Effect of spinal surgery on lung function in Duchenne muscular dystrophy.

BACKGROUND--The effect on subsequent respiratory function of spinal stabilisation for scoliosis in Duchenne muscular dystrophy is unclear. In order to clarify this clinical problem, changes in the forced vital capacity of a group of children with Duchenne muscular dystrophy who had undergone spinal surgery were measured and compared with a group of children with Duchenne muscular dystrophy who had not had surgery. METHODS--In this retrospective study 17 boys with Duchenne muscular dystrophy who underwent spinal stabilisation at a mean age of 14.9 years (surgical group) were compared with 21 boys with Duchenne muscular dystrophy who had not had surgery (non-surgical group). The mean (SD) Cobb angle of the surgical group at 14.9 years was 57 (16.4) degrees, and of the non-surgical group at 15 years was 45 (29.9) degrees. Forced vital capacity expressed as percentage predicted (% FVC) was measured in total over a seven year period in the surgical group and over 6.5 years in the non-surgical group, and regression equations were calculated. Survival curves for both groups were also constructed. RESULTS--No difference was found between spinal stabilisation (surgical group) and the non-surgical group in the rate of deterioration of % FVC which was 3-5% per year. There was no difference in survival in either group. CONCLUSIONS--Spinal stabilisation in Duchenne muscular dystrophy does not alter the decline in pulmonary function, nor does it improve survival.     

Autologous transplantation of muscle-derived CD133+ stem cells in Duchenne muscle patients

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive muscle disease due to defect on the gene encoding dystrophin. The lack of a functional dystrophin in muscles results in the fragility of the muscle fiber membrane with progressive muscle weakness and premature death. There is no cure for DMD and current treatment options focus primarily on respiratory assistance, comfort care, and delaying the loss of ambulation. Recent works support the idea that stem cells can contribute to muscle repair as well as to replenishment of the satellite cell pool. Here we tested the safety of autologous transplantation of muscle-derived CD133+ cells in eight boys with Duchenne muscular dystrophy in a 7-month, double-blind phase I clinical trial. Stem cell safety was tested by measuring muscle strength and evaluating muscle structures with MRI and histological analysis. Timed cardiac and pulmonary function tests were secondary outcome measures. No local or systemic side effects were observed in all treated DMD patients. Treated patients had an increased ratio of capillary per muscle fibers with a switch from slow to fast myosin-positive myofibers.     

Progression of scoliosis in Duchenne muscular dystrophy

We reviewed the clinical charts and spinal radiographs of fifty-one boys who had Duchenne muscular dystrophy, had not had surgical treatment of the spine, and had been followed until death. All had scoliosis. None of the following variables was useful in predicting which curves would become severe: age when the patient initially walked, age when he ceased walking, age at onset of spinal collapse, surgical release of the iliotibial bands, or age at the time of death. Radiographs were made within eighteen months before death for thirty-three patients; in thirty-one of them, the final curve exceeded 40 degrees and in seventeen, 90 degrees. For the remaining eighteen patients, final radiographs were made more than eighteen months before death; at that time, eight of them already had a curve of more than 90 degrees. Although there was a relationship between extension of the lumbar spine and severity of scoliosis at the time of final follow-up, early maintenance of the lumbar spine in extension rarely prevented the development of a severe curve. For most of the patients who had a severe curve, sitting was difficult and was accompanied by breakdown of the skin and pain. When a patient's curve exceeded 35 degrees, the vital capacity usually was less than 40 per cent of the predicted normal value. Therefore, when walking becomes impossible for boys who have Duchenne muscular dystrophy, routine spinal arthrodesis should be considered.     

Scoliosis in neuromuscular disorders

Summary Hundred-seventy patients with the 4 commonest degenerative neuro-muscular disorders (limbgirdle and Duchenne muscular dystrophy, Kugelberg-Welander's spinal muscular atrophy and peroneal muscular atrophy) were screened for scoliosis, which was found in 56%. Of 76 patients in the early stages of their respective discorders (stages 1–6 of Gardner-Medwin and Walton), scoliosis was found in 72%. The incidence of scoliosis was not related to the duration or degree of clinical weakness. Morphologically, scoliosis in these disorders was not found to differ from idiopathic scoliosis.Neither side nor site of the scoliosis were related to the distribution of muscle weakness as determined by manual testing.Presented at XIV World Congress of SICOT, Kyoto, 1978     

The patterns of spinal deformity in Duchenne muscular dystrophy.

