Botulinum toxin type a neuromuscular blockade in the treatment of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial.

BACKGROUND: Focal spasticity of the gastrocnemius-soleus muscles causes equinus gait in children with cerebral palsy (CP). Botulinum toxin type A (BTX-A), a neuromuscular blocking agent, reduces muscle tone/overactivity in dystonia, stroke, and CP. OBJECTIVE: A prospective, open-label, multicenter clinical trial evaluated the long-term safety and efficacy of repeated intramuscular injections of BTX-A on equinus gait in CP children. METHODS: Nine centers enrolled 207 children. BTX-A injections (4 U/Kg) were given approximately every 3 months (maximum dose 200 U per treatment). Outcome measures included a Physician Rating Scale of gait, ankle range of motion measurements, and the incidence and profile of adverse events. RESULTS: One hundred fifty-five (75%) of 207 children completed at least 1 year with a total of 302 patient years of BTX-A treatment. The mean duration of BTX-A exposure was 1.46 years per patient. Dynamic gait pattern on the Physician Rating Scale improved in 46% of patients (86/185) at first follow-up. The response was maintained in 41% to 58% of patients for 2 years. Both gait pattern and ankle position improved at every visit. The most common treatment-related adverse events included increased stumbling, leg cramps, leg weakness, and calf atrophy in 1% to 11% of patients. No treatment-related serious adverse events were reported. Only 6% (7/117) of patients with pre- and postantibody samples had both detectable antibodies and a subsequent treatment failure. CONCLUSION: BTX-A proved both safe and effective in the chronic management of focal muscle spasticity in children with equinus gait.

A controlled study of the effects of alendronate in a growing mouse model of osteogenesis imperfecta.

Recent studies have reported that bisphosphonates reduce fracture incidence and improve bone density in children with osteogenesis imperfecta (OI). However, questions still persist concerning the effect of these drugs on bone properties such as ultrastructure and quality, particularly in the growing patient. To address these issues, the third-generation bisphosphonate alendronate was evaluated in the growing oim/oim mouse, an animal model of moderate-to-severe OI. Alendronate was administered to 6-week-old mice during a period of active growth at a dosage of 73 microg alendronate/kg/day for the first 4 weeks and 26 microg alendronate/kg/day for the next 4 weeks. Positive treatment effects included a reduction in the number of fractures sustained by the alendronate-treated oim/oim mice compared with untreated oim/oim mice (2.1+/-2.0 vs 3.2+/-1.6 fractures per mouse), increased femoral metaphyseal density (0.111+/-0.02 vs 0.034+/-0.04 g/cm2), a tendency towards reduced tibial bowing (4.0+/-3.7 vs 6.1+/-5.8 degrees), and towards increased femoral diameter (1.22+/-0.12 vs 1.15+/-0.11 mm). Potential negative effects included a persistence of calcified cartilage in the treated oim/oim metaphyses compared with treated wildtype (+/+) (33.8+/-11.1 vs 22.1+/-10.2%), and significantly shorter femora compared with nontreated oim/oim mice (14.8+/-0.67 vs 15.3+/-0.37 mm). This preclinical study demonstrates that alendronate is effective in reducing fractures in a growing mouse model of OI, and is also an important indicator of potential positive and negative outcomes of third-generation bisphosphonate therapy in children with OI.

Normal human fibroblasts produce membrane-bound and soluble isoforms of FGFR-1.

Fibroblast growth factors (FGFs) are polypeptide mitogens for a wide variety of cell types and are involved in other processes such as angiogenesis and cell differentiation. FGFs mediate their biological responses by activating high-affinity tyrosine kinase receptors. Currently, there are four human fibroblast growth factor receptor (FGFR) genes. To investigate the mechanisms by which alpha FGF and beta FGF may mediate mitogenic signal transduction in human skin-derived fibroblasts, we analyzed these cells for the presence of high-affinity FGFRs. We show that normal human dermal fibroblasts express a single high-affinity FGFR gene, FGFR-1. Cloning and sequencing of two distinct FGFR-1 cDNAs suggested that normal human dermal fibroblasts express a membrane-bound and a putatively secreted form of FGFR-1. We show that normal human dermal fibroblasts produce two FGFR-1 proteins, one of which exists in conditioned media. The mRNA for the putatively secreted form of FGFR-1 appears to be down-regulated by serum treatment of the cells.

