Neuromuscular Diseases
Daniel Weltsch, MD
Keith D. Baldwin, MD, MSPT, MPH
Dr. Baldwin serves as a paid consultant to or is an employee of Pfizer and Synthes Trauma and has stock or stock options held in Pfizer. Neither Dr. Weltsch nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.
Keywords: motor neuron disease; muscular dystrophy; myopathy; neuromuscular junction; neuropathy
INTRODUCTION
The nervous system in conjunction with the musculoskeletal system confers the ability to perform voluntary movements, maintain an erect posture, and perform activities of daily living. Neuromuscular diseases are pathological conditions that originate in either the musculoskeletal system, the nervous system, or the interface between the two. The clinical presentation of neuromuscular disorders may vary, as specific pathologies originate in different anatomic areas of the neuraxis, nervous system, neuromuscular junction (NMJ), or muscle tissue itself. These injuries can be progressive or static in nature. Additionally, host factors and medical treatment rendered may play a role in the phenotypical expression of the disease. There is a wide variety of neuromuscular disorders, and recent advances have been made in the understanding of the genetic basis of neuromuscular disorders. Diseases may possess congenital, developmental, or acquired etiologies. The impact on patients and families are burdensome, and as such, these conditions require an early establishment of an accurate diagnosis and multidisciplinary treatment planning. This chapter focuses on the pathological basis of these diseases (Figure 1) and the basic science relevant to the orthopaedic surgeon treating them.
ANATOMIC CONSIDERATIONS
NERVOUS SYSTEM
The nervous system is a complex network of intercellular communications that control and regulate many processes throughout the body. In broad generality, nervous functions may be:
1. Sensory—providing data about the outside world to the central nervous system for the organism to interpret its surroundings.
2. Motor—providing action potentials to muscles to allow the organism to locomote or perform tasks on its surroundings.
3. Autonomic—providing internal regulation of bodily maintenance functions such as heart rate, blood pressure, vascular tone, and internal temperature.
The nervous system is broken up into the central nervous system (brain and spinal cord) and peripheral nervous system (peripheral nerves and effector organs). The principal cell of the nervous system is the neuron. A neuron consists of a cell body where all genetic and metabolic activity takes place at, proximal signal-recipient processes (dendrites), and a distal elongation (axon) responsible for further transmitting electrical signals to other neurons or effector organs. There are several types of neurons differentiated by size and by insulation with myelin. Electrical signals travel faster in axons that are myelinated via a process known as saltatory conduction.
The myelin layout on the neuron is in segments. Between two myelin segments, areas named Nodes of Ranvier are found. Only these areas provide the surface for neuronal ion exchange. This specific layout in myelinated nerves leads to a faster propagation of action potentials, as sodium gradients are efficiently conducted to the Nodes of Ranvier. It is important to note that all motor neuron bodies exist within the central nervous system, whereas generally the peripheral nervous system is occupied by the axons which relay the signals of the central nervous system to effector muscles through peripheral motor nerves. In the case of the sensory and autonomic nervous systems ganglia exist in the peripheral nervous system, which contain clusters of relay neurons. Although this chapter will primarily concern itself with motor nerves, sensory loss and autonomic dysfunction are highly essential parts of disorders of the nervous system and have a significant impact on patient function, safety, and health.
The myelin layout on the neuron is in segments. Between two myelin segments, areas named Nodes of Ranvier are found. Only these areas provide the surface for neuronal ion exchange. This specific layout in myelinated nerves leads to a faster propagation of action potentials, as sodium gradients are efficiently conducted to the Nodes of Ranvier. It is important to note that all motor neuron bodies exist within the central nervous system, whereas generally the peripheral nervous system is occupied by the axons which relay the signals of the central nervous system to effector muscles through peripheral motor nerves. In the case of the sensory and autonomic nervous systems ganglia exist in the peripheral nervous system, which contain clusters of relay neurons. Although this chapter will primarily concern itself with motor nerves, sensory loss and autonomic dysfunction are highly essential parts of disorders of the nervous system and have a significant impact on patient function, safety, and health.
