Long-term Safety and Dosing of OnabotulinumtoxinA: A Prospective, Observational Study.

BACKGROUND: Although therapeutic treatments are intended to help alleviate symptoms associated with disease, safety must be carefully considered and monitored to confirm continued positive benefit/risk balance. The objective of MOBILITY was to study the long-term safety of onabotulinumtoxinA for treatment of various therapeutic indications. METHODS: A prospective, multicenter, observational, Phase IV Canadian study in patients treated with onabotulinumtoxinA for a therapeutic indication. Dosing was determined by the participating physician. Adverse events (AEs) were recorded throughout the study. RESULTS: Patients (n = 1372) with adult focal spasticity, blepharospasm, cerebral palsy, cervical dystonia, hemifacial spasm, hyperhidrosis, or "other" diagnoses were enrolled into the safety cohort. Eighty-three patients (6%) reported 209 AEs; 44 AEs in 24 patients (2%) were considered treatment-related AEs. Seventy-two serious AEs were reported by 38 patients (3%); 10 serious AEs in 5 patients (0.4%) were considered treatment related. Most commonly reported treatment-related AEs were muscular weakness (n = 7/44) and dysphagia (n = 6/44). CONCLUSIONS: In patients with follow-up for up to six treatments with onabotulinumtoxinA, treatment-related AEs were reported in <2% of the safety population over the course of nearly 5 years. Our findings from MOBILITY provide further evidence that onabotulinumtoxinA treatment is safe for long-term use across a variety of therapeutic indications.

Dosage et sécurité à long terme de l'onabotulinumtoxinA : une étude prospective et observationnelle. Contexte : Bien que les traitements thérapeutiques soient destinés à soulager les symptômes associés à une maladie, il importe d'examiner avec grand soin leur sécurité et d'en assurer un suivi afin de maintenir un rapport bénéfice/risque qui soit positif. L'objectif de MOBILITY a donc été d'étudier la sécurité à long terme de l'onabotulinumtoxinA dans le traitement de plusieurs indications thérapeutiques. Méthodes : Nous avons ainsi fait appel à une étude canadienne prospective et observationnelle menée dans plusieurs centres de santé. Dans cette étude de phase IV, des patients ont été traités avec l'onabotulinumtoxinA en vertu d'indications thérapeutiques. Ce sont des médecins participants qui en avaient déterminé le dosage. De plus, tout événement indésirable a été noté en cours d'étude. Résultats : Au total 1372 patients ont été inclus dans cette cohorte (n = 1372). Ces patients étaient atteints des troubles suivants : spasticité focale chez l'adulte, blépharospasme, infirmité motrice cérébrale, dystonie cervicale, spasmes hémifaciaux, hyperhidrose, etc. On a signalé chez 83 patients, soit 6 % d'entre eux, des événements indésirables. On a aussi estimé que 44 événements indésirables ayant affecté 24 patients (2 %) étaient reliés au traitement proprement dit. Ajoutons que 38 patients (3 %) ont signalé avoir été victimes d'événements indésirables et que 10 événements indésirables ont été reliés au traitement chez 5 patients (0,4 %). Enfin, les événements indésirables les plus communément signalés ont été la faiblesse musculaire (n = 7/44) et la dysphagie (n = 6/44). Conclusions : Dans le cas de patients ayant bénéficié de six traitements ou moins avec l'onabotulinumtoxinA, des événements indésirables ont été signalés chez < 2 % d'entre eux au cours des presque cinq prochaines années. Tirés de MOBILITY, nos résultats apportent une preuve additionnelle que les traitements avec l'onabotulinumtoxinA sont à long terme sécuritaires dans le cas de nombreuses indications thérapeutiques.

Real-World, Long-Term Quality of Life Following Therapeutic OnabotulinumtoxinA Treatment.

