eMedicine Specialties > Physical Medicine and Rehabilitation > Rehabilitation Protocols
Rehabilitation Management of Neuromuscular Disease
Updated: Jul 1, 2009
Abstract
Introduction
Most neuromuscular diseases (NMDs) are incurable. However, an effective rehabilitation program can help maintain a patient's quality of life (QOL), as well as maximize the patient's physical and psychosocial functions. An effective rehabilitation program can also minimize secondary medical comorbidity, prevent or limit physical deformity, and allow the patient to integrate into society. Modalities such as range of motion and strengthening exercise, along with bracing and appropriate surgical intervention, may prolong ambulation. Today, adaptive devices such as wheelchairs and lifts are now often interfaced with computer technology, providing better strategies for improving the patient's mobility. (See image below and Images 1-2.)
Werdnig-Hoffman disease (a type of spinal muscular atrophy). Small muscle fibers within separate muscle fascicles.
Axial magnetic resonance imaging (MRI) scan of the calves, demonstrating significant atrophy and increased signal intensity (arrows) throughout the anterior and posterior compartment muscles in the right calf, in comparison with the left calf, in a patient with focal motor neuron disease.
Endurance (aerobic) exercise may cause functional improvement and more independence in activities of daily living. Advancements in noninvasive positive pressure ventilation technology have greatly reduced pulmonary morbidity in NMDs. Cardiac complications, although severe in some NMDs, often respond to medical management. Psychosocial and vocational issues should be addressed as part of the management of NMDs. This level of comprehensive management usually requires a multidisciplinary team consisting of physicians, nurses, therapists, social and vocational counselors, and psychologists. This level of care is frequently provided in a tertiary care setting. This article discusses the key aspects of this type of care, which is critical to maximizing the quality of life for these individuals.
An exact definition of a neuromuscular disease or disorder is important. Even astute clinicians who do not work directly in this field often confuse the definition and refer to patients with NMDs as having muscular sclerosis (MS). This application is a common and gross misnomer. MS is a demyelinating disease of the CNS and is not an NMD, even though the symptoms of a patient with MS may sometimes superficially resemble the symptoms associated with NMDs.
Neuromuscular disorders are a group of diseases that affect any part of the nerve and muscle. These disorders include motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), which may involve motor neurons in the brain, spinal cord, and periphery, and ultimately weaken the muscle. Neuromuscular disorders also include peripheral neuropathies such as Charcot-Marie-Tooth disease (CMT) that affect not only motor but also sensory nerves. Peripheral neuropathies start at the level of the dorsal root ganglion by definition. The neuromuscular junction may also be directly involved in diseases such as myasthenia gravis.
Finally, NMDs may directly affect all forms of muscle, particularly skeletal and cardiac muscle. This stage of NMD-associated muscular deterioration is what causes the frequent misapplication of the term muscular dystrophy. The term dystrophy (taken from the Greek myo, meaning muscle, and dys-troph, meaning abnormal growth) is also a misnomer based on initial descriptions over 150 years ago, when a lack of proper growth nutrients was blamed for damaging muscle. These disorders classified as muscular dystrophies fall under the broader category of myopathies (again Greek myo, and pathos, meaning disease).
The dystrophies are now known to consist largely of genetic defects resulting from structural damage to the muscle because of a missing protein product as the result of a DNA abnormality. Other forms of myopathy may involve damage to the muscle's mitochondria or contractile filaments. The lack of a metabolic enzyme, such as in maltase deficiency (Pompe disease), may be a cause of myopathies.
An accurate confirmation of the diagnosis is critical and involves thorough clinical evaluation, as well as electrodiagnostic studies, and, often, a muscle or nerve biopsy. For many of the diseases, a DNA analysis of leukocytes or other cellular components obtained through a blood draw is commercially available and contributes greatly to the accuracy of the diagnosis. Once the diagnosis has been confirmed, the patient and family members should be educated thoroughly about the expected outcome and what problems may develop. The physician should then assess the patient's and family's goals and orchestrate a palliative and rehabilitative program that matches those goals. Enrollment in an experimental protocol should be encouraged and facilitated, furthering science and providing some hope for the patient.
Comprehensive management of the complex group of disorders is an arduous task under the best of circumstances. For this reason, a multidisciplinary approach, as mentioned above, is much more effective and takes advantage of the expertise of many clinicians, rather than placing the burden on one. This team would consist of physicians; nurses; physical, occupational, and speech therapists; social workers; vocational counselors; and psychologists, among others. Treatment should be goal oriented, with clear input regarding the patient's expectations and personal goals. While not curable, these diseases are treatable and do respond to rehabilitation. Ideally, because of the significant mobility problems associated with most NMDs, all key clinic personnel should be available at each visit. Tertiary care medical centers in larger urban areas can usually provide this type of service.
A number of organizations sponsor research and clinical care for people with NMDs; these include the Muscular Dystrophy Association, the Amyotrophic Lateral Sclerosis Association, the Charcot-Marie-Tooth Association, and the Facioscapulohumeral Society, among others. Governmental agencies that support research in NMDs include the National Institute on Disability and Rehabilitation Research, a division of the Department of Education, and the National Institutes of Health.
Neuromuscular Disease: A Clinical Overview
This section provides the reader with a brief clinical overview of the most common major NMDs. Any medical practice is likely to encounter these disorders. Please refer to articles on the specific diseases for a more in-depth discussion.
Motor Neuron Diseases
Amyotrophic lateral sclerosis
ALS is perhaps the most severe of all the major NMDs. ALS is a rapidly progressive NMD that destroys upper and lower motor neurons. This results in diffuse muscular weakness and atrophy. Unlike most primary nerve disorders, ALS also produces spasticity because of the loss of upper motor neurons. This creates unique clinical management issues.
An estimated 10% of all ALS cases are familial, usually inherited as an autosomal dominant trait. About 15% of these cases result from a gene defect on chromosome band 21q12.1, which leads to a mutation in the antioxidant enzyme Cu/Zn superoxide dismutase (SOD1). Approximately 100 SOD1 mutations have been identified and nearly all are single missense dominant mutations causing toxic gain of function. Over 50 unique superoxide dismutase mutations have been identified. Emerging evidence suggests that these mutations result in increased oxidative stress for the motor neurons, leading to cell death, which is presumably related to free radical toxicity.1
However, most ALS cases occur sporadically, with unknown etiology. Studies suggest that excessive glutamate, an excitatory neurotransmitter, in the CNS is involved in the disease process. Serum, spinal fluid, and brain tissue of patients with ALS contain excessive levels of glutamate, which is apparently due to reduced clearance of glutamate from the motor cortex and decreased activity of glutamate transport proteins.
Population studies indicate that the prevalence of ALS is increasing, although this may be because of better recognition of the condition and increased longevity of people with ALS.2 The worldwide prevalence rate is 5-7 cases per 100,000 population, making ALS one of the more common NMDs. ALS seems to affect men more commonly than it affects women, with a male-to-female ratio of approximately 1.5:1. ALS primarily affects adults aged 40-60 years, with a mean onset age of 58 years. A higher prevalence of ALS exists in urban areas, possibly due to environmental factors. Considerable geographic clustering has been seen in association with ALS, most notably in the Western Pacific region of the world, but also in Gulf War veterans. Despite clustering, environmental or causal factors remain to be determined.
A population-based case-control study conducted in 3 counties of western Washington State showed that a history of smoking cigarettes was associated with a twofold increase in risk, while a 3-fold increase was seen in current smokers. The duration and amount of smoking (packs per year, years having smoked) correlated with risk for ALS. Dietary fat increased the risk for ALS, although alcohol consumption did not. Dietary fiber intake decreased risk, although consumption of antioxidant vitamins from diet or supplement sources did not alter the risk. Interestingly, glutamate consumption did correlate with an increased risk for ALS. The fact that smoking and glutamate consumption are risk factors for ALS supports the current theory that implicates oxidative stress and excitotoxicity in the pathogenesis of ALS.
The major neuropathologic finding in ALS is degeneration and subsequent loss of motor neurons due to apoptosis, or programmed cell death. Apoptosis is characterized by neuronal contraction (to approximately one fifth its normal size) with an extremely condensed nucleus and cytoplasm. Apoptotic bodies can usually be seen in macrophages. Other neuropathologic findings in ALS include axonal loss in the descending motor tracts, anterior roots, and nerves. There also appears to be subtle involvement of the frontal lobes, hippocampal area, substantia nigra, and dorsal columns. Motor neuron degeneration begins focally and spreads to contiguous regions in the neuraxis until the neurons controlling respiration are affected, which ultimately leads to death from respiratory failure. The number of motor neurons involved and the spectrum of motor neuron degeneration varies for any individual patient, which accounts for the clinical variability in disease progression.
A number of prognostic predictors exist for determining the severity of a person's ALS course. Presentation with bulbar or pulmonary dysfunction (or both), short time period from symptom onset to diagnosis, findings primarily involving lower motor neuron on electrodiagnostic testing, and advanced age all potentially indicate a poor prognosis. Women present with bulbar symptoms more frequently than men do. Bulbar palsy appears to progress more rapidly in women; this indicates a poor prognosis. Young males with ALS have the best prognosis and may have a longer life expectancy. Overall, the median 50% survival rate is 2.5 years after diagnosis. In patients who present with bulbar symptoms, the 50% survival rate drops to 1 year. Survival rates vary depending on the patient's decision to use a feeding tube and assisted ventilation. Nonetheless, by 5 years postdiagnosis, the overall survival rate is only 28%.
A review by Benatar et al of randomized, controlled trials sought to determine whether treatment response differed between patients with familial ALS and persons with the sporadic form of the disease.3 Analyzing data from 4 trials that included, altogether, 41 patients with familial ALS and 822 patients with the sporadic condition, the authors found no statistically significant difference in treatment response between the 2 groups.
Spinal muscular atrophy
All forms of SMA involve selective destruction of anterior horn cells. The distinct types of SMA clinically differ. Some rare forms affect only distal or bulbar muscles. SMA is usually classified as types I, II, and III. Most forms of SMA are autosomal recessive traits. SMA I, also known as Werdnig-Hoffmann disease or acute infantile-onset SMA, is a severe disorder that causes death before age 2 years. SMA II, also known as chronic Werdnig-Hoffmann disease or early-onset intermediate SMA, is less severe. SMA II may not become apparent until age 6-18 months. SMA III, also known as Kugelberg-Welander disease, has a much later onset, typically age 5-15 years, and is associated with much less morbidity. (See image below and Image 3.)