 FIGURE 1 Illustration demonstrating neuromuscular diseases geographic classification. |
MUSCULAR SYSTEM
Muscle in the human body can be skeletal, smooth, or cardiac. Smooth muscle and cardiac muscle are primarily governed by the autonomic nervous system and will not be covered extensively here. Skeletal muscle is a specific muscle type involved in voluntary movements and activities of daily living. Skeletal muscles are innervated by axons of motor nerves, which dwell
in the anterior horn of the spinal cord. Upon activation, the muscle fibers shorten across the axis of one or more joints producing motion. Nerves transmit their electrical action potential to muscles calcium-mediated chemical gates by way of the NMJ.
in the anterior horn of the spinal cord. Upon activation, the muscle fibers shorten across the axis of one or more joints producing motion. Nerves transmit their electrical action potential to muscles calcium-mediated chemical gates by way of the NMJ.
NEUROMUSCULAR JUNCTION
The neuromuscular junction (NMJ) is the conduit which bridges the nervous system and the muscular effector. This junction transforms an electrical impulse which can be conducted by the nerve to a chemical signal which is used by the muscle. Action potentials which propagate down a motor nerve terminate in the NMJ at the presynaptic terminal. This impulse activates calcium channels in the NMJ which in turn cause the release of acetylcholine (ACh) which binds to receptors in the cell membrane of the muscle. ACh receptor (AChR) activation results in depolarization of the muscle fibers and subsequent contraction (shortening) of the muscle.
DIAGNOSIS
HISTORY AND PHYSICAL EXAMINATION
History and physical examination are important with respect to diagnosis, treatment, and surgical planning for neuromuscular disorders. Upon presentation of a new patient with a neuromuscular finding, defining the onset of symptoms is critical. Acute weakness, facial droop, or loss of bowel or bladder function is highly concerning and warrants emergent diagnostic workup and potentially urgent or emergent intervention. Alternatively, findings or a time course that is more subacute may be worked up on a less urgent, elective outpatient schedule and time course. For concerning lesions which are slowly progressive, a neurology consult is often warranted to provide specific diagnostic and prognostic information which could be clinically useful to the orthopaedic surgeon. The pattern of “positive” (findings in addition to normal) and “negative” (missing or deficient factors from neurotypical function) symptoms along with pathologic reflexes is often helpful in localizing the lesion geographically as an upper motor neuron injury (brain and spinal cord), versus lower motor neuron (peripheral nervous system). Broadly, there are several differences (Table 1) between these groups. Localizing signs can additionally be used to estimate the site of the lesion and direct imaging and neurodiagnostic studies.
MUSCLE ENZYME STUDIES
Laboratory blood tests can be a clinically useful diagnostic modality in a variety of settings. Serum muscle enzyme assays are valuable indicators for muscle pathology. Serum creatinine kinase (CK) levels are elevated in the setting of muscle damage and necrosis and as such can be increased in a variety of syndromes such as rhabdomyolysis, compartment syndrome, dystrophinopathies, and even in direct trauma. CK concentrations are often more than 10 times higher than normal value in the presence of myopathies. However, in later stages as more muscle is replaced by fibrofatty infiltration, CK levels may decrease because not as much muscle tissue is available. In this setting, other enzymes may be measured but are often not as specific for muscle damage.
TABLE 1 Main Characteristics of Motor Neuron Diseases | ||||||||||||||||
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It is important to keep in mind that an elevated CK is highly nonspecific and indicates only that muscle has been damaged. As such it is not pathognomic for any specific condition. Contrarily, normal CK concentrations, especially in patients with decreased muscle mass or slowly progressive disease, do not rule out muscular myopathies. CK levels provide supportive data and should be considered in the context of the clinical picture and other diagnostic results.
ELECTROMYOGRAPHY AND NERVE CONDUCTION VELOCITY STUDIES
Electromyography (EMG) and Nerve conduction velocity (NCV) studies are highly useful diagnostic procedures that can help localize the site of a lesion and identify functionally working nerves and muscles from nonworking ones. Recognizing the patterns of activation and findings on EMG can assist in concluding the diagnosis.
MYOPATHIC DISEASES
Typically myopathies involve wasting of muscle and relative preservation of the nerve signal to that muscle. As such signal picked up by EMG will typically be lower amplitude, because of the lower amount of muscle available to activate. Increased frequency will be observed as well as decreased duration of signals and insertional activity. This is referred to as a “myogenic” pattern.
