Brief youth self-report screener for tics: Can a subscale of the Motor tic, Obsession and compulsion, and Vocal tic Evaluation Survey (MOVES) identify tic disorders in youth?

Tics are unwanted, repetitive movements and sounds that frequently present during childhood. They are typically brief and purposeless, but can create significant distress for individuals, and often co-occur with other neuropsychiatric conditions. Thus, early identification of tics is warranted. Unfortunately, tics are often misdiagnosed, and because tics may wax and wane, identification can be difficult, especially in the context of routine clinical visits. There are limited tools that can be used to reliably identify tics in clinical practice, especially in non-specialty settings. The purpose of the current study was to evaluate the performance of the Motor tic, Obsession and compulsion, and Vocal tic Evaluation Survey (MOVES), a self-report scale with some support as a screening tool. In addition, the performance of a subset of questions (the MOVES-6) was evaluated for rapid screening. Participants were recruited across two study sites and included children and adolescents diagnosed with Tourette syndrome (n = 151) or another persistent tic disorder (n = 10) and community controls (n = 74). Results suggest both the MOVES and the MOVES-6 have high sensitivity (90% and 88%, respectively) and at least acceptable specificity (77% and 86%, respectively) compared with expert assessment of tic disorders, suggesting that both versions can identify tic disorders without high proportions of false negatives. Both versions were highly sensitive with acceptable specificity regardless of sex, race/ethnicity, and age. The MOVES and MOVES-6 show promise as a screener for tics or tic disorders, but additional research is needed, particularly in a general population setting.

Teacher Knowledge of Tourette Syndrome and Associated Factors.

BACKGROUND: Tourette syndrome (TS) is associated with learning disabilities and educational impairment. Teacher knowledge about TS may have a positive impact on students with TS, but factors associated with teacher knowledge of TS are not known. METHODS: In this cross-sectional study, teachers of youth with TS and of a community control group completed a Teacher Understanding of Tourette Syndrome Survey (TUTS), a pilot questionnaire enquiring about self-perceived understanding, teacher knowledge, and sources of information. We compared TUTS scores between TS and control groups and between those who did and did not use specific sources of information about TS using Wilcoxon rank-sum tests. Bivariate correlation analyses were used to evaluate associations between teacher knowledge and potential contributing factors. RESULTS: Data from 114 teachers of children with TS and 78 teachers of control subjects were included. Teachers of youth with TS had significantly more knowledge, had higher self-perceived understanding, and used more sources of information than teachers of the control group. Teachers who knew of the Tourette Association of America and who gathered information themselves had higher knowledge about TS than those who did not. CONCLUSION: Teachers of children with TS know more about TS and use more sources to learn about TS than teachers of children without TS.

Validation of the Diagnostic Interview Schedule for Children (DISC-5) Tic Disorder and Attention-Deficit/Hyperactivity Disorder Modules.

Effective methods to assess mental disorders in children are necessary for accurate prevalence estimates and to monitor prevalence over time. This study assessed updates of the tic disorder and attention-deficit/hyperactivity disorder (ADHD) modules of the Diagnostic Interview Schedule for Children, Version 5 (DISC-5) that reflect changes in diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (Fifth edition, DSM-5). The DISC-5 tic disorder and ADHD parent- and child-report modules were compared to expert clinical assessment for 100 children aged 6-17 years (40 with tic disorder alone, 17 with tic disorder and ADHD, 9 with ADHD alone, and 34 with neither) for validation. For the tic disorder module, parent-report had high (>90%) sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, while the youth-report had high specificity and PPV, moderate accuracy (81.4%), and lower sensitivity (69.8%) and NPV (67.3%). The ADHD module performed less well: parent-report had high NPV (91.4%), moderate sensitivity (80.8%), and lower specificity (71.6%), PPV (50.0%), and accuracy (74.0%); youth-report had moderate specificity (82.8%) and NPV (88.3%), and lower sensitivity (65.0%), PPV (54.2%), and accuracy (78.6%). Adding teacher-report of ADHD symptoms to DISC-5 parent-report of ADHD increased sensitivity (94.7%) and NPV (97.1%), but decreased specificity (64.2%), PPV (48.7%), and accuracy (72.2%). These findings support using the parent-report tic disorder module alone or in combination with the child report module in future research and epidemiologic studies; additional validation studies are warranted for the ADHD module.