BACKGROUND: OnabotulinumtoxinA is an efficacious treatment option for patients with various conditions. Although studies have reported on the efficacy of onabotulinumtoxinA, quality of life (QoL) data are limited. This study evaluated QoL in patients treated with onabotulinumtoxinA across various therapeutic indications. METHODS: MDs on BOTOX Utility (MOBILITY) was a prospective, multicenter, observational Canadian study in patients initiating (naïve) or receiving ongoing (maintenance) onabotulinumtoxinA treatment. Health utility was the primary outcome measure and was obtained from the Short Form-12 Health Survey using the Short Form-6D at baseline, week 4 posttreatment, and up to five subsequent treatment visits. The safety cohort included patients who received ≥1 onabotulinumtoxinA treatment. RESULTS: The efficacy cohort included 1062 patients; the majority were Caucasian, female, and on maintenance onabotulinumtoxinA treatment. Adult focal spasticity (n=398), blepharospasm (n=81), cerebral palsy (n=22), cervical dystonia (n=234), hemifacial spasm (n=116), and hyperhidrosis (n=211) patients were included. Baseline health utility was generally higher in maintenance versus naïve patients; however, naïve patients showed the greatest improvements over time. Health utility was generally maintained or trended toward improvement across all cohorts, including maintenance patients who had been treated for up to 22 years before study entry. Eighteen of 1222 patients (2%) in the safety cohort reported 28 treatment-related adverse events; eight were serious in four patients. CONCLUSION: MOBILITY is the largest prospective study to date to provide QoL data over a variety of therapeutic indications following treatment with onabotulinumtoxinA. Although the QoL burden varies by disease, data suggest that long-term treatment may help improve or maintain QoL over time.

Long-term outcome after selective dorsal rhizotomy in children with spastic cerebral palsy.

PURPOSE: The purpose of this study is to evaluate long-term outcomes after selective dorsal rhizotomy (SDR) for children with spastic cerebral palsy. METHODS: This is a retrospective review of a prospective database of patients who underwent SDR at British Columbia Children's Hospital. Hip adductor spasticity, hip range of motion (ROM), quadriceps strength, and motor function were assessed pre-operatively, at 6 months to 5 years and more than 10 years postoperatively. Patients were stratified by Gross Motor Function Classification System (GMFCS) level into group 1 (GMFCS II and III) and group 2 (GMFCS IV and V). RESULTS: Forty-four patients, with mean age at SDR of 4.5 years (range 2.9-7.7), were followed for a mean 14.4 years. Spasticity (Modified Ashworth Scale) decreased 1.5 (p < 0.0001) by early postoperative evaluation with further decrease at late evaluation of 0.8 (p < 0.0001). Early improvement in hip ROM of 13.7 degrees (p < 0.0001) was not sustained at late assessment. Motor function improved in both groups at early assessment but was only sustained in group 1. Group 1 increased 10.0 points (p < 0.0001) at early evaluation with subsequent decrease of 3.5, resulting in an overall increase of 6.6 (p = 0.04) from baseline. Group 2 patients had an initial increase of 8.3 [2.0, 14.6] (p = 0.01) but then declined to 4.9 below baseline (p = 0.3). CONCLUSIONS: SDR yields durable reduction in spasticity after 10 years. Early improvements in motor function are present, but at long-term follow-up, these improvements were attenuated in GMFCS II and III and were not sustained in GMFCS IV and V.

Classification of midfoot break using multi-segment foot kinematics and pedobarography.