Resection arthroplasty of the hip for patients with cerebral palsy: an outcome study.

Thirteen patients (18 hips) with cerebral palsy and painful hip subluxation or dislocation underwent proximal femoral resection-interposition arthroplasty (PFRIA) as a salvage procedure for intractable pain or seating difficulty. Eleven patients (14 hips) had a prior failed soft-tissue or bony reconstruction. The average age at surgery was 26.6 years (range, 10.7-45.5 years), and average follow-up was 7.4 years (range, 2.2-20.8 years). All patients/caregivers noted significant improvement in subjective assessment of pain after the surgery. Upright sitting tolerance improved from an average preoperative value of 3.2-8.9 h postoperatively (p < 0.01). Four patients who were unable even to sit in a customized wheelchair before the operation could be easily seated in a custom chair after surgery. Hip range of motion including flexion, extension, and abduction was significantly improved postoperatively (p < 0.05). Single-dose radiation therapy was used postoperatively for five hips and resulted in a significantly lower grade of heterotopic ossification at final follow-up (p < 0.005). Skeletal traction in the postoperative period did not prevent proximal migration of the femur compared with skin traction. Maximal pain relief was achieved at an average of 5.6 months postoperatively (range, 0.03-14 months). Complications included transient postoperative decubitus ulceration (four patients), pneumonia (two patients), and symptomatic heterotopic bone (two patients). The significant improvements in pain management, sitting tolerance, and range of motion suggest that PFRIA is a reasonable salvage procedure for the painful, dislocated hip in cerebral palsy. Resolution of pain may not be immediate, as was noted in this series.

The material basis for reduced mechanical properties in oim mice bones.

Osteogenesis imperfecta (OI), a heritable disease caused by molecular defects in type I collagen, is characterized by skeletal deformities and brittle bones. The heterozygous and homozygous oim mice (oim/+ and oim/oim) exhibit mild and severe OI phenotypes, respectively, serving as controlled animal models of this disease. In the current study, bone geometry, mechanics, and material properties of 1-year-old mice were evaluated to determine factors that influence the severity of phenotype in OI. The oim/oim mice exhibited significantly smaller body size, femur length, and moment of area compared with oim/+ and wild-type (+/+) controls. The oim/oim femur mechanical properties of failure torque and stiffness were 40% and 30%, respectively, of the +/+ values, and 53% and 36% of the oim/+ values. Collagen content was reduced by 20% in the oim/oim compared with +/+ bone and tended to be intermediate to these values for the oim/+. Mineral content was not significantly different between the oim/oim and +/+ bones. However, the oim/oim ash content was significantly reduced compared with that of the oim/+. Mineral carbonate content was reduced by 23% in the oim/oim bone compared with controls. Mineral crystallinity was reduced in the oim/oim and oim/+ bone compared with controls. Overall, for the majority of parameters examined (geometrical, mechanical, and material), the oim/+ values were intermediate to those of the oim/oim and +/+, a finding that parallels the phenotypes of the mice. This provides evidence that specific material properties, such as mineral crystallinity and collagen content, are indicative and possibly predictive of bone fragility in this mouse model, and by analogy in human OI.

Identification of the oim mutation by dye terminator chemistry combined with automated direct DNA sequencing.