Risk Behaviors in Youth With and Without Tourette Syndrome.

BACKGROUND: Specific health-risk behaviors are present in older adolescents and young adults wtih Tourette syndrome (TS), but little is known about health-risk behaviors in youth with TS. METHODS: We compared responses on the Youth Risk Behavior Surveillance System (YRBS) in youth with TS with those in a concurrent community control group. The YRBS evaluates risk behaviors most closely associated with morbidity and mortality in young people. Tic severity, presence of comorbid attention-deficit/hyperactivity disorder (ADHD), measures of ADHD symptom severity, and whether or not the individual had been bullied in school were also compared between the groups. RESULTS: Data from 52 youth with TS and 48 control youth were included. We did not detect any differences between control youth and youth with TS in the reporting of risky behaviors. Tic severity was not significantly associated with high-risk behavior. However, ADHD was significantly more common in youth with TS (P < 0.0002), and youth with TS who identified themselves as victims of bullying had significantly higher ADHD symptom severity scores (P = 0.04) compared with those who were not bullied. CONCLUSIONS: Risk behaviors are not reliably or clinically different in youth with TS compared with control youth. ADHD severity, but not tic severity, was associated with being bullied in youth with TS.

A diagnostic confidence scheme for CLN3 disease.

Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long-term natural history studies. Using genotype and phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3-PLUS. Phenotypes included the classical juvenile-onset syndromic phenotype, a "vision loss only" phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test-retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.

Anxiety Symptoms Differ in Youth With and Without Tic Disorders.

We compared anxiety symptoms in youth with and without tic disorders by comparing scores on the Multidimensional Anxiety Scale for Children (MASC) in youth with tic disorders to those in a concurrent community control group and in a group of treatment-seeking anxious youth from the Child/Adolescent Anxiety Multimodal Study (CAMS). Data from 176 youth with tic disorders, 93 control subjects, and 488 CAMS participants were included. Compared to youth with tic disorders, controls had lower total MASC scores (p < 0.0001) and CAMS participants had similar total MASC scores (p = 0.13). Separation Anxiety (p = 0.0003) and Physical Symptom (p < 0.0001) subscale scores were higher in youth with tic disorders than in CAMS participants. We conclude that the anxiety symptom profile differs in youth with and without tic disorders, which may have important implications for targeting treatment of anxiety in youth with tic disorders.

Intracerebroventricular Cerliponase Alfa for Neuronal Ceroid Lipofuscinosis Type 2 Disease: Clinical Practice Considerations From US Clinics.

BACKGROUND: Neuronal ceroid lipofuscinosis type 2 or CLN2 disease is a rare, autosomal recessive, neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 deficiency. Cerliponase alfa, a recombinant human tripeptidyl peptidase 1 enzyme, is the first and only approved treatment for CLN2 disease and the first approved enzyme replacement therapy administered via intracerebroventricular infusion. METHODS: A meeting of health care professionals from US institutions with experience in cerliponase alfa treatment of children with CLN2 disease was held in November 2018. Key common practices were identified, and later refined during the drafting of this article, that facilitate safe chronic administration of cerliponase alfa. RESULTS: Key practices include developing a multidisciplinary team of clinicians, pharmacists, and coordinators, and institution-specific processes. Infection risk may be reduced through strict aseptic techniques and minimizing connections and disconnections during infusion. The impact of intracerebroventricular device design on port needle stability during extended intracerebroventricular infusion is a critical consideration in device selection. Monitoring for central nervous system infection is performed at each patient contact, but with flexibility in the degree of monitoring. Although few institutions had experienced positive cerebrospinal fluid test results, the response to a positive cerebrospinal fluid culture should be determined on a case-by-case basis, and the intracerebroventricular device should be removed if cerebrospinal fluid infection is confirmed. CONCLUSIONS: The key common practices and flexible practices used by institutions with cerliponase alfa experience may assist other institutions in process development. Continued sharing of experiences will be essential for developing standards and patient care guidelines.

The CLN3 Disease Staging System: A new tool for clinical research in Batten disease.

