Color Atlas of Neurology

Myopathic Syndromes

Myopathies are diseases of muscle. Many different hereditary and acquired diseases attack muscle, sometimes in combination with other organs. The diagnosis and classification of the myopathies have been transformed in recent years by the introduction of molecular biological tests for the hereditary myopathies, but their treatment remains problematic. The management of the hereditary myopathies currently consists mainly of genetic counseling and the attempt to provide an accurate prognosis.

!Symptoms and Signs (Table 64, p. 397)

Weakness (p. 52) is the most common sign of myopathy; it may be of acute, rapidly progressive, or gradual onset, fluctuating, or exerciseinduced. It may be local (restricted to the muscles of the eye, face, tongue, larynx, pharynx, neck, arms, legs, or trunk), proximal, or distal, asymmetric or symmetric. Myalgia, muscle stiffness, and muscle spasms are less common. There may be muscle atrophy or hypertrophy, often in a typical distribution, whose severity depends on the type of myopathy. Skeletal deformity and/or abnormal posture may be a primary component of the disease or a consequence of weakness. Other features include acute paralysis, myoglobulinemia, cardiac arrhythmia, and visual disturbances.

!Causes

For a list of causes of hereditary and acquired myopathies, see Tables 65 and 66, p. 398.

! Diagnosis (Table 67, p. 399)

The myopathies are diagnosed primarily by history and physical examination (p. 52). Pharmacological tests are used for the differential diagnosis of myasthenia. Neurophysiological studies are used to rule out neuropathy (p. 391), to determine the specific type of acute muscle change, or to identify disturbances of muscular impulse generation and conduction. Various laboratory tests are helpful in myopathies due to biochemical abnormalities; imaging studies of muscle aid in the differential diagnosis of atrophy and hypertrophy. Muscle biopsy is often needed for a definitive diagnosis. Molecular biological studies are used in the diagnosis of hereditary myopathies.

Sympathetic trunk

Myelinated nerve fiber

Neuromuscular synapse (motor end plate)

Muscle fiber

Connective Blood tissue vessel

Lack of head and trunk control (congenital myopathy)

Spinal nerve

Thinly myelinated nerve fibers

Nerve fiber bundle

Blood vessel

Structures involved in neuromuscular disturbances

Weakness in pelvic girdle and thigh (Gowers’ sign)

Myotonic reaction (adduction of thumb on thenar percussion)

Congenital Myopathies

The typical pathological findings on muscle biopsy distinguish this group of disorders both from the congenital muscular dystrophies and from muscle changes secondary to peripheral neuropathy. Some congenital myopathies have distinctive clinical features. Proximal flaccid weakness is usually present at birth (floppy baby); skeletal deformities may also be seen (e. g., high palate, hip luxation, pes cavus, chest deformities). Many congenital myopathies progress slowly, causing little or no disability; the CK and EMG may be only mildly abnormal, or not at all. Some types can be diagnosed by genetic analysis (Table 70, p. 402).

Metabolic Myopathies

In most metabolic myopathies (Table 71, p. 402 f), exercise induces myalgia, weakness, and muscle cramps, and myoglobinuria. Progressive proximal weakness is seen in myopathy due to acid-maltase deficiency (glycogen storage disease type II), debrancher deficiency (glycogen storage disease type III), or primary myopathic carnitine deficiency.

!Ear (hearing loss)

!Heart (arrhythmia, heart failure)

!Gastrointestinal system (diarrhea, vomiting)

!Endocrine system (diabetes mellitus, hypothyroidism)

!ANS (impotence, sweating)

The diagnosis is based on the clinical features, laboratory tests (elevated lactate concentration at rest in serum, sometimes also in CSF, with sustained increase after exercise), muscle biopsy (ragged red fibers, sometimes with cy- tochrome-c oxidase deficiency), and molecular studies (mtDNA analysis of muscle, platelets, leukocytes). There is no etiological treatment for the mitochondrial myopathies at present; a lowfat, carbohydrate-rich diet is recommended in disorders with defective !-oxidation, and carnitine supplementation in those with systemic carnitine deficiency. Coenzyme Q10, vitamin K3, vitamin C, and/or thioctic acid supplements are recommended in disorders with impaired respiratory chain function.

Myasthenic Syndromes

! Myasthenia Gravis (MG)

Pathogenesis. The exercise-induced weakness that typifies MG is due to impaired transmission at the neuromuscular junction, which is, in turn, due to an underlying molecular lesion affecting the nicotinic acetylcholine receptor (AChR) in the postsynaptic membrane of the muscle cell. Circulating IgG autoantibodies to this receptor impair its function, speed its breakdown, and induce complement-mediated damage to the muscle cell membrane. Recently the anti-MuSK (receptor tyrosine kinase) antibody has been detected in about half of patients who are seronegative for AChR antibodies. The thymus plays an important role in this autoimmune disorder (it is normally a site of maturation and removal of autoreactive T lymphocytes). MG is usually acquired late in life; there are also rare congenital and familial forms.

tor, such as pyridostigmine bromide; if the response is insufficient, corticosteroids or azathioprine can be added. Generalized MG is treated initially with AChE inhibitors and, if the response is insufficient, with corticosteroids, azathioprine, intravenous gammaglobulin, or plasmapheresis; once the patient’s condition has stabilized, thymectomy is performed. Further treatment depends on the degree of improvement achieved by these measures. The mortality of MG with optimal management is less than 1%. Most patients can lead a normal life but need lifelong immunosuppression. Specific measures are needed to manage respiratory crises, thymoma, and pregnancy in patients with MG, and for the treatment of neonatal, congenital, and hereditary forms of MG.

!Lambert–Eaton Myasthenic Syndrome (LEMS)

Symptoms and signs. MG is characterized by asymmetric weakness and fatigability of skeletal muscle that worsens on exertion and improves at rest. Weakness often appears first in the extraocular muscles and remains limited to them in some 15% of cases (ocular myasthenia), but progresses to other muscles in the rest (generalized myasthenia). The facial and pharyngeal muscles may be affected, resulting in a blank facial expression, dysarthria, difficulty in chewing and swallowing, poor muscular control of the head, and rhinorrhea. Respiratory weakness leads to impairment of coughing and an increased risk of aspiration. It may become difficult or impossible for the patient stand up, remain standing, or walk, and total disability may ensue. Myasthenia can be aggravated by certain medications (Table 72, p. 403), infections, emotional stress, electrolyte imbalances, hormonal changes, and bright light (eyes), and is often found in association with hyperthyroidism, thyroiditis, rheumatoid arthritis, and connective tissue disease. Myasthenic or cholinergic crises can be life-threatening (Table 73, p. 404). Diagnosis. The diagnosis is based on the characteristic history and clinical findings, supported by further tests that are listed in Table 74 (p. 404).

Treatment. Ocular MG is treated symptomatically with an acetylcholinesterase (AChE) inhibi-

LEMS is caused by autoantibodies directed mainly against voltage-gated calcium channels in the presynaptic terminal of the neuromuscular junction; diminished release of acetylcholine from the presynaptic terminal is the result. LEMS is often a paraneoplastic manifestation of bronchial carcinoma, sometimes appearing before the tumor becomes clinically evident. It is characterized by proximal (leg) weakness that improves transiently with exercise but worsens shortly afterward. There are also autonomic symptoms (dry mouth) and hyporeflexia. EMG reveals a diminished amplitude of the summated muscle action potential, which increases on high-frequency serial stimulation. The treatment is with 3,4-diaminopyridine (which increases acetylcholine release) and AChE inhibitors. Immune suppression and chemotherapy of the underlying malignancy can also improve LEMS.