Strategies of hip management in neuromuscular disorders: Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, Charcot-Marie-Tooth Disease and Arthrogryposis Multiplex Congenita.

Joint contractures, subluxation and dislocation are common problem in children with neuromuscular disorders. Medical, surgical and rehabilitative approaches can be used to maintain patient function and comfort. Contracture release, hip dysplasia correction and procedures to address or prevent hip subluxation or dislocation, are not always necessary since patients can be asymptomatic and surgical treatment will not always be successful in maintaining a reduced hip. In fact, controversy surrounds the management of hip disorder in children with Duchenne Muscular Dystrophy, Spinal Muscular Atrophy, Charcot-Marie-Tooth Disease and Arthrogryposis Multiplex Congenita. Patients with neuromuscular disorders also frequently develop a progressive scoliosis with pelvic obliquity which may affect sitting balance and become painful. Most subluxations and dislocations have the tendency to occur on the high side of a tilted pelvis. Spinal stabilisation is sometimes necessary to improve the pelvic tilt and to prevent further increase. The present article provides an overview of the current strategies of hip management in neuromuscular disorders.

Interobserver reliability of the gross motor performance measure: preliminary results.

Although assessment of the quality of movement in children with cerebral palsy (CP) is difficult, the development of the Gross Motor Performance Measure (GMPM) has facilitated this process. In order to determine the interobserver reliability of the GMPM, 36 children with spastic neuromuscular disorders (mean age 7 years, range 4 to 15 years) were evaluated using four of the five dimensions of the GMPM. Percent Agreement, Intraclass Correlations, and Kappas were calculated by both dimension and attribute to determine reliability. In addition, reliability measures were evaluated over time to determine whether reliability improved with continual use of the GMPM. Overall, interobserver reliability was in the 'fair to good' category regardless of the reliability measure used in the analysis. Reliability scores improved over time with a greater number of individual item scores moving from the 'fair to good' category to the 'excellent' category. Results from this study indicate that it is possible to assess reliably the quality of movement in children with CP.

Ethical requirements that must be met before the introduction of new procedures.

For orthopaedic care of patients to continue to improve, new approaches, both diagnostic and therapeutic, must be continually developed. To verify that a new approach actually provides improved outcomes, these innovations must be subjected to rigorous scientific study. However, because outcomes of clinical interventions only can be studied in human subjects, these studies must not only meet scientific criteria, they also must meet strict ethical criteria. The Declaration of Helsinki, a document prepared by the World Medical Association that originally was written in 1964, revised substantially in 1975, and most recently revised in 1996, provides guidelines for such studies. In addition to satisfying ethical requirements, clinical investigators also face various complex issues that must be dealt with in the performance of clinical research studies. One of the most difficult issues is the conflict between a physician's concern for the well-being of his or her patients and the need for protocol driven trials. No matter how enthusiastic surgeons may be about a new therapeutic approach, they must recognize that they are responsible to scientifically validate their innovative approach with a well controlled clinical trial using valid functional outcome measures.

The radiological analysis of pes cavus deformity in Charcot Marie Tooth disease.

Charcot Marie Tooth (CMT) is a progressive hereditary peripheral neuropathy. The most prevalent subtype is CMT-1A, wherein patients develop a characteristic cavovarus deformity. We have reviewed a series of standing lateral foot radiographs of patients with foot deformity due to CMT, and found that the hind foot of these patients is in dorsiflexion, not equinus, and that the apparent equinus is due to plantar flexion of the forefoot on the midfoot, and actually represents a cavus deformity.

The 'chef's hat' appearance of the femoral head in cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is inherited as an autosomal dominant disorder characterised by failure of membranous ossification. The condition is due to a mutation of the cbfa1 gene on chromosome 6 which has a role in the development of osteoblasts from the mesenchymal cells. In their growing years, these patients have an unusual shape of the femoral head reminiscent of a 'chef's hat'. In order to confirm the consistency of this sign, we have reviewed the radiographs of 28 patients with CCD. All except three had this appearance. The sign was also seen in patients with coxa vara associated with a variety of other conditions. The chef's hat sign may occur secondary to the particular mechanical environment created by coxa vara as well as abnormal cellular function in patients with CCD. Although coxa vara has some influence on the shape of the femoral head, it is not entirely responsible for its morphology since it was present in only six of the 28 patients with CCD.