In a clinical and roentgenographic study of spinal deformities in sixty-two patients in the later stages of Duchenne muscular dystrophy, many patients had marked scoliosis and kyphosis, while others with hyperextended spines had comparatively little scoliosis. Based on an analysis of the data, it is suggested that the development of spinal deformity in patients with Duchenne muscular dystrophy may progress in two ways: one leading to the early establishment of a position of extension and a maximum intrinsic stability with minor deformity, and the other leading to progressive deformity. It was concluded that management for these patients should be designed to guide the early straight spine toward the late extended pattern by attempting to prevent kyphosis and pelvic obliquity.     

Inhibiting myostatin with follistatin improves the success of myoblast transplantation in dystrophic mice

Duchenne muscular dystrophy is a recessive disease due to a mutation in the dystrophin gene. Myoblast transplantation permits to introduce the dystrophin gene in dystrophic muscle fibers. However, the success of this approach is reduced by the short duration of the regeneration following the transplantation, which reduces the number of hybrid fibers. Our aim was to verify whether the success of the myoblast transplantation is enhanced by blocking the myostatin signal with an antagonist, follistatin. Three different approaches were studied to overexpress follistatin in the muscles of mdx mice transplanted with myoblasts. First, transgenic follistatin/mdx mice were generated; second, a follistatin plasmid was electroporated in mdx muscles, and finally, follistatin was induced in mdx mice muscles by a treatment with a histone deacetylase inhibitor. The three approaches improved the success of the myoblast transplantation. Moreover, fiber hypertrophy was also observed in all muscles, demonstrating that myostatin inhibition by follistatin is a good method to improve myoblast transplantation and muscle function. Myostatin inhibition by follistatin in combination with myoblast transplantation is thus a promising novel therapeutic approach for the treatment of muscle wasting in diseases such as Duchenne muscular dystrophy.     

Treatment options for Duchenne muscular dystrophy

Opinion statement The main goal in the treatment of Duchenne muscular dystrophy (DMD) is to maintain ambulation for as long as possible and to anticipate and manage the associated complications, such as joint contractures, scoliosis, cardiomyopathy, respiratory insufficiency, and weight gain. Cognitive and behavioral symptoms occur in about one third of patients, and it is important to recognize and manage them promptly, developing an individualized plan at school and at home to maximize the patient’s cognitive abilities. In the late phase of the disease, palliative care is of paramount importance. Corticosteroid therapy (prednisone and deflazacort) is the only effective pharmacologic treatment for DMD. Daily prednisone treatment increases muscle strength and function, improves pulmonary function, and significantly slows the progression of weakness. Deflazacort has a similar effect on muscle strength, but it is not available in the United States. Treatment with corticosteroid should be offered to all patients with DMD, but the beneficial effects and potential adverse effects should be fully discussed before treatment begins. The optimal dose of prednisone is 0.75 mg/kg per day, up to a maximum of 40 mg/d. If adverse effects occur, a decrease in dosage is appropriate. Monitoring of muscle function and adverse effects by a neurologist or neuromuscular specialist is strongly recommended. Physical and occupational therapists should be involved early in the treatment of patients with DMD to develop a program that includes heel cord stretching and exercise. In the later phases, these therapists can recommend adaptive equipment and maximize independence. Orthopedic consultation is important in monitoring and managing scoliosis and joint contractures in the nonambulatory phase of the disease. Pulmonary evaluation for ventilatory care is important; pulmonary consultation is essential when vital capacity declines. The use of assistive cough devices, nasal bilevel positive airway pressure, and tracheostomy must be discussed with patients and their families. For all patients with DMD, particularly those receiving prednisone, consultation with a dietitian is very helpful to control weight and maintain a healthy diet.     

