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We review selected information on comorbidity and present a logic model with data-based examples of comorbidity. We utilize published data and results from two datasets to illustrate key features of comorbidity and their associated impact on complexity of care, cost of care, and service utilization. In many conditions, comorbidity is typical and may be considered as a part of the disorder phenotype. We present an 8-part logic model of comorbidity and discuss each component of the model in detail. Available research provides data from primarily single entity diagnoses. We suggest that future research should emphasize: (1) studies of participants with more representative comorbidity to make the results more generalizable to clinical populations; (2) examine benefits and risks from polytherapies used at the same time; (3) improve data on optimal timing of interventions in the context of developmental trajectory of infants, children, and adolescents; and (4) examine interventions and timing of intervention to optimize prevention of phenotype severity.

The published literature on the prevalence of pregnancy risk markers in patients with Tourette Syndrome (TS) was reviewed. PubMed was searched for papers describing studies of pregnancy risk markers in TS. All years and languages were searched, and the reference sections of each paper were also reviewed for additional citations. We identified 20 studies reporting on pregnancy risk markers in 1588 subjects with TS. Six studies used comparison populations and two utilized twins for comparisons. Three risk markers (decreased birth weight, father’s age, and number of prior terminations of pregnancy) were identified as possible risk markers for TS. To date, no pregnancy risk marker has been demonstrated to increase risk for development of TS, to increase syndromal severity, rates of comorbidity, or to increase duration of TS.

The aims of this descriptive study were to examine the prevalence and associations of coprophenomena (involuntary expression of socially unacceptable words or gestures) in individuals with Tourette syndrome. Participant data were obtained from the Tourette Syndrome International Database Consortium. A specialized data collection form was completed for each of a subset of 597 consecutive new patients with Tourette syndrome from 15 sites in seven countries. Coprolalia occurred at some point in the lifetime of 19.3% of males and 14.6% of females, and copropraxia in 5.9% of males and 4.9% of females. Coprolalia was three times as frequent as copropraxia, with a mean onset of each at about 11 years, 5 years after the onset of tics. In 11% of those with coprolalia and 12% of those with copropraxia these coprophenomena were one of the initial symptoms of Tourette syndrome. The onsets of tics, coprophenomena, smelling of non-food objects, and spitting were strongly intercorrelated. Early onset of coprophenomena was not associated with its longer persistence. The most robust associations of coprophenomena were with the number of non-tic repetitive behaviors, spitting, and inappropriate sexual behavior. Although coprophenomena are a frequently feared possibility in the course of Tourette syndrome, their emergence occurs in only about one in five referred patients. Because the course and actual impact of coprophenomena are variable, additional prospective research is needed to provide better counseling and prognostic information.

We examined the rates of comorbid pervasive developmental disorders in participants with Tourette syndrome. We used 7288 participants from the Tourette Syndrome International Database Consortium Registry. We found 334 (4.6%; 1 of every 22 participants) with Tourette syndrome had a comorbid pervasive developmental disorder. In participants with Tourette syndrome and comorbid pervasive developmental disorders, 98.8% had one or more comorbidities (pervasive developmental disorder was not counted) compared to 13.2% in the group of participants with Tourette syndrome only. Variables from logistic modeling that were significant predictors of Tourette syndrome and pervasive developmental disorders were: male gender; no family history of tics/Tourette syndrome; and an increased number of comorbidities (P < .001). We found rates of comorbid Tourette syndrome and pervasive developmental disorders to be increased by 13 times. Identification of differences between subgroups of patients with Tourette syndrome may increase understanding of syndromal susceptibility, severity, and outcome.

We propose the concept that anorexia nervosa is a neuropsychiatric developmental disorder. In support of the concept we present a case report of a 12-year-old girl with high functioning autistic disorder who developed Tourette syndrome and obsessive-compulsive disorder. She subsequently experienced a distinct onset of partial anorexia nervosa characterized by fear of gaining weight, body image distortions, food preference idiosyncrasies including avoidance of fat, dietary restriction, a pursuit of thinness, episodic self-induced vomiting, the missing of her menstrual cycles, and a 10% decrement in expected weight for height. She fell short of the required 15% decrement in expected weight for height to qualify for the full syndrome. Our case presentation emphasizes the longitudinal commonalities and symptomatic overlap of her multiple comorbidities. We discuss treatment approaches typically used with individuals with neuropsychiatric developmental disorders which might benefit higher functioning individuals with eating disorders. We conclude with examples of a neuropsychiatric developmental approach to generate a research agenda for anorexia nervosa.