Kugelberg-Welander disease (a type of spinal muscular atrophy). Marked variation in muscle fiber size along with increased perimysial connective tissue.
Mutations in exons 7 and 8 of the telomeric survival motor neuron gene are present in more than 98% of patients with SMA types I-III. Deletions in the neuronal apoptosis inhibitory protein gene are found in approximately 67% of patients with SMA I; 42% of patients with SMA II and III; and in some patients with adult-onset SMA, although the percentage is not known. Commercial blood tests (DNA analyses) are now available for use in diagnosing SMA. Prevalence rates for SMA types II and III have been estimated to be as high as 40 cases per million in the general population, although considerable variations exist in demographic studies.2
Two forms of later adult-onset SMA exist. The first type is spinobulbar muscular atrophy (SBMA), or Kennedy disease. This disorder, which was first described as recently as 1968, is a sex-linked recessive NMD characterized by progressive spinal and bulbar muscular atrophy, gynecomastia, and reduced fertility. SBMA has been mapped to the androgen receptor on the X chromosome. The mutation, which consists of an expansion of cytosine, adenine, and guanine (CAG) trinucleotide repeats, occurs in the first exon of the gene, producing decreased sensitivity of androgen receptors on motor neurons. The disease has some clinical variability; however, phenotypic expression does not correlate with the length of CAG repeats.
This phenomenon is in contrast to myotonic muscular dystrophy and fragile X syndrome, in which an increased number of tandem triplet repeats correlate directly with disease severity. SBMA can occur without any family history or gynecomastia, and all males with atypical ALS should undergo DNA testing for SBMA (the DNA test is commercially available).
The other form has onset age of 17-55 years, with either recessive or dominant types of inheritance. This form of SMA clinically resembles SMA III yet may be more progressive. This form of SMA has been mapped to chromosome band 5q11.2-13.3, although commercial testing is not yet available because adult-onset SMA and SBMA are far less common forms of SMA.
Peripheral Neuropathies
Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathies)
CMT can be divided into 2 basic types: primarily demyelinating (with secondary axonal loss) and primarily axonal. The remainder of the subclassification of CMT is based on genetic analysis. In CMT type 1 (CMT1), which is primarily a demyelinating neuropathy, anatomic changes directly affect the myelin sheath, with secondary axonal changes. In areas of focal demyelination, impulse conduction from one node of Ranvier to the next is slowed as current leakage occurs and the time for impulses to reach threshold at successive nodes of Ranvier is prolonged, producing slowing of conduction velocity along the nerve segment.
CMT type 2 (CMT2) is a primary axonal neuropathy producing changes in the axon and the nerve cell body. CMT2 tends to affect the lower extremities more than the upper extremities. CMT2 is often a clinically less severe disease than CMT1. Patients with CMT2 may have more lower extremity involvement, although clinically they are not easily distinguished from patients with CMT1. Previous studies have shown that no significant side-to-side difference exists in nerve conduction abnormalities or strength, and, like CMT1, the sensory deficit is usually less severe than the motor deficit. Most of the phenotypic descriptive studies in CMT were done before the advent of DNA testing.
Previous studies have shown that, overall, CMT is a slowly progressive disorder characterized by diffuse muscle weakness and prominent distal atrophy, predominantly involving the intrinsic muscles of the feet and the peroneal muscles. Subjects with CMT produce 20-40% less force than normal controls using quantitative isometric and isokinetic strength measures, even though manual muscle test scores may be normal. No significant side-to-side difference exists concerning strength. From a functional standpoint, the sensory deficit is usually less severe than the motor deficit. Prior studies have also documented that subjects with CMT have a marked reduction in functional aerobic capacity during exercise testing despite having normal or relatively normal preexercise pulmonary function, exercise heart rate, and blood pressure and maximum ventilation.
The number of molecular forms of CMT and related neuropathies is always growing. However, CMT1 is the most common type overall. CMT1A is the most common subtype of CMT1 and results from a duplication of chromosome segment 17p11.2, which contains the gene for peripheral myelin protein 22 (PMP22).4 (See image below and Image 4.) Interestingly, patients with a related disorder, hereditary neuropathy with liability to pressure palsies (HNPP), show a large deletion, rather than a duplication, in the PMP22 gene.5 HNPP is an autosomal dominant disorder that produces episodic recurrent nerve compression with focal demyelination at common sites of compression or entrapment (wrist, elbow, fibular head). Nerve compression can occur in the absence of true entrapment.
Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
CMT X is an X-linked dominant, primarily demyelinating neuropathy with a mutation in the connexin 32 gene (CX32) that codes for a membrane protein (gap junction protein, beta 1) involved in the formation of gap junctions. CMT X1 is clearly a distinct entity. Some varieties of CMT X1 may exhibit abnormal temporal dispersion and heterogeneous conduction velocities that are very atypical of other hereditary neuropathies. Mutations in the CX32 gene can produce a neuropathy with either demyelinating or axonal electrodiagnostic features. Some clinical and electrodiagnostic data in males with different missense mutations in the CX32 gene appear to differ significantly.6 Furthermore, males with a non-sense mutation have an earlier onset and a more severe phenotype than males with missense mutations.
Point mutations in the PMP22 or the myelin protein zero gene (MPZ) may cause Dejerine-Sottas disease.7 Thus, many cases of Dejerine-Sottas disease are now considered severe phenotypes within the genotypic spectrum of CMT1. Congenital hypomyelinating neuropathy is a severe and often fatal newborn disorder that presents with respiratory distress at birth and has been linked to the early growth response gene 2 (EGR2) in some families.
Muscular Dystrophy
Duchenne and Becker muscular dystrophies
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders that primarily affect skeletal and cardiac muscle. Dystrophin, a large cell wall (sarcolemma) structural protein, is absent in DMD and of abnormal molecular weight or of reduced amounts in BMD. Dystrophin stabilizes the sarcolemma during muscle contractions. Without dystrophin, the sarcolemma is unstable, cell homeostasis is impaired, and, ultimately, the myofiber deteriorates. Despite some regeneration, the repair capacity is rendered insufficient, and the muscle is replaced by fat and connective tissue. (See image below and Image 5.)
(A) Normal dystrophin staining; (B) intermediate dystrophin staining in a patient with Becker muscular dystrophy; (C) Absent dystrophin staining in a patient with Duchenne muscular dystrophy.
DMD is the most common childhood NMD with an estimated overall prevalence of 63 cases per million population.2 This is an ultimately fatal progressive myopathy, with death usually occurring in people younger than 30 years. Life expectancy has risen considerably over the past decade because of better management of respiratory or cardiac complications. Only a few decades ago, boys with DMD rarely lived to be older than 20 years. BMD is less common, with an estimated prevalence rate of 24 cases per million population.2 BMD is associated with the same muscle weakness that DMD is but with a much later onset age and slower rate of progression. The abnormal gene for DMD and BMD is on the short arm of the X chromosome at position Xp21.
Myotonic muscular dystrophy
Myotonic muscular dystrophy (MMD) is clinically characterized by progressive, primarily distal muscle weakness and myotonia (delayed muscle relaxation). Patients with MMD typically have characteristic facies, including frontal baldness and temporal wasting. Other problems include gonadal atrophy, cataracts, cardiac dysrhythmias, and an increased risk for diabetes. MMD is an autosomal dominant trait with a prevalence of 1 case per 8000 population.2
Several forms of MMD exist, primarily because of the unusual genetic basis of the disease. MMD is caused by a DNA sequence within the gene on chromosome band 19q13.3 that is repeated to varying degrees, producing an expanded, unstable area of the chromosome. This abnormal gene, referred to as a triplet repeat mutation, may grow as it is passed from generation to generation. This can cause the disease to present earlier and more severely in passing generations in a family line.
The most severe form of MMD is known as congenital MMD. Patients with congenital MMD have been shown to have substantially more repeats than those found in patients with typical MMD. The repeated DNA sequences known as CTG (trinucleotide cytosine, thymine guanidine) are linked to the production of the protein myotonin-protein kinase, which has important functions in smooth and skeletal muscle, eye, hair, and brain, and decreased levels of the mRNA and protein expression.8 A new form of MMD has been discovered that is known as type 2 MMD (MMD2 or DM2). It has also been referred to as proximal myotonic myopathy. A mutation on chromosome 3 causes MMD2, which is thought to be clinically less severe than typical MMD and congenital MMD. MMD2 may be associated with insulin insensitivity, diabetes, and low testosterone levels in males.
Facioscapulohumeral muscular dystrophy
Facioscapulohumeral dystrophy (FSHD) is a slowly progressive myopathy with prominent involvement of shoulder, pelvic, and facial musculature. FSHD is an autosomal dominant trait with an estimated prevalence of 10-20 cases per million population or possibly higher if accounting for undiagnosed, mild cases.2 The abnormal gene is on the end of chromosome 4, and DNA testing for diagnostic purposes is now commercially available. FSHD can be quite heterogeneous in its clinical presentation and course; this raises questions regarding genetic homogeneity.
Limb-girdle muscular dystrophy
Limb-girdle muscular dystrophies (LGMDs) are a very heterogeneous group of myopathies that share many clinical features. This family of dystrophic myopathies usually has an onset age ranging from 3-12 years with equal male and female prevalence. The distribution and pattern of weakness are similar to those of DMD but with a much slower rate of progression. These diseases have been linked to abnormalities of the dystrophin-associated glycoproteins (DAGs), alpha-sarcoglycan (adhalin) in particular, a 50-kd DAG, and gamma-sarcoglycan. The 50-kd DAG protein has been linked to the 17q12-q21.33 locus.9
Other forms of LGMD have been linked to chromosome band 13q12. Individuals with these forms may show a primary deficiency of gamma-sarcoglycan and a secondary deficiency of alpha-sarcoglycan. Patients with LGMD with a deletion on chromosome band 4q12 have a primary deficiency in beta-sarcoglycan, and patients with LGMD with a chromosome band 5q33-q34 deletion have a primary deficiency of delta-sarcoglycan. Most of the primary sarcoglycan abnormalities lead to secondary deficiencies of alpha-sarcoglycan. People with LGMD generally have normal results on tests for dystrophin. All the DAGs are reduced in patients with DMD because the C-terminal portion of dystrophin binds to the dystrophin-associated proteins and maintains their integrity. A less severe autosomal recessive form of LGMD has been linked to chromosome band 15q1-q21.1, the gene for the protein calpain 3. Diagnosis of all forms of LGMD subtypes is best confirmed based on muscle biopsy.