Vaccine genotype and route of administration affect pseudorabies field virus latency load after challenge.

The influence of vaccine genotype and route of administration on the efficacy of pseudorabies virus (PRV) vaccines against virulent PRV challenge was evaluated in a controlled experiment using five genotypically distinct modified live vaccines (MLVs) for PRV. Several of these MLVs share deletions in specific genes, however, each has its deletion in a different locus within that gene. Pigs were vaccinated with each vaccine, either via the intramuscular or intranasal route, and subsequently challenged with a highly virulent PRV field strain. During a 2-week period following challenge with virulent PRV, each of the vaccine strains used in this study was evaluated for its effectiveness in the reduction of clinical signs, prevention of growth retardation and virulent virus shedding. One month after challenge, tissues were collected and analyzed for virulent PRV latency load by a recently developed method for the electrochemiluminescent quantitation of latent herpesvirus DNA in animal tissues after PCR amplification. It was determined that all vaccination protocols provided protection against clinical signs resulting from field virus challenge and reduced both field virus shedding and latency load after field virus challenge. Our results indicated that vaccine efficacy was significantly influenced by the modified live vaccine strain and route of administration. Compared to unvaccinated pigs, vaccination reduced field virus latency load in trigeminal ganglia, but significant differences were found between vaccines and routes of administration. We conclude that vaccine genotype plays a role in the effectiveness of PRV MLVs.

Fibrillin-1 in human cartilage: developmental expression and formation of special banded fibers.

The molecular basis for Marfan's syndrome (MS), a heritable disorder of connective tissue, is now known to reside in mutations in FBN1, the gene for fibrillin-1. Classic phenotypic manifestations of MS include several skeletal abnormalities associated primarily with overgrowth of long bones. As a first step towards understanding how mutations in FBN1 result in skeletal abnormalities, the developmental expression of fibrillin-1 (Fib-1) in human skeletal tissues is documented using immunohistochemistry and monoclonal antibodies demonstrated here to be specific for Fib-1. At around 10-11 weeks of fetal gestation, Fib-1 is limited in tissue distribution to the loose connective tissue surrounding skeletal muscle and tendon in developing limbs. By 16 weeks, Fib-1 is widely expressed in developing limbs and digits, especially in the perichondrium, but it is apparently absent within cartilage matrix. Fib-1 appears as a loose meshwork of fibers within cartilage matrix by 20 weeks of fetal gestation. Until early adolescence, Fib-1 forms loose bundles of microfibrils within cartilage. However, by late adolescence, broad banded fibers composed of Fib-1 are found accumulated pericellularly within cartilage. Because these fibers can be extracted from cartilage using dissociative conditions, we postulate that they are laterally packed and crosslinked microfibrils. On the basis of these findings, we suggest that the growth-regulating function of Fib-1 may reside persistently within the perichondrium. In addition, the accumulation of special laterally crosslinked Fib-1 microfibrils around chondrocytes during late adolescence suggests that growth-regulating activities may also be performed by Fib-1 at these sites.

Recent developments in latency and recombination of Aujeszky's disease (pseudorabies) virus.

Latency is a characteristic and fascinating part of the biology of alphaherpesvirinae, including ADV. Tissue explanation, blot hybridization, in situ hybridization and more recently PCR are the experimental methods used to demonstrate that latent infections consistently occur in ganglionic neurons and, at a lower level, in tonsillar and possibly other cells. In vivo reactivation of ADV, resulting in shedding of virulent ADV, has been demonstrated experimentally following administration of high doses of corticosteriods. To determine the influence of vaccination with currently used gene deleted vaccines on field virus latency load, it is essential to use quantitative latency detection methods. We have developed chemiluminescence-based quantitative PCR assays specific for gG and gE, and are currently using these to determine field virus latency loads in tissues of pigs vaccinated with one of several gene deleted vaccines. Recombination between ADV strains has been demonstrated both in vitro and in vivo and has raised concerns about the generation of gene deleted virulent ADV strains. Recent studies in a mouse model have shown that high concentrations of both strains have to be present at the same anatomical site for recombination to take place. This led to the conclusion that ongoing ADV eradication programs, based upon the use of gene deleted vaccines and differential serological testing, are not likely to be threatened by recombination between virulent ADV and gene deleted vaccine strains.

