Nancy E. Jones

Gastrointestinal Conditions in Children With Autism Spectrum Disorder: Developing a Research Agenda

* Abbreviations: ASD — : autism spectrum disorder GI — : gastrointestinal 5-HT — : serotonin Autism spectrum disorders (ASDs) are a set of complex neurodevelopmental disorders defined behaviorally by impaired social interaction, delayed and disordered language, repetitive or stereotypic behavior, and a restricted range of interests. ASDs represent a significant public health issue with recent estimates indicating that as many as 1% of children in the United States are diagnosed with an ASD.1,2 Many individuals with ASDs have symptoms of associated medical conditions, including seizures, sleep problems, metabolic conditions, and gastrointestinal (GI) disorders, which have significant health, developmental, social, and educational impacts. Gastrointestinal complaints are a commonly reported concern for parents and may be related to problem behaviors and other medical issues such as dysregulated sleep (ATN Annual Registry Report, unpublished data, November 2009).3 Despite the magnitude of these issues, potential GI problems are not routinely considered in ASD evaluations. This likely reflects several factors, including variability in reported rates of GI disorders, controversies regarding the relationship between GI symptoms and the putative causes of autism, the limited verbal capacity of many ASD patients, and the lack of recognition by clinicians that certain behavioral manifestations in children with ASDs are indicators of GI problems (eg, pain, discomfort, or nausea).4–10 Whether GI issues in this population are directly related to the pathophysiology of autism, or are strictly a comorbid condition of ASD remains to be determined, but clinical practice and research to date indicate the important role of GI conditions in ASDs and their impact on children as well as their parents and clinicians.9 On November 15, 2009, a symposium addressing these issues was organized as an adjunct to the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. A … Address correspondence to Daniel L. Coury, MD, Professor of Pediatrics and Psychiatry, The Ohio State University, Chief, Developmental & Behavioral Pediatrics, Nationwide Childrens Hospital, 700 Childrens Dr, Timken G-350, Columbus OH 43205-2696

Measuring Anxiety as a Treatment Endpoint in Youth with Autism Spectrum Disorder

Despite the high rate of anxiety in individuals with autism spectrum disorder (ASD), measuring anxiety in ASD is fraught with uncertainty. This is due, in part, to incomplete consensus on the manifestations of anxiety in this population. Autism Speaks assembled a panel of experts to conduct a systematic review of available measures for anxiety in youth with ASD. To complete the review, the panel held monthly conference calls and two face-to-face meetings over a fourteen-month period. Thirty eight published studies were reviewed and ten assessment measures were examined: four were deemed appropriate for use in clinical trials, although with conditions; three were judged to be potentially appropriate, while three were considered not useful for clinical trials assessing anxiety. Despite recent advances, additional relevant, reliable and valid outcome measures are needed to evaluate treatments for anxiety in ASD.

Measuring social communication behaviors as a treatment endpoint in individuals with autism spectrum disorder

Social communication impairments are a core deficit in autism spectrum disorder. Social communication deficit is also an early indicator of autism spectrum disorder and a factor in long-term outcomes. Thus, this symptom domain represents a critical treatment target. Identifying reliable and valid outcome measures for social communication across a range of treatment approaches is essential. Autism Speaks engaged a panel of experts to evaluate the readiness of available measures of social communication for use as outcome measures in clinical trials. The panel held monthly conference calls and two face-to-face meetings over 14 months. Key criteria used to evaluate measures included the relevance to the clinical target, coverage of the symptom domain, and psychometric properties (validity and reliability, as well as evidence of sensitivity to change). In all, 38 measures were evaluated and 6 measures were considered appropriate for use, with some limitations. This report discusses the relative strengths and weaknesses of existing social communication measures for use in clinical trials and identifies specific areas in need of further development.

Healthcare for children with autism: the Autism Treatment Network.

Purpose of review Autism spectrum disorders (ASDs) are a group of a neurodevelopmental disorders affecting social, communicative, and behavioral functioning. ASD is a heterogeneous group of disorders, often accompanied by associated medical issues. Thus, the development of effective treatments is a complex task requiring consideration of diverse etiologic and phenotypic characteristics. Recent attention to the diagnosis and treatment of medical conditions in ASD children has led to the formation of a new international collaboration to improve autism care, the Autism Treatment Network (ATN). Recent findings Numerous studies have highlighted the high prevalence of gastrointestinal and sleep disorders among ASD children. Problems in communication – including being nonverbal – make the diagnosis and treatment of these conditions more difficult. Although a number of studies suggest links between neurologic impairments and gastrointestinal dysfunction and disordered sleep, these relationships remain unproven. Recent work by the ATN has begun the development of clinical guidelines in these areas, based on clinical consensus, adapting the model developed by the Cystic Fibrosis Foundation. New funding has also supported the networks development of a robust clinical research program focused on improving the physical health and care of children with ASD. These efforts promise more systematic and consistent approaches to diagnosis and treatment of these conditions. Summary Improved understanding of the underlying pathology of ASD and associated conditions, and the development of a common purpose across multiple treating sites, can improve the consistent and coordinated healthcare of children with autism.

