Rehabilitation Management of Neuromuscular Disease 

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.

Endurance (aerobic) exercise may yield functional improvement and greater independence in activities of daily living (ADLs). Advancements in noninvasive positive-pressure ventilation technology have greatly reduced pulmonary morbidity in NMDs. Cardiac complications, though severe in some NMDs, often respond to medical management.

Psychosocial and vocational issues should be addressed as part of the management of NMDs. Such comprehensive management usually requires the efforts of a multidisciplinary team. 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.

Definition and classification

An exact definition of what constitutes an NMD is important. Many clinicians who do not work directly in this field, even highly astute ones, incorrectly describe patients with NMDs as having muscular sclerosis (MS). In fact, MS is a demyelinating disease of the CNS; it is not an NMD, even though the symptoms of MS may sometimes superficially resemble the symptoms associated with NMDs.

NMDs 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, ultimately weakening the muscle.

NMDs also include peripheral neuropathies such as Charcot-Marie-Tooth disease (CMT), which 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 (MG).

Finally, NMDs may directly affect all forms of muscle, particularly skeletal and cardiac muscle. This stage of muscular deterioration is what causes the frequent misapplication of the term muscular dystrophy. The term dystrophy (from Greek dys-, “difficult or abnormal,”and trophe, “nutrition”) is also a misnomer based on descriptions from over 150 years ago, when lack of growth nutrients was blamed for damaging muscle. These disorders classified as muscular dystrophies fall under the broader category of myopathies (myo-, “muscle,” pathos, “disease”).

The dystrophies are now known to consist largely of structural damage to the muscle caused by a DNA abnormality that results in a missing protein product. Other forms of myopathy may involve damage to the muscle’s mitochondria or contractile filaments. The lack of a metabolic enzyme, as in maltase deficiency (Pompe disease), may be a cause of myopathies.

Diagnosis and management

Accurate confirmation of the diagnosis is critical and involves thorough clinical evaluation, as well as electrodiagnostic studies and, often, muscle or nerve biopsy. For many of the diseases, 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 the potential problems that 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 this 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 the following professionals, among others:

• Physicians
• Nurses
• Physical, occupational, and speech therapists
• Social workers
• Vocational counselors
• Psychologists

Treatment should be goal-oriented, with clear input regarding the patient’s expectations and personal goals. Although NMDs are not curable, they 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, including the following (among others):

• Muscular Dystrophy Association
• Amyotrophic Lateral Sclerosis Association
• Charcot-Marie-Tooth Association
• Facioscapulohumeral Society

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.

This section provides with a brief clinical overview of the most common major neuromuscular diseases (NMDs). Any medical practice is likely to encounter these disorders. More in-depth discussions of the NMDs may be found in the articles specifically describing these disorders.

Motor neuron diseases

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is perhaps the most severe of all the major NMDs. It 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 gene for 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, without a known cause. Studies suggest that an excess of the excitatory neurotransmitter glutamate in the central nervous system (CNS) is involved in the disease process. Serum, cerebrospinal fluid (CSF), and brain tissue of patients with ALS contain abnormally high levels of glutamate, apparently as a result of 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 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. It 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 2-fold increase in risk, whereas a 3-fold increase was seen in current smokers. The duration (years having smoked) and amount of smoking (packs per year) 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. Notably, glutamate consumption did correlate with an increased risk for ALS. That smoking and glutamate consumption are risk factors for ALS supports the theory implicating oxidative stress and excitotoxicity in the pathogenesis of ALS.

The major neuropathologic finding in ALS is the degeneration and subsequent loss of motor neurons as a consequence of apoptosis (programmed cell death). Apoptosis is characterized by neuronal contraction (to approximately one fifth the 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.

Several prognostic predictors exist for determining the course of ALS. Presentation with bulbar or pulmonary dysfunction, a short interval from symptom onset to diagnosis, electrodiagnostic findings primarily involving lower motor neurons, and advanced age all potentially indicate a poor prognosis. Women present with bulbar symptoms more often 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 after diagnosis, 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 collectively included 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 spinal muscular atrophy (SMA) involve selective destruction of anterior horn cells. The distinct types of SMA differ clinically. 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 (see the image below). 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 (see the image below), has a much later onset (typically, age 5-15 years) and is associated with much less morbidity.^{[4, 5]}

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 about 67% of patients with SMA I, 42% of patients with SMA II or III, and some patients with adult-onset SMA, though the precise percentage is not known.

Commercial blood tests (DNA analyses) are now available for use in diagnosing SMA. Prevalences for SMA types II and III have been estimated to be as high as 40 cases per million in the general population, though 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-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.