Partial trisomy 6p with duplications ranging from 6p21 to 6p25–pter is emerging as an established syndrome. We report a case of duplication of 6p (6p23–pter) and deletion of 2q37–qter. Features characteristic of 6p partial trisomy present in the patient are low birth-weight, and mental and developmental retardation. Major facial features include prominent forehead, flat occiput, multiple ocular abnormalities, low-set ears, prominent nasal bridge, long philtrum and small pointed mouth. Repeated examinations of the patient from birth to the age of over 5 years revealed that he has infantile autism. Since autistic children are generally not associated with chromosome anomalies, in view of the present case, it is suggested that karyotypic analysis be considered for such children. Where possible, extended study for autism in 6p trisomic children may also be desirable.

A case report of a 33-year-old woman wich atypical bipolar disorder, autistic disorder, profound mental retardation and a chromosomal anomaly is presented. This patient is behaviourally similar to a patient reported by Akuffo et al. (1986), who apparently did not have a chromosomal investigation. The chromosomal anomaly and similarities between the two patients are discussed.

In this article we review the relationship between Tourette's syndrome (TS) and speech, language, and communication disorders. We consider TS to be a neurodevelopmental disorder with an increased rate of co-occurring (comorbid) disorders. We have organized the available research into topical areas for convenience of review. These areas are tic insertion into speech, learning disabilities, speech abnormalities, expressive and receptive language impairments, coprophenomena, writing and tics, signing and tic premonitory phenomena, and TS. We conclude with a discussion of the interplay between neurological function and mental factors on expression and outcome of this relationship. We offer discussion of a research agenda to advance the science in this area.

We have established a multisite, international database of 3,500 individuals diagnosed with Tourette syndrome (TS). The male:female ratio is 4.3:1 for the total sample, with wide variation among sites; the male excess occurs at every site. Anger control problems, sleep difficulties, coprolalia, and self-injurious behavior only reach impressive levels in individuals with comorbidity. Anger control problems are strongly correlated with comorbidity, regardless of site, region, or whether assessed by neurologists or psychiatrists. The mean age at onset of tics is 6.4 years. At all ages, about 12% of individuals with TS have no reported comorbidity. The most common reported comorbidity is attention-deficit-hyperactivity disorder. Males are more likely to have comorbid disorders than females. The earlier the age at onset, the greater the likelihood of a positive family history of tics. An understanding of the factors producing these and other variations might assist in better subtyping of TS. Because behavioral problems are associated with comorbidity, their presence should dictate a high index of suspicion of the latter, whose treatment may be at least as important as tic reduction. The established database can be used as the entry point for further research when large samples are studied and generalizability of results is important.

Objective: Tourette syndrome (TS) is a common developmental disorder with childhood onset. This study utilizes the TIC consortium data to develop models of variables associated with increased severity of tics in people with TS. The TIC database comprised 5,500 people with TS. Method: This study included the 5,450 participants with clinician reported severity of tics (mild, moderate, or severe). We developed 3 models of tic severity. Results: Model 1 comprised age of diagnosis and total number of comorbidities and correctly classified 71% of mild–moderate cases, 46% of severe, and 68% of the total group. Model 2 comprised 7 of 21 comorbid conditions and classified 78% of mild–moderate cases, 53% of severe cases, and 74% of the total population. Model 3 comprised 6 comorbid conditions and correctly classified 75% of mild–moderate cases, 57% of severe cases, and 72% of the total cohort. We found the attention-deficit hyperactivity disorder was not associated with tic severity but obsessive compulsive disorder was an important variable associated with tic severity. Conclusion: This large dataset provides 3 models of variables associated with increased tic severity at the time of diagnosis. Further research is needed to identify factors associated with longitudinal changes in tic severity. This should include factors that are associated with both increased and decreased severity.

Fetal alcohol syndrome (FAS) is a common cause of developmental disability, neuropsychiatric impairment and birth defects. The disorder is identified by the presence of growth impairment, central nervous system dysfunction, and a characteristic pattern of craniofacial features. The reported prevalence of the disorder varies widely and recent estimates approach 1% of live births. Expression of these features varies by age. People with FAS have high rates of comorbid conditions: attention deficit hyperactivity disorder (40%), mental retardation (15-20%), learning disorders (25%), speech and language disorders (30%), sensory impairment (30%), cerebral palsy (4%), epilepsy (8-10%). Birth defects are common. In the United States, the annual birth cohort of persons with FAS could be as high as 39,000 cases annually. Cause-specific mortality is 6% for patients with FAS. The disorder is expensive to treat and most patients have lifelong impairment. The annual cost of care in the United States would approach US$5.0 billion. Early recognition and entry into appropriate treatment programs appear to improve outcome. Prevention efforts should involve screening for alcohol use prior to pregnancy and at the first prenatal care visit.