The homozygous oim/oim mouse, a model of moderate-to-severe human osteogenesis imperfecta, contains a G-nucleotide deletion in the Cola-2 gene (the murine pro alpha(I) collagen gene) that results in accumulation of alpha1(I) homotrimer collagen. Although these mice have a distinctive phenotype that includes multiple fractures and deformities, genotyping is necessary to distinguish them from their wildtype (+/+) and heterozygote (oim/+) littermates. In this study, the dye primer and dye terminator chemistry methods, in combination with automated direct DNA sequencing, were compared for accuracy and ease in genotyping. A total of 82 mice from 14 litters were bred and genotyped; this resulted in 18 +/+, 35 oim/+, and 29 oim/oim mice. The dye primer and dye terminator chemistry methods worked equally well for identification of the deletion mutation and thus the genotype of all of the mice. However, the dye terminator method was found to be superior on the basis of the reduced amount of sample handling and reduced quantity of reagent required.

Cervical cancer screening: are the 1989 recommendations still valid? National Workshop on Screening for Cancer of the Cervix.

Although screening for cervical cancer has been shown to be effective in reducing the morbidity and mortality associated with this disease, and despite many attempts to encourage the development of provincial programs, as of 1995 no province had a comprehensive screening program for cervical cancer. Participants at the Interchange '95 workshop, held in Ottawa in November 1995, reviewed the recommendations of the 1989 National Workshop on Screening for Cancer of the Cervix and identified factors that have impeded their implementation. Participants discussed the need for comprehensive information systems, quality control and strategies to increase recruitment of unscreened and underscreened women. They concluded that the formation of a Cervical Cancer Prevention Network involving key stakeholders will facilitate the development and implementation of provincial programs to ensure optimal screening. They agreed that, in the interim, recommendations for practising physicians should remain as they were following the 1989 workshop.

Discoid lateral meniscus in children. Long-term follow-up after excision.

We retrospectively reviewed the results for fifteen patients, eight girls and seven boys, who had had a total of eighteen meniscectomies performed for a discoid meniscus at The Hospital for Special Surgery between January 1, 1955, and December 31, 1983. The average age was ten and a half years (range, six to sixteen years) at the time of the operation and twenty-eight years (range, twenty to thirty-six years) at the time of follow-up. The average duration of follow-up was seventeen years (range, eight to twenty-eight years). The primary indication for the meniscectomy was continuing pain in fourteen knees and locking or snapping in three. One patient had tenderness and walked with a limp. A meniscal tear was found in twelve knees at the time of the operation. According to the scale of Ikeuchi, the result was excellent for ten knees, good for three, and fair for five. Of the five patients (five knees) who had a fair result, four had mild intermittent discomfort after strenuous physical activity as well as clicking (three knees) or swelling (one knee), and one had clicking. One of these five patients was subsequently found to have rheumatoid arthritis, and two subsequently had a patellar realignment. No degenerative changes were evident on the roentgenograms of the eight patients (nine knees) for whom they were made at the latest follow-up evaluation.

The severely unstable hip in cerebral palsy. Treatment with open reduction, pelvic osteotomy, and femoral osteotomy with shortening.

The results in thirty-one patients with cerebral palsy who had a total of thirty-five severely subluxated or dislocated hips were analyzed retrospectively a mean of seven years after open reduction, pelvic osteotomy, varus rotational osteotomy, and femoral shortening. Preoperatively, twenty-two patients had been unable to stand and thirteen had had pain; the mean acetabular index was 50 degrees, the mean center-edge angle was -19 degrees, and the mean migration index was 74 percent. At the latest follow-up examination, none of the hips were painful. Seven patients had an improvement of one level in their walking ability. All of the patients who were confined to a wheelchair had better sitting balance. The mean acetabular index was 40 degrees, the mean center-edge angle was 18 degrees, and the mean migration index was 25 percent. Four hips were subluxated (two of them posteriorly). One hip was treated with a repeat varus rotational osteotomy. Another hip, which was not dislocated, had a rotational osteotomy for excessive femoral anteversion. Eight femoral heads displayed signs of avascular necrosis. One tibial and two femoral fractures occurred after the cast was removed. Three of the four patients who had a subluxated hip had scoliosis. The combined approach improved coverage of the femoral head and decreased pain in the hip. Even though this procedure can be accompanied by serious complications, we believe that the results justify this extensive approach in these patients.