Of the 7 recessive loci identified to date, 4 are sarcoglycan genes. These 4 proteins make up the sarcoglycan complex, which may interact directly with the 43-kd DAG and with dystrophin. Dystrophin-associated glycoproteins probably provide connections between the extracellular matrix (the protein merosin) and the intracellular membrane cytoskeleton (attached to dystrophin). An abnormality of the dystrophin-glycoprotein complex, resulting from primary deficiencies of 1 or more of the dystrophin-associated glycoproteins, results in a disruption in the linkage between the intracellular sarcolemmal cytoskeleton and the extracellular matrix. Disruption of the membrane cytoskeleton is common to the pathophysiology of most muscular dystrophies, the dystrophinopathies.
Medical and Rehabilitation Management
Medical Management
Restrictive lung disease
Despite being referred to as restrictive lung disease, this NMD does not affect the lung. People with restrictive lung disease develop "weak bellows." The breathing muscles (diaphragm, chest wall, abdominals) are weak. Thus, patients with NMD may have difficulty inhaling and exhaling; this also includes coughing. This is a common problem in many NMDs but is typically the most severe in ALS, DMD, SMA, and MMD. Respiratory failure in FSHD is not typically seen. However, a study identified 10 patients with FSHD on nocturnal ventilatory support at home, representing approximately 1% of Dutch people with FSHD. Severe muscle disease, wheelchair dependency, and kyphoscoliosis appeared to be risk factors for respiratory failure in FSHD.
Numerous cases indicate respiratory failure in people with CMT, the etiology of which has remained elusive. Electrodiagnostic and pathologic studies on the phrenic nerve in patients with CMT confirm that respiratory failure is involved in the disease.10 In one study, phrenic nerve latency was abnormally prolonged in 96% of the subjects with CMT, but significant abnormalities in the results of pulmonary function tests and clinical symptoms were uncommon and did not correlate with the phrenic nerve latencies.11 Although phrenic nerve latencies are markedly prolonged in CMT, they are not useful in predicting respiratory dysfunction.
The results of routine pulmonary function tests, including forced vital capacity and maximal inspiratory and expiratory pressure, should be monitored closely. The maximal inspiratory pressure reflects diaphragm strength and ventilatory ability. Maximum expiratory pressure is indicative of abdominal and chest wall muscle strength and the ability to cough and clear secretions. Peak cough flow is another simple measurement that is indicative of the amount of pressure a patient can generate during a volitional cough.
The biggest problem in NMD is hypoventilation, which leads to hypercapnia (elevated carbon dioxide levels in the blood). End tidal carbon dioxide levels or arterial blood gases should be periodically measured, depending on the clinical circumstances. Pulse oximetry, which measures only oxygen saturation levels, may be inadequate. Performing a thorough review of systems is important. Patients who are hypoventilating become hypercapnic at night, resulting in a morning headache. They may also experience nocturnal restlessness, nightmares, and poor overall quality sleep, resulting in daytime somnolence. Insufficient respiration with hypoxia may also occur. This usually occurs much later in the disease process, particularly in cases of lung damage involving chronic pneumonias, infections, or aspiration.
Patients should be educated early in the disease process so that informed decisions can be made further down the line. Many options are available for noninvasive intermittent positive pressure ventilation. Bimodal positive airway pressure (BiPAP) is generally considered the preferred modality of assisted ventilation in NMDs. BiPAP is similar to the older technology of continuous positive airway pressure (CPAP), which is used to treat sleep apnea.
In CPAP, inhalation and exhalation are assisted with continuous positive airway pressure (which feels like breathing into a stiff headwind). BiPAP cycles the pressure down on exhalation, although a net positive pressure gradient remains (as if the wind died down a bit, but not completely, while exhaling). Typical pressures would be 8-10 cm water for inhalation and 4-6 cm water for exhalation. BiPAP can easily be used in the home but may take some work with a respiratory therapist to achieve a good face or lip seal on the pilot-type mask or nasal/oral orthotic interface that is typically used. If a mask fails to fit well or is too uncomfortable, a nose plug interface may be used, although this may not work as effectively.
Patients who use assisted oral ventilation, mainly at night, may initially avoid the need for tracheostomy and maintain a reasonable QOL. However, bulbar palsy may occur in ALS and in some rare forms of SMA. In these cases, if better airway access becomes necessary and the informed patient wishes more aggressive care, a tracheostomy may be performed. However, an alternative procedure, the laryngeal diversion (laryngotracheal separation) procedure, has several distinct advantages over the tracheostomy.
In laryngeal diversion, the trachea is surgically separated, and a cutaneous tracheostoma is formed with the distal segment. The proximal trachea is sewn either over or side-on-end into the esophagus. This completely eliminates the possibility of aspiration and requires much less deep suctioning than a tracheostomy does.12 The tracheostoma does not require any hardware, such as a tracheostomy tube, and the patient may still take some food for pleasure without risking aspiration. The primary disadvantage is the complete loss of phonation, since air no longer flows through the vocal cords. This procedure, thus, is recommended only when severe dysarthria accompanies the dysphagia and the patient's speech is unintelligible.
While preserving the ability to phonate, a tracheostomy actually increases the risk of aspiration, requires significantly more care, and provides no better airway access. Although the tracheostomy and the laryngeal diversion facilitate the use of mechanical ventilation, the patient must understand that neither procedure guarantees a better QOL. Fortunately, with the advancements in noninvasive ventilation, these surgical options are now infrequently used.
In addition to assisted ventilation, a number of new technologies may be used to improve respiratory hygiene. These technologies include cough assist machines that help a patient with NMD bring up secretions; the machines produce an artificial cough via a face mask by rapidly changing airway pressure from positive to negative. This technique has been used since the polio epidemics of over 40 years ago and is now available in the form of several commercial products, including the Cofflator (Respironics, Pittsburgh, Pa) or the In-Exsufflator (JH Emerson Co, Cambridge, Mass).
Dysphagia and dysarthria may occur in ALS and some rare forms of SMA because of the involvement of the bulbar musculature. Early signs of dysphagia include a hoarse voice and persistent cough, particularly after swallowing liquids. This may indicate microaspiration. At the first sign of dysphagia, consult a speech language pathologist, who can perform clinical swallowing evaluations and make recommendations on dietary modification and safe swallowing strategies. Such strategies include thickening liquids; using techniques such as double swallows, chin tucks, and head turns; and eating only foods that easily form into boluses.13
A modified barium swallow study, in which the patient swallows various textures of solid food and liquid laced with barium, is helpful for accurately determining the presence of aspiration, as well as defining which food textures the patient can safely swallow. However, this study does involve exposure to radiation. Flexible endoscopic evaluation of swallowing (FEES) is a new alternative test to the modified barium swallow that uses an endoscope specifically designed to assess the swallowing mechanism. FEES directly evaluates motor and sensory components of swallowing by direct visualization of the reaction of the larynx to a stimulus delivered by the endoscopic camera, which can then photograph the reaction. This test clearly shows sites where sensory reactions are impaired, and this can guide the clinician in determining what foods are associated with different types of the patient's swallows.
The main advantage of FEES is that it entails direct observation through a real-time endoscopic camera that visualizes food traveling down the patient's oropharynx and esophagus. During the test, a speech language pathologist can instruct the patient to make certain physical maneuvers to find the least restrictive method of travel for the food as it passes through the throat and into the stomach, all during the course of the FEES evaluation. The patient can also provide feedback to the clinician during the test so the therapist can alter the volume and thickness of the food to avoid choking sensations during the exam.
Despite all of these interventions, a percutaneous endoscopic gastrostomy (PEG) tube may be needed to administer nutrition. Malnutrition, and the resulting wasting or cachexia, are grave clinical situations that may quickly occur in rapidly progressive diseases such as ALS. A similar situation may also arise in an infant or young child with SMA who cannot take in enough nutrition orally to keep up with caloric needs. In SMA, caloric needs are often greatly increased because of respiratory compromise and the increased work necessary for breathing. A PEG can readily address these issues and provide access for supplemental nutrition. Again, educating the patient and family is critical early in the disease process so they can make informed decisions regarding these issues.
Cardiac complications
Cardiac involvement may occur in most of the primary myopathies, including DMD, BMD, MMD, and some cases of LGMD. Cardiac involvement is not seen in the peripheral neuropathies or motor neuron diseases. A high (60-80%) occurrence of cardiac involvement is present in patients of all ages with DMD and BMD. Dystrophin has been localized to the membrane surface of cardiac Purkinje fibers; this localization probably contributes to the cardiac conduction disturbances seen in DMD and BMD.14
A high prevalence of abnormalities found via electrocardiogram (ECG) and echocardiogram exists in preadolescent patients with DMD and BMD. In spite of this, only about 30% of patients with DMD have clinically significant cardiac complications. The myocardial impairment may remain clinically silent until the late stages of the disease. This may be because of the obligate lack of physical activity. Pulmonary hypertension also has been implicated in the cardiorespiratory insufficiency associated with DMD. Some investigators blame congestive heart failure as the cause of death in as many as 40% of patients with DMD.15
An important caveat to note is that severe cardiac involvement in BMD may occasionally precede the clinical presentation of skeletal myopathy. Moreover, the cardiac compromise may be disproportionately severe relative to respiratory compromise in some patients with BMD. Thus, ECG and echocardiography screening are indicated at regular intervals for all patients with BMD. Patients with myocardial involvement need close follow-up and treatment by a cardiologist with expertise in this area. Some patients with BMD may be suitable candidates for cardiac transplantation. Successful cardiac transplantation has been reported in patients with BMD with cardiac failure who were still ambulatory.