Diaphragm thickness and inspiratory strength in patients with Duchenne muscular dystrophy

BACKGROUND: There is little information on the morphometric characteristics of the diaphragm in patients with Duchenne muscular dystrophy. METHODS: The thickness of the diaphragm was measured at the zone of apposition using B mode ultrasonography in 10 boys with Duchenne muscular dystrophy of mean (SD) age 10.3 (1.3) years and 12 normal controls of mean (SD) age 11.3 (2.0) years during relaxation (DiTrelax) and during maximum effort inspiratory manoeuvres (DiTPimax) at functional residual capacity. RESULTS: DiTrelax was greater in the patients with Duchenne muscular dystrophy (1.74 (0.21) mm) than in controls (1.48 (0.20) mm), mean difference (95% CI) 0.26 (0.08 to 0.44), despite considerable impairment of maximum effort inspiratory mouth pressure (Pimax) (patients with Duchenne muscular dystrophy -37 (8) cm H2O, controls -80 (33) cm H2O), mean difference (95% CI) 43 (65 to 20). During a Pimax manoeuvre, compared with measurements taken during relaxation, the diaphragm thickened 1.6 times in patients with Duchenne muscular dystrophy and 2.3 times in controls (DiTPimax 2.62 (0.7) mm and 3.5 (0.85) mm, respectively), mean difference (95% CI) - 0.88 (-1.58 to -0.18). CONCLUSIONS: Resting diaphragm thickness is increased in young patients with Duchenne muscular dystrophy with impaired respiratory muscle force. This finding could be analogous to the pseudo-hypertrophy that is observed in some limb muscle groups.


     

One-stage versus two-stage spinal fusion in neuromuscular scolioses

The principles of the operative treatment of neuromuscular scolioses differ from those of idiopathic scolioses. Depending upon the deformity in the frontal and sagittal plane, the amount of pelvic obliquity and especially the etiology of the curve, consideration of a posterior, an anterior or a combined anterior-posterior procedure is necessary. Statistics demonstrate a higher preoperative angle and a higher rate of complications combined with worse corrections in comparison with idiopathic scolioses. The existing deterioration of vital capacity in patients with Duchenne muscular dystrophy, as in patients with spinal muscle atrophy, makes an anterior approach impossible. The correction of a severe pelvic obliquity combined with a rigid lumbar or thoracolumbar scoliosis requires a combined approach in most patients suffering from myelomeningcele (MMC) and cerebral palsy. In neurofibromatosis Recklinghausen associated with an angulated kyphotic curve the anterior approach is mandatory to avoid further deterioration. Multisegmental primary-stable anterior or posterior instrumentations allow postoperative care without external support.     

Duchenne muscular dystrophy: current knowledge,treatment, and future prospects

The cloning of the dystrophin gene has led to major advances in the understanding of the molecular genetic basis of Duchenne, Becker, and other muscular dystrophies associated with mutations in genes encoding members of the dystrophin-associated glycoprotein complex. The recent introduction of pharmaceutical agents such as prednisone has shown great promise in delaying the progression of Duchenne muscular dystrophy but there remains a need to develop more long-term therapeutic interventions. Knowledge of the nature of the dystrophin gene and the glycoprotein complex has led many researchers to think that somatic gene replacement represents the most promising approach to treatment. The potential use of this strategy has been shown in the mdx mouse model of Duchenne muscular dystrophy, where germ line gene transfer of either a full-length or a smaller Becker-type dystrophin minigene prevents necrosis and restores normal muscle function.     

Postural Control in Scoliosis: A Statokinesimetric Study in Patients with Scoliosis due to Neuromuscular Disorders and in Patients with Idiopathic Scoliosis

Statokinesimetric characteristics were analysed in patients with scoliosis which had developed in the course of degenerative neuromuscular disorders and in patients with adolescent idiopathic scoliosis. Patients with Duchenne and limb-girdle muscular dystrophy and spinal muscular atrophy showed markedly decreased oscillations of the body's centre of gravity, in addition to a forward shift of its mean position. Thus the postural equilibrium in neuromuscular patients with scoliosis is even more efficiently controlled than normal. On the other hand, patients with idiopathic scoliosis did not show any significant changes as compared with normal subjects. The present study therefore does not support the suggestion that the pathogenesis of scoliosis, at least in neuromuscular patients, is triggered by an impairment of descending postural control.     

