Twelve-Month Outcomes of Stand-Alone Excisional Goniotomy in Mild to Severe Glaucoma.

PURPOSE: To describe 12-month intraocular pressure (IOP) and medication use outcomes following excisional goniotomy (EG) as a stand-alone procedure in eyes with medically uncontrolled glaucoma. METHODS: This was a retrospective analysis of data from surgeons at 8 centers (6 US, 2 Mexico). Eyes with glaucoma undergoing standalone EG with a specialized instrument (Kahook Dual Blade, New World Medical, Rancho Cucamonga, CA) for IOP reduction and followed for 12 months postoperatively were included. Data were collected preoperatively, intraoperatively, and 1 day, 1 week, and 1, 3, 6, and 12 months postoperatively. The primary outcome was reduction from baseline in IOP, and key secondary outcomes included IOP-lowering medication reduction as well as adverse events. RESULTS: A total of 42 eyes were analyzed, of which 36 (85.7%) had mild to severe primary open-angle glaucoma (POAG). Mean (standard error) IOP at baseline was 21.6 (0.8) mmHg, and mean number of medications used at baseline was 2.6 (0.2). At 3, 6, and 12 months postoperatively, mean IOP reductions from baseline were 4.6 mmHg (22.3%), 5.6 mmHg (27.7%), and 3.9 mmHg (19.3%) (p≤0.001 at each time point). At the same time points, mean medications reductions of 0.7 (25.8%), 0.9 (32.6%), and 0.3 (12.5%) medications were seen (p<0.05 at months 3 and 6, not significant at month 12). Six eyes (14.3%) underwent additional glaucoma surgery during the 12-month follow-up period. DISCUSSION: Standalone EG with KDB can reduce IOP, and in many cases reduce medication use, through up to 12 months in eyes with mild to severe glaucoma. Statistically significant and clinically relevant reductions in IOP were seen at every time point. While the goal of surgery was not to reduce medication burden, mean medication use was significantly reduced at all but the last time point. In the majority of eyes, the need for a bleb-based glaucoma procedure was delayed or prevented for at least 12 months.

Reintroducing Dyslexia: Early Identification and Implications for Pediatric Practice.

Dyslexia is a common learning disorder that renders children susceptible to poor health outcomes and many elements of socioeconomic difficulty. It is commonly undiagnosed until a child has repeatedly failed to learn to read in elementary school; this late diagnosis not only places the child at an academic disadvantage but also can be a precursor to psychiatric comorbidities such as anxiety and depression. Genetic and neuroimaging research have revealed that dyslexia is heritable and that it is undergirded by brain differences that are present even before reading instruction begins. Cognitive-behavioral research has revealed that there are early literacy skill deficits that represent red flags for dyslexia risk and can be measured at a preschool age. Altogether, this evidence points to dyslexia as a disorder that can be flagged by a pediatrician before school entry, during a period of heightened brain plasticity when interventions are more likely to be effective. In this review, we discuss the clinical implications of the most recent advances in dyslexia research, which converge to indicate that early identification and screening are crucial to the prevention or mitigation of adverse secondary consequences of dyslexia. We further highlight evidence-based and practical strategies for the implementation of early risk identification in pediatric practice so that physicians can be empowered in their ability to treat, educate, and advocate for their patients and families with dyslexia.

Updating the neurodevelopmental profile of Alazami syndrome: Illustrating the role of developmental assessment in rare genetic disorders.

Alazami syndrome, caused by biallelic pathogenic variants in LARP7, is a recently-described rare genetic disorder, with 17 patients currently reported in the literature. We present a case of a male infant referred for genetics evaluation at 5 months of age, found at 17 months of age to have Alazami syndrome. He was promptly referred for developmental evaluation, where he was found to be higher functioning than prior reports of individuals with this condition. This demonstrates the neurodevelopmental phenotypic variability seen in rare genetic disorders; it also demonstrates the important role of developmental programs to measure and track outcomes and provide support for infants with genetic disorders that put them at risk of developmental disabilities.

Longitudinal Associations between Neurodevelopment and Psychosocial Health Status in Patients with Repaired D-Transposition of the Great Arteries.