A high prevalence of abnormalities found via ECG exists in MMD. Studies have shown that about one third of patients with MMD have first-degree atrioventricular block, while about one fifth have left axis deviation. Only 5% have left bundle branch block. Bundle of His conduction delays have also been rarely reported. Complete heart blockage, requiring pacemaker placement, is rare but can occur. Patients with MMD should receive routine cardiac evaluations.
Pain
Pain is a significant problem for most patients with NMD, although it is not typically a direct consequence of the disease. Immobility commonly causes the pain. This may lead to adhesive capsulitis, low back pain, pressure areas on the skin, and generalized myofascial pain. Neuropathic pain is a significant problem for patients with CMT and is likely a direct consequence of the neuropathy.16 Pharmacological pain management in NMD initially includes acetaminophen (1000 mg q6h). Acetaminophen may be used along with nonsteroidal anti-inflammatory drugs, which may be particularly helpful if evidence indicates any active inflammatory processes such as joint effusion or tenosynovitis.
Tricyclic antidepressants and antiepileptic drugs are often helpful, particularly for relieving neuropathic pain.17 Gabapentin, an antiepileptic drug, also has the added benefit of reducing spasticity via glutamate and gamma-amino butyric acid pathways. Opioids may be necessary for relieving refractory pain. If required, opioids are best administered on a regular dosing schedule and titrated to the point of comfort. However, close monitoring for respiratory suppression is necessary, even in opiate-tolerant patients.18
Cannabinoids, the active ingredients in marijuana (cannabis), have a number of pharmacologic properties that may be applicable to the management of ALS and other NMDs.19,20,21,22,23 The benefits of cannabinoids include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, cannabinoids have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. Cannabis does not suppress breathing and there is no risk for overdose, which, in this regard, makes it much safer than opiates. Further investigation into the usefulness of cannabinoids in this setting is warranted.
Nutritional management
Nutrition may be a significant problem in severe NMDs, in which obesity tends to follow shortly after the loss of functional ambulation. Obesity is common in patients with NMDs, particularly DMD, in which a prevalence of 54% has been reported. Weight control has its primary rationale in ease of care, particularly ease of transfers and skin care.
Conversely, malnutrition may mark the advanced stages of DMD, ALS, and SMA. As previously noted, if a severe respiratory compromise is present, the increased work of breathing may drastically increase caloric needs. The situation is complicated by the fact that this is often a time when the patient loses the ability to self-feed. A nutritionist should assess caloric requirements and construct proper dietary requirements for the patient. This should be routinely done for all patients with NMDs with a forced vital capacity of less than 50% predicted on pulmonary function testing. PEG tube placement may facilitate nutrition because it eases intake of large amounts of calories and fluids. Patients should be reassured that they may still eat food orally for enjoyment, provided they have intact swallowing function. Another complicating factor in patients with DMD is gastroparesis, which may make feeding more difficult.
Pharmaceuticals that may improve function or prolong life
Major pharmacologic advances have occurred over the past decade. Although a comprehensive discussion of clinical trials is beyond the scope of this article, some of the major advances are noted. Given the severity and rapid progression of the disease, ALS has received the most attention in terms of pharmaceuticals aimed at prolonging life. Riluzole is a neuroprotective agent that appears to inhibit glutaminergic neurotransmission in the spinal cord.24 Riluzole is the first agent approved by the Food and Drug Administration (FDA) for use in ALS patients. Although it is only modestly effective at improving life expectancy in patients with ALS, Riluzole is nonetheless a major advancement. Various neurotrophic growth factors also appear quite promising, particularly insulin-derived growth factor, commercially known as Myotrophin.
Data suggest that cannabidiol, a naturally occurring nonpsychotropic cannabinoid, has a potential role as a therapeutic agent for the neurodegenerative disorders produced by excessive cellular oxidation, such as ALS. This compound is chemically classified as a terpene, similar to tamoxifen, which also has been shown to prolong cell survival in a mouse model of ALS. This suggests a similar mechanism of action, although this remains to be delineated.
DMD, also a severe disease, has received a fair degree of study. Although not FDA-approved for this use, prednisone, at 1 mg/kg/d, given to boys aged 4-8 years with DMD, has been shown to prolong the time of ambulation and should at least be considered for use in this disease.25 Major adverse effects of prednisone include weight gain, osteoporosis, and mood lability. Deflazacort has similar beneficial effects and may have slightly fewer adverse effects than prednisone; however, deflazacort is not currently available in the United States.
Several randomized, crossover, double-blind, placebo-controlled pilot studies of extended release albuterol have been performed in patients with dystrophinopathies (DMD, BMD) and FSHD.26,27 Outcomes involved isometric knee extensor testing, flexor strength testing, and manual muscle testing. The results showed some small evidence of benefit in patients with the dystrophinopathies, but not with FSHD. Therefore, a 12-week treatment with extended-release albuterol may increase strength in patients with dystrophinopathies, but, clearly, larger double-blind randomized studies are necessary to confirm these results.
Some literature shows that the protein creatine monohydrate is modestly beneficial for transient improvement of strength in patients with DMDs. Initial studies of creatine in ALS showed no effect, which was disappointing since creatine was tremendously beneficial in the mouse model of ALS. Human trials of a timed-release form of creatine are ongoing in patients with ALS. A study showed that 200-400 mg of modafinil taken daily provided some relief from fatigue in patients with ALS. Further study is warranted before conclusive recommendations can be made.
Phase III trials are currently underway with recombinant human acid alpha-glucosidase enzyme replacement therapy (ERT) to treat patients with late-onset Pompe disease.
Rehabilitation
Exercise paradigms to improve strength
Skeletal muscle weakness is the ultimate cause of most clinical problems associated with NMDs. A number of well-controlled studies have documented the effect of exercise as a means for patients to gain strength in NMDs, although much remains to be learned in this area. In slowly progressive NMDs, a 12-week moderate resistance (30% of maximum isometric force) exercise program resulted in strength gains ranging from 4-20%, without any notable deleterious effects. However, in the same population, a 12-week high-resistance (training at the maximum weight a subject could lift 12 times) exercise program showed no benefit over the moderate resistance program, and evidence of overwork weakness was found in some of the subjects.
In a study comparing CMT to MMD, the only patients who appeared to benefit significantly from a strengthening program were the patients with CMT. The patients with MMD showed neither beneficial nor detrimental effects. This clearly demonstrates that the most effective exercise regimens for patients with neuropathies and myopathies most likely vary, although further investigation is needed. In rapidly progressive disorders like DMD and ALS, active ongoing muscle degeneration occurs, and the risk for overwork weakness and exercise-induced muscle injury is much greater. In this population, exercise should be prescribed with caution and a common sense approach.
Studies have compared mdx mice (mice lacking dystrophin) to normal control mice. The mdx mice are genetically homologous models of DMD. In voluntary running protocols, dystrophin-deficient muscle is clearly susceptible to exercise-induced muscle injury, particularly eccentric (lengthening) muscle contractions.28 Interestingly, mdx mice show considerable avoidance behavior for exercise compared to normal mice. This may be an intuitive survival strategy. Following ad libitum exercise on a flywheel, the extensor digitorum longus and soleus muscles of adult mdx mice significantly weakened. In addition, histochemical evidence showed considerably more damage to the exercise-weakened muscles compared to control nonexercised mdx muscles (see image below and Image 6).29,30
Photomicrograph of quadriceps muscle from an adult mdx mouse (a genetically homologous model of Duchene muscular dystrophy) 3 days following running exercise and subsequent tail vein injection of 10,000 molecular weight fluorescent dextran. Significant intracellular staining exists in several fibers (center), indicating membrane damage. Central nuclei, present in regenerating fibers, are shown by focal intense areas of fluorescence.
Considering the results from the animal studies and the available human studies, all patients with NMDs should be advised not to exercise to exhaustion because of the risk of exercised-induced muscle damage. Patients with NMDs in exercise programs should be monitored for signs of overwork weakness. This includes excessive delayed onset muscle soreness. This usually occurs 24-48 hours following exercise. Other warning signs include severe muscle cramping, heaviness in the extremities, and prolonged dyspnea.
Submaximal, low-impact aerobic exercise (walking, swimming, stationary bicycling) improves symptoms of fatigue via enhancement of cardiovascular performance and increased muscle oxygen and substrate utilization. This is important because fatigue is a significant limiting factor in physical performance in patients with NMDs. Fatigue in this setting is likely multifactorial because of deconditioning and impaired muscular activation.31 Improving cardiopulmonary performance through aerobic exercise improves not only physical functioning but also mood state and helps fight depression. Patients with NMD have been noted on the Minnesota Multiphasic Personality Inventory as having a higher frequency of depression than healthy populations. Aerobic exercise also helps achieve and maintain ideal body weight and improve pain tolerance.
In terms of monitoring progress in an exercise program, a number of reliable, functional assessment tools have facilitated assessing the effectiveness of exercise interventions, including the Timed Motor Performance assessment (see Timed Motor Performance Tasks), which is a useful and simple measurement scale that can be used during routine clinic visits. In terms of testing static muscle strength, manual muscle testing has been shown to be unreliable in patients with NMDs. A hand-held myometer or MicroFET type of strength measuring device is far more reproducible and just as easy to use in a clinical setting. Although very reliable, quantitative isokinetic strength testing requires too much sophisticated equipment to be useful in clinic. However, this is a good choice for research purposes.
Despite all the benefits, exercise does create some clinical problems. Muscle cramping is common in patients with NMD because of sarcolemmal instability and is often exacerbated by exercise. True muscle spasms, related to upper motor neuron spasticity, are also seen in ALS. A number of pharmaceuticals may help treat muscle spasms.
Baclofen is a good first choice because it acts via motor neuron inhibition at the spinal cord level. Tizanidine and gabapentin may also be helpful in this situation. Gabapentin would be a good choice if neuropathic pain were also present. Benzodiazepines (or other centrally acting muscle relaxants) are not recommended because of the risk of respiratory suppression. Dantrolene is contraindicated because of its mechanism of action (impairing excitation-contraction coupling), which produces too much muscle weakness to be used in patients with NMDs. Mexiletine is particularly useful in myotonia congenita, but cardiac conduction must be monitored while this drug is being used. Nonballistic sustained muscle stretching is also helpful and should be routinely performed after exercise.
