Myotonic Dystrophy.: The clinical presentation of myotonic dystrophy represents a spectrum of disease severity that is based on the size of the genetic triple repeat. Three phenotypes have been identified. The most severe is congenital myotonic dystrophy with weakness and myotonia at birth. The classic form is characterized by weakness and some degree of disability, with mild myotonia and cataracts.

The clinical symptomatology of myotonic dystrophy includes muscle weakness and wasting with a delayed relaxation of the muscle and increased excitability. Ocular cataracts are also a defining factor; cardiac conduction defects represent a serious comorbidity. A wide variety of other symptoms, including sensorineural hearing loss, hypersomnia, testicular atrophy (and sterility), and endocrine dysfunction, are also found in myotonic dystrophy.¹⁰

DIAGNOSIS.

Researchers continue to develop noninvasive imaging procedures for evaluating the localization, extent, subtype, and mechanisms of skeletal muscle damage in MD. Diagnosis is currently based on clinical presentation, family history, and diagnostic testing such as muscle ultrasound, genetic testing, electromyography (EMG), muscle biopsy, and serum enzymes. The use of these five diagnostic tests with each of the major types of MD is presented briefly in this section.

Duchenne’s and Becker’s Dystrophy.

Chorionic villi sampling and amniocentesis are prenatal diagnostic techniques in which deoxyribonucleic acid (DNA) is removed during gestation to determine the presence or absence of the defective gene. Currently, standard laboratory genetic testing can detect large deletions of the dystrophin gene in approximately 65% and large duplications in about 5% of fetuses and aid in identification of carriers; the accuracy partially depends on the genetic heterogeneity of the particular disease.

Most of the remaining 35% of cases represent point mutations and are more difficult to identify but can be found by sequencing the gene. New mutations cause 30% of cases of DMD. Mothers who are carriers of a dystrophin gene mutation will pass on the mutated gene to 50% of their daughters (making them carriers) and 50% of the sons who will be affected by DMD.

EMG studies in DMD/BMD demonstrate the presence of fibrillation potentials, positive sharp waves (more in DMD), and long-duration polyphasic motor unit action potentials (MUAPs) (more in BMD) with full recruitment at low force. Nerve conduction velocities are normal in both DMD and BMD.⁴² A muscle biopsy specimen shows variation in the size of muscle fibers; central nuclei, inflammatory cells, and fat and connective tissue deposits are prominent characteristics of the biopsy specimen. In DMD the muscle stains negative for dystrophin antibodies, whereas in BMD levels of dystrophin vary.

Serum enzyme levels are a final diagnostic test used to identify the presence of active muscle damage. Approximately 50% to 60% of female carriers of DMD/BMD have elevated creatinine kinase (CK). Males affected by DMD/BMD present with CK levels that are approximately 2 to 10 times normal, reflecting active muscle damage (see the section on Serum Enzymes in Chapter 40; see Table 40-15).

Levels are extremely high in the first years of life before the onset of clinical weakness and persist as symptoms develop. Eventually, after replacement of muscle substance has become chronic and extensive, the CK level may be either normal or only mildly elevated (less than five times normal). The CK isoenzyme may be increased in DMD, especially in the earlier phase of the illness.

TREATMENT.

At present no known treatment halts the progression of MD. Despite recent advances in our understanding of the MDs, current therapy for these disorders remains primarily supportive. Research in the area of molecular biology that has brought specific information about the molecular pathogenesis involved may one day lead to effective treatment.

Presently, treatment intervention is directed toward maintaining function in unaffected muscle groups for as long as possible, utilizing supportive measures such as physical and occupational therapy, orthopedic appliances, orthopedic surgery, and pharmaceuticals. Children who remain active as long as possible avoid complications (e.g., contractures, pressure ulcers, infections) and deconditioning that are common once they are wheelchair bound.

It is important to remember that there is an active muscle degeneration underlying the MDs. Strengthening, especially eccentric exercise, is not helpful and may cause increased weakness, particularly in DMD. Contracture management is the focus of treatment for the therapist and is important in maintaining function in clients with MD. Splinting, stretching, and serial casting are mainstays of treatment in this group and should be considered when approaching these clients.