OBJECTIVE: To develop a disease-specific staging system for CLN3 disease and to test the hypothesis that salient and discrete clinical features of CLN3 disease may be used to define disease stages by analyzed data from an 18-year-long natural history study. METHODS: A proposed staging system, the CLN3 Staging System (CLN3SS), was based on salient and clinically meaningful endpoints. The relationships between stage and age, stage and Unified Batten Disease Rating Scale (UBDRS) physical severity score, and stage and UBDRS capability impairment subscale scores were determined. We used t tests to determine whether the stages were significantly different from each other on the basis of age and scores. RESULTS: Data were analyzed from 322 evaluations in 108 individuals. There were significant differences among the stages based on age and severity scores. For individuals with longitudinal data, no individual reverted to a less severe stage over time. CONCLUSION: The CLN3SS is a disease-specific staging system that can be used to classify individuals into specific strata based on age and disease severity. The CLN3SS has potential applications in clinical trials for cohort stratification.

Tic Disorders are Associated With Lower Child and Parent Quality of Life and Worse Family Functioning.

OBJECTIVE: Chronic tic disorders occur in approximately 3% of children. Neuropsychiatric symptoms of attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety, and depression are common. We evaluated the impact of tic disorders and comorbid symptoms on individual and parent quality of life and family functioning. METHOD: In two cross-sectional studies children with tic disorders were enrolled at the University of Rochester or the University of South Florida; data were pooled for analyses. Control subjects were enrolled at the University of Rochester. We compared quality of life and function in youth and families with and without tic disorders. We evaluated the associations between comorbid symptoms and individual quality of life and family impact in youth with tic disorders using multiple regression analyses. RESULTS: We enrolled 205 youths with tic disorders and 100 control subjects. Psychosocial (P < 0.0001) and physical (P < 0.0001) quality of life were lower in individuals with tic disorders compared with controls. Severity of attention-deficit/hyperactivity disorder (P < 0.0001) and depression (P = 0.046) symptoms were associated with lower psychosocial quality of life in youth with tic disorders. Families of youths with tic disorders had worse parent quality of life (P < 0.001) and family functioning (P < 0.001) than control families. Severity of attention-deficit/hyperactivity disorder (P < 0.0001), obsessive-compulsive disorder (P = 0.0004), and depression (P = 0.01) symptoms were associated with predicted worse family impact. CONCLUSION: Youths with tic disorders had lower individual and parent quality of life and worse family functioning than controls. The impact of tic disorders on the family may have significant implications for approaches to providing comprehensive care to these families.

A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder.

BACKGROUND: Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. METHODS: We created a "hub and spoke" model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the "hub," conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating "spoke" site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. RESULTS: A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6-9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. CONCLUSIONS: This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

Short-Term Administration of Mycophenolate Is Well-Tolerated in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis).

Mycophenolate, an immunosuppressant, is commonly used off-label for autoimmune neurological conditions. In CLN3 disease, a neurodegenerative disorder of childhood, preclinical and clinical data suggest secondary autoimmunity and inflammation throughout the central nervous system are key components of pathogenesis. We tested the short-term tolerability of mycophenolate in individuals with CLN3 disease, in preparation for possible long-term efficacy trials of this drug. We conducted a randomized, double-blind, placebo-controlled, crossover study of mycophenolate in 19 ambulatory individuals with CLN3 disease to determine the safety and tolerability of short-term administration (NCT01399047). The study included two 8-week treatment periods with a 4-week intervening washout. Mycophenolate was well tolerated. 89.5% of participants completed the mycophenolate arm, on the assigned study dose (95% CI: 66.9-98.7%), and there were no significant differences in tolerability rates between mycophenolate and placebo arms (10.5%; 95% CI: -3.3-24.3%, p = 0.21). All reported adverse events were mild in severity; the most common adverse events on mycophenolate were vomiting (31.6%; 95% CI: 12.6-56.6%), diarrhea (15.8%; 95% CI: 3.4-39.6%), and cough (15.8%; 95% CI: 3.4-39.6%). These did not occur at a significantly increased frequency above placebo. There were no definite effects on measured autoimmunity or clinical outcomes in the setting of short-term administration. Study of long-term exposure is needed to test the impact of mycophenolate on key clinical features and CLN3 disease trajectory.

Diagnosis and treatment of attention deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by signs and symptoms of inattention, hyperactivity, and impulsivity that typically begin in childhood. ADHD can persist into adulthood, causing impairments in occupational performance and peer and family relationships. This article reviews the epidemiology, diagnosis, and treatment of ADHD.

Remote Assessment of Cognitive Function in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease): A Pilot Study of Feasibility and Reliability.

