Myopathy

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35 Myopathy

In the evaluation of patients with suspected myopathy, molecular genetics has supplanted the need for electrodiagnostic (EDX) studies or muscle biopsy in many patients with inherited conditions. Moreover, in patients with suspected myopathy and no evidence of an inherited condition, a muscle biopsy ultimately will be required for definitive diagnosis, regardless of EDX studies. Despite these facts, EDX studies, especially the needle electromyography (EMG) examination, continue to play an important role in the evaluation of patients with suspected myopathy (Figure 35–1). EMG can often confirm the presence of a myopathy, as well as add diagnostic information if certain types of spontaneous activity are present. For example, fibrillation potentials and positive sharp waves in a myopathy suggest the possibility of inflammation or necrosis, whereas myotonic discharges suggest one of the myotonic muscle or periodic paralysis disorders (see Chapter 36), acid maltase deficiency, myotubular myopathy, or certain toxic myopathies. Additionally, EMG may be helpful in suggesting alternate diagnoses that can mimic myopathy clinically.

EMG can also be useful in directing the site for a muscle biopsy in a patient with a myopathy. The EMG examination has the advantage that multiple muscles and sites can be sampled easily and often can suggest a suitable muscle to biopsy. It is always desirable to biopsy an unequivocally abnormal muscle yet one that is not end stage. However, biopsy is always recommended on the side contralateral to the EMG examination (see later).

Although the EMG examination may yield valuable information in the evaluation of suspected myopathy, mild cases may be especially difficult to interpret. Some myopathies, including steroid myopathy, may have minimal or no changes on EMG. In addition, some disorders of the neuromuscular junction (NMJ) may present with very similar clinical and EDX findings. Close attention to clinical detail, and often further EDX studies, including repetitive nerve stimulation and single-fiber EMG, may be required to differentiate between a myopathy and NMJ disorder.

Clinical

Myopathies present as pure motor syndromes without any disturbance of sensory or autonomic function. In most myopathies, symptoms tend to be bilateral and affect proximal muscles preferentially. Patients usually complain of difficulty rising from chairs, going up and down stairs, or reaching with their arms. Although most myopathies are symmetric and proximal, there are exceptions to both. For example, inclusion body myositis (IBM) and facioscapulohumeral muscular dystrophy may be very asymmetric. Myotonic dystrophy, distal hereditary myopathy, and IBM may preferentially affect distal more than proximal muscles. In some myopathies, ocular and bulbar muscles may be affected. Deep tendon reflexes are generally preserved or, if reduced, are in proportion to the degree of muscle wasting and weakness.

In evaluating a patient with suspected myopathy, it is important to determine whether symptoms are exercise induced. Such symptoms may manifest as fatigability, exercise-induced muscle cramps, or swelling. Patients who present with exercise-induced muscle cramps (see later) may develop frank weakness, swelling, and, if severe enough, myoglobulinuria. These latter symptoms suggest an inherited disorder of muscle energy metabolism. Note that although fatigability is certainly common in myopathies, frank muscle weakness that develops with exercise over a short period of time, if not accompanied by cramps, suggests a disorder of the NMJ rather than a myopathy. Additionally, patients with Lambert–Eaton myasthenic syndrome (LEMS) and some rare patients with myasthenia gravis (MG) present with isolated proximal muscle weakness mimicking a myopathy. In addition, adult onset spinal muscular atrophy, including X-linked bulbospinal muscular atrophy, usually presents with proximal muscle weakness and mimics the typical pattern of a myopathy.

Disorders of muscle can be simplified into the following categories: (1) muscular dystrophies, (2) inflammatory myopathies, (3) endocrine associated myopathies, (4) drug-induced and toxic myopathies, (5) metabolic myopathies, (6) congenital myopathies, and (7) myopathy associated with periodic paralysis.

Muscular dystrophies are inherited muscle disorders characterized by a progressive course and often an early onset, usually with a specific clinical and muscle biopsy pattern. In recent years, the chromosomal abnormality or specific gene product (e.g., dystrophin in Duchenne and Becker muscular dystrophy) has been discovered in several of these disorders. The more common muscular dystrophies include myotonic dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, Emery–Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, and limb girdle muscular dystrophies.

Inflammatory myopathies are associated most commonly with a presumed immunologic attack and include polymyositis (PM), dermatomyositis (DM), and IBM. Other types of inflammatory myopathy include those caused by muscle infection by parasites, viruses, or bacteria.

Endocrine myopathies are often seen in disorders of the thyroid and adrenal glands. In addition, myopathy can accompany some cases of acromegaly and parathyroid disease.

Drug-induced and toxic myopathies are becoming increasingly common. Examples of common drug-induced and toxic myopathies include those caused by steroids, alcohol, colchicine, azidothymidine (AZT), clofibrate, and many of the cholesterol-lowering agents.

Metabolic myopathies are disorders of muscle resulting from inherited enzyme deficiencies important in intracellular energy production. They may present in one of three ways: (1) as cramps and myoglobinuria, (2) as part of a more diffuse neurologic syndrome, often involving the central nervous system, or (3) as a typical clinical proximal myopathy. In patients with cramps and myoglobinuria, the genetic defect often is found either in the glycogen or lipid metabolism pathways. These patients may be completely normal at rest but become symptomatic during or after exercise. In patients with disorders along the lipid pathway, symptoms commonly occur after an episode of long or forced exercise (e.g., a long march or mountain climbing). In patients with disorders along the glycogen pathway, symptoms commonly occur after brief, intense isometric exercise. Muscle aches and fatigue may begin during the exercise, followed by frank myoglobinuria. Headache, nausea, and vomiting may occur. Muscles become painful and swollen. The creatine kinase (CK) level often is dramatically elevated into the thousands. The most common of these are caused by a deficiency of carnitine palmitoyltransferase (CPT) along the lipid pathway and myophosphorylase (McArdle’s disease) along the glycogen pathway. Patients with defects in mitochondrial metabolism often present with a myopathy, as well as abnormalities involving other systems, including the central nervous system. Short stature, hearing loss, seizures, cardiac abnormalities, learning disabilities, and stroke-like episodes are common. Lastly, some rare defects in metabolism (i.e., carnitine or acid maltase deficiency) may present as a typical clinical slowly progressive myopathy with proximal weakness.

