Autism spectrum disorders include autism, pervasive

Original Article Autism Spectrum Disorders: Concurrent Clinical Disorders Journal of Child Neurology Volume 23 Number 1 January 2008 6-13 © 2008 Sag...
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Original Article

Autism Spectrum Disorders: Concurrent Clinical Disorders

Journal of Child Neurology Volume 23 Number 1 January 2008 6-13 © 2008 Sage Publications 10.1177/0883073807307102 http://jcn.sagepub.com hosted at http://online.sagepub.com

Xue Ming, MD, PhD, Michael Brimacombe, PhD, Janti Chaaban, MD, Barbie Zimmerman-Bier, MD, and George C. Wagner, PhD Individuals with autism spectrum disorder are heterogeneous in clinical presentation, concurrent disorders, and developmental outcomes. This study characterized the clinical co-occurrences and potential subgroups in 160 children with autism spectrum disorders who presented to The Autism Center between 1999 and 2003. Medical and psychiatric co-occurrences included sleep disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood disorder, and aggressive and self-injurious behaviors. Sleep disorders were associated with gastrointestinal dysfunction (P < .05) and mood disorders (P < .01). Food intolerance was associated with gastrointestinal dysfunction (P = .001). Subjects with mood disorder tended to develop aggressive

or self-injurious behaviors (P < .05). Developmental regression was not associated with increased co-occurrence of medical or psychiatric disorders. Medical co-occurrence did not present as a risk factor for psychiatric co-occurrence, and vice versa. These results showed a high prevalence of multiple medical and psychiatric co-occurrences. There may be common pathophysiologic mechanisms resulting in clinical subgroups of autism spectrum disorders. Recognition of the co-occurrence of concurrent disorders may provide insight into the therapeutic strategy.

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children with autism spectrum disorders exhibit developmental regression where their cognitive and social maturation is followed by loss of mastered skills.13,24-26 With respect to gastrointestinal abnormalities, children with autism spectrum disorders have been found to exhibit colitis27,28 and duodenitis,29 perhaps consequent to an immune response targeted at the gut epithelium.30,31 Moderate to severe constipation has also been reported.32 With respect to immunologic deficiencies, some children with autism spectrum disorders exhibit changes in the number and activity of macrophages, T cells, B cells, and natural killer cells,33 and an increased production of tumor necrosis factor-α.34,35 Furthermore, there are reports that children with autism spectrum disorders also exhibit an increased prevalence of epilepsy13,24 and sleep disorders.14,15,36,37 The co-occurrence of psychiatric disorders in autism spectrum disorders has likewise been recognized.2,17,38 These include depression,16 obsessive compulsive-like behaviors,21,22 and aggressive and self-injurious behaviors.23 In addition, one of the most striking features of autism spectrum disorders is autistic regression. Approximately 35% of the children with autism spectrum disorders begin life exhibiting normal developmental progress, but this period of normal maturation is followed by a regression during which developed skills are lost,25 usually between ages of 18 and 36 months. In others, their developmental milestones were behind schedule but they still experience a period where previously mastered skills are lost.39,40 Often parents attribute the regression to

