The muscle examination and assessment of posture is very important. Manual muscle testing can help determine the distribution and degree of weakness and also help track progression of disease. Hyperlordosis with proximal muscle weakness is seen in myopathies. Distal muscle atrophy and weakness is more common in neuropathies. Muscle hypertrophy, especially in the calves, is common in muscular dystrophies. It is also important to assess general muscular tone to determine whether there is focal or global hypotonia, especially in infants. Gait assessment is also important as there is the waddling gait of myopathies, the steppage gait of neuropathies with footdrops, the ataxic gaits in neuropathies with proprioceptive involvement, and the circumducted gait in spasticity.

Assessment of eye and eyelid movements is important in diagnosing the ophthalmoplegia with Miller-Fisher syndrome. Paralysis of the eyes and eyelids is often seen in diabetic ophthalmoplegia and in certain oculopharyngeal dystrophies. Fluctuating ptosis and eye tracking problems may be seen in myasthenia gravis. Facial weakness can occur in various diseases as in Guillain-Barré syndrome and myasthenia gravis. Tongue atrophy and fasciculations are seen in motor neuron disease as in ALS. Weakness in the truncal muscles, especially the neck, can cause a head drop secondary to cervical extensor weakness.

Aggressive rehabilitation and symptom management can help prolong life and improve quality of life for patients with neuromuscular disorders. Rehabilitation needs are best addressed in a multidisciplinary setting as rehabilitation is important in the management of musculoskeletal dysfunction, pulmonary complications, dysarthria, pain, psychiatric issues, and cognition. One of the goals in rehabilitation is to predict or stay ahead of the disease process and recommend corrective interventions in a timely fashion.

Rehabilitation and management of symptoms are approached in a problem-oriented manner. Prescribing exercise is important in the management of deficits related to mobility and activities of daily living. Therapies include strengthening exercises, stretching or flexibility exercises, aerobic conditioning, and balance training. Most studies of exercise in patients with neuromuscular disorders result in strength gains. However, it is not clear if these strength gains translate into a functional improvement (1).

An exercise prescription should include intensity, duration, and frequency of training sessions. Flexibility and range of motion (ROM) exercises will help prevent or reduce contractures from immobility. Strength training appears safe with a moderate-resistance strengthening program. The goal of a resistance program is to maximize the strength of the unaffected muscles and delay the onset of weakness in minimally affected muscles. With regard to aerobic training, most patients with neuromuscular disorders will have a normal cardiopulmonary response to aerobic training. Use of a treadmill or exercise bicycle is sufficient. The American College of Sports Medicine (ACSM) currently recommends 150 minutes of aerobic exercise per week (2). Balance training is important, especially in patients with neuropathy, and will help reduce falls. An exercise bicycle can be used as a mode of exercise in patients with poor balance.

Pain is common in patients with neuromuscular disease. With the exception of some neuropathic syndromes, pain is not inherent to the disease itself but rather to the effects of the disease on the neuromuscular system. Pain can arise from improper positioning, contractures, joint instability, and overuse injuries. Deconditioning, depression, and other concomitant health conditions can affect pain. Pain should be assessed and can be treated with various medications, physical therapy, acupuncture, massage, biofeedback, and modalities.

Progressive respiratory failure can not only impair quality of life but also decrease the life expectancy in many neuromuscular disorders including anterior horn cell disease, Guillain-Barré syndrome, and certain forms of muscular dystrophies and myopathies. Understanding the patient’s respiratory status is important as it will affect the patient’s ability to participate in rehabilitation programs. Using noninvasive ventilatory techniques (such as noninvasive positive pressure ventilation) may be part of the rehabilitation plan. Some patients may need an insufflator–exsufflator machine or manually assisted coughing devices to help clear secretions. Pulmonary management along with respiratory therapy services is important in a comprehensive rehabilitation program.

Dysarthria is a motor speech disorder that reduces speech intelligibility and can interfere with verbal communication. The goal of the rehabilitation program is to focus on independent communication and communication strategies. Techniques such as slowing speech rate, overarticulating consonants, and energy conservation may help. Palatal lifts and palatal augmentation prosthesis may help address hypophonia and hypernasality. If the dysarthria progresses, augmentative and alternate communication systems may be used. Patients with severe dysarthria and concomitant severe motor weakness may benefit from brain–computer interfaces.