The prevalence and magnitude of effect of individual risk markers for specific developmental disorders vary widely across diagnostic category. The four study cohorts for this project were patients from four diagnostic registries in North Dakota for fetal alcohol syndrome (FAS), autism, sudden infant death syndrome (SIDS), and Tourette syndrome. These four cohorts were used to estimate prevalence and magnitude of effect of parental risk markers in patients with developmental disabilities. Cases with North Dakota birth certificates were matched with controls. Using birth certificate data, we then examined five parental risk markers for each cohort and estimated direct and indirect effects for each risk marker by cohort. The authors found two significant paternal risk markers (age in SIDS and education in FAS). Significant maternal markers were age in SIDS, education in FAS, autism, and SIDS. Marital status was a significant risk marker in FAS. Effect sizes were estimated using paired t tests, odds ratios, and population attributable risk (PAR) for both direct and indirect effects for each marker. We estimated both direct and indirect effects to allow for direct comparisons of the differential effect estimates of each of these markers. The direct effect of parental markers differs across diagnostic cohorts of patients. Use of cohorts from similar denominator populations obtained from prevalence studies is a useful methodological tool for estimating the prevalence and magnitude of effect of risk markers.

The objective of this study was to use population-based data to estimate the prevalence and cost of treatment for attention-deficit hyperactivity disorder (ADHD). The North Dakota Department of Health Claims Database was used to estimate the administrative prevalence, annual cost of care per case, and total annual cost of care for subjects with ADHD compared with controls. The case population was 7745, and the mean prevalence rate was 3.9%, with a peak prevalence at 10 years of age. For children with ADHD, the annual cost of care was 649 dollars compared with that of controls at 495 dollars. Cost of care attributable to ADHD was 649 dollars - 495 dollars = 54 dollars (31%). Utilization by children with ADHD with publicly funded payers was increased 25 to 175% over that of children with privately funded coverage. In North Dakota, the annual cost of care for children with ADHD was 5.1 million dollars, 5.6% of all health care costs for children. The annual attributable cost of care was 1.79 million dollars. Thus, 1.9% of total health expenditures for children was attributable to ADHD. In the United States, the cost of care attributable to children with ADHD would be 2.15 billion dollars annually.

We conducted a 12-year prospective study of children with pervasive developmental disorders from North Dakota. In a prospective longitudinal follow-up study, of 59 patients, we found 52 patients with pervasive developmental disorders (88%). Ten (17%) declined to participate. We collected data on 42 (71%) of the original cohort. Of the 42 subjects, 1 died (1.7%). The other 41 were followed up for 492 person-years. Severity scores for the Diagnostic and Statistical Manual of Mental Disorders-III-Revised (DSM-III-R) declined 20% and for DSM-IV 23%. Global Assessment of Functioning improved 19%, and the average number of comorbidities decreased 45%. Thirty-seven percent of patients improved in all four measures, whereas only 5% improved in only one measure. Pervasive developmental disorders are developmental disorders with a long-term course of limited improvement for most patients. Male subjects demonstrated substantially more variability in improvement but, overall, demonstrated more improvement than female subjects. (J Child Neurol 2002; 17:681-688).

The goal of this study was to collect prospective longitudinal information on the development of an epidemiologically defined cohort of patients with Tourette syndrome. These data may improve prognostic understanding of the condition. This information will also be important for specification of an adult phenotype for genetic marker studies. A prospective longitudinal cohort study was conducted. Fifty-four of 73 patients from our 1986 prevalence study of Tourette syndrome in North Dakota school-aged children were eligible for inclusion. The subjects were diagnosed in 1984 and 1985. We were able to interview 39 of 54 eligible patients for 507 person-years of follow-up. For the cohort, tic severity declined by 59%, global assessment of functioning improved by 50%, and the average number of comorbidities decreased by 42%. Forty-four percent of patients were essentially symptom free at follow-up. Only 22% were on medication as adults. Tourette syndrome is a developmental neuropsychiatric disorder with a long-term course that is favorable for most patients. Males demonstrated substantially more variability in improvement but overall demonstrated more improvement than females. (J Child Neurol 2001;16:431-437).

Although there is a proliferating literature on the pharmacotherapy of autism, the results of these studies are often conflicting. A definitive medical intervention for the core symptoms of autism continues to elude us. In the absence of a definitive research-based pathway for the pharmacotherapeutic treatment of autism, our approach is necessarily clinically based and research informed. Common medication side effects also may confound the clinical picture. A major factor in the application of our approach is an awareness of conditions comorbid with autism in an individual patient. These comorbid conditions then serve as a guide in choice of specific drug therapies. Use of medication must be guided by an awareness of habilitative, behavioral, social, administrative, and ethical issues.