Remote technology provides an opportunity to extend the reach of clinical care and research for pediatric rare disease. This pilot study evaluated the feasibility and reliability of neuropsychological evaluation, using remote audiovisual technology, in the assessment of children with juvenile Batten disease. Three children with Batten disease and 1 healthy sibling completed a standardized cognitive assessment. Results indicated high agreement between an in-person and a remote evaluator when comparing the subjects' cognitive test scores. This initial test of remote cognitive assessment suggests it is feasible and reliable in children with pediatric neurodegenerative disease, for whom disease burden may limit travel and access to expert care and/or clinical trials.

Pilot Testing Behavior Therapy for Chronic Tic Disorders in Neurology and Developmental Pediatrics Clinics.

Comprehensive Behavioral Intervention for Tics (CBIT) is an efficacious treatment with limited regional availability. As neurology and pediatric clinics are often the first point of therapeutic contact for individuals with tics, the present study assessed preliminary treatment response, acceptability, and feasibility of an abbreviated version, modified for child neurology and developmental pediatrics clinics. Fourteen youth (9-17) with Tourette disorder across 2 child neurology clinics and one developmental pediatrics clinic participated in a small case series. Clinician-rated tic severity (Yale Global Tic Severity Scale) decreased from pre- to posttreatment, z = -2.0, P < .05, r = -.48, as did tic-related impairment, z = -2.4, P < .05, r = -.57. Five of the 9 completers (56%) were classified as treatment responders. Satisfaction ratings were high, and therapeutic alliance ratings were moderately high. Results provide guidance for refinement of this modified CBIT protocol.

SUICIDAL THOUGHTS AND BEHAVIORS IN CHILDREN AND ADOLESCENTS WITH CHRONIC TIC DISORDERS.

OBJECTIVE: Despite evidence of elevated risk factors for suicidal thoughts and behavior in youth with Tourette syndrome and chronic tic disorders (CTD), few studies have actually examined that relationship. This study documented the frequency and clinical correlates of suicidal thoughts and behaviors in a sample of children and adolescents with CTD (N = 196, range 6-18 years old). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Centers for Disease Control. METHOD: Youth and parents completed a battery of measures that assessed co-occurring psychiatric diagnoses, child emotional and behavioral symptoms, and impairment due to tics or co-occurring conditions. RESULTS: A structured diagnostic interview identified that 19 youths with CTD (9.7%) experienced suicidal thoughts and/or behaviors, which was elevated compared to 3 youths (3%) who experienced these thoughts in a community control sample (N = 100, range 6-18 years old, P = .03). For youth with CTD, suicidal thoughts and behaviors were frequently endorsed in the context of anger and frustration. The Child Behavior Checklist (CBCL) anxious/depressed, withdrawn, social problems, thought problems, and aggressive behavior subscales, as well as the total internalizing problems scale, were associated with the presence of suicidal thoughts and/or behaviors. Suicidal thoughts and/or behaviors were significantly associated with tic symptom severity; tic-related impairment; and obsessive-compulsive, depressive, anxiety, and attention-deficit/hyperactivity disorders' symptom severity. CBCL anxiety/depression scores mediated the relationship between tic severity and suicidal thoughts and behaviors. CONCLUSIONS: Findings suggest that about 1 in 10 youth with CTD experience suicidal thoughts and/or behaviors, which are associated with a more complex clinical presentation and often occur in the presence of anger and frustration.

Standardized assessment of seizures in patients with juvenile neuronal ceroid lipofuscinosis.

AIM: To evaluate seizure phenomenology, treatment, and course in individuals with juvenile neuronal ceroid lipofuscinosis (JNCL). METHOD: Data from an ongoing natural history study of JNCL were analyzed using cross-sectional and longitudinal methods. Seizures were evaluated with the Unified Batten Disease Rating Scale, a disease-specific quantitative assessment tool. RESULTS: Eighty-six children (44 males, 42 females) with JNCL were assessed at an average of three annual visits (range 1-11). Eighty-six percent (n=74) experienced at least one seizure, most commonly generalized tonic-clonic, with mean age at onset of 9 years 7 months (SD 2y 10mo). Seizures were infrequent, typically occurring less often than once every 3 months, and were managed with one to two medications for most participants. Valproate (49%, n=36) and levetiracetam (41%, n=30) were the most commonly used seizure medications. Myoclonic seizures occurred infrequently (16%, n=14). Seizure severity did not vary by sex or genotype. Seizures showed mild worsening with increasing age. INTERPRETATION: The neuronal ceroid lipofuscinoses (NCLs) represent a group of disorders unified by neurodegeneration and symptoms of blindness, seizures, motor impairment, and dementia. While NCLs are considered in the differential diagnosis of progressive myoclonus epilepsy, we show that myoclonic seizures are infrequent in JNCL. This highlights the NCLs as consisting of genetically distinct disorders with differing natural history.