Scoliosis and hip flexion contracture in Duchenne muscular dystrophy

Spinal deformity is common in muscular dystrophy and usually occurs after loss of walking ability. Unlike in idiopathic and other scoliosis forms, there seems to be no side preference of the convexity. Aim of the study was to analyse, if there is any relation between incidence and extent of walking ability, lower limb contractures and development of scoliosis. METHODS: In a retrospective study, 45 patients with Duchenne muscular dystrophy who underwent surgery were analysed, concerning walking ability, contractures of lower extremities and scoliosis. RESULTS: 1: No scoliosis was observed in ambulatory patients. 2: 96% of the wheelchair bound patients suffered from scoliosis. 3: 96% of the scoliosis patients had hip flexion or abduction contractures. 4: In 12 of 15 cases with side-different contractures, scoliosis tended to the side with the greater contracture. CONCLUSIONS: The influence of hip contracture and pelvic obliquity on scoliosis is discussed controversially. Concerning muscular dystrophy, there seems to be a positive correlation between convexity and hip contracture. If this is a causal relation or if there is a faster progression of structural alteration of the muscles on one side has to be further investigated.     

The effect of Luque-Galveston fusion on curve, respiratory function and quality of life in Duchenne muscular dystrophy

The aim of this retrospective study was to evaluate the long-term effect of the Luque-Galveston spinal fusion in Duchenne muscular dystrophy (DMD) patients. Twenty patients had undergone this operation at a mean age of 153 years (surgical group, A). The correction of their scoliosis amounted to +/- 55.8%, after an average follow-up period of 3 years. This is in accordance with the literature. The authors would therefore advise to perform spinal fusion in an early stage of the disease, once a rapid evolution of the scoliosis is seen. The decline of respiratory function slightly diminished after surgery, but not significantly. This means that no expectations should be made to improve respiratory function, as respiratory function decline continues relentlessly. Most authors agree with this statement. Patient satisfaction after surgery was relatively high, mainly because of an improved sitting balance, but only 60% of the questionnaires were available. Twenty-five other patients were not operated upon (non-surgical group, B). They had better results at ages 153 and 183, but this was mainly due to the fact that group B contained more benign cases according to the Oda classification.     

Malignant hyperpyrexia and Duchenne muscular dystrophy: A case report

We report a patient with Duchenne muscular dystrophy who developed malignant hyperpyrexia during general anaesthesia. During anaesthesia bradycardia was followed by ventricular fibrillation, on which ventricular flutter supervened and a body temperature rise of 0.6 degrees C for 15 minutes, myoglobinuria and elevation of CPK level were observed. The caffeine sensitivity test of biopsied muscle fibers revealed an increase in sensitivity, although there was no sign of muscle rigidity during or after anaesthesia. Diagnosis of Duchenne muscular dystrophy was first established after the development of malignant hyperpyrexia in the present case as well as in previously reported cases. Determination of serum CPK is very important before general anaesthesia.     

Bone mineral density and fractures in boys with Duchenne muscular dystrophy

The relationships between bone density, mobility, and fractures were assessed in 41 boys with Duchenne muscular dystrophy. Bone density in the lumbar spine was only slightly decreased while the boys were ambulatory (mean z-score, -0.8), but significantly decreased with loss of ambulation (mean z-score, -1.7). In contrast, bone density in the proximal femur was profoundly diminished even when gait was minimally affected (mean z-score, -1.6), and then progressively decreased to nearly 4 standard deviations below age-matched normals (mean z-score, -3.9). These are consistent with the findings that 18 (44%) of the boys sustained a fracture, 66% of these fractures involved the lower extremities, and there were no spinal compression fractures. Furthermore, four (44%) of nine boys who were walking with aids or support at the time of fracture never resumed walking after the fracture. Osteoporosis is most profound in the lower extremities of boys with Duchenne muscular dystrophy, and begins to develop early while still ambulating. Frequent fractures that may result in loss of ambulation are the clinical consequences.     