NEUROGENIC DISEASES
Neurogenic diseases such as polio or amyotrophic lateral sclerosis (ALS) involve loss of motor neurons, as such muscles
hypotrophy and the remaining motor units are forced to innervate a greater number of muscle fibers. Secondary to this, the amplitude of action potentials is larger with lower frequency and higher duration. Fibrillations can be detected by EMG-NCV studies and are noted in several neurogenic diseases.
hypotrophy and the remaining motor units are forced to innervate a greater number of muscle fibers. Secondary to this, the amplitude of action potentials is larger with lower frequency and higher duration. Fibrillations can be detected by EMG-NCV studies and are noted in several neurogenic diseases.
EMG is also useful after trauma to assess if a nerve is damaged or severed. Typically, an EMG is obtained 3 to 6 months after a nerve injury is identified to determine if reinnervation is occurring or if nerve reconstruction or tendon transfers are warranted.
IMAGING STUDIES
Imaging studies are critically important in the assessment of neuromuscular disorders. Imaging is more commonly obtained in the setting of acute neuromuscular complaints but can also be of prognostic value for diseases such as cerebral palsy where localizing the area of damage can be helpful to guide treatment. CT is commonly used in the acute setting of a traumatic brain injury (TBI) to identify bleeding and change in the degree of hematoma in the short term to guide neurosurgical management and gauge safety of other surgical interventions. MRI has a higher resolution for soft tissues and is the work-horse of imaging of the neuraxis. Typically, MRI is employed following a physical examination or other investigations, which suggest a lesion at a particular level of the neuraxis. MRI can then characterize the lesion to assist in neurosurgical or orthopaedic management of that condition.
MUSCLE BIOPSY
Muscle biopsy is a classic method for assessing muscle tissue via various histochemical stains. It is clinically useful in the setting of muscle pathology and dystrophinopathies. In many ways, genetic testing has replaced muscle biopsy as a diagnostic modality. Occasionally, in atypical presentations, a muscle biopsy is thought to be diagnostically useful. When performed, ideally the biopsy should be performed on a muscle which still functions. The biopsy should be taken from an area where the muscle has been undisturbed (ie, not recently tested with EMG, or treated with botulinum toxin, or other intramuscular injection). The vastus lateralis is a popular location for muscle biopsy. Histochemical staining may be employed to detect abnormal proteins and discern between different types of myopathies:
MYOPATHIC PATTERN
Myopathic patterns of staining may find muscle necrosis, degeneration, and fibrofatty infiltrate. Additionally, there may be an abundance of nuclei and infiltration of connective tissue.
NEUROPATHIC PATTERN
Muscles in neuropathic disease are often atrophied, but otherwise healthy fibers will be present as well; connective tissue infiltration is typically not seen.
INFLAMMATORY PATTERN
In myositis, an abundance of inflammatory cells will be observed, along with perivascular infiltrates and edema.
GENETIC STUDIES
Genetic testing is a newer modality of diagnosis which can be clinically useful in dystrophinopathies, Charcot-Marie-Tooth, and congenital syndromes in which neuromuscular disease is a component. The process generally involves obtaining a sample of DNA from the patient and amplifying the DNA, and then testing it against known disorders using assays. These tests are best to run in consultation with neurologic specialists. Several specific DNA mutations have been identified to be associated with expression of neuromuscular diseases and conditions. These tests are considered diagnostic for some diseases but are performed at highly specialized centers, and hence results can often take significant time to return.
EXAMINATION UNDER ANESTHESIA
Examination under anesthesia before surgery (typically as part of the same surgical episode) is a critically important part of the diagnostic matrix when planning surgery. It is difficult to assess muscle length while the patient is awake in patients with hypertonia, as such the examination under anesthesia provides the ability to evaluate muscle length in the absence of tone. This can help the surgeon gauge the “dose” of surgery and finalize the surgical plan.
GAIT ANALYSIS
Gait analysis has changed the way operational decisions are made in neuromuscular diseases in ambulatory patients. This tool is important both for surgical decision making and for measuring postoperative outcomes. Gait analysis commonly starts with an observational part and includes preexamination slow motion videotaping of the gait and a standardized physical examination. The recorded video can be archived for further longitudinal comparison. The standardized physical examination evaluates skeletal deformities and fixed muscular contractures, joint range of motion, muscle force, and muscle tone. Instrumented analysis forms the basis of modern gait analytics. It combines inputs from videotaping, using body markers, EMG electrodes, and pressure sensors simultaneously. These inputs are recorded and provide detailed information including gait kinematics and kinetics, spatiotemporal, and EMG data, that is further broken down into gait cycle time, speed and length characters, plantar pressure maps, multiplanar alignment, movement arcs, joint moments, and muscle recruitment patterns including timing and intensity activation of specific muscle groups. Gait analysis allows a better understanding of the mechanics of each
neuromuscular patient and assists in formulating a treatment plan to produce normal gait patterns with decreased energy expenditure.
neuromuscular patient and assists in formulating a treatment plan to produce normal gait patterns with decreased energy expenditure.