Femoral anteversion and neck-shaft angles in hip instability in cerebral palsy.

A consecutive sample of 411 hip roentgenograms in 215 patients with cerebral palsy was evaluated. Femoral anteversion and neck-shaft angles were measured and compared with hip stability indexes to determine which of the two angles is more important in hip instability. The correlation coefficients were higher and statistically significant for femoral anteversion and lower and statistically nonsignificant for neck-shaft angles. These findings suggest that increased femoral anteversion has greater correlation than increased coxa valga with hip instability in cerebral palsy patients and therefore should be addressed primarily when surgically treating these hips.

Total hip arthroplasty in cerebral palsy. Long-term follow-up results.

Patients with cerebral palsy frequently develop coxarthrosis after acquired hip dislocation or dysplasia. Nineteen total hip arthroplasties (THA) were performed in 18 patients with cerebral palsy and end-stage hip degeneration. The average age at arthroplasty was 30 years (range, 16-52 years). All components were cemented, and four hips required bone graft augmentation of the deficient acetabulum. Spica casts were used in 16 of 18 patients to minimize the incidence of dislocation and trochanteric nonunion. The average follow-up time was ten years (range, three to 17 years). Seventeen of 18 patients (94%) had pain relief and improved function after arthroplasty. One stem loosened at three years, and one acetabular component loosened at 15 years. One stem and one acetabular component were revised for malposition. Survivorship analysis was 95% at ten years for loosening and 86% with removal for any reason. Total hip arthroplasty can provide long-term relief and improved function in cerebral palsy patients with severe coxarthrosis.

A musculoskeletal outreach screening, treatment, and education program for urban minority children.

PURPOSE: A hospital-based outreach program was initiated to screen minority children in medically underserved areas of New York City for musculoskeletal diseases. We examine the number of such diseases in this population, and evaluate the program's success to facilitate referral and follow-up of children with referral conditions. METHODS: Screenings were conducted at schools and day-care centers. Children requiring further evaluation were referred to the sponsoring hospital, a major referral center for musculoskeletal diseases. Bilingual educational strategies, transportation reimbursement, and coverage for uninsured children were used to foster participation and increase follow-up. RESULTS: A total of 2,523 children were screened, 168 (6.7%) of whom were referred for one of 45 different musculoskeletal disorders, including scoliosis and back problems, foot problems, in- and out-toeing, knee or hip pain, and problems of joint range of motion. Sixty-seven percent of those referred had a follow-up medical consultation. CONCLUSIONS: A substantial proportion of urban minority children have previously undiagnosed musculoskeletal disorders that, if left untreated, have the potential to lead to significant disability in later life. Targeted screening programs can be effective in identifying such disorders, and providing and opportunity for early diagnosis, treatment, and education.

Results of surgical treatment for growth hormone-secreting pituitary adenomas.

The results of surgical therapy for acromegaly were reviewed in a series of 175 patients treated between 1972 and 1983. Patients with prior surgery or radiation therapy were excluded from the study. Postoperative radiation therapy was given to 54 patients. The criterion of achieving a postoperative basal or glucose-suppressed growth hormone level of 2 ng/ml or less was used to indicate remission. Utilizing the most recently available growth hormone determinations, 90 (51.7%) of 174 patients were in remission. The actuarial probability of remission at 1 and 5 years after surgery was 48.8% and 62.7%, respectively. Tumor size and the preoperative basal growth hormone level were correlated with outcome. Surgical excision of a pituitary adenoma is the most effective therapy currently available for acromegaly.

Femoral torsion and neck-shaft angles in cerebral palsy.

