The clinical picture of the typical skin rash and proximal or diffuse muscle weakness has few causes other than DM. However, proximal muscle weakness without skin involvement can be due to many conditions other than PM or IBM.
Subacute or chronic progressive muscle weakness
This may be due to denervating conditions such as the spinal muscular atrophies or amyotrophic lateral sclerosis (Chap. 39). In addition to the muscle weakness, upper motor neuron signs in the latter and signs of denervation detected by electromyography (EMG) aid in the diagnosis. The muscular dystrophies (Chap. 56) may be additional considerations; however, these disorders usually develop over years rather than weeks or months and rarely present after the age of 30 years. It may be difficult, even with a muscle biopsy, to distinguish chronic PM from a rapidly advancing muscular dystrophy. This is particularly true of facioscapulohumeral muscular dystrophy, dysferlin myopathy, and the dystrophinopathies where inflammatory cell infiltration is often found early in the disease. Such doubtful cases should always be given an adequate trial of glucocorticoid therapy and undergo genetic testing to exclude muscular dystrophy. Identification of the MHC/CD8 lesion by muscle biopsy is helpful to identify cases of PM. Some metabolic myopathies, including glycogen storage disease due to myophosphorylase or acid maltase deficiency, lipid storage myopathies due to carnitine deficiency, and mitochondrial diseases produce weakness that is often associated with other characteristic clinical signs; diagnosis rests upon histochemical and biochemical studies of the muscle biopsy. The endocrine myopathies such as those due to hypercorticosteroidism, hyper- and hypothyroidism, and hyper- and hypoparathyroidism require the appropriate laboratory investigations for diagnosis. Muscle wasting in patients with an underlying neoplasm may be due to disuse, cachexia, or rarely a paraneoplastic neuromyopathy (Chap. 50).
Diseases of the neuromuscular junction, including myasthenia gravis or the Lambert-Eaton myasthenic syndrome, cause fatiguing weakness that also affects ocular and other cranial muscles (Chap. 55). Repetitive nerve stimulation and single-fiber EMG studies aid in diagnosis.
This may be caused by an acute neuropathy such as Guillain-Barré syndrome (Chap. 54), transverse myelitis (Chap. 43), a neurotoxin (Chap. 56), or a neurotropic viral infection such as poliomyelitis or West Nile virus (Chap. 46). When acute weakness is associated with very high levels of serum CK (often in the thousands), painful muscle cramps, rhabdomyolysis, and myoglobinuria, it may be due to a necrotizing autoimmune myositis, as discussed below, a viral infection or a metabolic disorder such as myophosphorylase deficiency, or carnitine palmitoyltransferase deficiency (Chap. 56). Several animal parasites, including protozoa (Toxoplasma, Trypanosoma), cestodes (cysticerci), and nematodes (trichinae), may produce a focal or diffuse inflammatory myopathy known as parasitic polymyositis. Staphylococcus aureus, Yersinia, Streptococcus, or anaerobic bacteria may produce a suppurative myositis, known as tropical polymyositis, or pyomyositis. Pyomyositis, previously rare in the west, is now occasionally seen in AIDS patients. Other bacteria, such as Borrelia burgdorferi (Lyme disease) and Legionella pneumophila (Legionnaire's disease), may infrequently cause myositis.
Patients with periodic paralysis experience recurrent episodes of acute muscle weakness without pain, always beginning in childhood. Chronic alcoholics may develop painful myopathy with myoglobinuria after a bout of heavy drinking. Acute painless muscle weakness with myoglobinuria may occur with prolonged hypokalemia, or hypophosphatemia and hypomagnesemia, usually in chronic alcoholics or in patients on nasogastric suction receiving parenteral hyperalimentation.
This distinctive inflammatory disorder affecting muscle and fascia presents as diffuse myalgias, skin induration, fatigue, and mild muscle weakness; mild elevations of serum CK are usually present. The most common form is eosinophilic myofasciitis characterized by peripheral blood eosinophilia and eosinophilic infiltrates in the endomysial tissue. In some patients, the eosinophilic myositis/fasciitis occurs in the context of parasitic infections, vasculitis, mixed connective tissue disease, hypereosinophilic syndrome, or toxic exposures (e.g., toxic oil syndrome, contaminated l-tryptophan) or with mutations in the calpain gene. A distinct subset of myofasciitis is characterized by pronounced infiltration of the connective tissue around the muscle by sheets of periodic acid–Schiff-positive macrophages and occasional CD8 T cells (macrophagic myofasciitis or inflammatory myositis with abundant macrophages [IMAM]). A focal form of this disorder, limited to sites of previous vaccinations, administered months or years earlier, has been linked to an aluminum-containing substrate in vaccines. This disorder, which to date has not been observed outside of France, responds to glucocorticoid therapy, and the overall prognosis seems favorable.