utism spectrum disorders include autism, pervasive developmental disorder-not otherwise specified, and Asperger disorder. The clinical presentation and prognosis of these subtypes are heterogenous1-3 leading to attempts to describe subtypes within the spectrum4-6 by using cognitive or neurobehavioral criteria to predict long-term functional outcome.7,8 It has been increasingly recognized that many individuals with autism spectrum disorders also have medical and psychiatric disorders,9 with a high prevalence of gastrointestinal disorders,10 immune dysregulation,11,12 epilepsy,13 sleep disorders,14,15 depression,16,17 mood disorder,17-20 obsessive compulsive disorder,21,22 and aggressive and self-injurious behaviors.23 In addition, many From the Departments of Neuroscience (XM, JC), Preventive Medicine (MB), and Pediatrics (XM, JC, BZB), University of Medicine and Dentistry, New Jersey (UMDNJ)-New Jersey Medical School, Newark, New Jersey; and the Department of Psychology, Rutgers University, New Brunswick, New Jersey (GCW). This study was conducted at University of Medicine and Dentistry, New Jersey (UMDNJ)-New Jersey Medical School, Newark, New Jersey. The study was presented as a poster at the Tenth International Conference of Child Neurology at Montreal, Ontario, Canada, on June 15, 2006. Address correspondence to: Xue Ming, MD, PhD, 90 Bergen St, Doctor’s Office Center, Ste 8100, Newark, NJ 07103; e-mail: [email protected] Ming X, Brimacombe M, Chaaban J, Zimmerman-Bier B, Wagner GC. Autism spectrum disorders: concurrent clinical disorders. J Child Neurol. 2008;23:6-13.

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Keywords: autism spectrum disorders; psychiatric disorders; regression

Autism Spectrum Disorders / Ming et al

particular events such as illness or medication.41 Although autistic regression is increasingly recognized, much work remains to be done in characterizing the clinical course, the associated factors, possible triggers, and its pathogenesis, as well as the possibility of clinical concurrent disorders. The aim of this study was to identify and characterize medical and psychiatric co-occurrence by retrospective analysis of a database collected through clinical practice. We also attempted to determine if children diagnosed with autism spectrum disorders could be further classified according to concurrent conditions of medical or psychiatric disorders.

Methods Participants were 218 children with autism spectrum disorders consecutively evaluated by either the pediatric neurologist (XM) or developmental pediatrician (BZB) through The Autism Center at University of Medicine and Dentistry, New Jersey (UMDNJ)-New Jersey Medical School. Parents referred nearly all of the subjects (>95%). Of the 218 children, 160 had complete history and information and were included in the data analysis. The remaining 58 subjects were excluded from data analysis owing to missing information, despite persistent efforts to acquire these data. Some of their symptoms were ambiguous or contradictory between caregivers in terms of duration, frequency, or severity, or a combination of these, and were therefore deemed to be missing data. Laboratory reports of some of the 58 children were not available or were not collected owing to logistic reasons; therefore, they were also excluded from the analysis. Of the 58 excluded children, 25 had autism, 32 had pervasive developmental disordersnot otherwise specified, and 1 had Asperger disorder. Of the 160 children in the cohort, 140 (88%) were previously diagnosed with autism spectrum disorders. The reasons for referral included confirmation of diagnosis, developmental assessment, medical evaluation, treatment for medical or behavioral disorders, seeking innovative treatment, seeking multidisciplinary comprehensive evaluation and care, or the possibility of enrollment in a research program. The diagnosis of autism spectrum disorders (autism, pervasive developmental disorders-not otherwise specified or Asperger disorder) was made or confirmed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV) criteria. Any or all of the Autism Diagnostic InterviewRevised, Autism Diagnostic Observation Schedule-Generic, or Childhood Autism Rating Scale were used for confirmation of diagnosis in approximately 2% of the subjects, performed in our center or elsewhere. Children with autism spectrum disorders whose etiology was known were excluded from data analysis. Known etiologies included children with Down syndrome, fragile X syndrome, premature birth, birth asphyxia, cerebral palsy, and

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Table 1. Clinical Characteristics of the 160 Subjects in the Study Characteristic Sex Male Female Age (y) 2-5 6-10 11-18 Diagnosis of autism spectrum disorder Autism Pervasive developmental disorders Asperger disorder