Dysphagia results from weakness and incoordination of swallowing muscles. This can result in aspiration of food and water resulting in pneumonia, weight loss, and malnutrition. Identifying dysphagia is an integral part of the rehabilitation plan. Changes in the quality of speech (“wet voice”), drooling and leaking of fluids, choking, and recurrent pneumonias are signs of dysphagia. When dysphagia is present, a program of interventions and compensatory techniques can be employed to allow safe oral intake. Positional changes such as chin tucks, head turning to the side of weakness, or double swallowing may help. Dietary changes by thickening liquids and altering food consistencies may also help. Behavioral strategies include eating during times of maximal arousal and minimizing distractions. Using modified utensils such as built-up handles, universal cuffs, or balanced forearm orthoses can help in patients with weakness in the extremities, limiting the ability to bring the food to their mouth. As a last resort, if oral intake remains inadequate, then a gastrostomy tube can be used to allow adequate nutrition. The American Academy of Neurology recommends the placement of gastrostomy tubes for individuals with ALS while they can still tolerate oral intake and before the forced vital capacity (FVC) falls below 50% of predicted to reduce the complications associated with the procedure, compared to patients without severe respiratory compromise (3).

Cognitive dysfunction is common in certain NMDs such as in congenital muscular dystrophies, myotonic dystrophies, and mitochondrial myopathies. Rehabilitation management is important in identifying cognitive dysfunction and treating reversible contributors to cognitive impairments. Management should address medication management, sleep-awake cycle, and nutritional deficiencies. Multidisciplinary services such as speech-language therapy and psychology for patients and family may help with adjustment and long-term planning.

MEDICAL KNOWLEDGE

GOALS

Demonstrate knowledge of established and evolving biomedical, clinical, epidemiological, and sociobehavioral sciences pertaining to NMDs, as well as the application of this knowledge to guide holistic patient care.

NMD describes any intrinsic disease to the nerves or muscles. The motor unit is considered the smallest functional unit of the neuromuscular system. The motor unit is composed of a motor neuron and the skeletal muscle fibers innervated by that axon. Groups of motor units often work together to coordinate the contraction of a single muscle. Diseases of the neuromuscular system can be divided into diseases of the motor neuron itself, the peripheral nervous system, the NMJ, or the muscle itself.

MOTOR NEURON DISEASE

ALS is the most common adult-onset motor neuron disease, affecting 1.8 per 100,000 with the average age of onset around 60 years of age. It is usually a progressive and fatal disease with an average survival of 3 to 5 years. Most cases of ALS are sporadic (90%), where a small percentage are familial and usually inherited in an autosomal dominant fashion (4). ALS results from progressive deterioration of motor neurons involving mainly anterior horn cells of the spinal cord and certain motor neurons in the brain and brainstem. The result is a mix of UMN and lower motor neuron (LMN) involvement causing weakness, spasticity, cramps, and atrophy. Usually patients with ALS present with focal weakness or problems with fine motor skills. Weakness usually progresses and can result in respiratory failure. Bulbar involvement may result in dysarthria, hypophonia, and dysphagia. Extraocular motions, bowel and bladder function, sensation, and cognition are generally spared.

Diagnosis of ALS is based on the El Escorial criteria which require both UMN and LMN signs. Clinically definite ALS is defined by the presence of UMN as well as LMN signs in three regions (bulbar, cervical, thoracic, or lumbosacral). Clinically probable ALS is defined by the presence of UMN and LMN signs in at least two regions, with some UMN signs rostral to the LMN signs (5). However, approximately 25% of patients who die from an idiopathic, rapidly progressive motor neuron disease will never achieve a probable or definite diagnosis of ALS by the El Escorial criteria despite postmortem confirmation of UMN and LMN degenerations (4).

Currently there are no effective treatments that can reverse or stop the progression of ALS. The major goals in ALS are to slow down disease progression and maintain patient function. Riluzole has been shown to be the only disease-specific treatment that positively affects the natural history of the disease. At a dose of 50 mg twice a day, there was a modest benefit resulting in an approximate 10% slowing of disease progression. Approximately one-quarter of the patients do not tolerate the gastrointestinal side effects and the medication is extremely expensive. Median survival benefit was 60 days and no functional benefit was derived (6).