Midfoot break (MFB) is a foot deformity that can occur when ankle dorsiflexion is restricted due to muscle spasticity or contractures, causing abnormal increased motion through the midfoot. MFB has been previously described in terms of forefoot (FF) and hindfoot (HF) motion in the sagittal plane. The purpose of this study was to further classify MFB by describing FF and HF motion in the coronal and transverse planes along with plantar pressures, with the goal of optimizing treatment of this deformity. Three-dimensional foot kinematics were assessed using a multi-segment foot model in children with MFB (n=30) and children with no foot or gait abnormalities (n=30). The MFB group was subdivided into three categories: (1) Pronated MFB, (2) Supinated MFB and (3) Flat Foot MFB. Unique patterns of plantar pressures and foot kinematics were identified for each MFB group. The Pronated MFB group had increased medial midfoot pressures, increased forefoot pronation, and increased external forefoot rotation (forefoot abductus). The Supinated MFB group had increased lateral midfoot pressures, increased forefoot supination, and increased internal forefoot rotation (forefoot adductus). In the Flat Foot MFB group, midfoot pressures were increased and distributed uniformly between the medial and lateral sides, forefoot pronation was increased, and internal forefoot rotation was present. By combining this new information with previously reported methods of measuring sagittal plane kinematics of MFB, it is now possible to characterize midfoot break in terms of severity and foot-floor contact pattern.

A kinematic description of dynamic midfoot break in children using a multi-segment foot model.

Midfoot break (MFB) is a foot deformity that occurs most commonly in children with cerebral palsy (CP), but may also affect children with other developmental disorders. Dynamic MFB develops because the muscles that cross the ankle joint are hypertonic, resulting in a breakdown and dysfunction of the bones within the foot. In turn, this creates excessive motion at the midfoot. With the resulting inefficient lever arm, the foot is then unable to push off the ground effectively, resulting in an inadequate and painful gait pattern. Currently, there is no standard quantitative method for detecting early stages of MFB, which would allow early intervention before further breakdown occurs. The first step in developing an objective tool for early MFB diagnosis is to examine the difference in dynamic function between a foot with MFB and a typical foot. Therefore, the main purpose of this study was to compare the differences in foot motion between children with MFB and children with typical feet (Controls) using a multi-segment kinematic foot model. We found that children with MFB had a significant decrease in peak ankle dorsiflexion compared to Controls (1.3 ± 6.4° versus 8.6 ± 3.4°) and a significant increase in peak midfoot dorsiflexion compared to Controls (15.2 ± 4.9° versus 6.4 ± 1.9°). This study may help clinicians track the progression of MFB and help standardize treatment recommendations for children with this type of foot deformity.

Inter-observer and intra-observer agreement in the radiographic diagnosis of avascular necrosis of the femoral head following slipped capital femoral epiphysis.

INTRODUCTION: Slipped capital femoral epiphysis (SCFE) is a common pediatric hip disorder. Avascular necrosis (AVN) of the femoral head is a devastating complication of SCFE. The frequency of this complication reported in the literature has been variable. It was the objective of this study to estimate the inter- and intra-observer agreement between two experienced pediatric orthopaedic surgeons for the radiographic diagnosis of AVN following SCFE. METHODS: A retrospective review of all cases of SCFE treated at our center between 1995 and 2005 was performed. All cases of AVN and a random sample of 19 of the remaining cases were selected for study. The most recent anteroposterior and lateral radiographs were presented to two experienced pediatric orthopaedic surgeons in a random order. Inter-observer reliability was determined by calculating the kappa statistic to assess for clinical agreement. Each observer repeated this process two weeks after the initial review. RESULTS: There were a total of 103 cases of SCFE, of which four were diagnosed with AVN. The inter-observer agreement in the first trial was 0.79. The intra-observer agreement for the first observer was 0.9 and for the second observer, it was 0.88. CONCLUSION: The agreement, both inter- and intra-observer, for the radiographic diagnosis of AVN amongst adolescents with previous SCFE is very high. The results of this study suggest that the reported discrepancy of AVN in the literature following SCFE is not likely due to the lack of inter- and intra-observer agreement.

A quality assessment of randomized clinical trials in pediatric orthopaedics.