Delay in diagnosing Duchenne muscular dystrophy in orthopaedic clinics

For clinical, psychological and social reasons the diagnosis of Duchenne muscular dystrophy should be established as early as possible. In a survey of 83 families with 93 affected boys, the diagnosis was missed in every case referred to an orthopaedic surgeon (37 patients). In the whole group there was a mean delay of 2.0 years (0 to 6 years) during which time inappropriate treatment, difficulties in communication with parents, much parental anxiety and further pregnancies occurred. A serum creatine kinase estimation is a simple outpatient test which should be carried out on any boy with clumsy or abnormal gait, with flat feet or with an unexplained equinus deformity.     

Bone tissue and muscle dystrophin deficiency in mdx mice

Duchenne muscular dystrophy is a neuromuscular disease caused by the lack of dystrophin that affects skeletal muscles, causing degeneration of muscle fibers and replacing them with fibrous and adipose tissue, events that gradually lead to functional loss. Patients with Duchenne muscular dystrophy have shown that bones become more fragile with age and with advancement of the disease. Muscle weakness and reduced mobility have been suggested to be the factors that promote bone deterioration. However, it seems that this does not occur in mdx mice. It has been identified in mdx mice the existence of a factor related or not to the lack of dystrophin that also participates in the impairment of bone quality. Mdx mice also exhibit muscle degeneration, but unlike human, it is compensated by muscle regeneration. In consequence, there is an increase in the muscle mass, but not necessarily of muscle contractile strength. The accommodation of this increased muscle mass promotes bone formation at specific sites, such as at tendo-osseous junctions. In addition, the inflammatory response to muscle injury may be responsible for the increase in angiogenesis and regeneration observed in mdx mice, inducing the release of cytokines and chemokines that play an important role in the recruitment of leukocytes and macrophages. Then, mdx mice may possess compensatory mechanisms in bone in response to a genetic defect.     

Peripheral nerve blocks as the sole anesthetic technique in a patient with severe Duchenne muscular dystrophy

General anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are associated with high risks of complications, including rhabdomyolysis, malignant hyperthermia, hemodynamic instability, and postoperative mechanical ventilation. Here, we describe peripheral nerve blocks as a safe approach to anesthesia in a patient with severe Duchenne muscular dystrophy who was scheduled to undergo surgery. A 22-year-old male patient was scheduled to undergo reduction and internal fixation of a left distal femur fracture. He had been diagnosed with Duchenne muscular dystrophy at 5 years of age, and had no locomotive capability except for that of the finger flexors and toe extensors. He had developed symptoms associated with dyspnea 5 years before and required intermittent ventilation. We blocked the femoral nerve, lateral femoral cutaneous nerve, and parasacral plexus under ultrasound on the left leg. The patient underwent a successful operation using peripheral nerve blocks with no complications. In conclusion general anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are unsafe approaches to anesthesia because of hemodynamic instability and respiratory depression. Peripheral nerve blocks are the best way to reduce the risks of critical complications, and are a safe and feasible approach to anesthesia in patients with severe Duchenne muscular dystrophy.     

Succinylcholine-induced cardiac arrest in unsuspected Duchenne muscular dystrophy

A case history is presented of a three-year-old boy with unsuspected Duchenne muscular dystrophy, who suffered a cardiac arrest following the administration of a single dose of succinylcholine during a halothane anaesthetic. The arrest was associated with lack of fasciculations, muscle rigidity, hyperkalemia, myoglobinuria, and massive elevation of serum creatine phosphokinase. Asystole was prolonged and refractory to treatment, although cardiac activity was eventually restored. The possible cause of the circulatory collapse is discussed and reports of similar cases reviewed. Neither succinylcholine nor halothane should be employed in cases with known or suspected Duchenne muscular dystrophy.