Vaccination of cats for feline rhinotracheitis results in a quantitative reduction of virulent feline herpesvirus-1 latency load after challenge.

We recently described the construction of a feline herpesvirus-1 (FHV-1) recombinant vaccine strain, FHV beta-galgLgE delta, containing a deletion in both the gI and the gE genes. We also reported comparative tests of its safety and efficacy in cats. These cats were unvaccinated or subcutaneously vaccinated with FHV beta-galgLgE delta, its isotypic parent strain (FHV-1SA), or a commercial FHV-1 vaccine strain (FHV-1CV) and subsequently challenged with a virulent field strain of FHV-1. Here we report the determination of FHV-1 field virus latency load after challenge in the same experimental animals. FHV-1 specific quantitative PCR was carried out on feline genomic DNA isolated from trigeminal ganglia, olfactory bulbs, and brain stems. We have determined that a reduction in field virus latency load in cats vaccinated subcutaneously with wild-type FHV-1 strains prior to challenge is dependent upon glycoproteins gL and gE deleted in FHV beta-galgLgE delta.

The fate of cartilage oligomeric matrix protein is determined by the cell type in the case of a novel mutation in pseudoachondroplasia.

We have identified a novel missense mutation in a pseudoachondroplasia (PSACH) patient in one of the type III repeats of cartilage oligomeric matrix protein (COMP). Enlarged lamellar rough endoplasmic reticulum vesicles were shown to contain accumulated COMP along with type IX collagen, a cartilage-specific component. COMP was secreted and assembled normally into the extracellular matrix of tendon, demonstrating that the accumulation of COMP in chondrocytes was a cell-specific phenomenon. We believe that the intracellular storage of COMP causes a nonspecific aggregation of cartilage-specific molecules and results in a cartilage matrix deficient in required structural components leading to impaired cartilage growth and maintenance. These data support a common pathogenetic mechanism behind two clinically related chondrodysplasias, PSACH and multiple epiphyseal dysplasia.

Glycoproteins gl and gE of feline herpesvirus-1 are virulence genes: safety and efficacy of a gl-gE deletion mutant in the natural host.

Feline rhinotracheitis virus (FRV) is an important upper respiratory tract pathogen of cats. FRV is a member of the subfamily Alphaherpesvirinae and is designated feline herpesvirus-1 (FHV-1). Besides upper respiratory clinical signs, FHV-1 may cause generalized infections in neonates or abortions in pregnant queens. Recently we described a recombinant FHV-1 strain with a deletion in the genes for glycoproteins gl and gE (FHB beta-galglgE delta) and reported that cats vaccinated subcutaneously with high doses of the recombinant FHV-1 strain responded with only mild clinical signs and developed strong immunity against subsequent virulent virus challenge. Here we compare the intranasal and subcutaneous routes of administration of this strain and assess its ability to induce protective immunity and prevent virus shedding after challenge. Cats vaccinated subcutaneously or intranasally with high doses of the recombinant FHV-1 strain responded with only mild clinical signs and developed strong immunity against subsequent virulent virus challenge. This was especially evident when the mutant vaccine was administered oronasally. In contrast, intranasal administration of two other FHV-1 isolates induced severe clinical signs in cats. We conclude from testing this FHV-1 mutant in the natural host that deletion of gE and a portion of gl genes strongly reduces viral virulence but that immunogenicity is maintained.

Posterior instrumentation and fusion of the thoracolumbar spine for treatment of neuromuscular scoliosis.

We reviewed the clinical and technical outcomes of 25 patients with neuromuscular scoliosis, who were treated by Luque instrumentation and posterior spinal fusion from the upper thoracic spine to L5 between 1981 and 1988. A mean curve correction of 46% was obtained operatively with a mean 8 degrees loss of correction during the follow-up period that ranged from 1.9 to 9.4 years (mean, 5.5). Pelvic obliquity was improved 50% from a mean of 16.1 degrees to a mean of 8.1 degrees in 24 patients for whom data were available. At final follow-up, the mean pelvic obliquity increased to 11.4 degrees with only two patients increasing > 8 degrees. The cause for major postoperative increase in pelvic obliquity was continued anterior spinal growth with torsion of the fusion mass and was not related to changes limited to the L5-S1 motion segment. Posterior fusion and instrumentation from the upper thoracic spine to L5 without anterior fusion provides adequate correction and control of spinal deformity for many patients with cerebral palsy. Those patients with significant growth remaining, or with severe deformities, may benefit by preliminary anterior release and fusion or inclusion of the pelvis and sacrum.