Patients, No. (%) (n = 160) 131 (82) 29 (18) 72 (45) 64 (40) 24 (15) 77 (48) 72 (45) 11 (7)

children with chromosomal abnormalities on a karyotype analysis. Children with Rett syndrome or disintegrative disorders were also excluded. These children of diverse racial background were drawn from throughout New Jersey. Their median age was 6 years, (range, 2-18 years). The male-to-female ratio was 4.9:1 to female. Patient demographics are summarized in Table 1. The study was conducted by using retrospective chart review and a 14-page clinical intake form that was designed before the study was initiated. The intake forms were completed by caregivers before office visits and were validated by the physicians during and after office visits between 1999 and 2003. The clinical information included the presence of medical or psychiatric concurrent disorders, the duration and frequency of symptoms, and diagnosis or treatment of the disorders. The clinical information was carefully evaluated by the physicians during the course of multiple clinical visits in many of the children. Medical history included sleep disorders, epilepsy, gastrointestinal dysfunction, food intolerance, and developmental regression: • Symptoms of chronic sleep disorders included any of the following: delayed sleep initiation (an estimate of more than 1 hour), chronic daily night awakening for an estimated duration of 10 or more minutes, sleep maintenance disorder (total nightly sleep time of less than 6 hours), sleep disordered breathing manifested as snoring or apnea, or enuresis. • Clinical history of epilepsy was confirmed by the pediatric neurologist, and epilepsy was defined as 2 or more unprovoked seizures. • Chronic gastrointestinal dysfunction included any of the following: diarrhea or unformed stools, constipation, gastroesophageal reflux, or bloating. These symptoms must have persisted for an estimate of more than 6 months. • Food intolerance was defined as chronic gastrointestinal symptoms or eczema dissipated after removal of a specific category of food.

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• Regression was defined as loss of any skill that was developed and used consistently for at least 1 week and then subsequently lost. These skills included all features of language and speech, eye contact, gesture(s), pointing, and other motor skills.

Psychiatric disorders and behaviors included mood disorders and aggressive/self-injurious behavior. Identification of mood disorders in individuals with autism spectrum disorders was based on clinical features of mood fluctuation and somatic signs of affect disorders according to DSM IV criteria 42. Because subjects with autism spectrum disorders have difficulty in verbal and emotional expression, the self-attitude component of mood disorder was used only in conjunction with somatic diagnostic criteria. The symptoms of mood disorder must have been present intermittently or persistently for an estimated period of at least 6 months. Aggressive/self-injurious behaviors were defined as unprovoked kicking, biting, pinching, hitting, or head-banging toward self or others that occurred daily and were persistent for an estimate of 6 months or more. The database was created in Access software (Microsoft Inc, Redmond, Washington). The data were subject to random spot-checking and verification and were imported into SPSS software (SPSS Inc, Chicago, Illinois) for statistical analysis. Frequency tallies were performed on all categorical variables, prevalence rates determined, and χ2 tests carried out as appropriate. The Institutional Review Board of UMDNJ-New Jersey Medical School approved this retrospective chart review study and monitored its human subject protection procedures.

Results Prevalence of the Co-occurrence A total of 218 subjects were in the database, of which 160 had a validated complete history of medical and psychiatric disorders records used for data analysis (Table 2). With respect to medical co-occurrence, 83 children (52%) exhibited sleep disorders sometime during their life, especially in early childhood. The most common symptoms were frequent night arousal in 36 and difficulty initiating sleep in 27. Six children were observed by parents to snore. Long-term food intolerance was present in 81 children (51%), and in 21, this onset occurred in infancy with infant formula intolerance. More than 50% of the parents reported an alteration in diet eliminated or improved the child’s gastrointestinal symptoms or eczema, or both. Of 94 subjects with gastrointestinal dysfunction, 28% exhibited constipation that ranged from straining for bowel movement or daily laxative use to the need for a colostomy in 1 subject. Diarrhea or unformed stool was reported in 36, and gastroesophageal reflux was reported in 18. Endoscopic studies

Table 2.