Necrotizing autoimmune myositis
This is an increasingly recognized entity that has distinct features, even though it is often labeled as PM. It presents as an acute or subacute onset of symmetric muscle weakness; CK is typically extremely high. The weakness can be severe. Coexisting interstitial lung disease and cardiomyopathy may be present. The disorder may develop after a viral infection, in association with cancer, or in patients taking statins when the myopathy continues to worsen after statin withdrawal. Some patients have antibodies against signal recognition particle (SRP) or against the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a 100-kDa protein considered the pharmacologic target of statins. The muscle biopsy demonstrates necrotic fibers infiltrated by macrophages but only rare, if any, T cell infiltrates. Muscle MHC-I expression is only slightly and focally upregulated. The capillaries may be swollen with hyalinization, thickening of the capillary wall, and deposition of complement. Most patients respond to immunotherapy, but some are resistant.
Hyperacute necrotizing fasciitis/myositis (flesh-eating disease)
This a fulminant infectious disease, seen most often in the tropics or in conditions with poor hygiene, characterized by widespread necrosis of the superficial fascia and muscle of a limb; if the scrotum, perineum, and abdominal wall are affected, the condition is referred to as Fournier's gangrene. It may be caused by group A β-hemolytic Streptococcus, methicillin-sensitive S. aureus, Pseudomonas aeruginosa, Vibrio vulnificus, clostridial species (gas gangrene), or polymicrobial infection with anaerobes and facultative bacteria; toxins from these bacteria may act as superantigens. The port of bacterial entry is usually a trivial cut or skin abrasion, and the source is contact with carriers of the organism. Individuals with diabetes mellitus, immunodeficiency states, or systemic illnesses such as liver failure are most susceptible. Systemic varicella is a predisposing factor in children.
The disease presents with swelling, pain, and redness in the involved area followed by a rapid tissue necrosis of fascia and muscle that progresses at an estimated rate of 3 cm/h. Emergency debridement, antibiotics, IV immunoglobulin (IVIg), and even hyperbaric oxygen have been recommended. In progressive or advanced cases, amputation of the affected limb may be necessary to avoid a fatal outcome.
D-Penicillamine, procainamide, and statins may produce a true myositis resembling PM or necrotizing myositis. A DM-like illness has been associated with the contaminated preparations of l-tryptophan. As noted above, AZT causes a mitochondrial myopathy. Other drugs may elicit a toxic noninflammatory myopathy that is histologically different from DM, PM, or IBM. These include cholesterol-lowering agents such as clofibrate, lovastatin, simvastatin, or pravastatin, especially when combined with cyclosporine, amiodarone, or gemfibrozil. Mild statin-induced myopathic symptoms (such as myalgia, fatigue, or asymptomatic elevations of CK) are self-limited and usually improve after discontinuation of the drug. In rare patients, however, muscle weakness continues to progress even after the statin is withdrawn; in these cases, a diagnostic muscle biopsy is indicated and search for antibodies to HMGCR is suggested; if histologic evidence of PM or necrotizing myositis is present, immunotherapy should be initiated. Rhabdomyolysis and myoglobinuria have been rarely associated with amphotericin B, ε-aminocaproic acid, fenfluramine, heroin, and phencyclidine. The use of amiodarone, chloroquine, colchicine, carbimazole, emetine, etretinate, and ipecac syrup; chronic laxative or licorice use resulting in hypokalemia; and glucocorticoid or growth hormone administration have also been associated with myopathic muscle weakness. Some neuromuscular blocking agents such as pancuronium, in combination with glucocorticoids, may cause an acute critical illness myopathy. A careful drug history is essential for diagnosis of these drug-induced myopathies, which do not require immunosuppressive therapy except when an autoimmune myopathy has been triggered, as noted above.
"Weakness" due to muscle pain and muscle tenderness
A number of conditions including polymyalgia rheumatica and arthritic disorders of adjacent joints may enter into the differential diagnosis of inflammatory myopathy, even though they do not cause myositis. The muscle biopsy is either normal or discloses type II muscle fiber atrophy. Patients with fibrositis and fibromyalgia complain of focal or diffuse muscle tenderness, fatigue, and aching, which is sometimes poorly differentiated from joint pain. Some patients, however, have muscle tenderness, painful muscles on movement, and signs suggestive of a collagen vascular disorder, such as an increased erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, or rheumatoid factor, along with modest elevation of the serum CK and aldolase. They demonstrate a "break-away" pattern of weakness with difficulty sustaining effort but not true muscle weakness. The muscle biopsy is usually normal or nonspecific. Many such patients show some response to nonsteroidal anti-inflammatory agents or glucocorticoids, although most continue to have indolent complaints. An indolent fasciitis in the setting of an ill-defined connective tissue disorder may be at times present, and these patients should not be labeled as having a psychosomatic disorder. Chronic fatigue syndrome, which may follow a viral infection, can present with debilitating fatigue, sore throat, painful lymphadenopathy, myalgia, arthralgia, sleep disorder, and headache (Chap. 59). These patients do not have muscle weakness, and the muscle biopsy is normal.