Jacques D'Astous

Alendronate for the Treatment of Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study

CONTEXT Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited. OBJECTIVE The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI. DESIGN AND PARTICIPANTS We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4-19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater. MAIN OUTCOME MEASURES Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured. RESULTS ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from -4.6 to -3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from -4.6 to -4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups. CONCLUSIONS Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.

Comparing botulinum toxin A with casting for treatment of dynamic equinus in children with cerebral palsy

The purpose of this study was to compare the cumulative efficacy (three treatment sessions) of botulinum toxin A (BTX‐A) alone, casting alone, and the combination of BTX‐A and casting in the management of dynamic equinus in ambulatory children with spastic cerebral palsy (CP). Thirty‐nine children with spastic CP (mean age 5y 10mo, range 3 to 9y) were enrolled in the study. A multicenter, randomized, double blind, placebo‐controlled prospective study was used. Children were randomly assigned to one of three treatment groups: BTX‐A only (B), placebo injection plus casting (C), or BTX‐A plus casting (B+C). The dosage for the BTX‐A injections was 4U/kg per extremity. Assessments were performed at baseline, 3,6,7.5, and 12 months with a total of three treatments administered after the evaluations at baseline, 3, and 6 months. Primary outcome measures were ankle kinematics, velocity, and stride length. Secondary outcome measures were ankle spasticity, strength, range of motion, and ankle kinetics. Group B made no significant change in any variable at any time. Groups C and B+C demonstrated significant improvements in ankle kinematics, spasticity, passive range of motion, and dorsiflexor strength. Results of this 1‐year study indicate that BTX‐A alone provided no improvement in the parameters measured in this study, while casting and BTX‐A/casting were effective in the short‐ and long‐term management of dynamic equinus in children with spastic CP.

Gross motor function classification System and outcome tools for assessing ambulatory cerebral palsy: a multicenter study

The relationships between different levels of severity of ambulatory cerebral palsy, defined by the Gross Motor Function Classification System (GMFCS), and several pediatric outcome instruments were examined. Data from the Gross Motor Function Measure (GMFM), Pediatric Orthopaedic Data Collection Instrument (PODCI), temporal-spatial gait parameters, and oxygen cost were collected from six sites. The sample size for each assessment tool ranged from 226 to 1047 participants. There were significant differences among GMFCS levels I, II, and III for many of the outcome tools assessed in this study. Strong correlations were seen between GMFCS level and each of the GMFM sections D and E scores, the PODCI measures of Transfer and Mobility, and Sports and Physical Function, Gait Velocity, and Oxygen Cost. Correlations among tools demonstrated that the GMFM sections D and E scores correlated with the largest number of other tools. Logistic regression showed GMFM section E score to be a significant predictor of GMFCS level. GMFM section E score can be used to predict GMFCS level relatively accurately (76.6%). Study data indicate that the assessed outcome tools can distinguish between children with different GMFCS levels. This study establishes justification for using the GMFCS as a classification system in clinical studies.

Function and well-being in ambulatory children with cerebral palsy

The purpose of this study was to determine whether there is a significant association between function and well-being in children with cerebral palsy. To determine this, the authors used validated measures of function (Gillette Functional Assessment Questionnaire, Gross Motor Function Classification System, Gross Motor Function Measure, and walking speed) and correlated them to health-related quality of life (HRQOL) measures (Pediatric Outcomes Data Collection Instrument, Pediatric Quality of Life instrument). In a cross-sectional study of ambulatory children with mild to moderate cerebral palsy aged 10.2 ± 3.2 years, mild to moderate decreases in function were found when compared with normative data. As the assessment of HRQOL comprises both functional well-being and psychosocial well-being, the authors decided to specify the aspect of well-being to which they were referring. It was found that the childs function was not correlated to psychosocial well-being. The children with mild cerebral palsy had greater effects on their psychosocial well-being than would be predicted by their functional disability. Functional measures were good at predicting the functional well-being but were weak at predicting the psychosocial arm of well-being.

Derotational casting for progressive infantile scoliosis.