OBJECTIVE: To examine associations between measurements of neurodevelopment and psychosocial health status at age 8 and 16 years in patients with repaired dextro-transposition of the great arteries. STUDY DESIGN: In the 16-year follow-up of the Boston Circulatory Arrest Study, 137 parents completed the Child Health Questionnaire-Parent Form-50, of whom 135 had completed the Child Health Questionnaire-Parent Form-50 when their child was age 8 years. Psychosocial and physical summary scores were used to assess change in health status from age 8 to 16 years. A comprehensive battery of neurodevelopmental testing was performed at ages 8 and 16 years to examine associations with adolescent health status. RESULTS: Lower psychosocial summary scores of 16 year old subjects with dextro-transposition of the great arteries were highly associated with numerous concurrent domains of neurodevelopmental function, most notably with higher (worse) scores on the Conners' Attention Deficit Hyperactivity Disorder/Diagnostic and Statistical Manual-4th Edition Scales (parent: r = -0.62, P < .001; adolescent: r = -0.43, P < .001) and the Behavior Rating Inventory of Executive Function Global Executive Composite (parent: r = -0.66, P < .001; adolescent: r = -0.39, P < .001). Psychosocial and physical summary scores tracked from ages 8 to 16 years (r = 0.44 and 0.47, respectively, P < .001 for each). Higher (worse) scores of multiple attention measures at age 8 years predicted worse psychosocial summary scores at age 16 years. CONCLUSIONS: Attention deficits at age 8 years were highly predictive of worse psychosocial health status in adolescence. Further studies are needed to assess whether treatment of childhood attention deficit hyperactivity disorder could improve adolescent well-being.

Six-Month Outcomes of Goniotomy Performed with the Kahook Dual Blade as a Stand-Alone Glaucoma Procedure.

INTRODUCTION: To characterize the reduction in intraocular pressure (IOP) and IOP-lowering medication use following goniotomy via trabecular meshwork excision performed using the Kahook Dual Blade as a stand-alone procedure in adult eyes with glaucoma uncontrolled on a regimen of 1-3 topical IOP-lowering medications. METHODS: In this retrospective analysis, data from consecutive patients undergoing goniotomy with the Kahook Dual Blade by 11 surgeons were analyzed. Preoperative, intraoperative, and postoperative follow-up data through 6 months of follow-up were collected. The primary efficacy endpoint was IOP reduction from preoperative baseline; reduction in IOP-lowering medication use was a secondary endpoint. RESULTS: Data were collected from 53 eyes of 42 subjects. Mean (± SE) preoperative IOP was 23.5 ± 1.1 mmHg, and from day 1 through 6 months of postoperative follow-up mean IOP reductions of 7.0-10.3 mmHg (29.8-43.8%; p < 0.001 at each time point) were observed. Mean preoperative medication use was 2.5 ± 0.2 medications per eye and was reduced by month 6 to 1.5 ± 0.2 (a 40.0% reduction; p < 0.05). Eyes with higher baseline IOP experienced mean IOP reductions of 13.7 mmHg (- 46.4%) at month 6, while eyes with lower baseline IOP experienced mean IOP reductions of 3.8 mmHg (- 21.0%) at month 6. Mean medications were reduced by 1.3 medications in high-IOP eyes and by 0.9 in low-IOP eyes at month 6. No significant sight-threatening adverse events were observed. CONCLUSIONS: Goniotomy via trabecular meshwork excision performed using the Kahook Dual Blade effectively and safely lowered IOP when performed as a stand-alone procedure in eyes with glaucoma. The significant drop in IOP met or exceeded the recommended targets for these glaucoma patients. FUNDING: New World Medical, Inc.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Using whole-exome sequencing to identify inherited causes of autism.

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Characteristics and predictive value of blood transcriptome signature in males with autism spectrum disorders.

Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62-0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65-0.82), but not for female samples (AUC 0.51, 95% CI 0.36-0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58-0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.

The co-morbidity burden of children and young adults with autism spectrum disorders.