In this way, SBMA differs markedly from myotonic muscular dystrophy and fragile X syndrome, in which an increased number of tandem triplet repeats correlates 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 of later adult-onset SMA has its onset in patients aged 17-55 years, with either recessive or dominant types of inheritance. This form of SMA clinically resembles SMA III but may be more progressive. It has been mapped to chromosome band 5q11.2-13.3; however, 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

Charcot-Marie-Tooth disease (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; 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. Clinically, CMT2 is often less severe than CMT1. Patients with CMT2 may have more lower extremity involvement, although in other respects they may not be easily distinguishable from patients with CMT1. Most of the phenotypic descriptive studies in CMT were done before the advent of DNA testing.

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 on quantitative isometric and isokinetic strength measures, even though manual muscle test scores may be normal. No significant side-to-side difference exists with regard to 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 (see the image below) 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).^[6]

Notably, 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.^[7] HNPP is an autosomal dominant disorder that produces episodic recurrent nerve compression with focal demyelination at common sites of compression or entrapment (eg, wrist, elbow, and fibular head). Nerve compression can occur in the absence of true entrapment.

CMT X is an X-linked dominant, primarily demyelinating neuropathy with a mutation in the connexin 32 gene (CX32), which 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.^[8] Furthermore, males with nonsense mutations have an earlier onset and a more severe phenotype than males with missense mutations.

Point mutations in PMP22 or the myelin protein zero gene (MPZ) may cause Dejerine-Sottas disease.^[9] 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 dystrophies

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 (see the image below). Dystrophin stabilizes the sarcolemma during muscle contractions. Without dystrophin, the sarcolemma is unstable, cell homeostasis is impaired, and the myofiber ultimately deteriorates. Despite some regeneration, repair capacity is rendered insufficient, and the muscle is replaced by fat and connective tissue.^[5]

DMD is the most common childhood NMD, with an estimated overall prevalence of 63 cases per million population.^[2] This myopathy is progressive and ultimately fatal, 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 of 24 cases per million population.^[2] BMD is associated with the same muscle weakness that DMD is but has a much later onset age and a 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 a characteristic facies, including frontal baldness and temporal wasting. Other problems include gonadal atrophy, cataracts, cardiac dysrhythmias, and an increased risk of diabetes. MMD is an autosomal dominant trait with a prevalence of 1 case per 8000 population.^{[2, 10]}

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 patients with typical MMD do. The repeated DNA sequences known as CTG (cytosine-thymine-guanidine) are linked to the production of 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.^[11]

Another form of MMD is known as type 2 MMD (MMD2 or DM2), also 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. It is an autosomal dominant trait with an estimated prevalence of 10-20 cases per million population—possibly higher, if undiagnosed, mild cases are taken into account.^[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 dystrophies

Limb-girdle muscular dystrophies (LGMDs) are a highly heterogeneous group of myopathies sharing many clinical features. The age of onset ranges from 3 to 12 years, with equal male and female prevalence. The distribution and pattern of weakness are similar to those of DMD, but progression is much slower. LGMDs have been linked to abnormalities of the dystrophin-associated glycoproteins (DAGs), especially alpha-sarcoglycan (adhalin), a 50-kd DAG, and gamma-sarcoglycan. The 50-kd DAG has been linked to the 17q12-q21.33 locus.^[12]

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 of 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. DAGs 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 DAGs, 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 (ie, the dystrophinopathies).

Respiratory dysfunction

Restrictive lung disease, despite its name, does not affect the lung. People with restrictive lung disease develop “weak bellows”—that is, their breathing muscles (diaphragm, chest wall, and abdominal muscles) are weak. Thus, patients with neuromuscular disease (NMD) may have difficulty inhaling and exhaling; this also includes coughing. This is a common problem in many NMDs but is typically most severe in amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic muscular dystrophy (MMD).

Respiratory failure in fascioscapulohumeral dystrophy (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.

There are numerous reported cases of respiratory failure in people with Charcot-Marie-Tooth disease (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.^[13]

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.^[14] 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 (FVC) and maximal inspiratory and expiratory pressure, should be monitored closely. 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 indicates 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 and experience a morning headache as a result. They may also have nocturnal restlessness, nightmares, and poor overall quality sleep, which result in daytime somnolence. Insufficient respiration with hypoxia may also develop; 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 (NIPPV). 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, though a net positive pressure gradient remains (as if the wind died down a bit, but not completely, during exhalation). Typical pressures would be 8-10 cm H₂ O for inhalation and 4-6 cm H₂ O for exhalation.