Pervasive developmental disorders are severe disorders of development with no consistent neurobiologic etiology and most often an idiopathic etiology. We report a 12-year-old male who met criteria for a pervasive developmental disorder (Asperger's syndrome) and a chronic tic disorder. The child also has an X-linked cognitive impairment (MRX23). The presence of tic symptomatology, pervasive developmental disorder, and fragile X syndrome has previously been reported. Since no singular etiology for Asperger's syndrome has been found, the possibility of other cases of Asperger's syndrome occurring with concurrent abnormalities on the X chromosome should be considered by clinicians, especially if tic symptomatology is present. (J Child Neurol 2000; 15:699-702).

Five patients with a fragile site at 16q22-23 and neuropsychiatric disorders are reported. Three of five had Tourette disorder, three had mental retardation, two had bipolar disorder, and one had autistic disorder. During our attempts to study the fragile sites in more detail we were unable to reproduce the fragile sites found several years earlier. The potential relationship between the fragile sites and the neuropsychiatric disorders in these patients is discussed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:69-73, 2000.

The co-occurrence of Tourette syndrome (TS) and Down's syndrome (DS) has been previously reported in the literature. In the present study, a retrospective record review was conducted using the North Dakota TS registry in order to ascertain the number of cases of TS and DS, and to develop case descriptions. We identified five cases from North Dakota. Two of these patients were simply comorbid for TS and DS. One was additionally comorbid for bipolar disorder, another for childhood disintegrative disorder and a third had a D/G group translocation. The association between DS and TS occured in 2% of TS patients. Contrary to the situation in patients with pervasive developmental disorders, the presence of TS in DS may be a negative prognostic indicator.

A 14-year-old girl developed a movement disorder after a streptococcal infection. In the acute phase of the illness she exhibited simple and complex motor tics and chorea, but all abnormal movements ceased over the following eight months, without recurrence. This case raises questions about the relationship between tics, chorea and auto-immune reactivity.

The use of human brain tissue in neuroscience research is increasing. Recent developments include transplanting neural tissue, growing or maintaining neural tissue in laboratories and using surgically removed tissue for experimentation. Also, it is likely that in the future there will be attempts at partial or complete brain transplants. A discussion of the ethical issues of using human brain tissue for research and brain transplantation has been organized around nine broadly defined topic areas. Criteria for human brain tissue transplantation and laboratory use of brain tissue are proposed.

In a previous study, the present authors reported on the prevalence of psychoactive (psychotropic and anticonvulsant) medication use among people with intellectual disability residing in community settings in the state of North Dakota, USA. The present study replicates the earlier survey. A questionnaire was sent to all group homes serving people with developmental disabilities. Questionnaires were obtained for 100% of North Dakota group home residents. Psychoactive medications (anticonvulsants included) were used by 38% of the 1384 residents represented. The results are discussed in relation to the previous study from North Dakota.

Body dysmorphic disorder (BOD) is a somatoform disorder characterized by an affected person's preoccupation with an imagined defect in appearance, which results in significant distress and impairment in functioning. '-7Onset of the disorder usually occurs in adolescence,2.3.5.7 and onset in childhood has not been previously described.2.3·7 High rates of affective and anxiety disorders in BOD patients and their relatives suggest that a significant relationship may exist between these disturbances and BDD,'-6 and it has been proposed that BOD should be conceptualized as an obsessive-compulsive spectrum disorder and more broadly as an affective spectrum disorder.3.s Favorable response to serotonergic antidepressants in open trials suggests an important role of central nervous system serotonergic dysfunction in the pathogenesis of BDD.'-4 Tourette's disorder (TO) is a common hereditary neurobehavioral spectrum disorder whose onset usually occurs in childhood or early adolescence.9-'5 In addition to motor and vocal tics, patients may experience a wide array of neuropsychiatric disturbances, including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OeD), and affective and anxiety disorders.9-'2 It has been proposed that the associated disorders are genetically related to the tic disorder9-12 and that the TO spectrum of disorders is identical 'o to the

This paper reviews the association of Huntington's Disease (HD) and tic disorder or Tourette Syndrome (TS) We also present the results of a follow-up study of a male with childhood-onset TS and adult-onset HD who died at 45 years of age. The developmental course and results of neuropathologic and molecular studies of this patient are reported. This is the first case of childhood onset of TS with adult onset of HD reported who has come to autopsy. A developmental model for childhood and adult neuropsychiatric disorders is presented.