The effective use of glucocorticoid therapy (e.g., prednisone and deflazacort) to slow the progression of DMD and BMD has been reported. The use of glucocorticoids has become the mainstay of treatment for many individuals with these forms of dystrophy. It has been demonstrated to increase myogenic differentiation, myoblast fusion, and laminin expression in animal models² and has been shown to improve muscle force and function in children with DMD. The functional advantage of this medical treatment is the child’s ability to maintain independent ambulation, respiratory function, and spinal alignment for longer periods of time.

Stem cell and gene therapy for MD is currently under investigation, exploring a variety of ways to exogenously deliver healthy copies of the dystrophin gene to dystrophic muscles^97,117 or pharmacologically treat the effects of this disease.²⁸ Experiments in the MDX mouse have investigated the use of viruses to implant a miniversion of the dystrophin gene into dystrophin-deficient muscles to delay or stop muscle degeneration. The main obstacle has been immunologic; however, human trials are on the horizon.

In other research models, attempts have been made to inject skeletal muscles with donor cells, a gene transfer method referred to as myoblast transfer therapy (MTT). These myoblasts fuse with diseased muscle fibers and provide the missing gene to replace dystrophin. To date, there have been no reports of improved strength in people with DMD with this procedure.^128,165,184

There are also treatments on the horizon for specific genetic defects. DMD is the end result of a variety of different genetic mutations. Most people with DMD have large mutations; others have point mutations, duplications, or early stop codon mutations. There is the potential that some of these may be amenable to drug treatments, either to reestablish the reading frame or to facilitate read through in the case of a premature stop codon.

In a small portion of people (up to 15%) with DMD and other genetic disorders, the underlying genetic defect is a premature stop codon or nonsense mutation (a stop codon normally directs the mRNA sequences for coding polypeptide chains to stop at the appropriate time).

The inability to read the genetic material and produce dystrophin in these individuals potentially can be suppressed by the use of the antibiotic gentamicin. This has been investigated in animal models and in cell culture with the production and incorporation of dystrophin noted in the muscle membrane.⁸ There are also drugs under development that bind to the ribosome and can induce the read through of the premature stop codon by the ribosome in individuals with premature stop codon mutations.

People with point mutations might be amenable to a treatment with antisense oligonucleotides designed to induce exon skipping. Genes are read in sets of three base pairs. When someone has a point mutation, if it is an out-of-frame mutation, everything after the mutation is shifted and the groups of three base pairs do not make sense. These drugs cause RNA to skip over the exon (a full set of three base pairs) where the point mutation is present during the transcription process when the introns are removed and the mRNA is formed.

In this way, the gene is allowed to continue reading in sets of three base pairs. If these drugs are effective in clinical trials, the hope is that this strategy could induce production of increased levels of dystrophin and result in an effective treatment for people with DMD.

PROGNOSIS.

Prognosis varies with the type of MD present. As a general rule, the earlier the clinical signs appear the more rapid, progressive, and disabling the dystrophy. DMD generally occurs during early childhood with rapid progression of symptoms and results in death in the third decade of life.

Pulmonary complications resulting from respiratory muscle dysfunction or cardiac dysfunction in the form of conduction defects or myopathy are the common sources of morbidity and mortality. People with BMD usually live into the fifth decade (their forties) or beyond; death occurs secondary to respiratory dysfunction or heart failure. Those with FSHD involvement may appear almost stable over a period of years; variable progression occurs among those with LGMD. People with both FSHD and LGMD have a relatively normal lifespan.

Congenital Myopathy

DIAGNOSIS.

Diagnosis of congenital myopathy is made first by clinical examination. The differentiation of central versus peripheral causes of the hypotonia will help guide the physician’s workup. These factors include deep tendon reflexes, upper motor neuron signs, and cognitive status.

If a peripheral process is suspected, an EMG can differentiate a neurogenic versus myogenic process and then a muscle biopsy can be performed to evaluate the pathologic characteristics. Special stains or electron microscopy can be ordered to further narrow the possible diagnoses. Finally, genetic testing can be ordered to confirm the diagnosis.

TREATMENT.

Treatment is primarily symptomatic. Management of contractures is important in maintaining function, and supportive pulmonary care is important, especially in those clients who develop nocturnal hypoventilation. Cardiac monitoring is important for those with a propensity toward cardiac symptoms.

Spinal Muscular Atrophy

DIAGNOSIS.