Spinal muscular atrophy (SMA) is an autosomal-recessive disorder that is linked to the abnormality of the survival motor neuron (SMN) gene on chromosome 5. SMA is characterized by diffuse weakness secondary to atrophy of the anterior horn cells/ventral nerve roots. Patients will have more truncal and proximal weakness. In general, there is no sensory or cognitive involvement. SMA is generally divided into three types depending on the severity and age of onset. Type I is known as Werdnig-Hoffmann disease where patients present with weakness before 6 months of age and are unable to sit anytime during their life. Infants often have difficulty moving against gravity and there may be a bell shape to the chest secondary to intercostal muscle weakness. Bulbar muscles are involved and infants may have difficulty with sucking and maintaining a patent airway. Life span is approximately 2 years. SMA Type II is a milder form of the disease with onset between 6 and 18 months. Depending on the severity of disease, patients may live into their adult years. Patients with SMA Type III, known as Kugelberg-Welander disease, can eventually stand and walk but still have profound weakness (7). Usually these patients require a wheelchair by 20 to 30 years of age. Some with Type III SMA can have near-normal life expectancies.

Postpolio syndrome (PPS) affects individuals with history of polio. Poliomyelitis is a viral infection that affects the anterior horn cells in the spinal cord. Patients who recover from the initial infection of polio may continue to have residual motor weakness. In PPS patients, previously affected muscles may present with new-onset weakness or pain after decades of stability. The current theory is that normal aging causes natural cell attrition resulting in dropout of large LMN units that have been working over their normal capacity for years (8).

NEUROPATHIES

Charcot-Marie-Tooth (CMT) disease is the most common genetically inherited neuropathy. It is also known as hereditary motor and sensory neuropathy and more than 300 genetic mutations have been described. CMT is generally initially painless with symmetric distal neuropathy. Onset is usually in the teenage to early adult years. Patients often present with a high arched foot with the toes flexed. Symptoms can progress to atrophy of the muscles below the knee described as looking like a stork or inverted champagne bottle. Weakness can also cause a claw hand, intrinsic wasting of the hands, and decreased fine motor skills. As the disease progresses, pain and paresthesias may become evident in the distal extremities. Genetic testing is available for some subtypes of CMT. Diagnosis is usually made by physical examination, family history, and electromyography (EMG) testing.

Acute inflammatory demyelinating neuropathy (AIDP), also known as Guillain-Barré syndrome, causes an acute generalized weakness with initial symptoms of distal numbness and areflexia/hyporeflexia. Usually a patient will experience an ascending paralysis and some patients may have respiratory compromise. Autonomic dysfunction is also common in some patients resulting in hypotension/hypertension and bowel/bladder dysfunction. Patients often will report a viral prodrome 2 to 3 weeks prior to onset of weakness. Campylobacter jejuni enteritis has been implicated as a trigger for AIDP. Cerebrospinal fluid (CSF) of AIDP patients shows increased proteins and low white blood cell counts (cytoalbumino-disassociation). Nerve conduction studies may show prolonged or absent F reflexes. Treatment includes medical stabilization and then treatment with plasmapheresis or intravenous immunoglobulin (IVIG). Chronic inflammatory demyelinating neuropathy (CIDP) manifests over weeks to months with weakness, loss of balance, and numbness. Similar to AIDP, CIDP patients will have reduced reflexes. Steroids and immunosuppressive medications may help with symptoms. Plasmapheresis and IVIG may be used if CIDP patients fail oral therapies.

Diabetic patients may present with a distal, symmetric sensory neuropathy usually resulting in decreased sensation and sometimes pain. Other nerve damages that may occur in diabetes include autonomic neuropathies, radiculopathies, and diabetic amyotrophy (lumbosacral plexitis). Medical treatment includes aggressive glycemic control and neuropathic pain medications.

Numerous other conditions can also cause neuropathies including drugs and occupational exposure. Alcohol abuse has also been linked to distal sensory loss, especially in the feet, with resulting balance deficits. HIV infection and related drug therapies along with coinfections may also result in numerous neuropathies. In the late stages of HIV, infection with the cytomegalovirus (CMV) may cause a rapidly progressive and often fatal polyradiculopathy (9).

NEUROMUSCULAR JUNCTION DISORDERS

Myasthenia gravis is an autoimmune disorder in which autoantibodies to the acetylcholine receptor at the postsynaptic NMJ cause destruction of the receptors. As a result, there are a reduced number of receptors and neuromuscular transmission is slowed. Use of medications that inhibit acetylcholinesterase (physostigmine, pyridostigmine) can increase concentrations of acetylcholine at the NMJ and help overcome this deficit.