A review of the relationship between speech and language disorders and tic disorders is presented. Selected aspects of neurophysiological functioning linking speech and language disorders are reviewed. A model for this relationship is presented. The utility of TS as a model for understanding cognitive and linguistic functioning is discussed.

We present a developmental psychobiologic framework to improve the understanding of developmental and mental disorders. Tourette syndrome (TS) is our model condition for the effort, as we review our studies on the condition in conjunction with the comorbidities with which it often presents. TS serves not only as a biologic marker for certain localizable and definable central nervous system processes, but also may serve a transacting function across biological and psychological levels of organization.

Fetal alcohol syndrome (FAS) is an important cause of mental retardation and developmental disabilities. A population based screening tool would allow for early diagnosis and entry into intervention programs. The aim of the study was to develop a brief screening tool for use in population-based settings to improve the identification of children with FAS. The FAS Screen was developed and tested in six sites. These were sites that served children and all were located in North Dakota. Screening was completed on 1013 children, 65 were found to have a positive screening score and were referred for further investigation. Forty were seen for evaluation by a medical geneticist and six were diagnosed with FAS. The estimated values for the screening tool were: specificity 94.1%, sensitivity 100%, positive predictive value 9.1% and negative predictive value 100%. The cost of screening was $13.00 per child and the cost per case identified was $4,100. The FAS Screen is a brief screening test with acceptable performance characteristics and is cost effective.

We reviewed the records of 42 consecutive cases of children with Tourette Syndrome (TS) who had IQs above 70, and contrasted the reading, reading comprehension, math, and spelling quotients with IQ scores to determine how many would meet criteria for a learning disability. The mean IQ of the 35 males and 7 females was 94.4 and was higher than the mean math score (82.8), spelling score (90.4), reading score (87.4), and reading comprehension score (853). Using a 1.5 standard deviation discrepancy, 51% met criteria for learning disability in at least one academic area; 21% had a 2-standard-deviation discrepancy. Children with TS frequently have learning disabilities, and assessment of academic achievement should be a routine aspect in the evaluation of such children.

Pyridoxine (vitamin B6) (2q31) dependency is a rare autosomalrecessive disorder that causes a severe seizure disorder of prenatal or neonatal onset. The abnormality appears to inhibit the binding of vitamin B6 to the enzyme glutamic acid decarboxylase-1, which is needed for the biosynthesis of γ-aminobutyric acid (GABA). Most patients with pyridoxine-dependent seizures require lifelong treatment with pyridoxine. The full range of associated symptomatology is unknown since fewer than 100 cases have been reported. A majority of cases are mentally retarded. We report a 15-year-old boy with pyridoxine-dependent seizures, nonpyridoxine-dependent seizures, severe mental retardation, autistic disorder, aerophagia, breath holding, and self-injury. This complex outcome should alert clinicians to the wide range of neuropsychiatric outcomes associated with this disorder. ( J Child Neurol 2000;15: 763-765).

Objective: A study of the shared phenomenology between Tourette syndrome (TS) and schizophrenia. Method: An illustrative case report is presented. We used a chart review of 399 clinically ascertained patients with TS to identify 10 cases meeting criteria for schizophrenia. From our 10 patients, salient clinical characteristics were then tabulated. We then extracted similar clinical characteristics from a previously published series of patients with comorbid TS and schizophrenia in order to combine cases and allow for a comparison between childhood-onset schizophrenia (COS), adolescent-onset schizophrenia (AdolOS), and adult-onset schizophrenia (AduOS) cases in these groups. Results: We found 10 cases of schizophrenia (all were males) in the 399 TS patients for a prevalence rate of 2.5% (95% CI 0.96– 4.04). Mean age of tic onset for TS diagnostic criteria ranged from 2-14 years with a mean of 8.2 years. The mean age of diagnosis for schizophrenia was 14.2 (range 9–23 years). We found six cases of schizophrenia with onset of positive psychotic symptoms by 13 years of age, two cases with onset after 13 years of age and before 18 years of age, and two cases with onset after 18 years of age. Attention deficit hyperactivity disorder was present at a higher rate (70%) than one would expect in a clinically ascertained group of patients with TS. Comparison between COS, AdolOS and AduOS in our pooled cases noted a sex bias skewed toward males. Catatonic symptoms may be more likely in child or adolescent onset cases and negative symptoms more likely in AduOS cases. Conclusions: The 2.5% prevalence of schizophrenia in our TS sample exceeds the 1% expected rate of schizophrenia in the general population (chi-square=9.14; P=.0025). The six cases of COS (before 13 years of age) exceeds the expected rate of 1–2 per 100,000 (chi-square=4499; P=.0001). The 752-fold increase in observed rates of comorbid TS and COS over expected rates suggests a role for unknown common underlying etiologic factors. Based on clinical features, patients with TS and comorbid COS, AdolOS, or AduOS do not have different conditions. We conclude with suggestions for further research. © 2009 Published by Elsevier Inc.