SPECIFIC DISEASES
MUSCLE DISORDERS
BACKGROUND
A disease of muscle tissue is termed a myopathy. Individual myopathies are rare. Myopathies are commonly divided into inherited diseases and acquired conditions. Inherited myopathies include conditions such as muscular dystrophies, mitochondrial myopathies, ion channel disorders, glycogen storage disorders, and fatty acid oxidation disorders. The acquired myopathies include inflammation (autoimmune) myopathies, infectious myopathies, endocrine myopathies, and myopathies associated with a toxic agent.
Muscular dystrophies have a prevalence of 19.8 to 25.1 cases per 100,000 people.1 These disorders are heterogeneous, and typically result in varying degrees and patterns of muscle weakness and degeneration of muscle tissue. The population, time of presentation, and severity may differ depending on the characters of the gene mutation and affected target protein (Table 2). The most common type of muscular dystrophies is dystrophinopathies including Duchenne and Becker’s dystrophy. The genetic mutation of both diseases occurs at the same location in the dystrophin (DMD) gene. The DMD gene is the largest gene yet identified in humans, and it includes the data to form a protein called dystrophin. Dystrophin is a cytoskeletal protein located on the inner (cytoplasmic) side of the myocyte membrane. It helps to stabilize the cellular membrane and links the actin cytoskeleton to the extracellular matrix. The presence of dystrophin prevents myocyte membrane from collapsing during a muscle contraction. When dystrophin is missing, the cellular membrane becomes weakened and compromised, leading to unregulated calcium influx that eventually leads to muscle cell necrosis. Other dystrophinopathies include limb-girdle muscular dystrophies, facioscapulohumeral muscular dystrophy, and Emery-Dreifuss muscular dystrophy.
DUCHENNE MUSCULAR DYSTROPHY
Duchenne muscular dystrophy (DMD) is a rare disease; however, it is the most common form of inherited muscle disease in childhood with an incidence of 1 in 3,500 live male births2 and prevalence of 1.7 to 4.2 cases per 100,000 people.1
Pathogenesis
DMD is an X-linked recessive disease, characterized by progressive deterioration of muscle mass in boys. In 70% to 80% of the cases a genetic link can be identified; the remainder of the cases are the result of “de-novo” mutation.3 Mutations in the DMD gene (Xp21.2) are most often caused by a deletion or duplication of a promoter region which leads to frameshift-type mutation and formation of nonsense dystrophin which undergoes rapid degradation. The result of this mutation is an absence (or insufficient levels) of dystrophin protein in muscle tissue. This lack of function results in the inability to shield muscle from mechanical stress during repeated contractions. As such the cell membrane becomes disrupted leading to cell death. At the tissue level, the repeated breakdown of cellular integrity leads to prolonged inflammation process and ultimately fibrosis and fat deposition of the muscles. Dystrophin protein is also found in cardiac muscle tissue; therefore, DMD patients are at risk for dilated cardiomyopathy.
Clinical Presentation
In the first few years of life, muscle regeneration is excellent; however, as the child ages, muscle tissue degeneration outpaces their ability to replace it. This is particularly true in proximal muscles. The first symptoms usually appear between 2 and 3 years of age. The symptoms may include flat feet, delay in motor milestones including walking, pseudohypertrophy of the calves, balance issues, and clumsiness. The so-called “Gower’s” sign is present when the child uses his hands to push up off the legs to aid the weak legs in standing. The plurality of patients will achieve the ability to walk; however, gait is characterized by a broad base of support, and toe walking is common. Flexion contractures of hips and knees and equinus contractures of the ankles are common as weakness progresses, eventually leading to the patient being restricted to a wheelchair. Hip flexion contractures will lead to lumbar hyperlordosis and scoliosis. Proximal muscle weakness in the upper limbs is manifested by difficulty with shoulder elevation during feeding. Cardiac and respiratory failure will ultimately lead to the patients’ demise typically in the third decade of life.