Leadership in Health Care, Research, and Quality Improvement for Children and Adolescents With Autism Spectrum Disorders: Autism Treatment Network and Autism Intervention Research Network on Physical Health

* Abbreviations: AIR-P — : Autism Intervention Research Network on Physical Health ASD — : autism spectrum disorder ATN — : Autism Treatment Network FAC — : Family Advisory Committee GI — : gastrointestinal HRSA — : Health Resources and Services Administration NICHQ — : National Initiative for Children’s Healthcare Quality Autism spectrum disorders (ASDs) are a group of highly prevalent, lifelong neurodevelopmental disorders affecting social, communicative, and behavioral functioning. Recent studies estimate the prevalence of ASDs as 1 in 88,1,2 indicating the public health importance of the disorders and making the development of effective care and treatment of ASD an urgent priority. Among the health care concerns for children and youth with ASD is a major need to strengthen awareness and treatment of associated medical conditions with standardized, comprehensive approaches to evaluation, treatment, and monitoring. Many individuals with ASD have symptoms associated with underlying medical conditions, including seizures, sleep problems, gastrointestinal (GI) disorders, psychiatric conditions, nutritional deficiencies, and metabolic conditions; when left untreated, these conditions may not only compromise general health but also have clear effects on behavior, development, and educational outcomes for individuals with ASD. The problems that many children with ASD have with communication make the diagnosis and monitoring of medical conditions more challenging. Furthermore, the underlying biology of ASD may change the manifestations of various medical conditions and their response to treatment. Thus, special attention to these conditions is crucial for improving the quality of life for individuals with ASD. Children and adolescents with ASD encounter difficulties obtaining appropriate and necessary health care services. They have decreased access to medical specialists,3–5 coupled with increased medical expenditures and unmet needs, compared with other children with special health care needs and typically developing children.6,7 Autism Speaks and its predecessor, Cure Autism Now, have recognized the significant unmet medical needs among children and adolescents with ASD as well as the many gaps in knowledge among providers regarding the general health care challenges of individuals with ASD. Parents shared their frustrations and all too familiar tales of having to travel far distances … Address correspondence to James M. Perrin, MD, Department of Pediatrics, Harvard Medical School, MassGeneral Hospital for Children, 100 Cambridge St #1542, Boston, MA 02114. E-mail: jperrin{at}partners.org

Measuring repetitive behaviors as a treatment endpoint in youth with autism spectrum disorder

Restricted interests and repetitive behaviors vary widely in type, frequency, and intensity among children and adolescents with autism spectrum disorder. They can be stigmatizing and interfere with more constructive activities. Accordingly, restricted interests and repetitive behaviors may be a target of intervention. Several standardized instruments have been developed to assess restricted interests and repetitive behaviors in the autism spectrum disorder population, but the rigor of psychometric assessment is variable. This article evaluated the readiness of available measures for use as outcome measures in clinical trials. The Autism Speaks Foundation assembled a panel of experts to examine available instruments used to measure restricted interests and repetitive behaviors in youth with autism spectrum disorder. The panel held monthly conference calls and two face-to-face meetings over 14 months to develop and apply evaluative criteria for available instruments. Twenty-four instruments were evaluated and five were considered “appropriate with conditions” for use as outcome measures in clinical trials. Ideally, primary outcome measures should be relevant to the clinical target, be reliable and valid, and cover the symptom domain without being burdensome to subjects. The goal of the report was to promote consensus across funding agencies, pharmaceutical companies, and clinical investigators about advantages and disadvantages of existing outcome measures.

Improving Treatment Trial Outcomes for Rett Syndrome: the development of Rett-specific anchors for the Clinical Global Impression Scale

Rett syndrome is a genetically based neurodevelopmental disorder. Although the clinical consequences of Rett syndrome are profound and lifelong, currently no approved drug treatments are available specifically targeted to Rett symptoms. High quality outcome measures, specific to the core symptoms of a disorder are a critical component of well-designed clinical trials for individuals with neurodevelopmental disorders. The Clinical Global Impression Scale is a measure of global clinical change with strong face validity that has been widely used as an outcome measure in clinical trials of central nervous system disorders. Despite its favorable assay sensitivity in clinical trials, as a global measure, the Clinical Global Impression Scale is not specific to the signs and symptoms of the disorder under study. Development of key anchors for the scale, specific to the disorder being assessed, holds promise for enhancing the validity and reliability of the measure for disorders such as Rett syndrome.

