DUCHENNE MUSCULAR DYSTROPHY (DMD)
Presenter: Michael Sussman, MD
Guillame-Benjamin Amand Duchenne described Paralysie musculaire hupertophique in 1886, noting the progressive nature of this disorder with stages of “feeble movements, apparent hypertrophy, and then paralysis.” He noted that this was a primary muscular disease and not a spinal cord abnormality. Little changed in the understanding of DMD for the next 130 years. It is known that it is an inherited X-linked degenerative disease of muscle. The incidence in the general population is 1/3500 live born male patients (2.5/10,000).1 The 2 main clinical types are DMD and a less severe form, Becker muscular dystrophy.
The diagnosis of DMD is often first made as a clinical diagnosis with a child who presents with new-onset weakness, perhaps new-onset toe walking, falling, or even progressively worsening flat feet. There are often gait changes with progression of waddling, increased lumbar lordosis, need for assistive devices, and eventually loss of ambulation. The Gower maneuver is often the first clinical sign to demonstrate the severe proximal weakness of DMD.
In 1989, Rahimov and Kunkel2 described dystrophin, a protein that is completely absent in DMD and deficient in Becker muscular dystrophy. Dystrophin acts with a glycoprotein complex to stabilize the myofiber membrane and supports muscle metabolism. Before the discovery of this protein, the only way to diagnose DMD was to obtain creatine phosphokinase levels, and to perform a muscle biopsy to evaluate the typical findings of variable fiber size with rounded small fibers, myopathic grouping, and muscle fiber degeneration.
For years the treatment of DMD has been support of the patient’s cardiorespiratory system, as cardiomyopathy and poor swallowing, leading to aspiration pneumonia, are often present. The muscle contractures were treated with splinting and early surgery for tendon lengthening and scoliosis. The orthopaedic surgeon and the rehabilitation specialists were tasked with providing comfortable seating systems and wheelchairs. Most children died in their teenage or young adult years.3 Potential complications of anesthesia included intraoperative cardiac failure, rhabdomyolysis in the absence of succinylcholine use, or rhabdomyolysis and life-threatening hypokalemia after succinylcholine administration. It is rare for children with DMD to have malignant hyperthermia.4
Steroids in DMD
In 1974, Drachman et al used steroids in an open-label study and noted a positive outcome, and there were several other nonrandomized trials in that era that showed variable results.5 In 1981, the Clinical Investigation group of Duchenne Dystrophy (CIDD) conducted randomized trials in DMD patients. They tested 14 different drugs, of which only steroids showed any positive findings. In 1991, Mendell and the CIDD group demonstrated short-term improvement in the strength of patients with prednisone.6 In 1994, an Italian group used deflazecort (DFZ), an axazolidine derivative of prednisone, with equally good results.7
It is not exactly clear how steroids act in DMD. They may act directly on signal transduction and have a direct nuclear effect, but they may also reduce muscle necrosis and inflammation. They may enhance the proliferation of myogenic precursor stem cells or myoblasts, which lead to increased muscle regeneration and growth with an anabolic effect. The clinical effects have been maintenance of pulmonary function, prolongation of functional walking, and preservation of cardiac function for a longer time. In 2012, Biggar et al, highlighting the Canadian experience with DFZ, noted that patients of the children treated with DFZ had a marked reduction in the need for scoliosis surgery, which was necessary in greater than 90 percent of untreated boys.8,9 However, there is a price to pay for the use of corticosteroids, including weight gain, decreased height, and cataract formation. Other problems include change in appearance and moon facies, possible delay in puberty, and nocturnal eneuresis. Perhaps the most concerning side effects are behavioral and mood changes, which are more common with prednisone than DFZ. This is the most common reason for discontinuing prednisone in the Portland Shriner’s Hospital. There is a possibility of increased osteoporosis, but it is difficult to assess, as being non-weightbearing is a potential confounder. Unfortunately, DFZ is not FDA-approved in the US and this poses challenges for patients to obtain medication legally.