Diagnosis
A high index of suspicion of DMD should arise in cases of unexplained increase in serum transaminases, a positive family history in the setting of abnormal muscle function, or a delay in walking beyond age 16 to 18 months. CK levels can serve as a screening test. The confirmation of DMD is usually made through genetic testing. The majority of cases (70%) are due to duplication or deletion in the gene that codes for dystrophin.4 In other instances, genetic sequencing is performed to screen for less common mutations. Finally, if a diagnosis cannot be made with genetic testing, a muscle biopsy should be obtained for further testing.
Management
The general goals for the management of DMD patients are the preservation of function, maintaining bone health, and reducing contractures. The orthopaedic surgeon’s role is to assist neurology and physical medicine by providing assessment and treatment of contractures, scoliosis, fractures, and optimization of bone health. Lengthening of muscles to produce braceable feet to preserve ambulatory function is critical as it can potentially decrease the rate of obesity and osteoporosis which is seen in later stage disease.
TABLE 2 Dystrophies Pathogenesis Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Disease severity dictates treatment methods. Ambulatory patients use orthoses to facilitate walking assist during longer distances; contractures (mostly of the ankle) are addressed by surgical lengthening followed by casting and physical therapy. Administration of long-term corticosteroids has been shown to improve muscle strength, delay the loss of ambulation, preserve upper limb and respiratory functions, and decrease the need for spinal fusion for scoliosis.5,6 In nonambulatory patients, great effort is directed at maintaining joint range of motion. Physical therapy and orthoses are used to delay the onset of contractures. Contractures of the lower limbs are addressed to maintain comfortable sitting and free movement of hip and knee joints. Scoliosis is addressed early with posterior spinal instrumented fusion to sustain an upright posture and decrease the work of breathing. In contrast to other disorders, spinal fusion is often encouraged much earlier in DMD than other disorders (as early as 20°) because of the natural history of cardiopulmonary decline shortly after scoliosis presents.
Pharmacological treatments including corticosteroids have been used in DMD patients in the last decade with great success. They have revolutionized the treatment of Duchenne’s boys and prolonged their lives and in some cases their independence.5 Theoretically, steroids may have an anti-inflammatory effect, which delays the muscle degeneration process while not explicitly addressing the underlying pathology.3 However, these medications can exacerbate osteoporosis in these patients. Fractures are extremely common, particularly as the disease progresses. More recently with a better understanding of the genetic pathogenesis, the goal of treatment has been directed toward of mutation-specific drugs. Examples include ataluren and eteplirsen. Ataluren targets a stop codon in the mature mRNA of the dystrophin gene; it blocks the stop codon and allows mRNA translation to be completed, so a functional protein is produced. Eteplirsen specifically recognizes exon 51 in the pre-mRNA sequence (which become the stop codon on mRNA); by binding the pre-mRNA it changes the splicing process allowing mRNA-reading to become in-frame and allows a functional protein to be formed.
Cardiac and pulmonary function should be assessed in DMD patients. Cardiologists and Pulmonologists are critical members of the team particularly in its later stages where patients experience such multisystem organ decline. Consultation with these specialists is vital before surgery because of the limited pulmonary reserve. Additionally, malignant hyperthermia is associated with muscle disease, so vigilance on the part of anesthesia and the surgical team is needed.
BECKER MUSCULAR DYSTROPHY
Becker muscular dystrophy (BMD) is the second most common type of dystrophinopathy, and its prevalence is estimated to be 0.4 to 3.6 cases per 100,000 people.1 It is a recessive, X-linked disease with a milder phenotypic expression than DMD. The mutation in BMD leads to a production of a shorter dystrophin protein with varying degrees of functionality. The severity of the disease depends on the quantity of functional dystrophin protein in the muscle cells. In contrast to DMD patients, BMD patients remain ambulatory until a mean of 27 years and survive into their fifth decade. Laboratory analysis shows moderately elevated CK levels, but genetic testing is the mainstay of confirmation of the disease. The goals of orthopaedic treatment are similar to DMD, but treatment is generally initiated later.