Background Serial cast correction by using the Cotrel derotation technique is one of several potential treatments for progressive infantile scoliosis. This study reviews our early experience to identify which, if any, patients are likely to benefit from or fail this technique. Methods We followed all patients treated at our institutions for progressive infantile scoliosis since 2003 prospectively at 1 institution and retrospectively at the other 2. Data, including etiology, Cobb angles, rib vertebral angle difference, Moe-Nash rotation, and space available for the lung, were recorded over time. Results Fifty-five patients with progressive infantile scoliosis had more than 1 year of follow-up from the initiation of casting. The diagnosis of progressive scoliosis was made based upon either a progressive Cobb angle or a rib vertebral angle difference of more than 20 degrees at presentation. All but 6 patients responded to cast correction. Nine patients have undergone surgery to date, 6 because of worsening and 3 by parent choice. As shown in the table, initiation of cast correction at a younger age, moderate curve size (<60 degrees), and an idiopathic diagnosis carry a better prognosis than an older age of initiation, curve >60 degrees, and a nonidiopathic diagnosis. The space available for the lung improved from 0.89 to 0.93. No patient experienced worsening of rib deformities. Conclusions Serial cast correction for infantile scoliosis often results in full correction in infants with idiopathic curves less than 60 degrees if started before 20 months of age. Cast correction for older patients with larger curves or nonidiopathic diagnosis still frequently results in curve improvement along with improvement in chest and body shape. Significance Derotational cast correction seems to play a role in the treatment of progressive infantile scoliosis with cures in young patients and reductions in curve size with a delay in surgery in older and syndromic patients. Level of Evidence Level 4, therapeutic study.

Evidence of Increased Bone Resorption in Neurofibromatosis Type 1 Using Urinary Pyridinium Crosslink Analysis

Although neurofibromatosis type 1 (NF1) is a neurocutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5–19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects.

The Rib Vertebra Angle Difference and its Measurement in 3D for the evaluation of early onset scoliosis.

The Rib Vertebra Angle Difference (RVAD) as defined by Mehta (1972) is used to predict the progression of early onset scoliosis. No clear physical significance has been established for this measurement. The purpose of this study was to evaluate the RVAD along the thoracic spine and the equivalent measurement on 3D reconstructions of the spine and rib cage of early onset scoliosis patients in order to determine their relationship with the geometry of the chest wall and evolution along the spine. The RVAD was measured on PA radiographs of 42 infantile scoliotic patients (Cobb >20°) from T4 to T10 according to the method described by Mehta. The RVAD 3D was computed using the same landmarks from the 3D reconstruction generated from the calibrated biplanar radiographs. Cases were divided into Phase I and Phase II using Mehtas classification based on the rib head overlap with the apical vertebral body on coronal plane radiographs. A linear relationship exists between the Metha (2D) and 3D RVAD for both Phase I (r = 0.87) and Phase II (r = 0.78) patients. For more severe deformities (RVAD 3D ≥ 35°), a relationship was found between RVAD 3D and the axial rotation of the thoracic vertebrae (r = 0.51) in Phase II patients. However, no significant relationship exists between axial rotation and RVAD 3D for Phase I patients as well as Mehtas RVAD. Maximal RVAD measurements were located 2 ½ levels above the apical vertebra. Results indicated that RVAD 3D provides additional information to Mehtas RVAD on the torsional nature of the deformity. Considering the importance of clinical indices to assess the progression of early onset scoliosis, this study raises some questions on looking solely at the RVAD measured on radiographs at the apical vertebra of Phase I patients and suggests considering also levels above the apex of the scoliotic curve and 3D measurements. Further investigation is required to fully understand the 3D nature of the spine and rib cage deformities.

Physical Significance of the Rib Vertebra Angle Difference and Its 3-Dimensional Counterpart in Early-Onset Scoliosis