BiPAP can easily be used in the home, but some work with a respiratory therapist may be required 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 quality of life (QOL). However, bulbar palsy may occur in ALS and in some rare forms of SMA. In such cases, if better airway access becomes necessary and an informed patient wishes more aggressive care, a tracheostomy may be performed.

However, an alternative procedure, laryngeal diversion (or laryngotracheal separation), has several distinct advantages over 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.^[15]

The tracheostoma does not require any hardware (eg, 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, given that air no longer flows through the vocal cords. Accordingly, this procedure is recommended only when severe dysarthria accompanies the dysphagia and the patient’s speech is unintelligible.

Although a tracheostomy preserves the ability to phonate, it actually increases the risk of aspiration, requires significantly more care, and provides no better airway access. Both tracheostomy and laryngeal diversion facilitate the use of mechanical ventilation, but the patient must understand that neither procedure guarantees a better QOL. Fortunately, with the advances in noninvasive ventilation, these surgical options are now infrequently used.

In addition to assisted ventilation, various newer technologies may be used to improve respiratory hygiene. These include cough assist machines that help NMD patients bring up secretions; the machines produce an artificial cough via a face mask by rapidly changing airway pressure from positive to negative. Several of these products are commercially available in the United States, including the Cofflator (Respironics, Pittsburgh, PA) and the In-Exsufflator (JH Emerson Co, Cambridge, MA).

Dysphagia and dysarthria

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 liquids are swallowed; 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 as the following^[16] :

• Thickening liquids
• Using techniques such as double swallows, chin tucks, and head turns
• Eating only foods that easily form into boluses

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 for defining which food textures the patient can safely swallow. However, this study does involve exposure to radiation. An alternative to the modified barium swallow is flexible endoscopic evaluation of swallowing (FEES), a test that uses an endoscope specifically designed to assess the swallowing mechanism.

FEES directly evaluates motor and sensory components of swallowing through 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 information can guide the clinician in determining which foods are associated with different types of the patient’s swallows.

The main advantage of FEES is that it entails direct real-time visualization of food traveling down the oropharynx and esophagus. During the FEES 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. The patient can also provide feedback to the clinician in the course of the test so that the therapist can alter the volume and thickness of the food to prevent choking sensations during FEES.

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.

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 primary myopathies, including DMD, Becker muscular dystrophy (BMD), MMD, and some cases of limb-girdle muscular dystrophy (LGMD). Cardiac involvement is not seen in peripheral neuropathies or motor neuron diseases. A high (60-80%) occurrence of cardiac involvement is present in DMD and BMD patients of all ages. 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.^[17]

A high prevalence of abnormalities found via electrocardiography (ECG) and echocardiography exists in preadolescent patients with DMD and BMD. Nevertheless, 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, possibly 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.^[18]

An important caveat is that severe cardiac involvement in BMD occasionally precedes 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, whereas 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, though 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.^[19]

Pharmacologic pain management in patients with NMD initially includes acetaminophen (1000 mg every 6 hours). Acetaminophen may be used along with nonsteroidal anti-inflammatory drugs (NSAIDs), which may be particularly helpful if evidence indicates any active inflammatory processes (eg, joint effusion or tenosynovitis).

Tricyclic antidepressants and antiepileptic drugs are often helpful, particularly for relieving neuropathic pain.^[20] Gabapentin, an antiepileptic drug, also has the added benefit of reducing spasticity via glutamate and gamma-aminobutyric acid (GABA) 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.^[21]

Cannabinoids, the active ingredients in marijuana, have a number of pharmacologic properties that may be applicable to the management of ALS and other NMDs.^{[22, 23, 24, 25, 26]} Their benefits include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, they have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. Cannabis does not suppress breathing and carries no risk of 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 for patients with severe NMDs, in whom 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. If a severe respiratory compromise is present, the increased work of breathing may drastically increase caloric needs. To complicate the situation, this is often a time when patients lose the ability to feed themselves. 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 predicted FVC of less than 50% on pulmonary function testing.

PEG tube placement may facilitate nutrition by easing the intake of large amounts of calories and fluids. Patients should be reassured that they may still eat food orally for enjoyment, provided that swallowing function is intact. Another complicating factor in patients with DMD is gastroparesis, which may make feeding more difficult.