LIMB-GIRDLE MUSCULAR DYSTROPHIES
Limb-girdle muscular dystrophy (LGMD) refers to a group of genetic muscle disorders characterized by reduced or absent expression of specific muscle proteins (eg, sarcoglycans). The estimated prevalence of LGMD is 0.9 to 2.3 cases in 100,000 people.1 It is common to divide the diseases based on the pattern of inheritance into autosomal dominant and autosomal recessive types. Currently, there are eight subtypes of LGMD type 1 (AD) and 26 subtypes of LGMD type 2 (AR). Type 2 variants are more common than the type 1 variants.7
Clinical Presentation
LGMD can be expressed in both genders. It mostly affects shoulder or pelvic girdle muscles with a phenotypic variation which depends on the type and severity of deficiency of the protein. As such the onset and the severity of disease, as well as the rate of progression, vary between different subtypes of LGMD. The disease onset is at the late first or second decade of life. Weakness and muscle wasting are the hallmark features. The upper limb muscles usually involve the trapezius, rhomboids, latissimus dorsi, serratus anterior, and the pectoralis major, whereas lower limb muscles mostly include the iliopsoas, gluteus maximus, and the quadriceps muscles.
Management
In the past, LGMD had been considered to be untreatable. Nowadays, molecular-based treatments are being developed to target genetic mutations; however, they are still in clinical trials stages. Orthopaedic management consists of supportive care with mobility aids, bracing treatment, and therapy.
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY
Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease and is the third most common muscular dystrophy with a prevalence of 3.2 to 4.6 cases per 100,000 people.1
Pathogenesis
FSHD-related mutations primarily affect DNA packaging, leading to exposure of normally silenced genes and their translation into abnormal proteins that damage the muscle. FSHD type 1 (70% to 90% of cases) is autosomal dominant, and it is associated with mutations on chromosome 4. The mutations cause a reduction in the number of copies of a repeated region named D4Z4. D4Z4 has a crucial effect on silencing genes that are toxic to skeletal muscle, that is, DUX4 (double homeobox 4) retrogene. Upon alteration in the number of D4Z4 regions, DUX4 may be translated. FSHD severity usually depends on the amount of DUX4 transcribed.8 FSHD type 2 is sporadic, and the related de novo mutations are associated with a packaging protein named SMCHD1, which lead to transcription of muscle-toxic proteins.
Clinical Presentation
Symptoms typically begin between the first and third decade. Weakness begins in the facial muscles with a typical presentation being difficulty drinking through a straw. Weakness progresses to the shoulder girdle (trapezius) and arms (biceps, triceps, pectoral). A winged scapula is a common report. Footdrop is also quite common and may be a presenting report. The Beevor sign which is an upward movement of the umbilicus with neck flexion is characteristic of FSHD. Other symptoms may include an absence of eye and forehead wrinkles, incomplete eye closure (seen mostly during sleep), transverse smile, difficulty with whistling. Extra-muscular manifestations include atrial arrhythmias, sensorineural hearing loss, retinal telangiectasias, restrictive respiratory disease, and seizures. People diagnosed with FSHD usually live a normal lifespan. Diagnosis is mostly at a clinical and genetic level because CPK levels are typically normal.
Management
There are currently no pharmacological disease-modifying treatments in FSHD. Nonpharmaceutical interventions that can be offered include physiotherapy to maintain strength and range of motion of affected muscles and ankle-foot orthoses (AFO) for patients with footdrop. Surgical intervention is primarily targeted at the shoulder girdle as scapulothoracic fusion can improve the elevation of the upper extremities.”
EMERY-DREIFUSS MUSCULAR DYSTROPHY
Emery-Dreifuss muscular dystrophy (EDMD) is a rare inherited condition with a prevalence of 0.1 to 0.4 cases per 100,000 people.1
Pathogenesis
EDMD primarily affect the production of proteins associated with the nuclear membrane of cells in both skeletal and cardiac muscles.9 The mutation affects the EMD gene and in turn the production of the protein called Emerin, an inner nuclear membrane protein which helps anchor the cell membrane to the cytoskeleton. Although ubiquitous, Emerin is more highly represented in skeletal and cardiac muscle. The LMNA is also associated with both the autosomal dominant and recessive types of EDMD. LMNA contains the codes for the production of lamin-A and lamin-C which are intermediate filaments in the nuclear membrane and nucleoplasm of most cells and contribute to the nuclear shape. They are essential for DNA replication and mRNA transcription.