The diagnosis is suspected on the basis of clinical manifestations but is established from muscle biopsy and EMG in which a neuropathic pattern is found. Nerve conduction velocities can be normal (slowing may be noted later in the course); motor action potentials are decreased in magnitude.

On needle EMG fibrillations and sharp waves are usually present and action potentials are high amplitude, long duration, and show polyphasic morphology with an increased firing rate.¹⁶⁷ Muscle biopsy specimens show groups of small atrophic fibers with large hypertrophic fibers, representing those without anterior horn cells and those with anterior horn cells, respectively. Genetic testing for SMA also confirms the diagnosis.

TREATMENT.

Treatment is symptomatic and preventive, primarily preventing pulmonary infection and treating or preventing orthopedic problems, the most serious of which is scoliosis. Feeding problems are common, especially in cases with bulbar muscle weakness; gastrostomy tube feedings are often necessary to optimally manage nutrition.

Respiratory problems (involvement of the intercostals) are common, and percussion and postural drainage and treatments with an in-exsufflator (also known as coughalator, a machine that helps in the removal of bronchial secretions from the respiratory tract) can aid in airway clearance, especially during intercurrent illness. Positive pressure ventilatory support, typically by BiPAP (initially at night), can extend the lifespan in these clients. Cardiac involvement is often secondary to the chronic respiratory insufficiency typical of this disease.

The majority of people with SMA type I or II develop some type of scoliosis; individuals with type III who become nonambulatory are also likely to develop scoliosis. Bracing has not been found to delay the progression of scoliosis but might help with sitting balance (Fig. 23-21). Care should be taken to allow good diaphragmatic movement and not create increased respiratory effort if a soft spinal orthosis is chosen to manage sitting posture.

Spinal fusion is the primary means of management for scoliosis. Although fusion is often necessary, there is some consequence to function. Many will not return completely to their prior functional level.⁵⁸ Individuals with type II SMA can develop hip subluxation or dislocation, but this is not typically painful and the literature on surgical correction is not supportive.

Individuals with type II SMA should participate in a standing program (Fig. 23-22). Knee-ankle-foot-orthoses (KAFOs) with ischial weight bearing are ideal for this in the younger age group. However, as contractures develop, standing will become more difficult despite the most aggressive splinting, ROM, and serial casting program.

SMA type III clients are most likely to ambulate, although about half of this group loses ambulatory skills in childhood or adolescence. Fractures are common and a significant source of morbidity and loss of functional skills.

PROGNOSIS.

Prognosis varies according to age of onset or type of SMA (see Table 23-6). The earlier the disease occurs, the faster the progression of muscle weakness and the poorer the prognosis. The presence of respiratory distress also contributes to a poorer prognosis.

SMA type I is the most severe and has a very poor prognosis, with death likely in the first 2 years of life as a result of respiratory failure or respiratory infection. Most children with this form of SMA do not survive past 3 years without the aid of mechanical ventilation. Clients with type III (with onset after 2 years of age) remain independently ambulatory throughout adult life; onset before 2 years results in loss of ambulatory ability at an average age of 12 years.¹⁵¹

DIAGNOSIS.

Clinical observation combined with the history forms the basis of the initial diagnostic process. Medical evaluation including radiographic studies of the spine is always indicated to rule out congenital deformities of the cervical spine, ocular anomalies, and less frequently tumors or other CNS pathology in children with presumed torticollis.

TREATMENT.

Initial management involves a period of active observation for spontaneous resolution. During this time physical therapy to correct the positional/deformational effects is the mainstay of treatment for CMT. Interventions include twice daily passive ROM to stretch the shortened muscle preceded by warm compresses, massage, and slight traction to relax the muscle before stretching; stabilization of the proximal attachment of the SCM and trapezius is important during ROM.

Positioning is also important to encourage erect and midline head posture. Strengthening activities should include both active and active assistive exercises in addition to the incorporation of postural reactions in treatment when these reactions begin to develop.⁸⁸

Splinting has been advocated by some for older children (older than 4 months) who continue to demon- strate head tilt.⁸⁴ A cervical collar or tubular orthosis for torticollis (TOT) can be helpful in providing tactile cueing for movement in the direction opposite the lateral tilt. Usually these collars are the most effective at a time that is compatible with active head control (Fig. 23-26).