OBJECTIVES: Use electronic health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden of ASD in children and young adults. STUDY DESIGN: A retrospective prevalence study was performed using a distributed query system across three general hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with ASD were characterized by their co-morbidities and conversely, the prevalence of ASD within these comorbidities was measured. The comorbidity prevalence of the younger (Age<18 years) and older (Age 18-34 years) individuals with ASD was compared. RESULTS: 19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58-14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89-2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13-0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72-6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41-10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3-0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26-0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79-1.14%). Autoimmune disorders (excluding DM1 and IBD) were not significantly different at 0.67% vs. 0.68% (95% CI -0.14-0.13%). Three of the studied comorbidities increased significantly when comparing ages 0-17 vs 18-34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I (0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel disorders (without IBD) and epilepsy did not change significantly. CONCLUSIONS: The comorbidities of ASD encompass disease states that are significantly overrepresented in ASD with respect to even the patient populations of tertiary health centers. This burden of comorbidities goes well beyond those routinely managed in developmental medicine centers and requires broad multidisciplinary management that payors and providers will have to plan for.

Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging.

BACKGROUND: We report neuropsychological and structural brain imaging assessments in children 16 years of age with d-transposition of the great arteries who underwent the arterial switch operation as infants. Children were randomly assigned to a vital organ support method, deep hypothermia with either total circulatory arrest or continuous low-flow cardiopulmonary bypass. METHODS AND RESULTS: Of 159 eligible adolescents, 139 (87%) participated. Academic achievement, memory, executive functions, visual-spatial skills, attention, and social cognition were assessed. Few significant treatment group differences were found. The occurrence of seizures in the postoperative period was the medical variable most consistently related to worse outcomes. The scores of both treatment groups tended to be lower than those of the test normative populations, with substantial proportions scoring ≥1 SDs below the expected mean. Although the test scores of most adolescents in this trial cohort are in the average range, a substantial proportion have received remedial academic or behavioral services (65%). Magnetic resonance imaging abnormalities were more frequent in the d-transposition of the great arteries group (33%) than in a referent group (4%). CONCLUSIONS: Adolescents with d-transposition of the great arteries who have undergone the arterial switch operation are at increased neurodevelopmental risk. These data suggest that children with congenital heart disease may benefit from ongoing surveillance to identify emerging difficulties. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000470.

Pediatrician-psychiatrist collaboration to care for children with attention deficit hyperactivity disorder, depression, and anxiety.

OBJECTIVE: To describe pediatrician experiences collaborating with psychiatrists when caring for children with attention deficit hyperactivity disorder (ADHD), depression, and anxiety. METHOD: A random sample of Massachusetts primary care pediatricians completed a mailed self-report survey. RESULTS: Response rate was 50% (100/198). Most pediatricians preferred psychiatrists to initiate medications for anxiety (87%) or depression (85%), but not ADHD (22%). Only 14% of respondents usually received information about a psychiatry consultation. For most (88%), the family was the primary conduit of information from psychiatrists, although few (14%) believed the family to be a dependable informant. Despite this lack of direct communication, most pediatricians reported refilling psychiatry-initiated prescriptions for ADHD (88%), depression (76%), and anxiety (72%). CONCLUSIONS: Pediatricians preferred closer collaboration with psychiatrists for managing children with anxiety and depression, but not ADHD. The communication gap between psychiatrists and pediatricians raises concerns about quality of care for children with psychiatric conditions.

Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.

Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.

Clinical genetic testing for patients with autism spectrum disorders.

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Behaviour at eight years in children with surgically corrected transposition: The Boston Circulatory Arrest Trial.