Managing neuromuscular contractures and scoliosis: stretching, bracing, and surgery
Joint contractures and scoliosis are major clinical problems in NMDs, particularly in patients with DMD and SMA II. (See image below and Image 7.) A routine examination of the spine and major joints in patients with NMDs should be performed during each clinic visit. Contractures appear to be related to prolonged static limb positioning. Contractures frequently develop shortly after the patient becomes wheelchair dependent. Several studies have documented that a lack of lower extremity weight bearing and wheelchair dependence contributes to the development of contractures.
Four-year-old boy with Werdnig-Hoffmann disease (a type of spinal muscular atrophy). A chest radiograph reveals the presence of significant 32º left thoracic scoliosis.
In ambulatory patients, upper extremity contractures may occur and can be complicated by joint subluxation, particularly in the shoulder girdle. Slings may help provide support but will not prevent contracture formation. Again, stretching and positional splinting may slow the progression of contractures, although the actual effectiveness of this has not been well studied or documented in the literature. Surgical release of contractures in the lower extremities may allow a patient to be functionally braced. This may prolong ambulation, although a number of studies have shown that weakness, not contractures, contributes most to the loss of functional ambulation.
In terms of scoliosis, an etiologic relationship does not appear to be associated with the loss of ambulation. Although scoliosis and wheelchair dependence are age-related phenomena, several studies have shown no relationship between the 2. One large study by Lord and colleagues reported an almost 4-year difference between wheelchair dependency and the onset of significant scoliosis in patients with DMDs.32
Indeed, many patients with DMD and SMA II develop scoliosis before they become wheelchair dependent. Disease progression with increasing weakness of trunk musculature is more likely the major underlying cause of neuromuscular scoliosis. However, trunk flexor or extensor strength is very hard to measure quantitatively. In NMD patients, scoliosis did not appear to correlate with trunk strength assessed by manual muscle test, although this method is not capable of measuring asymmetric strength and, as discussed earlier, has not been shown to be a reliable method of strength testing in this population.
Patients with DMD typically develop scoliosis around the time of the adolescent growth spurt.33 However, patients with SMA II may develop scoliosis much earlier. In DMD and SMA, studies have shown that thoracolumbar curves are much more common than lumbar curves. Patients with DMD and SMA should be monitored closely with serial radiographs because the curve may suddenly progress.
An important note is that spinal bracing has not been shown to be effective in preventing progression of neuromuscular scoliosis, although most of the studies were performed involving patients with SMA. Thus, spinal instrumentation and fusion is the only known, effective treatment option. This should be performed before the primary curve exceeds 25° and the forced vital capacity has not dropped below 50% of predicted. Complications substantially increase if the patient already has compromised breathing, although, unfortunately, correction of the scoliosis with fusion has not been shown to improve pulmonary function.34
Nonetheless, fusion does improve QOL by facilitating positioning, seating, and transfers. If the curve progresses much beyond 40°, successful correction via fusion is much less likely.
For the extremities, the goals of bracing should be to improve function and joint stability. Long leg bracing to prolong ambulation time in DMD has been one of the better-studied uses in NMDs. A number of studies have shown that ambulatory ability may be prolonged by up to 2 years with the use of long leg braces and appropriate contracture release. However, whether this represents a subset of patients with a slower disease progression and relatively less weakness is unclear. Further, no clear association exists between prolonging ambulation with long-leg bracing and delaying or decreasing scoliosis in patients with DMD. If bracing is used, a long leg brace or knee-ankle-foot orthosis is generally needed because of the amount of weakness in hip and knee extension as well as ankle plantar flexion and dorsiflexion.
Most patients with CMT require short leg braces or ankle-foot orthoses. These are best when they are custom made with a lightweight polymer (polypropylene or carbon fiber). They should fit intimately to avoid skin problems and to provide good stability. If a pressure sore occurs, the brace should be removed until the patient heals. Double metal upright ankle-foot orthoses may be built into the shoe but are usually too heavy and may limit ambulation. If the ankle is significantly unstable, the braces should be high profile (come around in front of the malleoli). Pes cavus and hammertoe deformities can be accommodated with built-up arches and metatarsal bars. Patients with CMT and other sensory neuropathies are at very high risk for skin ulcers and neuropathic arthritis (Charcot joint). Thus, skin integrity and joint stability should be checked during every clinic visit.
Any patient with weakness due to an NMD may benefit from bracing depending on the distribution of weakness, gait problems, and joint instability. The decision to brace should include the risk of the brace's added weight and the willingness of the patient to use the brace. Patients with NMDs should be referred for a course of physical therapy after being fitted with braces to help them learn to use the devices effectively.
Vocational, psychosocial, and quality of life issues
Patients with NMDs, particularly those with advanced ALS and DMD, may experience reactive clinical depression. As noted previously, studies involving patients with NMDs have shown elevated scores for depression on Minnesota Multiphasic Personality Inventory testing. In one study, depression was more closely associated with the level of independent functioning than with limb strength. Thus, good family, social, and religious support systems are critical.
Other family members and caregivers may also become depressed, and this should not be overlooked. Group and family counseling may be beneficial. Patients with NMDs should be referred to support groups, which are also excellent resources for psychological support and problem solving. If necessary, a patient should be referred to a mental health professional.35,36 Antidepressant medicine may also help with mood elevation and may improve appetite and sleep. In patients with ALS, tricyclic antidepressants with significant anticholinergic activity dry up oral secretions. This can help minimize drooling.
Significant cognitive involvement is common in patients with MMD and some congenital mitochondrial myopathies. Learning disabilities are also seen in about one third of boys with DMD. Beyond that, most people with NMD show normal intelligence. Unfortunately, employment rates for people with NMDs are significantly lower than for the able-bodied population. In the NMD population, a higher level of education correlated more closely with employment rate than with functional level or physical performance. The self-esteem levels noted on personality testing also correlated positively with the level of education and employment. This implies that altered personality profiles in patients with NMDs may be a significant factor concerning their ability to integrate into mainstream society and to hold steady employment rates. In this regard, education appears to be at least as important as physical abilities with respect to employability and self-esteem in people with NMDs.
Individuals who have NMDs are incredibly diverse. This may be why very few QOL studies have been conducted to determine the effect of a NMD on QOL. Studies that have been performed have been criticized because many differing NMDs were lumped together in a poorly defined study group and the studies predominately used generic instruments to define QOL. Thus, they rarely used clinically meaningful data on physical and emotional functioning. Instead, they focused on the extreme manifestations, such as severe pain, rather than looking at how patients experience and deal with their NMD.
Some disease-specific QOL assessment tools, most notably the NeuroQOL and the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), among others, have been developed specifically for NMD patients. These disease-specific measures are especially useful in differentiating QOL and psychosocial functioning of patients as their NMD progresses. Beyond ALS, there has been a dearth of studies using QOL measurements to study NMDs.37 This is an area that greatly warrants further investigation.
Equipment
Proper equipment can significantly improve QOL for a patient with an NMD. Common examples of equipment include hospital beds, commode chairs, wheelchairs and wheelchair ramps, handheld showers, bathtub benches, grab bars, raised toilet seats, among many others. An occupational therapist is best qualified to help determine if any of these devices would be useful for a patient with an NMD.
Wheelchairs are a critical component of mobility for people with NMDs. Wheelchairs need to be fitted appropriately with the right frame size, type of seat, lumbar support, and cushioning to avoid pressure ulcers. The wheelchair should be equipped with other mechanical accessorial devices such as tilt ability to provide comfort and to protect the skin. A physical or occupational therapist should evaluate the patient to ensure proper wheelchair prescription. Patients who are simply given a prescription for a wheelchair frequently get a chair that does not fit properly or have the proper components. Power wheelchairs are indicated for most patients with NMDs who can no longer ambulate. These patients do not have enough upper extremity strength to propel a manual chair by themselves. Although expensive, power wheelchairs can be justified to third party payers on the basis that they help prolong independent mobility, thus decreasing medical and psychological comorbidity.
In patients who can still ambulate, walkers or quad (4-point) canes help reduce the risk of falling. Pressure-relieving mattresses, along with foam wedges for proper positioning, help prevent pressure skin ulcers. In some patients with NMDs, particularly ALS, severe weakness in the neck musculature causes neck pain and muscle spasms. A cervical collar, particularly the Freeman or Headmaster type, which is a wire-frame collar with padding over the pressure points, may be very helpful. In patients with dysarthria, typically patients with ALS, augmentative communicative aids, including an alphabet board, word board, or computer based speech synthesizer, can be very helpful to maintain functional communication. A speech language pathologist is best qualified to determine which, if any, of these devices would work best.
Future Research
Major molecular, physiological, and pharmacological advances have occurred over the past decade in the field of NMD research. Stem cell therapy holds some promise for replacing diseased nerve and muscle. However, the clinician and patient should realize that stem cell treatment would not cure most NMDs because stem cell treatment would not correct the underlying genetic defect. Despite this, growing new nerve or muscle tissue through stem cell therapy may significantly improve function.
Further, these diseases may be treatable with genetically modified (corrected) stem cells, which would not only improve function but also partially correct the genetic abnormality. Increased understanding of the molecular basis of many NMDs has greatly enhanced diagnostic accuracy and the ability to perform prenatal diagnostic screening. This has also provided the groundwork for therapeutic intervention. Techniques are being developed for gene insertion and DNA repair using a number of vectors, including gutted viruses. This may ultimately lead to a true cure.
The functional imaging of nerve and muscle has improved significantly, particularly in the field of magnetic resonance imaging. This has helped facilitate more accurate and earlier diagnoses of NMDs (see image below and Image 2). The interfacing of biomedical engineering and computer science continues to provide patients with NMDs with better equipment and QOL improvement. This progress has altered the expectations of the patients, even those with severe NMDs, who now expect to enjoy a more functional, mainstream life. Using the comprehensive treatment paradigms described here will help the clinician fulfill these expectations.
Axial magnetic resonance imaging (MRI) scan of the calves, demonstrating significant atrophy and increased signal intensity (arrows) throughout the anterior and posterior compartment muscles in the right calf, in comparison with the left calf, in a patient with focal motor neuron disease.