Prevalence of Concurrent Disorders in the Study Subjects

Disorder Sleep disorders Food intolerance Gastrointestinal dysfunction Epilepsy Mood disorder Aggression None

Subjects, No. (%) (n = 160) a 83 81 94 22 42 51 19

(52) (51) (59) (14) (26) (32) (12)

a. The absolute number of subjects in this cohort who presented with the concurrent disorder. Note that a subject can have more than 1 disorder (or none).

were done in 16 subjects with gastrointestinal dysfunction, with 8 of these showing pathologic results such as lymphoid nodular hyperplasia, colitis, ulcerative colitis, or hiatal hernia. Epilepsy (predominantly complex partial epilepsy with or without secondary generalization) was found in 22 children (14%), a prevalence consistent with previous reports.43,44 An electroencephalographic (EEG) analysis was done in 71 children, 60 of which had results available. The EEG recordings were only 30 to 60 minutes long in 36, and 24 had EEG recordings of at least 24 hours. Abnormal EEG results were found in 18 children, including focal slowing, focal intermittent sharp activity, transient epileptiform activities, abnormal background, and clinical seizure during EEG recording in 2 subjects with known seizure disorder. The psychiatric co-occurrence found in this cohort included mood disorder in 42 children (26%) and aggressive/ self-injurious behaviors in 51 (32%). The range of mood change reported by parents or teachers, or both, included crying spells, irritability, unexplained tantrums, sadness, depression, loss of interest in favorite activities or food, “hysterical laughing,” increased frequency of vocalization, increased motor stereotypies, reduced sleep time, and episodic difficulty in sleep initiation that was correlated with depression or other variables. In nonverbal children, the diagnosis of mood disorder was based mostly on somatic symptoms such as decreased sleep, hyperactivity or psychomotor agitation, irritability, reduced appetite or motor activity compared with the child’s activity, and signs of fatigue, among others. The most frequent somatic signs reported by parents were increased activity levels and new onset of or worsened sleep disorders. Most of the children experienced mood disorder symptoms during the elementary school years. The most frequently reported aggressive behaviors were towards the mother or a younger sibling. The most frequently reported self-injurious behavior was the child biting his or her own hands or forearms. Examination of the age breakdown of the concurrent disorders revealed that their prevalence roughly corresponded

Autism Spectrum Disorders / Ming et al

Table 3.

Concurrent Disorders Within Age Groups Age (y), No. (%) Disorder (n = 160) 2-5

Sleep disorders Food intolerance Gastrointestinal dysfunction Epilepsy Mood disorders Aggression/self-injury

Table 4.

35 37 45 5 11 24

6-10

(42) (45) (49) (23) (26) (47)

35 30 39 8 21 17

(42) (37) (41) (36) (50) (33)

11-18 13 14 10 9 10 10

(16) (17) (10) (41) (24) (20)

Total 83 81 94 22 42 51

Distribution of Concurrent Disorders in Specific Autism Spectrum Disorders Groups Autism Spectrum Disorder Diagnosis, No. (%), n = 160

Concurrent Disorder

Autism

Pervasive Developmental Disorders

Sleep disorders Food intolerance Gastrointestinal dysfunction Epilepsy Mood disorders Aggression/self-injury

46 (55) 39 (48) 42 (45)

33 (40) 37 (46) 48 (51)

4 (5) 5 (6) 4 (4)

83 81 94

13 (59) 25 (60) 29 (57)

9 (41) 10 (24) 19 (37)

0 (0) 7 (16) 3 (6)

22 42 51

Asperger Disorder

Total

to the percentage of the subjects in each age group, with the exceptions of epilepsy and mood disorder (Tables 1 and 3). The prevalence of epilepsy in this cohort was higher in the school age and adolescent groups than in the preschool age group. Likewise, the prevalence of mood disorders in this cohort appeared to be higher in school age and adolescent groups relative to the percentage of children in these age groups. The occurrence of the comorbidities in children with specific autism spectrum disorders diagnosis is summarized in Table 4. The occurrence of most of the comorbidities was consistent with the percentage of children with the specific diagnoses. However, the occurrence of epilepsy and mood disorders was higher in autism than expected from the percentage of children with autism in this cohort. Medical and Psychiatric Co-occurrence Clusters We determined the potential associations among co-occurrences in this cohort. Using the χ2 test, we found that food intolerance was associated with gastrointestinal dysfunction (P = .001). Sleep disorder was also associated with gastrointestinal dysfunction (P = .02) and with mood disorders (P = .009). Aggression/self-injurious behaviors were found to be associated with mood disorder (P = .01). However, no significant association was found between epilepsy and any of the medical co-occurrences (Table 5).