Uncertainty exists regarding the degree to which infants with congenitally malformed hearts are at risk of behavioural disorders in childhood. Data was collected as part of a randomized clinical trial involving 155 children with surgically corrected transposition (concordant atrioventricular and ventriculo-arterial connections or alignments). As infants, they underwent the arterial switch operation, involving deep hypothermia with predominantly total circulatory arrest or predominantly low-flow continuous cardiopulmonary bypass as the method of providing support to the vital organs. Parents completed the Child Behavior Checklist when the patients were aged 4 and 8 years, and the Connors' Parent Rating Scale at the age of 8 years. When the children were aged 8, teachers completed the Teacher's Report Form and the Connors' Teacher Rating Scale. In the cohort as a whole, the frequencies of behavioural problems identified by both parents and teachers were elevated, particularly on the scales for competence of the Child Behavior Checklist, and the Adaptive scales of the Teacher's Report Form. Approximately 1 in 5 patients had scores for Total Problem Behavior in the range of clinical concern on both the Child Behavior Checklist and the Teacher's Report Form. Few differences were found, however, according to the method of operative treatment. Postoperative seizures were associated with social and attention problems. Children experiencing academic problems at the age of 8 showed a larger increase in behavioural problems between the ages of 4 and 8 than did children making adequate academic progress. Children with congenitally malformed hearts who underwent reparative surgery in infancy using a strategy of severe haemodilution and alpha stat are at increased risk of behavioural problems in middle childhood.

Randomized trial of hematocrit 25% versus 35% during hypothermic cardiopulmonary bypass in infant heart surgery.

OBJECTIVES: We previously reported that postoperative hemodynamics and developmental outcomes were better among infants randomized to a higher hematocrit value during hypothermic cardiopulmonary bypass. However, worse outcomes were concentrated in patients with hematocrit values of 20% or below, and the benefits of hematocrit values higher than 25% were uncertain. METHODS: We compared perioperative hemodynamics and, at 1 year, developmental outcome and brain magnetic resonance imaging in a single-center, randomized trial of hemodilution to a hematocrit value of 25% versus 35% during hypothermic radiopulmonary bypass for reparative heart surgery in infants undergoing 2-ventricle repairs without aortic arch obstruction. RESULTS: Among 124 subjects, 56 were assigned to the lower-hematocrit strategy (24.8% +/- 3.1%, mean +/- SD) and 68 to the higher-hematocrit strategy (32.6% +/- 3.5%). Infants randomized to the 25% strategy, compared with the 35% strategy, had a more positive intraoperative fluid balance (P = .007) and lower regional cerebral oxygen saturation at 10 minutes after cooling (P = .04) and onset of low flow (P = .03). Infants with dextro-transposition of the great arteries in the 25% group had significantly longer hospital stay. Other postoperative outcomes, blood product usage, and adverse events were similar in the treatment groups. At age 1 year (n = 106), the treatment groups had similar scores on the Psychomotor and Mental Development Indexes of the Bayley Scales; both groups scored significantly worse than population norms. CONCLUSIONS: Hemodilution to hematocrit levels of 35% compared with those of 25% had no major benefits or risks overall among infants undergoing 2-ventricle repair. Developmental outcomes at age 1 year in both randomized groups were below those in the normative population.

Prediction of IQ and achievement at age 8 years from neurodevelopmental status at age 1 year in children with D-transposition of the great arteries.

OBJECTIVE: Studies of developmental outcomes in children with congenital heart disease (CHD) frequently use assessments conducted in infancy as primary endpoints. Whether test scores of CHD patients in infancy are predictive of status at school age has not been evaluated, however. METHODS: In the Boston Circulatory Arrest Study, 135 children with D-transposition of the great arteries repaired by arterial switch operation were administered the Bayley Scales of Infant Development and the Fagan Test of Infant Intelligence at 1 year of age and the Wechsler Intelligence Scale for Children, Third Edition and the Wechsler Individual Achievement Test at 8 years. RESULTS: Although most 1-year test scores were significantly associated with 8-year test scores, the amounts of shared variance were modest (<10%). All 1-year test scores had poor sensitivity (16%-32%) and poor positive predictive value (35%-42%) but good specificity (80%-93%) and negative predictive value (78%-79%). More than half of the children with low scores at 8 years (< or =85) had had scores >84 at 1 year. CONCLUSION: This pattern suggests that although test scores at 1 year are modestly associated with test scores at 8 years, many children who are at risk for poor late outcomes will not be identified on the basis of 1-year test scores. Long-term follow-up of children with CHD is necessary to draw inferences about the developmental sequelae of preoperative, intraoperative, and postoperative factors.