Timed Motor Performance Tasks
Time to perform the following tasks is measured in seconds with a stopwatch. Inability to complete the task in 120 seconds is considered a failure.
- Rise to a standing position a supine position.
- Climb 4 standard stairs (begin and end while standing with arms at sides).
- Run or walk 30 feet (as fast as safety allows).
- Rise to a standing position from a seated position on a chair (chair height should allow the feet to touch the floor).
- Propel a wheelchair 30 feet.
- Put on a T-shirt (while sitting in chair).
- Cut a 3" X 3" premarked square from a piece of paper with safety scissors (even if the lines are not followed precisely).
Multimedia
 | Media file 1: Werdnig-Hoffman disease (a type of spinal muscular atrophy). Small muscle fibers within separate muscle fascicles. |
 | Media file 2: Axial magnetic resonance imaging (MRI) scan of the calves, demonstrating significant atrophy and increased signal intensity (arrows) throughout the anterior and posterior compartment muscles in the right calf, in comparison with the left calf, in a patient with focal motor neuron disease. |
 | Media file 3: Kugelberg-Welander disease (a type of spinal muscular atrophy). Marked variation in muscle fiber size along with increased perimysial connective tissue. |
 | Media file 4: Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A. |
 | Media file 5: (A) Normal dystrophin staining; (B) intermediate dystrophin staining in a patient with Becker muscular dystrophy; (C) Absent dystrophin staining in a patient with Duchenne muscular dystrophy. |
 | Media file 6: Photomicrograph of quadriceps muscle from an adult mdx mouse (a genetically homologous model of Duchene muscular dystrophy) 3 days following running exercise and subsequent tail vein injection of 10,000 molecular weight fluorescent dextran. Significant intracellular staining exists in several fibers (center), indicating membrane damage. Central nuclei, present in regenerating fibers, are shown by focal intense areas of fluorescence. |
 | Media file 7: Four-year-old boy with Werdnig-Hoffmann disease (a type of spinal muscular atrophy). A chest radiograph reveals the presence of significant 32º left thoracic scoliosis. |
Keywords
neuromuscular disease, NMD, neuromuscular disorder, muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, LGMD, BMD, DMD, muscular dystrophy rehabilitation, amyotrophic lateral sclerosis, ALS, Lou Gehrig disease, Lou Gehrig's disease, spinal muscular atrophy, SMA, SMA I, SMA II, SMA III, Charcot-Marie-Tooth disease, CMT, CMT1, CMT2, facioscapulohumeral muscular dystrophy, FSHD, motor neuron disease, peripheral neuropathies, myopathy, Werdnig-Hoffmann disease
acute infantile-onset SMA, early onset intermediate SMA, Kugelberg-Welander disease, spinobulbar muscular atrophy, SBMA, Kennedy disease, bulbar muscular atrophy, myotonic muscular dystrophy, MMD, congenital MMD, MMD2, primary axonal neuropathy, primary demyelinating neuropathy, proximal myotonic myopathy, restrictive lung disease, laryngeal diversion, dysphagia, dysarthria, dystrophinopathy, bracing, long-leg brace, ankle-foot orthosis, short-leg brace, reactive clinical depression
Related eMedicine topics:
Amyotrophic Lateral Sclerosis [Emergency Medicine]
Amyotrophic Lateral Sclerosis [Neurology]
Becker Muscular Dystrophy
Charcot-Marie-Tooth and Other Hereditary Motor and Sensory Neuropathies
Charcot-Marie-Tooth Disease
Dystrophinopathies
Facioscapulohumeral Dystrophy
Hereditary Neuropathies of the Charcot-Marie-Tooth Disease Type
Limb-Girdle Muscular Dystrophy [Neurology]
Limb-Girdle Muscular Dystrophy [Physical Medicine and Rehabilitation]
Muscular Dystrophy
Spinal Muscle Atrophy
Spinal Muscular Atrophy
Clinical guidelines:
Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. American Academy of Pediatrics - Medical Specialty Society. 2005 Dec. 5 pages. NGC:004714
EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. An evidence-based review with good practice points. European Federation of Neurological Societies - Medical Specialty Society. 2005 Dec. 18 pages. NGC:005168
Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. American Academy of Neurology - Medical Specialty Society. 2005 Jan. 8 pages. NGC:004041
Clinical trials:
CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I
Cortex Changes in Real/Imagined Movements in Amyotrophic Lateral Sclerosis (ALS)
Genetics of ALS: Identification of Genes With Roles in Familial and Sporadic Amyotrophic Lateral Sclerosis (ALS) and Amyotrophic Lateral Sclerosis (ALS) With Frontotemporal Dementia (FALS)
Noninvasive Examination of the Work of Breathing in Patients With Amyotrophic Lateral Sclerosis (ALS)
Ramipril Versus Carvedilol in Duchenne and Becker Patients
Test-Retest Reliability of Pulmonary Function Tests in Patients With Duchenne's Muscular Dystrophy
Valproic Acid in Ambulant Adults With Spinal Muscular Atrophy (VALIANT SMA)
More on Rehabilitation Management of Neuromuscular Disease |
| References |
References
Lev N, Ickowicz D, Barhum Y, et al. DJ-1 Changes in G93A-SOD1 Transgenic Mice: Implications for Oxidative Stress in ALS. J Mol Neurosci. Aug 19 2008;[Medline].
Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1(1):19-29. [Medline].
[Best Evidence] Benatar M, Kurent J, Moore DH. Treatment for familial amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. Jan 21 2009;CD006153. [Medline].
Chance PF, Matsunami N, Lensch W, et al. Analysis of the DNA duplication 17p11.2 in Charcot-Marie-Tooth neuropathy type 1 pedigrees: additional evidence for a third autosomal CMT1 locus. Neurology. Oct 1992;42(10):2037-41. [Medline].
Chance PF, Alderson MK, Leppig KA, et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell. Jan 15 1993;72(1):143-51. [Medline].
Street VA, Meekins G, Lipe HP, et al. Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes. Neuromuscul Disord. Oct 2002;12(7-8):643-50. [Medline].
Al-Thihli K, Rudkin T, Carson N, et al. Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine-Sottas disease phenotype. Am J Med Genet A. Sep 15 2008;146A(18):2412-6. [Medline].
Fu YH, Friedman DL, Richards S, et al. Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science. Apr 9 1993;260(5105):235-8. [Medline].
Matsumura K, Tome FM, Collin H, et al. Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy. Nature. Sep 24 1992;359(6393):320-2. [Medline].
Carter GT. Phrenic nerve involvement in Charcot-Marie-Tooth. Muscle Nerve. Oct 1995;18(10):1215-6. [Medline].
Carter GT, Kilmer DD, Bonekat HW, et al. Evaluation of phrenic nerve and pulmonary function in hereditary motor and sensory neuropathy, type I. Muscle Nerve. Apr 1992;15(4):459-62. [Medline].
Carter GT, Johnson ER, Bonekat HW, Lieberman JS. Laryngeal diversion in the treatment of intractable aspiration in motor neuron disease. Arch Phys Med Rehabil. Jul 1992;73(7):680-2. [Medline].
Strand EA, Miller RM, Yorkston KM, Hillel AD. Management of oral-pharyngeal dysphagia symptoms in amyotrophic lateral sclerosis. Dysphagia. Spring 1996;11(2):129-39. [Medline].
Bies RD, Friedman D, Roberts R, et al. Expression and localization of dystrophin in human cardiac Purkinje fibers. Circulation. Jul 1992;86(1):147-53. [Medline].
Backman E, Nylander E. The heart in Duchenne muscular dystrophy: a non-invasive longitudinal study. Eur Heart J. Sep 1992;13(9):1239-44. [Medline].
Carter GT, Jensen MP, Galer BS, et al. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. Dec 1998;79(12):1560-4. [Medline].
Carter GT, Sullivan MD. Antidepressants in pain management. Curr Opin Investig Drugs. Mar 2002;3(3):454-8. [Medline].
Carter GT, Galer BS. Advances in the management of neuropathic pain. Phys Med Rehabil Clin N Am. May 2001;12(2):447-59. [Medline].
Amtmann D, Weydt P, Johnson KL, et al. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat Care. Mar-Apr 2004;21(2):95-104. [Medline].
Carter GT, Weydt P. Cannabis: old medicine with new promise for neurological disorders. Curr Opin Investig Drugs. Mar 2002;3(3):437-40. [Medline].
Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs. May 2004;7(5):464-70.
Carter GT, Rosen BS. Marijuana in the management of amyotrophic lateral sclerosis. Am J Hosp Palliat Care. Jul-Aug 2001;18(4):264-70. [Medline].
Carter GT, Ugalde V. Medical marijuana: emerging applications for the management of neurologic disorders. Phys Med Rehabil Clin N Am. Nov 2004;15(4):943-54, ix.
Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. Mar 3 1994;330(9):585-91. [Medline].
Backman E, Henriksson KG. Low-dose prednisolone treatment in Duchenne and Becker muscular dystrophy. Neuromuscul Disord. May 1995;5(3):233-41. [Medline].
Fowler EG, Graves MC, Wetzel GT, Spencer MJ. Pilot trial of albuterol in Duchenne and Becker muscular dystrophy. Neurology. Mar 23 2004;62(6):1006-8.
van der Kooi EL, Vogels OJ, van Asseldonk RJ, et al. Strength training and albuterol in facioscapulohumeral muscular dystrophy. Neurology. Aug 24 2004;63(4):702-8.
Carter GT, Wineinger MA, Walsh SA, et al. Effect of voluntary wheel-running exercise on muscles of the mdx mouse. Neuromuscul Disord. Jul 1995;5(4):323-32. [Medline].
Carter GT, Longley KJ, Entrikin RK. Electromyographic and nerve conduction studies in the mdx mouse. Am J Phys Med Rehabil. Feb 1992;71(1):2-5. [Medline].
Han JJ, Carter GT, Ra JJ. Electromyographic studies in mdx and wild-type C57 mice. Muscle Nerve. 2006;33:208-214.
Sharma KR, Kent-Braun JA, Majumdar S, et al. Physiology of fatigue in amyotrophic lateral sclerosis. Neurology. Apr 1995;45(4):733-40. [Medline].