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We then determined whether medical disorders were risk factors for psychiatric disorders. The data in Table 6 show that there was no association between “With Any Medical Co-occurrence” and “With Any Psychiatric Co-occurrence” (Pearson χ2 = 0.884; degree of freedom, 1; P = .347; Fisher exact test, P = .416). The result suggests that having a medical co-occurrence does not increase the risk of developing a psychiatric co-occurrence, or vice versa. Co-occurrence and Regression We also examined whether autistic regression was associated with medical or psychiatric co-occurrences. Forty-six children (28%) exhibited developmental regression. Analysis of regression against medical or psychiatric co-occurrence showed no significant association for either. Language regression was found in 8 of the 22 subjects with epilepsy, and no association was found between epilepsy and regression (P = .364). Comorbidity and Specific Autism Diagnosis We investigated whether the diagnosis of autism, pervasive developmental disorders-not otherwise specified, or Asperger disorder is a significant factor in predicting medical or psychiatric comorbidity. Analysis of association between medical or psychiatric comorbidities and the specific diagnosis of autism spectrum disorder showed that subjects with pervasive developmental disorders-not otherwise specified are more likely to have a medical disorder (Pearson χ2, P = .001), whereas subjects with Asperger disorder are more likely to have psychiatric comorbidities (Pearson χ2, P < .001). The study included 11 children with Asperger disorder and all had psychiatric comorbidity.

Discussion To our knowledge, this is the first report to describe a medical approach using a comprehensive set of medical and psychiatric occurrences in autism. Unlike previous reports linking the etiology of autism spectrum disorders to other known medical disorders (eg, “double syndrome”),2,44 our study focused on medical or psychiatric co-occurrences in idiopathic autism spectrum disorders. Like any retrospective study, this study has its inherent limitations, such as recall bias, missing data, and laboratory tests performed in different laboratories that were subject to different interpretation. We only included subjects whose data were complete in this study. Medial Co-occurrence We found a high prevalence of medical co-occurrence in this cohort. More than half of our subjects had sleep disorders, food intolerance, and gastrointestinal dysfunction. Many children presented with more than 1 co-occurrence, as

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Statistical Analysis of the Occurrence of the Concurrent Disorders a

Table 5. Concurrent Disorders Sleep Disorder Gastrointestinal Dysfunction Epilepsy Food Intolerance Mood Disorder

Sleep Disorder

Gastrointestinal Dysfunction

Epilepsy

Food Intolerance

Mood Disorder

⎯ 0.02 b 0.79 0.53 0.009 b

⎯ ⎯ 0.97 0.001b 0.81

⎯ ⎯ ⎯ 0.69 0.25

⎯ ⎯ ⎯ ⎯ 0.33

⎯ ⎯ ⎯ ⎯ ⎯

a. P-values shown for corresponding χ2 test of association between row and column vatiables. b. Statistical significance set as P < .05.

Table 6.