Clinical Presentation
EDMD presents in the second decade. It is a slowly progressive disease in which contractures and weakness are prevalent and primarily affect muscles of the arms, legs, and neck. Patients usually are able to walk up until the fifth decade. Scoliosis may be seen and often characterized by slow progression of curves. Cardiac arrhythmias are common and sudden cardiac death is a frequent cause of mortality.
Management
No specific treatment exists for EDMD. Bracing treatment, physical therapy, or orthopaedic surgery can mitigate some of the effects of the contractures on walking and function.
DISEASES AT THE LEVEL OF THE NMJ
MYASTHENIA GRAVIS
Myasthenia gravis (MG) is an autoimmune disorder affecting the NMJ. Prevalence is estimated between 10 to 20 cases per 100,000 population in the United States.10
Pathogenesis
Myasthenia gravis is caused by antibodies directed mainly against postsynaptic acetylcholine receptors (AChRs). Although ACh is released from the nerve in normal concentration, a relatively decreased concentration of AChRs present on the end plate muscle membrane (because of auto-destruction of AChRs) leads to interference of neuromuscular transmission. In about 15% of patients with myasthenia gravis, AChR antibodies are absent, and these patients may have antibodies against other NMJ proteins, such as muscle-specific kinase (MuSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane.11
Clinical Presentation
MG follows a typical bimodal age and gender pattern, with one peak in young females around age 30 and another peak in population (mostly males) at age 50, followed by a steady rise in incidence as age increases.12 MG presentation includes painless fatigue and muscle weakness. Weakness may be fluctuating and generally gets worse with exertion and increased repetitive muscle use (“end of day weakness”). Weakness distribution may vary: about two-thirds initially present with ocular symptoms (ptosis and miosis). Bulbar fascial symptoms (dysphagia, dysarthria, reduced facial expression) and proximal muscles weakness of limbs may also occur. About 75% of patients will develop generalized weakness, mostly within the first 2 to 3 years following the initial presentation.10 MG exacerbations are commonly triggered by an infection, increased emotional stress, sudden decrease in MG treatment (steroids), warmer environment temperature. Thymoma is associated with myasthenia gravis, 30% to 60% of thymomas are associated with myasthenia gravis, and about 10% of patients with MG have a thymic tumor.11 Although it is more common in younger patients, all MG patients should be screened with mediastinal imaging (CT or MRI). Thymomas have slow growth pattern, but also have an increased ability to invade locally and metastasize regionally. Surgical removal is the mainstay of treatment mainly in younger patients, and adjuvant radiation is recommended for invasive thymoma.13
Management
Oral anticholinesterase (pyridostigmine) is the first-line treatment for symptomatic relief. Second-line treatment includes corticosteroids. It is more effective in earlier phases of the diseases and should be started as a low dose with a gradual increase by need. Azathioprine suppresses the inflammation process, but its response is slow, so it is typically used as an adjunct to steroids. Cyclosporine, methotrexate, and cyclophosphamide can be useful for those who do not respond to or cannot tolerate azathioprine.11
Myasthenic Crisis
Myasthenic crisis is a term describing respiratory failure caused by weakness of respiratory musculature. Forced vital capacity (FVC) is critically reduced on pulmonary function testing. The treatment is based on supportive measures including intubation and mechanical ventilation, as well as an intense immune suppression with high-dose steroids or intravenous immunoglobulin. In extreme cases, plasmapheresis may be used. Early diagnosis and treatment make this condition fully reversible.
DISEASES LEVEL OF THE LOWER MOTOR NEURON
BACKGROUND
The nervous system employs a sequence of motor neurons to carry out signals from the brain to the skeletal muscle cells. This, in turn, causes muscles to contract, which effects the movement of joints. A hierarchical description is commonly used to describe this sequence in the motor nervous system. This description is useful clinically albeit somewhat oversimplified. This system though useful ignores the neurons in the premotor area along with the delicate interplay of posture, balance, and lower brain function, which all serve to modulate motor nerve function. For the purposes of this chapter, the lower motor neuron is the second-order neuron. The body of a lower motor neuron is located in a motor nucleus in the anterior horn of the spinal cord. Upon activation, the lower motor neuron then transmits its signal via its projecting axon bundled in a peripheral nerve to its designated set of muscle fibers leading to muscle activation.
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