Lord J, Behrman B, Varzos N, et al. Scoliosis associated with Duchenne muscular dystrophy. Arch Phys Med Rehabil. Jan 1990;71(1):13-7. [Medline].
Cambridge W, Drennan JC. Scoliosis associated with Duchenne muscular dystrophy. J Pediatr Orthop. Jul-Aug 1987;7(4):436-40. [Medline].
Miller RG, Chalmers AC, Dao H, et al. The effect of spine fusion on respiratory function in Duchenne muscular dystrophy. Neurology. Jan 1991;41(1):38-40. [Medline].
Vignola A, Guzzo A, Calvo A, et al. Anxiety undermines quality of life in ALS patients and caregivers. Eur J Neurol. Nov 2008;15(11):1231-6. [Medline].
Steele M, Taylor E, Young C, et al. Mental health of children and adolescents with Duchenne muscular dystrophy. Dev Med Child Neurol. Aug 2008;50(8):638-9. [Medline].
Lamb C, Peden A. Understanding the experience of living with spinal muscular atrophy: a qualitative description. J Neurosci Nurs. Aug 2008;40(4):250-6. [Medline].
Abresch RT, Carter GT, Jensen MP, Kilmer DD. Assessment of pain and health-related quality of life in slowly progressive neuromuscular disease. Am J Hosp Palliat Care. Jan-Feb 2002;19(1):39-48. [Medline].
Abresch RT, Jensen MP, Carter GT. Health-related quality of life in peripheral neuropathy. Phys Med Rehabil Clin N Am. May 2001;12(2):461-72. [Medline].
Aitkens S, Lord J, Bernauer E, et al. Relationship of manual muscle testing to objective strength measurements. Muscle Nerve. Mar 1989;12(3):173-7. [Medline].
Aitkens SG, McCrory MA, Kilmer DD, Bernauer EM. Moderate resistance exercise program: its effect in slowly progressive neuromuscular disease. Arch Phys Med Rehabil. Jul 1993;74(7):711-5. [Medline].
Bach JR. Amyotrophic lateral sclerosis. Communication status and survival with ventilatory support. Am J Phys Med Rehabil. Dec 1993;72(6):343-9. [Medline].
Bach JR. Amyotrophic lateral sclerosis: predictors for prolongation of life by noninvasive respiratory aids. Arch Phys Med Rehabil. Sep 1995;76(9):828-32. [Medline].
Bach JR, McKeon J. Orthopedic surgery and rehabilitation for the prolongation of brace- free ambulation of patients with Duchenne muscular dystrophy. Am J Phys Med Rehabil. Dec 1991;70(6):323-31. [Medline].
Brooke MH, Griggs RC, Mendell JR, et al. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve. May-Jun 1981;4(3):186-97. [Medline].
Carter G, Morris GM, Stolick M, Hentz P. Case study: when should the scope of care extend beyond the patient?. Am J Hosp Palliat Care. Jul-Aug 2004;21(4):294-6. [Medline].
Carter GT. Neuromuscular disorders. In: Dell Orto AE, Marinelli RP, eds. Encyclopedia of Disability and Rehabilitation. NY:. Simon & Schuster;1995:509-515.
Carter GT. Rehabilitation Management of Peripheral Neuropathy. Semin Neurol. 2005;25:229-237.
Carter GT, Abresch RT, Fowler WM. Adaptations to exercise training and contraction-induced muscle injury in animal models of muscular dystrophy. Am J Phys Med Rehabil. Nov 2002;81(11 Suppl):S151-61. [Medline].
Carter GT, Abresch RT, Fowler WM Jr, et al. Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S140-9. [Medline].
Carter GT, Abresch RT, Fowler WM Jr, et al. Profiles of neuromuscular diseases. Spinal muscular atrophy. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S150-9. [Medline].
Carter GT, Bednar-Butler LM, Abresch RT, Ugalde VO. Expanding the role of hospice care in amyotrophic lateral sclerosis. Am J Hosp Palliat Care. Nov 1999;16(6):707-10.
Carter GT, Bird TD. Facioscapulohumeral muscular dystrophy presenting as respiratory failure. Neurology. 2005;64:401.
Carter GT, Bonekat HW, Milio L. Successful pregnancies in the presence of spinal muscular atrophy: two case reports. Arch Phys Med Rehabil. Feb 1994;75(2):229-31. [Medline].
Carter GT, England JD, Chance PF. Charcot-Marie-Tooth disease: electrophysiology, molecular genetics and clinical management. IDrugs. Feb 2004;7(2):151-9.
Carter GT, England JD, Hecht TW, et al. Electrodiagnostic evaluation of hereditary motor and sensory neuropathies. Phys Med Rehabil Clin N Am. May 2003;14(2):347-63, ix-x. [Medline].
Carter GT, Kikuchi N, Abresch RT, et al. Effects of exhaustive concentric and eccentric exercise on murine skeletal muscle. Arch Phys Med Rehabil. May 1994;75(5):555-9. [Medline].
Carter GT, Kikuchi N, Horasek SJ, Walsh SA. The use of fluorescent dextrans as a marker of sarcolemmal injury. Histol Histopathol. Jul 1994;9(3):443-7. [Medline].
Carter GT, Kilmer DD, Szabo RM. Focal posterior interosseous neuropathy in the presence of hereditary motor and sensory neuropathy, type I. Muscle Nerve. May 1996;19(5):644-8. [Medline].
Carter GT, Krivickas LS, Weydt P, et al. Drug therapy for amyotrophic lateral sclerosis: Where are we now?. IDrugs. Feb 2003;6(2):147-53. [Medline].
Carter GT, Longley KJ, Walsh SA, Entrikin RK. Lack of effect of amitriptyline in murine myotonia. Am J Phys Med Rehabil. Oct 1992;71(5):279-82. [Medline].
Carter GT, McDonald CM. Preserving function in Duchenne dystrophy with long-term pulse prednisone therapy. Am J Phys Med Rehabil. Sep-Oct 2000;79(5):455-8. [Medline].
Carter GT, Miller RG. Comprehensive management of amyotrophic lateral sclerosis. Phys Med Rehabil Clin N Am. Feb 1998;9(1):271-84, viii-ix. [Medline].
Chance PF, Ashizawa T, Hoffman EP, Crawford TO. Molecular basis of neuromuscular diseases. Phys Med Rehabil Clin N Am. Feb 1998;9(1):49-81, vi. [Medline].
Colbert AP, Craig C. Scoliosis management in Duchenne muscular dystrophy: prospective study of modified Jewett hyperextension brace. Arch Phys Med Rehabil. May 1987;68(5 Pt 1):302-4. [Medline].
D''Orsogna L, O''Shea JP, Miller G. Cardiomyopathy of Duchenne muscular dystrophy. Pediatr Cardiol. 1988;9(4):205-13. [Medline].
de Lateur BJ, Giaconi RM. Effect on maximal strength of submaximal exercise in Duchenne muscular dystrophy. Am J Phys Med. Feb 1979;58(1):26-36. [Medline].
Eisen A. Amyotrophic lateral sclerosis is a multifactorial disease. Muscle Nerve. Jul 1995;18(7):741-52. [Medline].
England JD, Gronseth GS, Franklin G. Distal symmetrical polyneuropathy: Definition for clinical research. Muscle Nerve. 11 9 2004.
Fowler WM Jr, Abresch RT, Aitkens S, et al. Profiles of neuromuscular diseases. Design of the protocol. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S62-9. [Medline].
Fritz RC, Domroese ME, Carter GT. Physiological and anatomical basis of muscle magnetic resonance imaging. Phys Med Rehabil Clin N Am. 2005;16:1033-1051.
Fukunaga H, Okubo R, Moritoyo T, et al. Long-term follow-up of patients with Duchenne muscular dystrophy receiving ventilatory support. Muscle Nerve. May 1993;16(5):554-8. [Medline].
Griggs RC, Donohoe KM, Utell MJ, et al. Evaluation of pulmonary function in neuromuscular disease. Arch Neurol. Jan 1981;38(1):9-12. [Medline].
Han JJ, Carter GT, Weiss MD. Using electromyography to assess function in humans and animal models of muscular dystrophy. Phys Med Rehabil Clin N Am. 2005;16:981-997.
Hodapp JA, Carter GT, Lipe HP. Double trouble in hereditary neuropathy: concommitant mutations in the PMP-22 gene and another gene produce novel phenotypes. Arch Neurol. 2006;63:112-117.
Hoffman AJ, Jensen MP, Abresch RT. Chronic pain in persons with neuromuscular disorders. Phys Med Rehabil Clin N Am. 2005;16:1009-1112.
Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. Dec 24 1987;51(6):919-28. [Medline].
Hsu JD. The natural history of spine curvature progression in the nonambulatory Duchenne muscular dystrophy patient. Spine. Oct 1983;8(7):771-5. [Medline].
Ionasescu VV. Charcot-Marie-Tooth neuropathies: from clinical description to molecular genetics. Muscle Nerve. Mar 1995;18(3):267-75. [Medline].
Jaffe KM, McDonald CM, Ingman E, Haas J. Symptoms of upper gastrointestinal dysfunction in Duchenne muscular dystrophy: case-control study. Arch Phys Med Rehabil. Sep 1990;71(10):742-4. [Medline].
Jenkins JG, Bohn D, Edmonds JF, et al. Evaluation of pulmonary function in muscular dystrophy patients requiring spinal surgery. Crit Care Med. Oct 1982;10(10):645-9. [Medline].
Jensen MP, Abresch RT, Carter GT. The reliability and validity of a self-reported version of the functional independence measure in persons with neuromuscular disease and chronic pain. Arch Phys Med Rehabil. 2005;86:116-122.
Jensen MP, Carter GT, Abresch RT. Chronic pain in persons with neuromuscular disorders. Arch Phys Med Rehabil. 2005;86:1155-1163.
Johnson ER, Abresch RT, Carter GT, et al. Profiles of neuromuscular diseases. Myotonic dystrophy. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S104-16. [Medline].
Johnson EW, Yarnell SK. Hand dominance and scoliosis in Duchenne muscular dystrophy. Arch Phys Med Rehabil. Oct 1976;57(10):462-4. [Medline].
Kawashima S, Ueno M, Kondo T, et al. Marked cardiac involvement in limb-girdle muscular dystrophy. Am J Med Sci. Jun 1990;299(6):411-4. [Medline].