Patients with myasthenia gravis experience slowed or failing NMJ transmission. This may result in weakness and fatigue of all muscles, especially with the ocular muscles. The disease can be fatal if respiratory muscles fail; thus, pulmonary function should be assessed during exacerbations (10). Early symptoms of myasthenia include ptosis and double vision secondary to ocular muscle weakness. As the muscles are activated, they tend to fatigue over a period of time. For example, patients may be able to enunciate well at first and then, as they talk more, the muscles weaken, resulting in worsening voice intelligibility. Approximately 10% of patients will have a thymoma; thus, imaging with chest x-ray (CXR) or CT scan is often indicated. Acetylcholine receptor antibodies can be identified in most patients. Specialized EMG testing with increased jitter on single-fiber EMG or a decremental response on repetitive stimulation at slow rates help confirm myasthenia gravis. Acute therapies include IVIG and plasmapheresis. Long-term management involves use of steroids, immunomodulators, and thymectomy.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune antibody mediated disease that prevents the presynaptic NMJ transmission by blocking the voltage-gated calcium channels needed for acetylcholine to release from the presynaptic junction. LEMS is often associated with small-cell lung cancer and other cancers and may appear years before clinically diagnosable cancer. Symptoms of LEMS usually involve weakness of the proximal legs and trunk, usually manifested by the inability to get out of a chair or negotiating stairs. Weakness is usually worse in the morning and gradually improves as the day progresses. This can also be seen on physical examination when initial muscle testing may show profound weakness, but with continued testing the muscles may gradually strengthen even to near-normal strength. This is called facilitation phenomenon and is seen in EMG when repetitive stimulation at high frequency produces a supramaximal response which is not seen in myasthenia gravis. Ocular findings such as double vision and ptosis are uncommon in LEMS patients but are common in myasthenia gravis patients. Treatment of LEMS revolves around treating the underlying neoplastic syndrome. IVIG and plasmapheresis are also used as adjunctive treatments (4).

DISEASES OF MUSCLES

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder involving the dystrophin gene. The incidence is approximately 1 per 3,500 male births with a prevalence of about 1 per 18,000 men. Dystrophin is important in the sarcolemmal cytoskeletal protein structure. Muscle biopsy usually demonstrates reduced or absent dystrophin on the sarcolemma. Serum creatine kinase (CK) levels are markedly elevated (50–100 times normal) at birth and peak at around 3 years of age. The serum CK levels decline approximately 20% per year as a result of decreasing muscle bulk (11).

Becker muscular dystrophy (BMD) is a less severe mutation to the dystrophin gene and can be distinguished from DMD by its slower rate of progression. The incidence of BMD is approximately 5 per 100,000. Children with BMD can have onset of disease at 5 to 15 years of age or even later. Patients usually are ambulatory past the age of 15 years. Approximately 50% of affected patients lose the ability to walk independently by the fourth decade. Cardiac abnormalities are similar to DMD. Life expectancy is reduced compared to the general population (4).

Limb-girdle muscular dystrophy (LGMD) is a group of muscular dystrophies that clinically resembles the dystrophinopathies except for the equal occurrence in men and women. The prevalence of LGMD ranges from 8 to 70 per million. Onset and severity of LGMD is variable and characteristically involves weakness of the hips and shoulders. The facial muscles, swallowing, and cognition are usually spared.

Facioscapulohumeral dystrophy (FSH) is an autosomal dominant disorder with an incidence of approximately 4 per million. It is generally a benign, autosomal dominant progressive disease that causes weakness in the face, shoulders, and upper arms. Weakness usually occurs between 3 and 44 years and can occur even later in life. The muscles of facial expression are usually affected early and FSH patients may have a horizontal smile and weak puckering of lips. Winging of the scapula with weakness of the triceps and biceps is common but with relative sparing of the deltoids. Life expectancy is near normal but some patients may require a wheelchair later in life. FSH muscular dystrophy is linked to the telomeric region of chromosome 4q35 (4).