In cases of delayed treatment or where craniofacial asymmetry persists, nonsurgical remodeling of the skull using externally applied pressure can be used (Fig. 23-27). With advances in computer software and technology (e.g., pressure scanners), researchers are determining the pressure per square inch (PSI) that applies the appropriate force needed to achieve the remodeling process for each individual head diameter, volume, and topography.^181,182

Surgical intervention is rare (e.g., SCM tenotomy, plastic surgery for craniofacial asymmetry) and is considered only if the individual continues to demonstrate significant motion restrictions of 30 degrees after 6 months of age or the deformity persists past 12 months of age. Increased thickening of the SCM or increased deformity are also indications to consider surgical intervention.⁸⁸

PROGNOSIS.

CMT usually resolves with conservative treatment. Complete recovery, including full passive ROM, can be expected to take approximately 3 to 12 months, with fewer than 16% of children presenting in the first year requiring surgery.⁴⁵ Left untreated or poorly managed, chronic, unresolved torticollis can result in persistent deformity and asymmetry of the head shape and position.

DIAGNOSIS.

Some injuries are recognizable readily at or soon after birth. Radiographs may be taken to rule out associated fractures of the clavicle. Imaging of the brachial plexus using MRI is not invasive and can demonstrate proximal and distal lesions.

MRI can be used to detect nerve root avulsions, nerve ruptures, brachial plexus scarring, posttraumatic neuroma, brachial plexus edema, spinal cord damage, abnormalities of the shoulder joint, trauma, neoplasms, and infection. This type of imaging allows diagnosis and careful preoperative evaluation of children with brachial plexus injuries.¹¹

EMG can be used to delineate the extent of injury and aid in the prognosis and assist the surgeon in identifying appropriate surgical procedures. EMG usually is delayed until 4 to 6 weeks after birth and may be followed serially over time to track recovery. Conduction studies can aid in separating actual axonal loss from conduction block. Needle EMG can help determine the portion of the plexus damaged as well as the severity of the damage.⁴²

TREATMENT.

Although medical intervention may include the use of botulinum toxin (Botox) to address contractures that may develop over time¹⁵⁰ or surgery, treatment is primarily with a therapist following the strategies outlined in Table 23-7. Surgery has found renewed favor as evidence is increasing that microneurosurgical intervention at an early stage can improve the outcome in some cases. For example, some children have no chance of recovery unless they undergo early aggressive surgical reconstruction of the injured brachial plexus. In children with global or total paralysis, surgery is performed by 3 to 4 months to maximize ultimate extremity function and minimize disability.^66,173

Options for surgical care include tendon transfers considered after a plateau in recovery has occurred or microneurosurgery (e.g., nerve decompression, neurolysis, nerve repair, and nerve reconstruction with grafts or tubes). The latter procedure is best considered between the ages of 6 and 12 months for optimal functional results.¹⁵² Unfortunately, skepticism exists about the role of surgery, and many cases are referred too late for primary nerve surgery. Secondary reconstructive procedures at a later date can still improve the outcome in many cases.⁸⁹

PROGNOSIS.

In most instances full recovery can be expected; however, some children do have long-term disability as an outcome and require careful follow-up to prevent the development of contractures and facilitate active motor control.

The first muscles to return are the elbow, wrist, and finger extensors followed by the deltoid and biceps and later the external rotators. The timely recovery of these muscles (beginning at 6 weeks and continuing through 3 months) is prognostic of good functional recovery.⁴²

The long-term prognosis for recovery of motor control is poor beyond 18 months (Table 23-8), and probably 15% of infants experience significant disability, with reports showing a wide range of long-term impairments.¹⁵² Recovery of shoulder external rotation is highly indicative of a good long-term outcome and is a key movement for performing a variety of functional tasks. Almost half of those with the Erb-Duchenne type of injuries do not recover shoulder external rotation, and contractures of the shoulder and elbow joint with atrophy of the affected muscles can occur.

DIAGNOSIS.

Diagnosis of OI is based on clinical manifestations and skin biopsy that looks at collagen. The collagen defect is used to determine what type of OI the person has according to the Sillence classification. Bone scans and x-ray films show evidence of multiple old fractures and skeletal deformities. Skull radiographs show wide sutures with small, irregularly shaped islands of bone called wormian bones.