Congenital myopathies are a group of myopathies in which each disorder has a fairly specific muscle biopsy finding on histochemical staining (e.g., nemaline rods, central cores, fiber type disproportion, myotubular myopathy). Typically, hematoxylin and eosin paraffin staining is normal or nonspecific. Although most patients present in the first few years of life, an occasional patient with a congenital myopathy presents in adulthood with one of these disorders. The clinical syndromes are nonspecific and tend to be slowly progressive or static. Muscle biopsy usually is needed for definitive diagnosis.

Myopathy associated with periodic paralysis occurs in the setting of hypokalemic and hyperkalemic periodic paralysis (see Chapter 36). Patients develop proximal weakness in the fifth or sixth decade. Even those patients with hypokalemic periodic paralysis who have never experienced episodic weakness, a common scenario in affected females, invariably will develop a proximal vacuolar myopathy in adulthood.

Electrophysiologic Evaluation

Nerve Conduction Studies

Routine nerve conduction studies should always be done in patients with suspected myopathy (Box 35–1). Sensory nerve conduction studies are always normal, unless there is a coexistent neuropathy. Because most myopathies preferentially affect proximal muscles and routine motor nerve conduction studies record distal muscles, motor nerve conduction studies are also usually normal. If the myopathy is severe enough to affect distal and proximal muscles or is one of the rare myopathies that preferentially affects distal muscles, motor studies may show decreased compound muscle action potential (CMAP) amplitudes with normal latencies and conduction velocities.

The major reason nerve conduction studies must be performed is to exclude other motor disorders that may mimic myopathy (Box 35–2). Other than myopathy, pure motor disorders include motor neuron disease, rare cases of demyelinating polyneuropathy, and NMJ disorders. The nerve conduction studies in motor neuron disease and myopathies that affect distal muscles may be very similar. Differentiation is made based on the associated clinical features and needle EMG findings. Nerve conduction studies can easily differentiate demyelinating polyneuropathy from myopathy by the presence of conduction block or temporal dispersion, marked slowing of distal latencies and conduction velocity, or a combination of these findings.

Disorders of the NMJ present more of a challenge. NMJ disorders may present with proximal muscle weakness similar to myopathies. Postsynaptic disorders (e.g., MG) typically have normal CMAP amplitudes at rest. To demonstrate the NMJ abnormality, slow (3 Hz), repetitive nerve stimulation is required to demonstrate a decrement (see Chapter 34). Presynaptic disorders (e.g., LEMS) have a more characteristic nerve conduction pattern: CMAP amplitudes are low at rest with normal latencies and conduction velocities. Brief exercise (10 seconds) characteristically results in a marked increment of CMAP amplitude (typically >100% of baseline).

Electromyographic Approach

For the patient with suspected myopathy, the needle EMG examination must be individualized based on the distribution of the patient’s symptoms (Box 35–3). Overall, examining distal and proximal muscles in both the upper and lower extremities is indicated. Sampling the paraspinal muscles (the most proximal muscles) often is very useful. As most myopathies affect proximal muscles, the yield of finding abnormalities increases as progressively more proximal muscles are sampled. In adult-onset acid maltase deficiency myopathy, for instance, prominent changes may be seen only in the paraspinal muscles.

There are two other issues to keep in mind when performing EMG studies. First, measuring the serum CK immediately after the EMG examination probably is not wise. The CK level may rise slightly as a consequence of the EMG examination (typically 1.5× normal). The second issue is that of which muscle to biopsy, because patients with suspected myopathy often go on to muscle biopsy. The EMG can be very helpful in identifying an appropriate muscle to biopsy. One should biopsy a muscle that is abnormal but not at end stage. It usually is advisable to biopsy a muscle contralateral to the side sampled by the EMG needle. Because the EMG needle may induce transient inflammatory changes on the muscle biopsy, it is best not to biopsy muscles that have been sampled by the EMG needle. One would not like to diagnose an inflammatory myopathy and inappropriately place a patient on high-dose steroids based on spurious inflammation on a biopsy caused by the EMG needle.

Spontaneous Activity in Myopathies

Fibrillation potentials and positive sharp waves usually are associated with neuropathic disorders (i.e., neuropathy, radiculopathy, motor neuron disease). However, denervating potentials occur frequently in many myopathic disorders. They are thought to most likely occur as a consequence of segmental inflammation or necrosis of muscle fibers, separating a distal, healthy portion of the muscle fiber from the part attached to the endplate (Figure 35–2). Infarction of small intramuscular nerve twigs by surrounding interstitial inflammation also is speculated to be a possible cause of denervation in inflammatory myopathies. Although the presence of denervating potentials in a patient with myopathy often suggests the diagnosis of an inflammatory myopathy, denervating potentials can occur in a variety of myopathies (Box 35–4). In chronic myopathies, complex repetitive discharges may also be seen.