The NIH has approved an FOR-DMD study trial where prednisone, DFZ, and 10 days on/10 days off prednisone will be compared for 3 years. This randomized study on 300 boys seeks to demonstrate the efficacy of these various drugs and drug-delivery protocols. A potentially exciting new method of treatment is also on the horizon: exon 51 skipping drugs in the treatment of DMD. In DMD, the open reading frame of the dystrophin gene can be affected by deletions, duplications, or point mutations. Conversion of the DMD dystrophin to a shorter but more functional protein (BMD type), using antisense oligonucleotides (a complimentary sequence of 20-30 nucleotides that allows the skipping of exon 51), has been suggested. Several unpublished studies have demonstrated increased walking distance, and muscle biopsies have demonstrated dystrophin positive muscle cells.
THE ORTHOPAEDIC MANAGEMENT OF SPINA BIFIDA
Presenter: Vineeta Swaroop, MD
Neural tube defects results from the failure of the neural tube and are the cause of chronic disability of 70,000 to 100,000 individuals in the United States. The incidence (1.9/10,000 births) of spina bifida has decreased in recent years. This has been primarily secondary to the addition of folate in the diet of women of childbearing age.10,11
Dysplasia of the spinal cord and nerve roots leads to bladder, bowel, motor, and sensory paralysis below the level of the lesion. Other associated problems include spinal cord lesions such as diastematomyelia, hydromelia, and structural abnormalities of the brain such as hydrocephalus, which may also affect neurological function.
Children with spina bifida have both congenital and acquired problems. The congenital problems include kyphosis, hemivertebrae, teratologic hip dislocation, clubfoot, and vertical talus. Acquired developmental deformities are caused by muscle imbalance, paralysis, and decreased sensation of the lower extremities. Other orthopaedic problems may be affected by a postoperative tethered cord.
The main goal of orthopaedic care of the child with spina bifida is to correct the deformities that may prevent the patient from using an orthosis to ambulate. A multidisciplinary team approach is important, as there are associated problems such as the aforementioned congenital and acquired neurological problems, insensate skin, latex allergies, renal anomalies, and bowel and bladder incontinence.
Level of Neurological Involvement
Spina bifida is classified according to the level of the lesion. Group 1 consists of patients with thoracic or high lumbar lesions. These patients lack quadricep function and children require hip spanning orthoses and in adulthood require wheelchairs. Group 2 consists of patients with low lumbar lesions. These patients lack gluteus medius and maximus function. They will require crutches and AFOs for ambulation, and most retain community ambulation as adults. Group 3 consists of three subsets: sacral, high-sacral, and low-sacral. Sacral-level lesions retain quadriceps and gluteus medius function; high-sacral-level lesions lack gastrocnemius-soleus function and can ambulate with AFOs and no support; and low-sacral-level patients retain gastrocnemius-soleus function and can ambulate without braces or support.
The Function Mobility Scale is used for spina bifida as well as cerebral palsy. It is a practical method for assessing the level of mobility using independent ambulation, through the use of crutches, walkers, or wheelchairs. A level is given depending on what level of ambulation occurs at 5, 50, and 500 meters. Other ratings include N for a child who cannot move over a certain distance and C for a child who is crawling.12
All children with the exception of low-sacral-level ambulators will use some sort of orthotic to ambulate. Depending on the level of involvement, this may be a reciprocating gait orthosis (RGO) or an HKAFO (Hip-Knee-Ankle-Foot Orthosis). In lower level lesions, a KFO is used, and in the lowest levels an AFO may be used.
In Groups 1 and 2, there is a high incidence of hip dislocation. There were many papers in the past that suggested ways to reduce the hips with various muscle transfers and pelvic osteotomies. However, subsequent studies have demonstrated that these surgeries did not improve the function of these patients and often lead to increased stiffness and more weakness than before surgery. Therefore, it is not recommended to treat dislocated hips in any level of spina bifida. There is a controversy about reducing a unilateral dislocated hip; yet research suggests that performing only soft tissue lengthenings has better outcomes than surgical reconstruction.