The promotion and practice of evidence-based medicine necessitates a critical evaluation of medical literature, including the criterion standard of randomized clinical trials (RCTs). Recent studies have examined the quality of RCTs in various surgical specialties, but no study has focused on pediatric orthopaedics. The purpose of this study was to assess and describe the quality of RCTs published in the last 10 years in journals with high clinical impact in pediatric orthopaedics. All of the RCTs in pediatric orthopaedics published in 5 well-recognized journals between 1995 and 2005 were reviewed using the Detsky Quality Assessment Scale. The mean percentage score on the Detsky scale was 53% (95% confidence interval, 46%-60%). Only 7 (19%) of the articles satisfied the threshold for a satisfactory level of methodological quality (Detsky >75%). Most RCTs in pediatric orthopaedics that are published in well-recognized peer-reviewed journals demonstrate substantial deficiencies in methodological quality. Particular areas of weakness include inadequate rigor and reporting of randomization methods, use of inappropriate or poorly described outcome measures, inadequate description of inclusion and exclusion criteria, and inappropriate statistical analysis. Further efforts are necessary to improve the conduct and reporting of clinical trials in this field to avoid inadvertent misinformation of the clinical community.

Classification of idiopathic toe walking based on gait analysis: development and application of the ITW severity classification.

Idiopathic toe walking (ITW), considered abnormal after the age of 3 years, is a common complaint seen by medical professionals, especially orthopaedic surgeons and physiotherapists. A classification for idiopathic toe walking would be helpful to better understand the condition, delineate true idiopathic toe walkers from patients with other conditions, and allow for assignment of a severity gradation, thereby directing management of ITW. The purpose of this study was to describe idiopathic toe walking and develop a toe walking classification scheme in a large sample of children. Three primary criteria, presence of a first ankle rocker, presence of an early third ankle rocker, and predominant early ankle moment, were used to classify idiopathic toe walking into three severity groups: Type 1 mild; Type 2 moderate; and Type 3 severe. Supporting data, based on ankle range of motion, sagittal joint powers, knee kinematics, and EMG data were also analyzed. Prospectively collected gait analysis data of 133 children (266 feet) with idiopathic toe walking were analyzed. Subjects' age range was from 4.19 to 15.96 years with a mean age of 8.80 years. Pooling right and left foot data, 40 feet were classified as Type 1, 129 were classified as Type 2, and 90 were classified as Type 3. Seven feet were unclassifiable. Statistical analysis of continuous variables comprising the primary criteria showed that the toe walking severity classification was able to differentiate between three levels of toe walking severity. This classification allowed for the quantitative description of the idiopathic toe walking pattern as well as the delineation of three distinct types of ITW patients (mild, moderate, and severe).

Paraparesis caused by an angiolipomatous hamartoma in an adolescent with Proteus syndrome and scoliosis.

This 16-year-old boy with Proteus syndrome suffered acute spinal cord compression secondary to hemorrhage into an extradural paraspinal angiolipomatous hamartoma. A magnetic resonance (MR) imaging study performed 12 years earlier had revealed the presence of this tumor at the apex of a mild thoracic scoliosis, which had been stable during the intervening decade. Spinal cord neurological deficit in Proteus syndrome is rare. It can arise either from vertebral abnormalities and kyphoscoliotic deformities or from tumor encroachment. The authors describe the temporal evolution of scoliosis and acute spinal cord compression caused by a paraspinal angiolipomatous hamartoma over a period of 12 years. A review of the literature suggests that regular follow up, including serial MR imaging, is indicated in children with Proteus syndrome and scoliosis. Earlier resection of extradural tumor mass encroaching on the cord is warranted in the treatment of these children.

Hip joint subluxation after selective dorsal rhizotomy for spastic cerebral palsy.