Utility of the diagnostic interview schedule for children for assessing Tourette syndrome in children.

OBJECTIVE: The Diagnostic Interview Schedule for Children IV (DISC) has been used extensively in research and screening. Despite wide use, little information exists on the validity of the DISC for diagnosing tic disorders. METHODS: Participants were 181 youth with expert clinician-diagnosed Tourette syndrome (TS). RESULTS: Using expert clinician-diagnosed TS as the gold standard, the sensitivity of the DISC-Y (youth, 0.27) and DISC-P (parent, 0.44) was poor. The DISC-Y identified 29.7% of youth with diagnosed TS whereas the DISC-P identified 47.4% of cases. Only 54% of cases of TS were detected by either the DISC-Y or -P. Diagnostic agreement between the DISC and expert clinician diagnosis was poor. The DISC-Y/P results did not differ as a function of tic severity. CONCLUSIONS: Despite utility for assessing child psychiatric disorders, the sensitivity of the DISC for detecting TS appears poor. This study suggests that DISC has low agreement with expert clinician diagnosis of TS. Findings highlight the need for modification of the DISC and/or the identification and development of more sensitive measures for TS screening.

Experience, knowledge, and opinions about childhood genetic testing in Batten disease.

BACKGROUND AND OBJECTIVES: Policies for genetic testing in children (GTIC) focus on medical or psychosocial benefit to the child, discouraging or prohibiting carrier testing, and advising caution regarding pre-symptomatic diagnosis if no treatment exists. This study sought to understand parents' perspectives on these issues and determine their experiences and knowledge related to genetic testing for Batten disease - a set of inherited neurodegenerative diseases of childhood onset for which no disease modifying therapies yet exist. METHODS: Parents of children with Batten disease completed a survey of their knowledge of genetics, experience with genetic testing, and opinions regarding GTIC. RESULTS: 54% had sought genetic testing for non-affected family members, including predictive diagnosis of healthy, at-risk children. Participation in any genetic counseling was associated with greater knowledge on questions about genetics. The majority of parents felt it was better to know ahead of time that a child would develop Batten disease, believed that this knowledge would not alter how they related to their child, and that parents should have the final say in deciding whether to obtain GTIC. CONCLUSIONS: Parents of children with an inherited disease are knowledgeable about genetics and wish to establish predictive or carrier status of at-risk children.

Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates.

INTRODUCTION: Juvenile neuronal ceroid lipofuscinosis (JNCL; Batten disease) is a rare, inherited, fatal lysosomal storage childhood disorder. True for many rare diseases, there are no treatments that impact the course of JNCL. The University of Rochester Batten Center's (URBC) mission is to find treatments to slow, halt, or prevent JNCL. OBJECTIVES: Our initial objective was to develop clinical research infrastructure preparatory to clinical trials, establish a JNCL research cohort, construct a disease-specific clinical outcome measure, and validate a non-invasive diagnostic sampling method. The long-term objective is to design and implement JNCL clinical trials. METHODS: The Unified Batten Disease Rating Scale (UBDRS) was developed. The Batten Disease Support and Research Association (BDSRA) referred participants; annual BDSRA meetings provided a mobile research setting for registry enrollment and UBDRS piloting. Neuropsychological examinations were performed, enabling external validation of the UBDRS. Buccal epithelial cell collection for genotyping was introduced. Telemedicine for remote UBDRS assessment was piloted. RESULTS: The registry enrolled 198 families representing 237 children with NCL. The UBDRS was piloted, was validated and has been used to collect natural history data from 120 subjects. Funding and regulatory approval were obtained for a recently launched phase II clinical trial. Several additional lines of inquiry were reported. CONCLUSION: The registry and BDSRA collaboration have enabled development of a clinical rating scale, natural history and neuropsychological studies, and genetic studies for disease confirmation. This work highlights an approach for preparatory natural history research and infrastructure development needed to facilitate efficient implementation of clinical trials in rare diseases.