Pharmaceuticals that may improve function or prolong life

Although a comprehensive discussion of clinical trials of drugs developed to treat NMD is beyond the scope of this article, some of the major advances are worth noting. Because of its severity and rapid progression, ALS is the NMD that, to date, 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.^[27] It is the first agent approved by the US Food and Drug Administration (FDA) for use in ALS patients. Although riluzole is only modestly effective at improving life expectancy in patients with ALS, it nonetheless represents a major advance. Various neurotrophic growth factors also appear quite promising, particularly insulin-derived growth factor (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, like tamoxifen, which also has been shown to prolong cell survival in a mouse model of ALS. This suggests a similar mechanism of action, though 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 1 mg/kg/day has been shown to prolong the time of ambulation in 4- to 8-year-old boys with DMD and should at least be considered for use in this disease.^[28] 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, it is not currently available in the United States.

Several randomized, crossover, double-blind, placebo-controlled pilot studies found that extended-release albuterol yielded some small benefit in patients with dystrophinopathies (DMD and BMD), but not in those with FSHD.^{[29, 30]} Outcomes involved isometric knee extensor testing, flexor strength testing, and manual muscle testing. A 12-week course of extended-release albuterol may increase strength in patients with dystrophinopathies, but clearly, larger double-blind randomized studies are necessary to confirm these results.

Some data suggest that 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 in that 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.

Exercise paradigms to improve strength

Skeletal muscle weakness is the ultimate cause of most clinical problems associated with neuromuscular diseases (NMDs). A number of well-controlled studies have documented the effect of exercise as a means for NMD patients to gain strength, although much remains to be learned in this area.^[31]

In slowly progressive NMDs, a 12-week moderate-resistance exercise program (training at 30% of maximum isometric force) resulted in strength gains ranging from 4% to 20%, without any notable deleterious effects. However, in the same population, a 12-week high-resistance exercise program (training at the maximum weight a subject could lift 12 times) showed no benefit over the moderate-resistance program, and evidence of overwork weakness was found in some of the subjects.

In a study comparing patients who had Charcot-Marie-Tooth disease (CMT) with patients who had myotonic muscular dystrophy (MMD), the only patients who appeared to benefit significantly from a strengthening program were those with CMT; those 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 Duchenne muscular dystrophy (DMD) and amyotrophic lateral sclerosis (ALS), active ongoing muscle degeneration occurs, and the risk of 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 comparing mdx mice (mice that lack dystrophin and are genetically homologous models of DMD) with normal control mice found that in voluntary running protocols, dystrophin-deficient muscle is clearly susceptible to exercise-induced muscle injury, particularly eccentric (lengthening) muscle contractions.^[32] Compared with normal mice, mdx mice show considerable avoidance behavior for exercise; this may be an intuitive survival strategy.

After 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 than to the control nonexercised mdx muscles (see the image below).^{[33, 34]}

In view of 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. NMD patients in exercise programs should be monitored for signs of overwork weakness, including excessive delayed onset muscle soreness, which usually occurs 24-48 hours after 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 by enhancing cardiovascular performance and increasing utilization of oxygen and substrate by muscle. This is important because fatigue is a significant limiting factor in physical performance in patients with NMDs. Fatigue in this setting is likely to be multifactorial, related to deconditioning and impaired muscular activation.^[35]

Improving cardiopulmonary performance through aerobic exercise not only enhances physical functioning but also leads to a better mood state and helps fight depression. Patients with NMD have a higher frequency of depression on the Minnesota Multiphasic Personality Inventory (MMPI) than healthy populations do. Aerobic exercise also helps patients achieve and maintain ideal body weight and improves pain tolerance.

In terms of monitoring progress in an exercise program, a number of reliable, functional assessment tools are available for evaluating the effectiveness of exercise interventions, including the Timed Motor Performance assessment, which is a useful and simple measurement scale that can be used during routine clinic visits.

In the Timed Motor Performance assessment, the time required to perform selected tasks is measured in seconds with a stopwatch. Inability to complete any of the following tasks within 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” × 3” premarked square from a piece of paper with safety scissors (even if the lines are not followed precisely)

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 yields far more reproducible results and is just as easy to use in a clinical setting. Quantitative isokinetic strength testing, though highly reliable, requires too much sophisticated equipment to be useful in clinical settings. However, it is a good choice for research purposes.

Its many benefits notwithstanding, 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.

Stretching, bracing, and surgery for contractures and scoliosis:

Joint contractures and scoliosis (see the image below) are major clinical problems in NMDs, particularly in patients with DMD and spinal muscular atrophy (SMA) type II. Consequently, 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 contribute to the development of contractures.

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 contracture, is the factor that makes the greatest contribution to the loss of functional ambulation.