Excessive femoral and coxa valga have been reported to be major contributors leading to hip dislocation in patients with cerebral palsy (CP). Femoral torsion angle (FT) and neck-shaft angle (NSA) were measured by the radiographic technique described by Rippstein and Müller in 157 patients with CP (289 hips). Factors associated with the degree of FT and NSA were evaluated. The researchers explored the correlation between the two angles and hip pathology. A large database of measurements was constructed. Our findings suggest that age and ambulatory status are the main factors correlated with FT and NSA.

Cerebral palsy in twins.

Eighty-six children with cerebral palsy (CP) born as a product of twin pregnancies were studied. Data regarding their co-twins were also gathered. The authors' findings suggest that (1) monozygotic twins have a higher risk of CP than dizygotic twins, (2) twin order at birth does not seem to be a relevant factor in the etiology of CP, (3) mothers less than 24 or more than 34 years of age had the highest incidence of children with CP as a product of a twin pregnancy, and (4) the data do not support a genetic basis for the disease.

Distal lengthening of the hamstrings in patients who have cerebral palsy. Long-term retrospective analysis.

One hundred and twenty-six patients who had cerebral palsy and who had been managed with distal lengthening of the hamstrings were followed for three to fourteen years so that the long-term results of the procedure could be determined. Twenty-four of sixty-two patients who could not walk before the procedure were able to walk about the house postoperatively. Mild recurvatum developed in only ten patients, and twenty-two patients had a reoperation because of recurrence. Although straight-leg raising and the popliteal angle had improved markedly at one year in all but two patients, both parameters regressed gradually over time. Of several selected variables, only limitation of straight-leg raising preoperatively was of statistical significance (p < 0.001) for the prediction of recurrence. Age, preoperative walking ability, concomitant operations, and postoperative immobilization had no significant effect on the rates of recurrence or recurvatum.

Human dermal fibroblasts express multiple bFGF and aFGF proteins.

We investigated the regulation of expression of bFGF and aFGF in cultures of normal human dermal fibroblasts grown in a defined, serum-free medium which did not contain FGF. Under these conditions we detected three molecular weight forms of bFGF protein [18.0, 23.0, and 26.6 kiloDaltons (kD)] and three molecular weight forms of aFGF protein (18.4, 19.2, and 28.6 kD) in these cells using western blot analysis. The addition of fetal bovine serum (FBS) to these cultures caused an accumulation of all three molecular weight forms of bFGF protein with a more dramatic accumulation of the 23.0 and 26.6 kD forms. In contrast, the addition of FBS to the cultures had no effect on the level of aFGF proteins. Analysis of mRNA isolated from cells grown in serum-free medium revealed multiple species of both bFGF and aFGF RNA with molecular weights that correlated with our previous observations. The abundance of all bFGF mRNA species increased dramatically after serum treatment while the abundance of aFGF mRNA species increased only slightly. Our observations demonstrate that factor(s) present in FBS elevate the levels of bFGF mRNA and protein beyond the levels already present in the cultures growing in serum-free medium. Moreover, both bFGF and aFGF protein are present in these cells as multiple molecular weight species. Some of these forms are higher in apparent molecular weight than would be predicted from ATG-initiated primary translation products of these genes. We also show that the cells used for this study proliferate in response to bFGF and aFGF, thus, it is possible that the growth of these cells could be subject to autocrine/paracrine control in certain conditions.

Selective peripheral denervation for torticollis: preliminary results.

Herein we report the preliminary results in nine patients who have undergone selective peripheral denervation for spasmodic torticollis and have been followed up for at least 13 months. All patients had improvement immediately after surgical intervention, and the results have been maintained in five patients. In one patient who had recurrent torticollis, a second procedure in conjunction with injection of botulinum toxin has produced substantial improvement; however, follow-up was brief (6 months). No surgical complications occurred. We believe that selective peripheral denervation is safe and that it can benefit patients with torticollis who have not responded to other types of therapy. These favorable results confirm other published reports on the efficacy of selective peripheral denervation. Long-term follow-up, however, is necessary for determining the role of this procedure in the management of torticollis.