The problems encountered at the knee joint include knee flexion or extension contracture, knee valgus deformity, or late knee instability or pain. In ambulatory patients with greater than 20 degrees of flexion deformity, brace use and ambulation can be affected. Surgical release of the tendons and capsule are appropriate for these patients. Knee extension contractures are often congenital and bilateral. Treatment for this abnormality includes a V-Y quadricepsplasty. For nonambulators, a simple quadricep tenotomy suffices to allow knee flexion in a wheelchair. Those patients with severe valgus deformities benefit from osteotomies of the femur or tibia to correct both the valgus as well as rotational abnormalities. This leads to improved function, less instability, and may prevent long-term degenerative changes in the knee.
Rotational abnormalities are common in patients with spina bifida. Most of the deformities occur at the tibia, either with internal or external rotation. Correction of these deformities, when greater than 20 degrees, leads to improved functional outcomes of ease of brace wear, less skin breakdown, and improved gait. There is little need to address rotational problems in nonambulatory patients.
Foot and ankle deformities are common in children with spina bifida. Clubfoot is the most common deformity and occurs in 30 to 50% of the patients, although in 90% of thoracic-level or lumbar-level patients, and 50% of sacral-level patients. The clubfoot is usually rigid and severe. The Ponseti method, a manipulative method, and Achilles tenotomy have been used successfully with this group, although the skin complication rate and the recurrence rate are higher. In patients whose clubfoot is recalcitrant to the Ponseti Method, a complete posteromedial and lateral release is performed, excising all of the deforming tendons (not a tenotomy) and a complete release of the subtalar, calcaneocuboid, and talonavicular joints. The reduced joints are held in place with K-wires and casted postoperatively. There is a 20 to 50% recurrence even with this complete release, and thus the surgeon must be prepared to perform osteotomies of the bones of the foot to achieve a braceable foot. Those patients who cannot be corrected or who have a severe deformity can be treated with a talectomy. Equinus is treated in all patients with an Achilles tendon excision. Severe equinus may require a complete posterior release.
Vertical talus occurs in about 10% of patients; this is a rigid rocker-bottom flatfoot. Historically, these patients required extensive surgery; however, new techniques of serial manipulation followed by open talonavicular pinning with percutaneous tenotomy have excellent short-term results. If this is not successful, then a single-stage surgical correction of the hindfoot and forefoot should be performed to make the foot braceable.
Calcaneus deformities occur in 17 to 35% of patients, especially in the L4-5 patients. Treatment includes anterior tibialis transfer to the heel, which is often combined with ostetomy. Valgus deformities of the ankle are treated either with guided growth of the medial tibia or osteotomy. Those patients with cavus/varus or cavovarus deformities can be treated with osteotomies. Once again, the goal of all of these surgeries is to provide a braceable foot that will not develop skin breakdown. It is contraindicated to perform a triple arthrodesis in a patient with an insensate foot.
UPDATE ON CEREBRAL PALSY
Presenters: H. Kerr Graham, MD; Scott Hoffinger, MD; Freeman Miller, MD; Henry Chambers, MD
The cerebral palsies are a group of disorders caused by an injury or developmental abnormality of the brain. Most of these occur in the prenatal or perinatal period; however, any injury to the brain until the age of 2 years may have similar signs and symptoms. Cerebral palsy (CP) is one of the most common childhood disorders, with a prevalence of 38/10,000.
One of the most clinically important contributions to the field of CP over the past 15 years has been the introduction and application of the Gross Motor Function Classification System.13 This system based on the Gross Motor Function test categorizes patients into 5 levels: Level I: those ambulatory patients who have some difficulty walking and may have some balance and spasticity issues; Level II: those ambulatory patients who have difficulty walking over uneven ground and can be recognized clinically (at least in the First World) as those who are wearing an AFO; Level III: those patients who use assistive devices such as crutches or a walker, or those who can power their wheelchairs by hand; Level IV: those patients who are nonambulatory with the exception of help from therapists or gait trainers; and Level V: those patients who are completely dependent on others for all aspects of mobility and care.