Analysis of Association of Co-occurrences

Co-occurrences Without any Medical Co-occurrence With Any Medical Co-occurrence

Without Any Psychiatric Co-occurrence

With Any Psychiatric Co-occurrence

3

31

19

107

NOTE: Pearson χ2 = 0.884, degrees of freedom = 1, P = .347; Fisher exact test: P = .416.

shown by the association between gastrointestinal dysfunction and sleep disorders, and between food intolerance and gastrointestinal dysfunction. The presence of gastrointestinal dysfunction may contribute to the sleep disorders; gastrointestinal dysfunction is known to be associated with increased night awakening and pain.45 Likewise, the presence of food intolerance may lead to gastrointestinal dysfunction such as diarrhea, bloating, or constipation. Taken together, it is possible that the symptoms of 1 medical cooccurrence were related to the other medical co-occurrences and, perhaps, that all symptoms arose from a common pathogenesis, or as symptoms of a common disorder. Epilepsy occurred in 14% of the subjects, and the highest prevalence was within the adolescent age group. As noted, the prevalence of epilepsy in children aged 6 to 10 years old and in the adolescent age group was higher than expected compared with the percentage of children who were in these age groups in this cohort. Such a finding is consistent with the peak prevalence of epilepsy in autism spectrum disorders.2,13 In addition, children with autism appeared to have a higher prevalence of epilepsy than children with pervasive developmental disorders-not otherwise specified or Asperger disorder. It has been reported that the risk factor of epilepsy in autism spectrum disorders is associated with the degree of mental retardation.13 From these observations, we speculate that children with autism may be more globally impaired than children with pervasive developmental disorders-not otherwise specified or Asperger disorder because of their increased prevalence of epilepsy and its association with mental retardation.

In subjects who had EEG recordings, we found interictal epileptiform activities as well as focal sharp activity, focal slowing, and abnormal background. The occurrence of epilepsy was independent of other medical co-occurrences. We did not find continuous epileptiform activity in subjects without clinical epilepsy, a finding that has been reported by other investigators.13,46 The explanation for this apparent discrepancy is that the EEG studies were performed at different laboratories in which the lengths of the EEG recordings varied and multiple EEG interpreters were used. In contrast to a previous report,13 developmental regression in autism spectrum disorders was not associated with epilepsy or epileptiform activity. Furthermore, we found that developmental regression did not increase the risk of a psychiatric or medical co-occurrence. Finally, medical comorbidity was associated with pervasive developmental disorders-not otherwise specified, but not with autism or Asperger disorder. Thus, the presence of medical comorbidity was independent of the severity of developmental disability. It has been reported that individuals with pervasive developmental disorders-not otherwise specified are less likely to have severe mental retardation than those with autism,47 whereas those with Asperger disorder are characterized by normal intelligence. Thus, children meeting the DSM-IV diagnosis of autism are most likely to have impairment in intelligence.47 The medical comorbidities found in this cohort of children with autism spectrum disorders therefore suggest that these medical disorders are not mere results of mental retardation. Psychiatric Co-occurrence The diagnosis of psychiatric co-occurrences involving expression of affect, appreciation of self-value, or thought obsession in individuals with autism spectrum disorders is challenging and likely under-reported in this study. This type of information can only be elicited in older, verbal, less severely affected individuals. Nevertheless, the psychiatric co-occurrence in this cohort appears to be higher than in the general population. For example, the frequency of mood disorders was found to be 26.3% in this cohort compared with 1% to 4% in youths aged 14 to 18 years48-50 from the