Myotonic dystrophy type I (DM1) is an autosomal dominant disease that is linked to chromosome 19. The incidence is approximately 13.5 per 100,000 live births. DM1 can present at any age including infancy and results in limb weakness that begins in the distal extremities and can progress slowly to affect the proximal extremities. The neck flexors are affected early and atrophy and weakness of the facial and jaw muscles results in a “hatchet face” appearance. Many patients are not aware of their myotonia, but usually on examination there is delayed relaxation of the fingers after forceful hand grip. Percussion of muscle groups gives rise to a delayed relaxation. Associated manifestations include cataract, mild mental retardation, infertility, and cardiac arrhythmias/cardiomyopathy (12). Myotonic dystrophy type II (DM2) has also been described with more proximal weakness and less pronounced myotonia. Myotonic dystrophy is a multisystem, autosomal dominant disorder with associated cataract, testicular failure, glucose intolerance, and cardiac conduction defects.

Myositis includes polymyositis (PM) and dermatomyositis (DM). PM is a T-cell-mediated autoimmune disease that causes direct destruction of muscle. PM usually presents over weeks to months with a progressing fluctuating weakness of proximal muscles. In addition to fatigue, patients may have muscle pains, cramps, and dysphagia. PM can be confirmed with muscle biopsy and the treatment is usually with corticosteroid therapy. DM is an antibody-mediated autoimmune process that targets the small blood vessels, leading to necrosis and microinfarctions of muscles. DM manifests with a heliotropic discoloration of the upper eyelids. Gottron lesions, scaly erythematous eruptions, or red patches overlying the knuckles, elbow, and knees are characteristic for DM. Associated symptoms include fever, arthralgias, pain and tenderness, cardiac abnormalities, and gastrointestinal ulcers. Malignancy has been linked with patients diagnosed with dermatomyositis. Treatment is with corticosteroid and immunomodulatory therapy.

Inclusion body myositis is a slowly progressive weakness of the arms and legs. Weakness comes on over a period of months to years. It is an age-related disease with its incidence increasing with age and symptoms usually beginning after 50 years of age. Although rare, it is the most common acquired muscle disorder seen in people over 50. Muscle biopsy may show inflammatory cells invading muscle cells, vacuolar degeneration, or inclusions/plaques of abnormal proteins.

Metabolic myopathies are a group of rare hereditary disorders of deficient enzymes that results in impaired muscle energy metabolism. Metabolic myopathies include abnormalities in carbohydrate, lipid, and adenosine nucleotide metabolism. Acid maltase deficiency and McArdle disease (myophosphorlyase enzyme defect) are the common syndromes. Biochemical muscle testing can confirm the diagnosis. A deficiency in muscle enzyme can cause cramping, pain, and myoglobinuria with exercise (13).

Congenital myopathies occur at birth, usually result in hypotonia, and are usually nonprogressive. Examples of congenital myopathies include central core myopathy, nemaline rod myopathy, and centronuclear myopathy. The diagnosis is usually made by muscle biopsy.

REHABILITATION

The goal of neuromuscular rehabilitation is to maintain or improve strength, ROM, mobility, and activities of daily living. Educating both the family and patient is important. Rehabilitation is beyond just attending physical and occupational therapy sessions. Ideally, rehabilitation takes place daily and will require not only motivation from the patient but sometimes active participation of caregivers.

Rehabilitation is a team or holistic effort and will require multiple team players including the physical therapist, occupational therapist, recreational therapist, speech and language pathologist, psychologist, social worker, orthotist, nutritionist, and consult physicians. The physiatrist is responsible for designing a rehabilitation program that is accessible to the patient. The therapy prescription should include the diagnosis, frequency, and duration of therapy; description of treatments to be utilized; goals; and precautions. Part of the therapy is to train caregivers in providing continued care at home.

NMDs are often characterized by a gradual decline in motor function that can lead to severe respiratory compromise or even death. Caring for such patients involves the use of life-sustaining interventions. There are ethical challenges with regard to decisions to withhold and withdraw care. In providing care for patients the physician should follow the ethical principles of autonomy, beneficence, nonmaleficence, and justice (14). Autonomy is the basis for informed consent, allowing the patient to act without controlling influences. Beneficence is the duty of health care providers to be a benefit to the patient. Nonmaleficence is the duty that health care providers do not create needless harm or injury to the patient. Justice is a form of fairness that can involve allocation of limited resources. It is important to anticipate end-of-life issues early in order to allow the patient and family ample time to prepare. The physician should help the patient set up advance directives, designate a durable power of attorney, and plan end-of-life care. Some patients may refuse life-sustaining therapies such as a ventilator and these requests should be honored. Patient comfort and dignity are important, especially in a palliative care setting.