This system has enabled clinicians and researchers to make comparisons within and between similar groups when evaluating outcomes and care of their patients. Throughout childhood, these levels are maintained until adulthood when some patients do lose some function. The goal of the clinician is to help the child maintain their GMFCS level until they are adults and perhaps beyond the onset of adulthood.
Management of Cerebral Palsy
Although spasticity is thought to be the hallmark of cerebral palsy, there is a vast array of additional problems including loss of balance (ataxia), weakness, and lack of selective motor control. Patients have significant comorbidities, especially in GMFCS IV and V, including but not limited to: seizure disorders, gastrointestinal problems, problems with speech and hearing, problems swallowing, increased drooling, urinary tract problems, behavioral issues, etc. Management of the patient with CP is often a team approach, with the pediatric orthopaedic surgeon being a critical part of the team.
Movement disorders such as spasticity, choreoathetosis, dystonia, and ataxia are prominent problems for children with cerebral palsy. This, combined with muscle imbalance, leads to contractures and persistence of childhood bony rotational alignment, which are the paramount treatment issues for orthopaedic surgeons and physiatrists. There have been many exciting innovations in the treatment of spasticity in the past 15 years, including an understanding of the dosage of antispasticity drugs such as diazepam and baclofen, the introduction of the botulinum toxins for the management of focal spasticity, and the introduction of the intrathecal baclofen pump for the treatment of diffuse spasticity and dystonia.14 It is crucial that the orthopaedic surgeon understand the evaluation and management of these movement disorders, such as inappropriate tendon lengthening, for example, can occur in patients with dystonia and/or choreoathetosis, leading to unintended consequences.
Orthopaedic Treatment of Cerebral Palsy
There are many different patterns of gait in the GMFCS I-III patient and any intervention should be tailored to improve their gait. Careful assessment of their gait can be performed clinically and this may be appropriate for the majority of the patients; however, a sizeable minority can only be assessed by 3-dimensional gait analysis. Often there are subtleties that can only be elucidated by this technology. GMFCS Level I patients rarely need more intervention than management of their spasticity and therapy. Level II patients may require tendon lengthening to enable them to be braced with AFOs. Level III patients usually present the most challenge to the orthopaedic surgeons. They are ambulatory, and it is our desire to keep them ambulating. This group may require spasticity and dystonia management, treatment of their rotatory abnormalities (femoral anteversion, internal or external tibial torsion, and pes valgus – the so-called “lever arm syndrome”), and tendon lengthening and/or transfer to maintain their walking ability.15,16
Level IV and V patients should have interventions aimed at maintaining their ability to help in transfers, but more importantly to sit comfortably for long periods. More of these patients will have dystonia combined with their spasticity and this will need to be addressed. It is at this level that the intrathecal baclofen pump becomes a useful intervention. Surgery is aimed at maintaining hip stability or at least hip balance to provide adequate and painless sitting. There is a 70 to 90% chance that these patients will have hip dislocations.16 There is also a 70 to 90% chance that these patients will have scoliosis, which will require fusion, usually to the pelvis.17
There are many new possible treatments on the horizon. The real treatment, of course, would be to prevent this disorder, and there are many strategies such as body and brain cooling and decrease in inflammatory chemicals in the neonatal period being used to decrease the incidence of CP. The current hope is that embryonic stem cells can be utilized to treat the brain injuries, although many of the GMFCS IV and V patients have chromosomal abnormalities or have syndromes that probably are not amenable to stem cell treatment.18
Neuromuscular seminar participants:
Michael Sussman, MD: Portland Shriner’s Hospital, Portland, OR
Vinetta Swaroop, MD: Lurie Children’s Hospital, Northwestern, Chicago, IL
H. Kerr Graham, MD: Royal Children’s Hospital, Melbourne, Australia
Freeman Miller, MD: Alfred I. duPont Hospital for Children, Wilmington, DE
Scott Hoffinger, MD: Lucille Packard Children’s Hospital, Palo Alto, CA
Henry Chambers, MD: Rady Children’s Hospital, San Diego, CA
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