With regard to scoliosis, there does not appear to be an etiologic relation with loss of ambulation. Although both scoliosis and wheelchair dependence are age-related, several studies have found there to be no relation between the 2 phenomena. A large study by Lord et al reported an almost 4-year difference between wheelchair dependence and the onset of significant scoliosis in patients with DMD.^[36]

Indeed, many DMD and SMA II patients develop scoliosis before becoming 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 hard to measure quantitatively. In NMD patients, scoliosis did not appear to correlate with trunk strength on manual muscle testing (though this method cannot measure asymmetric strength and is not a reliable strength-assessment method in this population).

Patients with DMD typically develop scoliosis around the time of the adolescent growth spurt.^[37] 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.

Spinal bracing has not been shown to be effective in preventing progression of neuromuscular scoliosis (though most studies involved patients with SMA). Thus, spinal instrumentation and fusion is the only treatment option known to be effective. This should be performed before the primary curve exceeds 25° and FVC has not dropped below 50% of predicted. Complications substantially increase if the patient already has compromised breathing.

Unfortunately, correction of the scoliosis with fusion does not appear to improve pulmonary function.^[38] Nonetheless, fusion does improve quality of life (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 of bracing 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.

Furthermore, 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 a knee-ankle-foot orthosis is generally needed because of the amount of weakness in hip and knee extension, as well as in ankle plantar flexion and dorsiflexion.

Most patients with CMT require short leg braces or ankle-foot orthoses. Ideally, these should be custom-made with a lightweight polymer (polypropylene or carbon fiber). They should fit intimately to prevent 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 (ie, should 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. After being fitted with braces, patients with NMDs should be referred for a course of physical therapy 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 (see above), studies involving patients with NMDs have shown elevated scores for depression on MMPI 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.

The possibility that other family members and caregivers may also become depressed 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.^{[39, 40]}

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 have a significant effect on 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.

NMD patients are incredibly diverse, and this may be why very few studies have attempted to determine the effect of NMDs on QOL. The studies that have been done were criticized for lumping together many differing NMDs in a poorly defined study group and for mainly using generic instruments to define QOL. Thus, these studies rarely used clinically meaningful data on physical and emotional functioning; they focused on the extreme manifestations (eg, 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), have been developed specifically for NMD patients. These disease-specific measures are especially useful for evaluating patients’ QOL and psychosocial functioning as their NMD progresses. Beyond ALS, there has been a dearth of studies using QOL measurements to study NMDs.^[41] This is an area where further investigation is strongly warranted.

Equipment

Proper equipment can significantly improve QOL for NMD patients. Common examples of equipment include hospital beds, commode chairs, wheelchairs and wheelchair ramps, handheld showers, bathtub benches, grab bars, raised toilet seats, and many others. An occupational therapist is best qualified to help determine whether any of these devices would be useful for a patient with an NMD.

Wheelchairs are a critical component of mobility for people with NMDs. They must be fitted with the appropriate frame size, type of seat, lumbar support, and cushioning to avoid pressure ulcers. They should be equipped with other mechanical accessorial devices (eg, tilt ability) to provide comfort and to protect the skin. A physical or occupational therapist should evaluate the patient to ensure a proper wheelchair prescription. Patients who are simply given a prescription for a wheelchair often get a chair that fits poorly or lacks 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 power wheelchairs are expensive, they can be justified to third-party payers on the grounds 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 (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, a word board, or a computer-based speech synthesizer, can be very helpful for maintaining functional communication. A speech language pathologist is best qualified to determine which, if any, of these devices would work best.

Major molecular, physiologic, and pharmacologic advances have occurred in the field of NMD research over the past few years. Stem cell therapy holds some promise for replacing diseased nerve and muscle. However, clinicians and patients should be aware that stem cell treatment would not cure most NMDs, because it would not correct the underlying genetic defect. Nevertheless, growing new nerve or muscle tissue through stem cell therapy may improve function substantially.

In fact, these diseases may be treatable with genetically modified (corrected) stem cells, which would not only improve function but also partially correct genetic abnormalities. Increased understanding of the molecular basis of many NMDs has enhanced diagnostic accuracy and the ability to perform prenatal diagnostic screening, as well as provided the groundwork for therapeutic intervention. Techniques are being developed for gene insertion and DNA repair using a number of vectors (eg, gutted viruses). This approach may ultimately lead to a true cure.

Functional imaging of nerve and muscle has improved significantly, particularly in the field of magnetic resonance imaging (MRI). This has helped facilitate more accurate and earlier diagnoses of NMDs (see the image below).

The interfacing of biomedical engineering and computer science continues to provide NMD patients with better equipment and improved QOL. This progress has raised the expectations of patients, even those with severe NMDs, who now expect to enjoy a more functional, mainstream life. Using the comprehensive treatment paradigms described in this article will help clinicians fulfill these expectations.