STUDY DESIGN Analysis of the rib vertebra angle difference (RVAD) on coronal plane radiographs and the 3-dimensional (3D) RVAD and Local RVAD in the vertebral reference frame from 3D reconstructions of the spine and rib cage of early-onset scoliosis patients (cross-sectional study). OBJECTIVES To determine the relationship of RVAD with the geometry of the chest wall. SUMMARY OF BACKGROUND DATA Although scoliosis is a complex 3D deformity, RVAD is measured on coronal plane radiographs. No clear physical significance has been established for this measurement from a 3D perspective. METHODS We measured RVAD on posteroanterior radiographs of 42 infantile scoliotic patients (Cobb > 20°) from T4 to T10 using Mehtas method. We computed RVAD 3D using the same landmarks from the 3D reconstruction generated from the calibrated biplanar radiographs. Local RVAD was measured in the local vertebral frontal plane, based on the axial rotation of each vertebra. We divided cases into Phase I and II, based on the rib head overlap with the apical vertebral body on coronal plane radiographs. RESULTS Apical Local RVAD correlated with Methas RVAD (Phase I: r = 0.690; Phase II: r = 0.666), and RVAD 3D (Phase I: r = 0.908; Phase II: r = 0.862). Maximal values of RVAD and RVAD 3D were above the apex. Rib vertebra angle difference and Local RVAD were significantly different at the level of maximal RVAD (p < .001) but not at the apex (p = .800). The difference between Local RVAD and maximal RVAD correlated with vertebral axial rotation (Phase I: r = 0.691; Phase II: r = 0.659). CONCLUSIONS Rib vertebra angle difference not only indicates asymmetry of the ribs in relation to the spine, it is a compound of physical factors including vertebral axial rotation. The root of its prognostic value remains unclear. Rib vertebra angle difference 3D can serve as an alternative to determine true asymmetry in the costovertebral geometry.

Utilization of Whole-Exome Next-Generation Sequencing Variant Read Frequency for Detection of Lesion-Specific, Somatic Loss of Heterozygosity in a Neurofibromatosis Type 1 Cohort with Tibial Pseudarthrosis

A subset of neurofibromatosis type 1 patients develop tibial dysplasia, which can lead to pseudarthrosis. The tissue from the tibial pseudarthrosis region commonly has a somatic second hit in NF1: single-nucleotide variants, small deletions, or loss of heterozygosity (LOH). We used exome next-generation sequencing (NGS) variant frequency data (allelic imbalance analysis) to detect somatic LOH in pseudarthrosis tissue from three individuals with clinically and diagnostically confirmed neurofibromatosis type 1, and verified the results with microarray. The variant files were parsed and plotted using python scripts, and the NGS variant frequencies between the affected tissue and blood sample were compared. Individuals without somatic single-nucleotide variants or small insertions/deletions were tested for somatic LOH using the NGS variant allele frequencies. One individuals NGS data indicated no LOH in chromosome 17. The other two individuals demonstrated somatic LOH inclusive of NF1: one had an LOH region of approximately one million bases and Contra (NGS copy number program) indicated a somatic deletion and the other individual had LOH for most of chromosome 17q and Contra indicated no copy number change (microarray data verified this sample as copy neutral somatic LOH). Both LOH and copy number variation detected by NGS data correlated with microarray data, demonstrating the somatic LOH second hit can be detected directly from the NGS data.

Initial Cast Correction as a Predictor of Treatment Outcome Success for Infantile Idiopathic Scoliosis

Background: Cast treatment for infantile idiopathic scoliosis patients ultimately corrects deformity in varying amounts. As the reasons for these differential outcomes are not fully elucidated, the aim of this study was to identify clinical and radiographic variables correlated with better cast correction. Methods: Patients in the Children’s Spine Study Group and Growing Spine Study Group registries who underwent cast treatment for idiopathic scoliosis between 2005 and 2013 with 1-year minimum follow-up were included. Data including major curve and rib-vertebra angle difference before cast, initial in-cast application, after cast treatment, and at most recent follow-up were collected. Univariable and multivariable regression analyses were used to identify factors associated with lower major curves at most recent follow-up. Results: A total of 68 patients were identified and followed for a mean of 2.5 (range, 1.1 to 5.4) years after cast treatment. Cast treatment lasted an average of 16.7 months, with a median of 6 cast applications (range, 2 to 19). Twenty-five subjects (37%) had a most recent major curve <15 degrees (success), whereas 43 had a curve that was >15 degrees (unresolved). Multivariable linear regression determined that younger age (P=0.02), smaller precast major curve (P<0.001), and greater percent major curve correction in initial cast (P=0.006) were associated with smaller major curve at most recent follow-up. Multivariable logistic regression determined that success patients were younger than unresolved patients (average age, 1.4 vs. 2.1 y; P=0.003), and had smaller in-cast major curves after initial cast application (average, 18 vs. 27 degrees; P=0.002). Conclusions: Infantile idiopathic scoliosis patients casted at an earlier age, with smaller major curves, and greater percent major curve correction in initial cast have the best prognosis. Patients’ percent major curve correction, which may represent curve flexibility and/or cast quality, is a predictor of treatment success when age and precast major curve are also taken into account. Level of Evidence: Level III—retrospective study.