TREATMENT.

Orthopedic management is central to the overall care of symptomatic OI. Fracture prevention and control are the primary focus; careful positioning and handling are required to prevent fractures in the neonate. Lightweight HKAFOs and splints also may be used to help support the limbs, prevent fractures, and aid in ambulation. HKAFOs are used more often than KAFOs because KAFOs have a longer lever arm for rotational force, resulting in greater risk for proximal femur fractures.⁶¹

Fracture immobilization is as minimal as possible to prevent disuse atrophy. A repeated cycle of fractures-immobilization of the same bone can inhibit progress in mobility and the development of strength (Fig. 23-31). The use of intramedullary rods is one way of managing recurring fractures (Fig. 23-32). Indications for this procedure include more than two fractures in the same long bone within a 6-month period, lower extremity bone angles greater than 40 degrees, or very unstable lower extremities in a child who appears ready to walk. Telescoping intramedullary rods are used to stabilize the bones, elongating as the bone grows, although this procedure is not without risk.

The reoperation rate is significant, with complications related to osteopenia that occurs around the rods (greater around thicker rods), rod migration, and bony growth even beyond the available expansion. Osteotomies also are performed to help control rotational deformities, with appropriate bracing to prolong the time period between potential surgeries.

Medical management has included the use of bisphosphonates, a class of medications (including pamidronate) that inhibit osteoclast function, improve bone mineral density, and decrease the incidence of fractures. Some data exist on the use of growth hormone in OI, but reports of an increased rate of fractures have prevented the use of growth hormone as a first-line drug in the treatment of OI.¹⁹³

Initial reports of allogeneic bone marrow transplantation of mesenchymal cells (progenitors of osteoblasts) have been promising, with increased bone mineral content and histologic evidence of new bone formation 3 months after engraftment.⁸⁰ Studies in cell cultures and in mice have raised the possibility that several additional strategies may be developed to treat OI through the use of gene therapy; a review of current gene therapy strategies under investigation is available.⁵³ At present, no effective treatment exists for type II (perinatal lethal) OI.

PROGNOSIS.

People with OI types I and IV have a milder course and live a relatively normal lifespan. In type III OI mortality can be related to cardiorespiratory failure stemming from kyphoscoliotic deformity. A significant risk also exists of basilar invagination of the skull and intracranial bleeding.¹¹⁵

Incomplete and relatively painless fractures after birth that receive no treatment can produce deformities from bones healing in poor alignment. Short stature and deformities give some individuals with OI the appearance of having achondroplasia. Milder forms of this condition have fewer clinical problems, and these children survive into adulthood.

DIAGNOSIS.

Prenatal diagnosis may be made by ultrasonic examination based on diminished fetal movement and detection of joint contractures. These findings usually do not become evident until 16 to 18 weeks’ gestation.¹⁵⁸ A definitive diagnosis is made by neonatal examination and, if needed, radiographs. However, congenital joint contractures may be secondary to many conditions, requiring differential diagnosis.

TREATMENT AND PROGNOSIS.

Physical therapy and occupational therapy are the mainstays of early treatment, with passive mobilization of the joints, positioning, strengthening, and enhancement of functional adaptation skills (e.g., prevention of falls, mobility training, movement up and down stairs or on uneven terrain).

Orthopedic surgery often is used to address the many musculoskeletal limitations associated with AMC and often is combined with serial casting. Some of the more common surgical procedures include posterior spinal fusion for thoracolumbar scoliosis; quadriceps lengthening to increase knee flexion for functional movement; and posterior capsulotomies, hamstring lengthening, and wedge osteotomies to allow for increased functional knee extension.

Clubfoot deformity (Fig. 23-33) often is treated with a heel cord lengthening and capsulotomy in addition to a talar procedure if needed to achieve a good correction. Hip procedures are associated with a fairly high risk of avascular necrosis and failed reduction.

Other less common procedures are being attempted, such as the successful use of the latissimus dorsi muscle to restore elbow flexion.⁵⁹ A variety of opinions exist regarding the place for the various soft tissue and bony procedures available, with some advocating nontreatment.

The long-term prognosis depends on the underlying cause of joint contractures. The contractures found in this condition are nonprogressive and not life-threatening; however, the underlying cause can be both.

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