Service providers for children in the state of North Dakota were surveyed to determine the prevalence rate of Rett syndrome (RS). Five patients with definite RS were identified in a population of 203,801 children (98,932 girls) 0-18 years of age yielding a prevalence rate of RS of 1 in 40,760 in North Dakota children. For girls the rate of RS is 1 in 19,786. Similar surveys of other states using comparable modes of ascertainment will be important as points of comparison for prevalence rates of RS.

Fetal alcohol spectrum disorders (FASD) are a common cause of developmental disability, birth defects, and mortality. The performance characteristics of current diagnostic tools for FASD are not adequately reported. This study examines the performance characteristics of the Fetal Alcohol Syndrome Diagnostic Checklist (FASDC). In a population of 658 subjects from North Dakota, we used the FASDC score to examine the agreement between FASDC score, clinical diagnosis, and the Institute of Medicine criteria for FASD. All subjects were seen for evaluation in the genetic/dysmorphology clinics, which are funded by the state to provide genetic diagnostic services for residents of North Dakota. We compared the clinical diagnosis and the FASDC scores to determine the performance characteristics of the FASDC in the categorical diagnosis of fetal alcohol spectrum (FAS), other-FASD, and a group with No-FASD. Comparisons were made using univariate and logistic models of outcomes using both the presence and the absence of alcohol exposure or FASDC phenotype data. The FASDC performance characteristics for differentiation of the FAS group from non-FASD were excellent (accuracy 99%, sensitivity 99%, and specificity 99%). Logistic models for subjects with scores in the FASD range were differentiated with an accuracy of 82%, sensitivity 85%, and specificity 80% using the data on phenotype and exposure. We were able to delineate subjects with scores in the No-FASD range with an accuracy of 78%, sensitivity 64%, and specificity 81% without including the exposure and phenotype data by use of the other descriptive data (maternal characteristics, birth records, and demographic data) from the FASDC. All diagnostic tools should have performance characteristics assessed and available before adoption for use in clinical settings. The FASDC scores produce diagnostic groupings that approximate expert clinical judgment. The tool may be useful in other clinical settings for the diagnosis of FASD or as an FASD registry or research database.

BACKGROUND: Our objective was to estimate the mortality rate in subjects with fetal alcohol spectrum disorders (FASD) and their siblings whose FASD status was unknown. METHODS: We used the state FASD Registry to link subjects with FASD to a North Dakota birth certificate. We were able to link 304 of 486 cases (63%). We used the birth certificates to identify the mother and children born to the mother (siblings). We then searched for death certificates for both the FASD cases and their siblings. We then calculated the annual and age-adjusted mortality rates for the siblings of the Registry cases and compared them with mortality rates from North Dakota. RESULTS: The FASD case mortality rate was 2.4%, with a 4.5% mortality rate for their sibings, accounting for 14% of all deaths when compared to the North Dakota residents matched by age and year of death. The sibling deaths accounted for 21.5% of all cause mortality matched by age and year of death. The age-standardized mortality ratios were 4.9 for the FASD cases and 2.6 for their siblings whose FASD status was unknown. CONCLUSIONS: Mortality rates for FASD cases and their siblings were increased and represent a substantial proportion of all cause mortality in North Dakota. Prevention of FASD may be a useful strategy to decrease mortality. Birth Defects Research (Part A), 2008. © 2008 Wiley-Liss, Inc.

We present the case of a boy who over time sequentially exhibited symptoms consistent with a pervasive developmental disorder, schizophreniform symptomatology, multiple motor and vocal tics, and myoclonus. During this period he experienced multiple episodes of group A beta-haemolytic streptococcal (strep) infection confirmed by culture and serological studies. We speculate that paediatric autoimmune neuropsychiatric disorder associated with strep (PANDAS) may have served as an element in a complex chain of causation influencing the expression of his symptoms. Our main emphasis is to utilize our case study as an example of the application in case formulation of the neuropsychiatric developmental model and of the neurodevelopmental model on symptom ontogenesis and clinical outcome.