The Autism Treatment Network and Autism Intervention Research Network on Physical Health: Future Directions

* Abbreviations: AIR-P — : Autism Intervention Research Network on Physical Health ASD — : autism spectrum disorder ATN — : Autism Treatment Network CER — : comparative effectiveness research CTSAs — : Clinical Translational Science programs Autism spectrum disorders (ASDs) represent complex neurodevelopmental disorders with multiple etiologies.1 The resulting variability of behavioral, medical, and developmental concerns that affect individuals with ASDs has made it extremely difficult to predict which treatments work best for which individuals. Developing effective treatments and improving care for individuals with ASDs throughout the life span remain urgent priorities. Comprehensive coordinated care for individuals with ASDs will require further advances in our knowledge of medical and behavioral interventions and a health care system that can deliver them consistently. Over the past 7 years, the Autism Speaks Autism Treatment Network (ATN) and more recently the Autism Intervention Research Network on Physical Health (AIR-P) have significantly increased understanding of the prevalence, nature, and treatment of medical conditions in children with ASDs, such as gastrointestinal conditions, sleep disorders, metabolic disorders, and seizures. The network has pioneered in standardizing the clinical evaluation of children with ASDs, based on a comprehensive, multidisciplinary model of care. The network has also developed key partnerships that have helped the field move from limited consensus toward evidence-based autism-specific guidelines in key areas of medical concern, and has acquired the infrastructure and expertise to develop more targeted treatment studies that can help move the most effective therapies through the research pipeline and into the hands of consumers. The ATN has led in the application of quality improvement methods to autism care and in systematic efforts to bring the experience and lessons of the network to broader communities of professionals and parents. This effort, led by Autism Speaks, has allowed strong synergy among research, clinical, and family communities. Key areas of continued growth for the research activities of network include (1) on-going enhancement of research infrastructure, including increased availability of biological samples; (2) expansion of the research agenda to include more focused research … Address correspondence to James M. Perrin, MD, Department of Pediatrics, Harvard Medical School, MassGeneral Hospital for Children, 100 Cambridge St, #1542, Boston, MA 02114. E-mail: jperrin{at}partners.org

Assessment of Caregiver Inventory for Rett Syndrome.

Rett syndrome (RTT) requires total caregiver attention and leads to potential difficulties throughout life. The Caregiver Burden Inventory, designed for Alzheimer disease, was modified to a RTT Caregiver Inventory Assessment (RTT CIA). Reliability and face, construct, and concurrent validity were assessed in caregivers of individuals with RTT. Chi square or Fisher’s exact test for categorical variables and t tests or Wilcoxon two-sample tests for continuous variables were utilized. Survey completed by 198 caregivers; 70 caregivers completed follow-up assessment. Exploratory factor analysis revealed good agreement for physical burden, emotional burden, and social burden. Internal reliability was high (Cronbach’s alpha 0.898). RTT CIA represents a reliable and valid measure, providing a needed metric of caregiver burden in this disorder.

Population pharmacokinetics of NNZ-2566 in healthy subjects

Abstract NNZ‐2566 is a novel, small molecule being developed as a treatment for cognitive impairment in different CNS conditions, including Rett and Fragile‐X syndrome, both of which are associated with moderate to severe neurodevelopmental disorder. In the current study we characterise the population pharmacokinetics of NNZ‐2566 after administration of single and repeated ascending doses to healthy subjects. A meta‐analytical approach was used to analyse pharmacokinetic data from 3 different studies, in which a total of 61 healthy subjects (median age: 23 years, range: 19 to 38) were treated with NNZ‐2566. Doses of NNZ‐2566 ranged from 6.0 to 100 mg/kg after oral administration and from 0.1 to 30 mg/kg after intravenous administration. A two‐compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of NNZ‐2566. Inter‐individual variability was identified in clearance, absorption rate, central volume of distribution, peripheral volume of distribution and inter‐compartmental clearance. Population predicted clearance and central volume of distribution were 10.35 L/h and 20.23 L, respectively. Dose proportionality was observed across the dose range evaluated in healthy subjects. No accumulation, metabolic inhibition or induction was observed during the course of treatment. In addition, oral bioavailability appeared to vary with food intake. The relatively short half‐life of 1.4 h suggests the need for a twice or three times daily regimen to maintain relevant blood levels of NNZ‐2566. Graphical abstract No caption available.