Viral infections of the feline urinary tract.

The exact cause of hematuria, dysuria, and urethral obstruction remains unknown in a large percentage of naturally occurring cases of feline lower urinary tract disease (FLUTD). One attractive hypothesis implicates viruses as the cause of some idiopathic forms of FLUTD; supporting this hypothesis is the fact that a gamma herpesvirus, a calicivirus, and a retrovirus have been isolated from urine and tissues obtained from cats with this type of disease. Although the clinical course and laboratory findings of cats with idiopathic FLUTD are suggestive of an infectious cause, the question of whether viruses have a pathologic role in some forms of naturally acquired FLUTDs has not been completely answered.

Cerebellar dysplasia and unilateral cataract in Marinesco-Sjögren syndrome.

The classic features of Marinesco-Sjögren syndrome include bilateral cataracts, cerebellar ataxia, and mental deficiency with an autosomal recessive inheritance pattern. Weakness and a variety of other characteristics are present inconsistently. A limited number of neuroimaging studies have indicated that cerebellar hypoplasia is the most common finding. We report a patient with near normal intelligence, unilateral cataract, and the previously unreported magnetic resonance imaging findings of cerebellar dysplasia, arachnoid cyst, and absent septum pellucidum. A review of the literature suggests significant heterogeneity in the Marinesco-Sjögren syndrome.

A feline herpesvirus-1 recombinant with a deletion in the genes for glycoproteins gI and gE is effective as a vaccine for feline rhinotracheitis.

Using a site-directed mutagenesis technique we constructed a new feline herpesvirus-1 recombinant strain containing a deletion in two genes encoding glycoproteins gI and gE. These proteins may have a role in virulence, the establishment of latency, and viral recurrence as shown in other herpesviruses of the varicella and simplex types. This recombinant was characterized and used to immunize juvenile cats against virulent virus challenge. Significant protection resulted from vaccination of cats by the subcutaneous route.

Hip pathology in the trichorhinophalangeal syndrome.

Up to 50% of individuals with trichorhinophalangeal syndrome may have Perthes-like hip changes. Thirteen hips in nine skeletally immature patients were studied. Follow-up averaged 4.7 years. The patients were categorized as juvenile (4-8 years) and adolescent (12-14 years) according to their age at presentation. The universal severity of involvement, often older age at presentation, and disproportionate number developing severe deformity with hinge abduction and pain in adolescence distinguished these patients from those with true Perthes' disease. Whether the process can be modified significantly to produce a better outcome is unclear, but management must be directed at avoiding the development of hinge abduction.

Direct spinal stimulation for intraoperative monitoring during scoliosis surgery.

Intraoperative electrophysiological monitoring of the spinal cord has traditionally been done by recording somatosensory evoked potentials (SEP). There is a risk that SEPs can be unaltered when significant injury to the anterior spinal cord has occurred. The purpose of this report is to describe a simple technique for intraoperative spinal cord stimulation which monitors descending pathways in the anterior spinal cord. Stimulation occurs through needle electrodes inserted into spinous processes in the rostral surgical wound, and recordings are made from electrodes in the popliteal spaces. We report our experience in monitoring spinal instrumentation in 45 patients with idiopathic scoliosis and 20 with some form of neurological disease causing scoliosis. The neurogenic motor evoked potentials (NMEP) are stable and easily recorded from the popliteal spaces in the majority of patients. We describe the case of 1 patient with Friedreich's ataxia in whom no SEPs could be recorded, but NMEPs were used successfully for monitoring. We have fond that combining traditional SEP monitoring with NMEP recording provides a safe and effective method to monitor the spinal cord during surgical procedures where it is at risk.

The Risser sign: a critical analysis.

Orthopedic surgeons commonly use the Risser sign to estimate skeletal maturity; however, the data presented in the orthopedic literature supporting the accuracy of the Risser sign in estimating skeletal maturity do not stand up to critical statistical analysis. The Risser sign is less accurate than chronologic age as a predictor of skeletal age and should not be used as a substitute for a hand and wrist radiograph in most cases. The Risser sign is also no better a predictor of scoliosis progression than is chronologic age.