Autism Spectrum Disorders / Ming et al

general pediatric population. The overall prevalence rate of psychiatric disorders (including conduct disorder, obsessive compulsive disorder, and mood disorders) among children aged 8 to 11 years old was estimated to be 12.4% in The Charters Study in France.50 As noted in Tables 3 and 4, mood disorders appeared to be higher in older age groups and in autism in this cohort. Affective disorder in autism first noted during childhood has been reported,17 and the rate of mood disorder rises with age.16 It has also been reported that individuals with mental retardation have an increased risk for psychiatric disorders.51 Because individuals with autism are more likely to have mental retardation than those with pervasive developmental disorders-not otherwise specified or Asperger disorder,47 this may partly account for their increased prevalence of mood disorders. It is not clear whether aggression or self-injurious behaviors, or both, are a symptom of another psychiatric disorder. Study subjects with mood disorder were co-occurrent with sleep disorder, an entity that is well recognized both in the field of sleep medicine and mood disorder.53 We found that some children showed evidence of mood disorder or obsessivecompulsive disorder. However, we did not report obsessivecompulsive disorder as an independent psychiatric disorder because we could not reliably distinguish the autistic rituals from obsessive-compulsive disorder symptoms. Further study is required in delineating obsessive-compulsive disorder and aggression in individuals with autism spectrum disorders. The high prevalence of psychiatric co-occurrences found in this cohort of autism spectrum disorders is supportive of the reported neurotransmitter abnormalities in autism spectrum disorders. In turn, many of the affected neurotransmitters are associated with behavioral or psychiatric disorders. The coexistence of more than 1 psychiatric disorder in the same individuals suggests that these psychiatric disorders may arise from a common neurobiologic basis. In general, the high prevalence of medical and psychiatric disorders observed in this cohort of children with autism spectrum disorders may suggest that the pathogenesis of autism spectrum disorders involves multiple systems and organs, either de novo or secondarily. Significance of the Co-occurrence of the Concurrent Disorders The associations between sleep disorders and gastrointestinal dysfunction, sleep disorders and mood disorder, and gastrointestinal dysfunction and food intolerance in this cohort of subjects with autism spectrum disorders suggests that one concurrent disorder may be responsible for the other concurrent disorder, or that they both stem from a common pathology. It is important to recognize which disorder is the primary cause of the symptoms, because treatment targeted towards primary causes should be more effective than symptomatic control of the disorders. For example, our anecdotal experience showed

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some success in treating sleep disorders by treating gastrointestinal dysfunction. Are There Clinical Subgroups? Our data showed that medical co-occurrences tended to cluster in the same subjects and that psychiatric co-occurrences are associated with each other. Children in this study with autism spectrum disorders who had a medical co-occurrence did not exhibit an increased risk for a psychiatric cooccurrence in general, suggesting that the psychiatric co-occurrence was not the result of a medical co-occurrence, or that medical and psychiatric co-occurrences were independent of each other. This raises the possibility of potential clinical subgroups based on the co-occurrences. We do not have a sufficient number of subjects for in-depth evaluation of such a possibility. Further study is warranted in examining the potential for subgroups, ideally with a prospective longitudinal study design. Study Significance Three important implications can be drawn from our finding that there was a high prevalence of multiple medical and psychiatric co-occurrences and potential clinical subgroups in this cohort of autism spectrum disorders. First, it renders a better understanding of autism spectrum disorders pathogenesis. The high prevalence of cooccurrences suggests that autism spectrum disorders involve multiple systems, perhaps resulting from disorders involving a common pathway. Second, it influences the clinical evaluation and management. It has been reported that the traditional medical evaluation, such as chromosomal studies, magnetic resonance imaging, metabolic work up, and even EEG, has a low yield in autism spectrum disorders, 54 and therefore, the American Academy of Neurology Task Force Practice Parameter recommended against intensive medical evaluation unless there was an indication to pursue it.55 However, symptom-directed evaluations such as sleep disorder evaluation, epilepsy, or gastrointestinal evaluation may produce a better yield than is currently believed and may provide valuable guidance to treatment. Third, and most important, the clinical subgroups, once confirmed, will help provide more homogenous groups of individuals with autism spectrum disorders for biologic research to aid in the definition of biologic subtypes and their underlying etiology and pathophysiology, as many studies on autism spectrum disorders have been complicated by the heterogeneity of autism spectrum disorders.

Conclusion This study adopted a comprehensive medical approach in monitoring the concurrent disorders associated with autism

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spectrum disorders and the classification of autism spectrum disorders by their medical or psychiatric co-occurrences. We hope that such an approach is more sensitive toward the biologic pathogenesis of this heterogeneous disorder and that it will be useful for investigating the underlying etiology, biochemical mechanisms, and clinical intervention of autism spectrum disorders.

20.

21.

22.

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