OBJECT: The effects of selective dorsal rhizotomy (SDR) procedures on the hip joints of children with spastic cerebral palsy (CP) are not well described. This study was performed to determine the incidence of hip subluxation in children with CP who underwent SDR at a single institution. METHODS: The study group comprised 82 patients (164 hip joints) with a mean follow up of 3.9 years. Forty-four patients had spastic diplegia (53.6%), 35 had spastic quadriplegia (42.7%), two had spastic triplegia (2.4%), and one had spastic hemiplegia (1.2%). The mean patient age at SDR was 5.2 +/- 2.4 years. Preoperative and postoperative hip radiographs were reviewed and the femoral head center edge (CE) angles were recorded. The mean pre- and postoperative right CE angles were 14.1 and 17.2 degrees, respectively, and those of the left were 13.6 and 15.1 degrees, respectively. Considering a change in CE angle greater than 5 degrees as clinically significant, 72 hips (43.5%) remained unchanged, 63 (38.4%) improved, and 29 (17.7%) worsened. Of a number of preoperative variables, including age at time of surgery, Gross Motor Function Classification System (GMFCS) level, ambulatory status, extent of hip subluxation, preoperative scoliosis, and asymmetry of hip subluxation, only GMFCS level was associated with worsening of hip subluxation. CONCLUSIONS: Selective dorsal rhizotomy is more likely to have a positive effect or no effect on hip joint subluxation rather than to have a negative effect. More severe involvement, as measured using the GMFCS, may predispose to worsening of hip subluxation after SDR.

Spinal deformities after selective dorsal rhizotomy for spastic cerebral palsy.

OBJECT: Spinal deformities are significant problems in children with spastic cerebral palsy. The treatment of their spasticity by selective dorsal rhizotomy (SDR) may worsen or improve these problems. The purpose of this study was to determine the incidence of and change in degree of thoracolumbar scoliosis, thoracic kyphosis, and lumbar lordosis in children who have undergone SDR. METHODS: A retrospective review was conducted of children younger than 18 years of age, who had undergone SDR at British Columbia's Children's Hospital from 1987 to 2001 and in whom preoperative and postoperative spine radiographs have been obtained. Angles for thoracolumbar scoliosis, thoracic kyphosis, and lumbar lordosis were measured. The study group comprised 105 patients. The mean age at surgery was 5.2 years (range 2.7-14.6 years), with a mean time to most recent follow-up radiographs of 4.3 years (1-13.6 years). Sixty-two children had spastic diplegia (59%), 34 spastic quadriplegia (32%), and nine quadriplegia and intellectual delay (9%). A total of 104 children underwent laminoplasty with replacement of the laminae, usually from L-1 to S-1 and 54.8% of children had scoliosis at last follow up, with 25% having worsening of 10 degrees or more. The incidence of abnormal kyphosis at the last follow-up visit was 38.6%, with 31.8% having worsening of 15 degrees or more. The incidence of hyperlordosis at last follow up was 21.3%, with 36% having worsening of 15 degrees or more. The factors in this series impacting development of spinal deformities have been analyzed and are discussed. CONCLUSIONS: The relatively high incidence of spinal deformity in children who have undergone SDR via multi-level lumbosacral laminoplasties should raise some concern.

Treatment of idiopathic clubfoot utilizing botulinum A toxin: a new method and its short-term outcomes.

A pivotal point in most clubfoot management protocols is Achilles tendon lengthening or tenotomy to address hindfoot deformity. The effectiveness of botulinum A toxin (BTX-A) in attenuating the function of the triceps surae muscle complex as an alternative to tenotomy was investigated. Fifty-one patients with 73 idiopathic clubfeet were recruited. Outcome measures included surgical rate, Pirani clubfoot score, ankle dorsiflexion with knee in flexion and extension, and recurrences. Patients were divided according to age: group 1 (<30 days old) and group 2 (>30 days and <8 months old). Ankle dorsiflexion in knee flexion and extension remained above 20 degrees and 15 degrees, respectively, and Pirani scores below 0.5 following BTX-A injection for both groups. One of the 51 patients required limited posterior release and 9 patients required repeat manipulation and casting plus or minus BTX-A injection. The use of BTX-A as an adjunctive therapy in the noninvasive approach of manipulation and casting in idiopathic clubfoot is a safe and effective treatment.