Aims: To present an incremental process for a staged screening strategy to identify women at increased risk of having a child with fetal alcohol spectrum disorder (FASD) and to enhance the management of women using alcohol during pregnancy. We include an illustrative example of the development of a screening component using an existing data set. Methods: We describe a seven-step protocol to screen for alcohol use during pregnancy. The screening process begins with a one-question initial screen, followed by exposure assessment, maternal risk stratification to estimate risk for FASD, and concludes with recommendations for intervention and monitoring of exposure for women drinking during pregnancy. Conclusions: This screening process has very modest time commitments in the early stages. Time commitments increase for women drinking during pregnancy and the process focuses on the population at highest risk of having a child with FASD. The process has the benefit of risk specificity, since the process refines risk estimates for an adverse outcome specific for FASD. The process concludes with a programme to facilitate intervention and to monitor changes in prenatal alcohol exposure during pregnancy. Prevention of FASD is an important public health priority. In addition to the ongoing study of clinical strategies to improve detection rates of alcohol exposure at all stages of pregnancy, additional research on the tools and the process used in screening efforts is urgently needed. The efforts should also include research on both the screening tools and the outcome of the screening process in routine prenatal care settings.

Background Tourette Syndrome (TS) is a neurodevelopmental disorder of childhood. Learning disabilities are frequently comorbid with TS. Using the largest sample of TS patients ever reported, we sought to identify differences between subjects with TS only and subjects with TS and a comorbid learning disability. Methods We used the Tourette Syndrome International Consortium database (TIC) to compare subjects with comorbid Tourette Syndrome and learning disabilities (TS + LD) to subjects who did not have a comorbid learning disability (TS - LD). The TIC database contained 5,500 subjects. We had usable data on 5,450 subjects. Results We found 1,235 subjects with TS + LD. Significant differences between the TS + LD group and the TS - LD group were found for gender (.001), age onset (.030), age first seen (.001), age at diagnosis (.001), prenatal problems (.001), sibling or other family member with tics (.024), two or more affected family members (.009), and severe tics (.046). We used logistic modeling to identify the optimal prediction model of group membership. This resulted in a five variable model with the epidemiologic performance characteristics of accuracy 65.2% (model correctly classified 4,406 of 5,450 subjects), sensitivity 66.1%, and specificity 62.2%. Conclusion Subjects with TS have high prevalence rates of comorbid learning disabilities. We identified phenotype differences between the TS - LD group compared to TS + LD group. In the evaluation of subjects with TS, the presence of a learning disability should always be a consideration. ADHD may be an important comorbid condition in the diagnosis of LD or may also be a potential confounder. Further research on etiology, course and response to intervention for subjects with TS only and TS with learning disabilities is needed.

Fetal alcohol syndrome (FAS) is a common cause of neuropsychiatric disorders, growth impairment and craniofacial abnormalities. The syndrome may be more common than has been previously reported. Considerable controversy exists over the approaches for diagnosis of the syndrome. Method : In this study, we examined the rate of agreement for two diagnostic schema using 385 subjects that had been referred for assessment of possible FAS. Cases had initially been diagnosed using the Fetal Alcohol Syndrome Diagnostic Checklist (FASDC). We then reviewed the chart of each of the 385 subjects referred and assigned each subject to a category from the Institute of Medicine (IOM) Criteria or to a NOFAS category. We then compared the IOM categories with the FASDC. Results: Rates of agreement with the IOM Criteria ranged from 59–71% using the FASDC. Poorest agreement was found in conjunction with partial FAS (PFAS)/alcohol-related neurodevelopmental disorder (ARND). Removal of exposure data from the scores greatly affected accuracy for the FASDC scores. Discussion : The schema had only modest rates of agreement for classification of subjects with a diagnosis of FAS. This study does not determine if the diagnosis used in the development of the cohort was accurate. Further study utilizing multiple diagnostic schema in a single population will help examine the rates of diagnostic agreement between differing diagnostic schema. A valuable cohort to study would be the subjects in the CDC surveillance system. A perspective study utilizing a single cohort and applying multiple diagnostic criteria at the same time would be useful.

Fetal alcohol syndrome (FAS) is a common developmental disorder with impairments in multiple neuropsychiatric spheres of varying severity. Few population-derived studies of the behavioral phenotype are available. The purpose of this study was to estimate the prevalence of neuropsychiatric disorders in three groups: subjects who met criteria for FAS (n=152); subjects who met criteria for partial FAS/ARND (n=150); and referred subjects who did not meet criteria for either FAS or partial FAS/ARND (n=86). Each subject had a standardized evaluation by a medical geneticist. All subjects were from North Dakota. We found increases in the prevalence rates of neuropsychiatric disorders in subjects with FAS compared to subjects with partial FAS/ARND and the lowest rates in the group that did not meet criteria for either FAS or partial FAS/ARND. Comorbid attention deficit hyperactivity disorder occurred in 73% of cases with FAS, in 72% cases with partial FAS/ARND, and in 36% subjects who did not meet criteria for either. For other neuropsychiatric disorders, a similar distribution of comorbidity was found. This study supports the concept of a continuum of impairment resulting from prenatal alcohol exposure. The presence of complex cognitive, behavioral, and physical symptomatology in the affected subjects with prenatal alcohol exposure would seem to fit well under the diagnostic rubric of fetal alcohol spectrum disorder (FASD). Diagnosis and long-term management will require increasing access to multidisciplinary child development teams including mental health professionals who treat children and adolescents. Adults will require care primarily from teams with expertise in mental health and developmental disabilities.

