in and activities related to his areas of intense focus (e.g., he reported that baseball was less enjoy- able). Recommended interventions in- cluded working with an autism specialist, privately or through the school district, who could advocate for Marc and his par- ents to ensure that he received addi- tional specialized education services and accommodations to address his aca- demic difficulties. For Marc’s anxiety and depression, treatment with a selective se- rotonin reuptake inhibitor as well as indi- vidual psychotherapy was recom- mended. Since individuals with AS, even those who are highly verbal, tend to re- spond best to behavioral strategies, a concrete, skills-based approach to psy- chotherapy was recommended rather than a primarily cognitive approach. Tar- geted social skills interventions to pro- mote prosocial skills and expand Marc’s peer group were recommended for im- plementation once his anxiety and de- pression improved. Finally, a recommen- dation for private speech and language therapy to address pragmatic deficits as well as social skills deficits was made. Marc’s parents were directed to state and local resources and support groups. The diagnosis was discussed with Marc di- rectly, and he was given a list of excellent web sites that provide both information and community for adolescents and adults with AS. Received Feb. 21, 2008; revision received April 26, 2008; accepted April 28, 2008 (doi: 10.1176/appi.ajp.2008.08020272). From the Chil- dren’s Hospital and Regional Medical Center; and the Department of Psychiatry and Behavioral Sciences, University of Washington, Seat- tle. Address correspondence and reprint requests to Dr. King, Direc- tor of Child and Adolescent Psychiatry, Children’s Hospital and Re- gional Medical Center, 4800 Sand Point Way, N.E., Seattle, WA 98105; bryan.king@seattlechildrens.org (e-mail). Dr. Toth receives support from NIH. Dr. King has received research funding from Autism Speaks and NIH and has served as a consultant for Biomarin and Neuropharm and as an unpaid consultant for Sea- side Therapeutics and Nastech. References 1. Asperger H: Die “autistischen Psychopathen” im Kindesalter. Archiv für Psychiatrie und Nervenkrankheiten 1944; 117:76–
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