Kilmer DD. Response to aerobic exercise training in humans with neuromuscular disease. Am J Phys Med Rehabil. Nov 2002;81(11 Suppl):S148-50. [Medline].
Kilmer DD. Response to resistive strengthening exercise training in humans with neuromuscular disease. Am J Phys Med Rehabil. Nov 2002;81(11 Suppl):S121-6. [Medline].
Kilmer DD, Abresch RT, Fowler WM Jr. Serial manual muscle testing in Duchenne muscular dystrophy. Arch Phys Med Rehabil. Nov 1993;74(11):1168-71. [Medline].
Kilmer DD, Abresch RT, McCrory MA, et al. Profiles of neuromuscular diseases. Facioscapulohumeral muscular dystrophy. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S131-9. [Medline].
Kilmer DD, McCrory MA, Wright NC, et al. The effect of a high resistance exercise program in slowly progressive neuromuscular disease. Arch Phys Med Rehabil. May 1994;75(5):560-3. [Medline].
Kurz LT, Mubarak SJ, Schultz P, et al. Correlation of scoliosis and pulmonary function in Duchenne muscular dystrophy. J Pediatr Orthop. Jul 1983;3(3):347-53. [Medline].
Lindeman E, Leffers P, Spaans F, et al. Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: a randomized clinical trial. Arch Phys Med Rehabil. Jul 1995;76(7):612-20. [Medline].
Liu J, Lissens W, Van Broeckhoven C, et al. Normal pregnancy after preimplantation DNA diagnosis of a dystrophin gene deletion. Prenat Diagn. Apr 1995;15(4):351-8. [Medline].
Lord JP, Portwood MM, Lieberman JS, et al. Upper extremity functional rating for patients with Duchenne muscular dystrophy. Arch Phys Med Rehabil. Mar 1987;68(3):151-4. [Medline].
MacKenzie AE, Jacob P, Surh L, Besner A. Genetic heterogeneity in spinal muscular atrophy: a linkage analysis- based assessment. Neurology. May 1994;44(5):919-24. [Medline].
Manzur AY, Hyde SA, Rodillo E, et al. A randomized controlled trial of early surgery in Duchenne muscular dystrophy. Neuromuscul Disord. 1992;2(5-6):379-87. [Medline].
Marsh GG, Munsat TL. Evidence of early impairment of verbal intelligence in Duchenne muscular dystrophy. Arch Dis Child. Feb 1974;49(2):118-22. [Medline].
Matsumura K, Campbell KP. Dystrophin-glycoprotein complex: its role in the molecular pathogenesis of muscular dystrophies. Muscle Nerve. Jan 1994;17(1):2-15. [Medline].
McDonald CM, Abresch RT, Carter GT, et al. Profiles of neuromuscular diseases. Becker''s muscular dystrophy. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S93-103. [Medline].
McDonald CM, Abresch RT, Carter GT, et al. Profiles of neuromuscular diseases. Duchenne muscular dystrophy. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S70-92. [Medline].
McDonald CM, Carter GT, Abresch RT. Body Composition in Duchenne Dystrophy using Impedance Analysis and Dual X-ray Absorptiometry. Am J Phys Med Rehabil. 2005;84:483-491.
McDonald CM, Carter GT, Fritz RC, et al. Magnetic resonance imaging of denervated muscle: comparison to electromyography. Muscle Nerve. Sep 2000;23(9):1431-4. [Medline].
McDonald CM, Johnson ER, Abresch RT, et al. Profiles of neuromuscular diseases. Limb-girdle syndromes. Am J Phys Med Rehabil. Sep-Oct 1995;74(5 Suppl):S117-30. [Medline].
Miller RG, Petajan JH, Bryan WW, et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann Neurol. Feb 1996;39(2):256-60. [Medline].
Mitsumoto H, Norris FH. Amyotrophic Lateral Sclerosis: A Comprehensive Guide to Management. NY:. Demos Vermande;1994.
Norris F, Shepherd R, Denys E, et al. Onset, natural history and outcome in idiopathic adult motor neuron disease. J Neurol Sci. Aug 1993;118(1):48-55. [Medline].
Oda T, Shimizu N, Yonenobu K, et al. Longitudinal study of spinal deformity in Duchenne muscular dystrophy. J Pediatr Orthop. Jul-Aug 1993;13(4):478-88. [Medline].
Pecak F, Trontelj JV, Dimitrijevic MR. Scoliosis in neuromuscular disorders. Int Orthop. 1980;3(4):323-8. [Medline].
Rideau Y, Jankowski LW, Grellet J. Respiratory function in the muscular dystrophies. Muscle Nerve. Mar-Apr 1981;4(2):155-64. [Medline].
Ringel SP, Murphy JR, Alderson MK, et al. The natural history of amyotrophic lateral sclerosis. Neurology. Jul 1993;43(7):1316-22. [Medline].
Rodillo EB, Fernandez-Bermejo E, Heckmatt JZ, Dubowitz VA. Prevention of rapidly progressive scoliosis in Duchenne muscular dystrophy by prolongation of walking with orthoses. J Child Neurol. Oct 1988;3(4):269-74. [Medline].
Rose MR, Tawil R. Drug treatment for facioscapulohumeral muscular dystrophy. Cochrane Database Syst Rev. 2004;CD002276.
Sakai DN, Hsu JD, Bonnett CA, Brown JC. Stabilization of the collapsing spine in duchenne muscular dystrophy. Clin Orthop. Oct 1977;(128):256-60. [Medline].
Seeger BR, Sutherland AD, Clark MS. Orthotic management of scoliosis in Duchenne muscular dystrophy. Arch Phys Med Rehabil. Feb 1984;65(2):83-6. [Medline].
Smith AD, Koreska J, Moseley CF. Progression of scoliosis in Duchenne muscular dystrophy. J Bone Joint Surg Am. Aug 1989;71(7):1066-74. [Medline].
Stern LM, Clark BE. Investigation of scoliosis in Duchenne dystrophy using computerized tomography. Muscle Nerve. Jul 1988;11(7):775-83. [Medline].
Tysnes OB, Vollset SE, Larsen JP, Aarli JA. Prognostic factors and survival in amyotrophic lateral sclerosis. Neuroepidemiology. 1994;13(5):226-35. [Medline].
Vignos PJ. Management of musculoskeletal complications in neuromuscular disease: limb contractures and the role of stretching, braces and surgery. In: Physical Medicine and Rehabilitation: State of the Art Reviews. Vol 2. 1988:509-536.
Weiss MD, Weydt P, Carter GT. Current pharmacological management of amyotrophic [corrected] lateral sclerosis and a role for rational polypharmacy. Expert Opin Pharmacother. Apr 2004;5(4):735-46.
Weydt P, Weiss MD, Moller T, Carter GT. Neuro-inflammation as a therapeutic target in amyotrophic lateral sclerosis. Curr Opin Investig Drugs. Dec 2002;3(12):1720-4. [Medline].
Willig TN, Carlier L, Legrand M, et al. Nutritional assessment in Duchenne muscular dystrophy. Dev Med Child Neurol. Dec 1993;35(12):1074-82. [Medline].
Wohlgemuth M, van der Kooi EL, van Kesteren RG, et al. Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology. Jul 13 2004;63(1):176-8.
Further Reading
Related eMedicine topics:
Amyotrophic Lateral Sclerosis [Emergency Medicine]
Amyotrophic Lateral Sclerosis [Neurology]
Becker Muscular Dystrophy
Charcot-Marie-Tooth and Other Hereditary Motor and Sensory Neuropathies
Charcot-Marie-Tooth Disease
Dystrophinopathies
Facioscapulohumeral Dystrophy
Hereditary Neuropathies of the Charcot-Marie-Tooth Disease Type
Limb-Girdle Muscular Dystrophy [Neurology]
Limb-Girdle Muscular Dystrophy [Physical Medicine and Rehabilitation]
Muscular Dystrophy
Spinal Muscle Atrophy
Spinal Muscular Atrophy
Clinical guidelines:
Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. American Academy of Pediatrics - Medical Specialty Society. 2005 Dec. 5 pages. NGC:004714
EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. An evidence-based review with good practice points. European Federation of Neurological Societies - Medical Specialty Society. 2005 Dec. 18 pages. NGC:005168
Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. American Academy of Neurology - Medical Specialty Society. 2005 Jan. 8 pages. NGC:004041
Clinical trials:
CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I
Cortex Changes in Real/Imagined Movements in Amyotrophic Lateral Sclerosis (ALS)
Genetics of ALS: Identification of Genes With Roles in Familial and Sporadic Amyotrophic Lateral Sclerosis (ALS) and Amyotrophic Lateral Sclerosis (ALS) With Frontotemporal Dementia (FALS)
Noninvasive Examination of the Work of Breathing in Patients With Amyotrophic Lateral Sclerosis (ALS)
Ramipril Versus Carvedilol in Duchenne and Becker Patients
Test-Retest Reliability of Pulmonary Function Tests in Patients With Duchenne's Muscular Dystrophy
Valproic Acid in Ambulant Adults With Spinal Muscular Atrophy (VALIANT SMA)
Keywords
neuromuscular disease, NMD, neuromuscular disorder, muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, LGMD, BMD, DMD, muscular dystrophy rehabilitation, amyotrophic lateral sclerosis, ALS, Lou Gehrig disease, Lou Gehrig's disease, spinal muscular atrophy, SMA, SMA I, SMA II, SMA III, Charcot-Marie-Tooth disease, CMT, CMT1, CMT2, facioscapulohumeral muscular dystrophy, FSHD, motor neuron disease, peripheral neuropathies, myopathy, Werdnig-Hoffmann disease
acute infantile-onset SMA, early onset intermediate SMA, Kugelberg-Welander disease, spinobulbar muscular atrophy, SBMA, Kennedy disease, bulbar muscular atrophy, myotonic muscular dystrophy, MMD, congenital MMD, MMD2, primary axonal neuropathy, primary demyelinating neuropathy, proximal myotonic myopathy, restrictive lung disease, laryngeal diversion, dysphagia, dysarthria, dystrophinopathy, bracing, long-leg brace, ankle-foot orthosis, short-leg brace, reactive clinical depression