The objective of this study was to use population-based data to estimate the cost and phenotypic variation of conditions comorbid with attention-deficit hyperactivity disorder (ADHD). The North Dakota Department of Health's Claims Database was used to estimate the administrative prevalence, rates of comorbidity, and cost of care for subjects with ADHD. The case population was 7745 children. We then examined the 10 most frequent comorbidities for a defined condition in the International Classification of Diseases-9th edition ( ICD-9). The observed prevalence of general health conditions was 12 to 70% less than expected. The presence of a comorbid condition resulted in increases in costs of care of $381 to $731 per case per year. The observed prevalence of comorbid mental health conditions was 97 to 5286% higher than expected. The prevalence of conditions comorbid with ADHD varies widely, with rates of general medical conditions decreased and rates of most mental disorders increased. The costs for comorbidity with general health conditions were offset by large decreases in prevalence rates compared with controls. We identified an ADHD paradox: decreased rates of comorbid general health conditions and increased rates of comorbid mental disorders. Further research on comorbidity in ADHD is required. ( J Child Neurol 2003; 18:653-660).

Research on neuropsychiatric disorders has produced a number of very important findings in the last few decades. However, several problems continue to hinder research in this area. One problem area has been the appropriate classification of disease status for probands and extended family members in linkage studies. In this article, we examine rates of misclassification in a 12-year follow-up study of children previously diagnosed with Tourette syndrome. At the 12-year follow-up, we found a 5 to 12% rate of misclassification of previously diagnosed cases. We present a model of a linkage study with three classification steps. The model demonstrates that an error rate of 5% would result in misclassification of 20% of true cases by step three. Adding additional steps to improve diagnostic accuracy may increase rather than decrease classification error. (J Child Neurol 2001;16:499-504).

Aim : To identify pre- and perinatal risk factors for autism. Method: Case control study. We matched names of patients from North Dakota who met DSM criteria for autism, a pervasive developmental disorder, and autistic disorder with their birth certificates. Five matched controls were selected for each case. Results: Univariate analysis of the 78 cases and 390 controls identified seven risk factors. Logistic modeling to control for confounding produced a five variable model. The model parameters were X 2 = 36.6 and p < 0.001. The five variables in the model were decreased birth weight, low maternal education, later start of prenatal care, and having a previous termination of pregnancy. Increasing father's age was associated with increased risk of autism. Conclusion: This methodology may provide an inexpensive method for clinics and public health providers to identify risk factors and to identify maternal characteristics of patients with mental illness and developmental disorders.

A 40-year-old man with childhood-onset Tourette syndrome (TS) developed Huntington disease (HD). We believe this to be the first reported case of childhood-onset TS with adult onset HD. Discovery of other cases with both disorders may provide clues to the pathophysiology of both conditions.

A prevalence study of Prader-Willi syndrome (PWS) has been conducted in North Dakota. All pediatricians, neurologists, child psychiatrists, psychologists, and clinical geneticists were surveyed. The state's comprehensive evaluation center, the state hospital, the state institution for the mentally retarded, and group homes for the developmentally disabled, including one for persons with PWS, were also contacted. Seventeen patients were identified, 8 males, 8 females, and one patient whose sex was not specified. This suggests a prevalence rate of 1 per 16,062 in North Dakota.

Aims: To identify pre- and perinatal risk factors for Tourette disorder. Methods: Case control study. We matched names of patients who met DSM criteria for Tourette disorder with their birth certificates. For each case five controls were selected. The controls were matched by sex, year and month of birth. Results: Univariate analysis of the 92 cases and the 460 matched controls identified 4 risk factors; one categorical variable- trimester prenatal care begun and 3 continuous variables - apgar score at 5 minutes, month prenatal began and number of prenatal visits. Logistic modeling to control for confounding produced a three variahle model (apgar score at 5 minutes (OR = 1.31), number of prenatal visits (OR = .904) and fathers age (OR = .909). The model parameters were; X 2 = 19.76; df = 3; p