Myopathies of systemic disease

INTRODUCTION — Skeletal muscle is a complex tissue that is composed of many structural proteins and several energy-producing pathways. Thus, it can be perturbed by a number of systemic disorders.

This topic will review the myopathies associated with endocrine disease, malabsorption, electrolyte disturbance, critical illness, and rheumatic disease.

ENDOCRINE MYOPATHIES — Endocrine diseases are generally associated with hormonally mediated systemic alterations in metabolism. At any time during the course of many endocrinopathies, muscle may become affected. The diagnosis of such a myopathy may be more difficult if it is the presenting manifestation of the endocrinopathy.

Adrenal insufficiency — Severe, subjective, generalized weakness has been described in up to 100 percent of patients with Addison disease [1,2]. Cramping and fatigue may also occur. Some patients develop lower extremity flexion contractures and myalgias as their primary complaints [3,4]. Symptoms improve with the administration of glucocorticoids. (See "Clinical manifestations of adrenal insufficiency in adults".)

Adequate clinicopathologic studies are lacking; therefore, it is difficult to clearly categorize the weakness as myopathic.

The mechanism of adrenal insufficiency-associated weakness is not established, but potential causes include changes in carbohydrate metabolism and electrolyte abnormalities (hyponatremia and hyperkalemia), a loss of exercise-induced glycogenolysis, and circulatory insufficiency [5].

Cushing syndrome — Muscle weakness is a common accompaniment of all types of hypercortisolism, both endogenous (Cushing syndrome and Cushing disease) and exogenous. The clinical features are similar in all of the cortisol excess states. (See "Epidemiology and clinical manifestations of Cushing syndrome" and "Glucocorticoid-induced myopathy".)

Muscle weakness in Cushing syndrome may be due to glucocorticoid-induced inhibition of protein synthesis with impairment in ribosome function [6]. Accelerated protein catabolism [7], changes in amino acid export from muscle [8], and alteration of carbohydrate metabolism [5] are all likely to play a role. Altered gene regulation and cell signaling by steroid hormones probably leads to some of these metabolic changes [9]. In particular, the forkhead box O3a promoter is upregulated along with atrogin-1 and muscle-ring finger protein-1 [10]. There is also enhanced protein turnover mediated by the ubiquitin-proteosome proteolytic pathway, which is stimulated by glucocorticoids [11].

Clinically, weakness with atrophy occurs insidiously in 50 to 90 percent of patients with Cushing syndrome [12,13]. Patients usually have other physical features of hypercortisolism such as "moon facies." The weakness, which may or may not be accompanied by myalgias, is proximal in distribution, first affecting the lower extremities and then the upper extremities. Facial and bulbar muscles are generally not involved, and diaphragm weakness occurs rarely. This respiratory involvement can be severe, however [14].

On laboratory evaluation, the serum CK is normal. In fact, the serum CK and myoglobin are low when compared with controls [15]. Electromyography is sometimes normal, but some short-duration, low-amplitude motor unit potentials, compatible with myopathy, are often detected. Occasionally, insertional activity is increased [16,17].

The major histologic finding is atrophy of type 2 muscle fibers [18], especially type 2B (high glycolytic, low oxidative potential) muscle fibers.

Patients generally improve over months with treatment of the endocrinopathy [14,17]. The greatest improvement occurs within three months, but strength and muscle mass may continue to increase for over a year. Improvement may be incomplete [19,20].

The treatment of Cushing syndrome depends on the etiology; options include pituitary or adrenal tumor removal, medical therapy to reduce hypothalamic corticotropin-releasing hormone, and chemical adrenalectomy. Physical therapy may be helpful [21]. (See "Overview of the treatment of Cushing syndrome".)

Diabetic muscle infarction — Diabetic muscle infarction is a rare disorder that affects patients who have relatively longstanding diabetes, many of whom have other micro- or macrovascular complications. Clinical manifestations include acute or subacute onset of muscle pain, swelling, and associated tenderness. The muscles of the thigh and calf are most commonly affected. Frequent but nonspecific laboratory findings include elevation of plasma CK enzyme activity, leukocytosis, and elevated erythrocyte sedimentation rate (ESR).

Diabetic muscle infarction is discussed in greater detail separately. (See "Diabetic muscle infarction".)

Hyperaldosteronism with myopathy — Weakness is a very common complaint in patients with hyperaldosteronism [22], and it has been ascribed to potassium deficiency [23]. On the other hand, objective weakness is rare and in one report was seen in only 1 of 12 patients [23]. Other reported features include the following:

●In a study describing two patients with hyperaldosteronism and myopathy, serum CK levels were elevated in both, and the electromyography findings were "myopathic" in one [24]. Electron microscopy revealed dilatation of the T-tubule system and sarcoplasmic reticulum. Muscle strength improved with treatment of the underlying condition.

●Rhabdomyolysis from hypokalemia was a presenting manifestation of hyperaldosteronism in a 40-year-old woman [25].

●Activity-dependent conduction block was identified in a patient with acute weakness and hyperaldosteronism [26]. This conduction block may contribute to weakness and paralysis in patients with hypokalemia and hyperaldosteronism.

The general clinical features and treatment of primary aldosteronism are discussed separately. (See "Pathophysiology and clinical features of primary aldosteronism" and "Treatment of primary aldosteronism".)

Hyperparathyroid myopathy — The insidious development of proximal weakness (legs involved more than arms), fatigue, musculoskeletal pain, and hyperreflexia has been reported in approximately 25 percent of patients with primary hyperparathyroidism [27,28]. (See "Primary hyperparathyroidism: Clinical manifestations" and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

Patients with secondary hyperparathyroidism may be similarly affected, but a coexistent neuropathy is usually present [5]. Some patients with secondary hyperparathyroidism also have osteomalacia, which alone is commonly associated with myopathy. (See 'Osteomalacic myopathy and celiac sprue' below.)

Rarely, a malignant necrotizing myopathy with vascular calcifications occurs in patients with hyperparathyroidism and uremia [29].

On laboratory testing, serum calcium, alkaline phosphatase, and parathyroid hormone (PTH) are elevated, while the serum CK is normal. Electromyography findings are mixed and include short-duration, low-amplitude motor unit potentials as well as high-amplitude, long-duration motor unit potentials [30-32]. Limited reports of nerve conduction studies have been normal. Histopathologic studies of muscle reveal mostly atrophy of type 2 more than type 1 fibers.

The pathogenesis of hyperparathyroid myopathy is uncertain. There may be a neuronal or motor axonal component. Increased regulators of calcium homeostasis, namely PTH and vitamin D, may be important in inducing weakness [5].

Patients usually regain strength within weeks of treatment of the endocrinopathy [32,33]. (See "Primary hyperparathyroidism: Management".)

Hyperthyroid myopathy — Muscle weakness with or without atrophy and myalgias occurs in 60 to 80 percent of patients with untreated hyperthyroidism. This discussion will briefly review hyperthyroid myopathy. A more detailed discussion is found separately. (See "Neurologic manifestations of hyperthyroidism and Graves' disease", section on 'Myopathy'.)

Cramps are less common than with hypothyroidism. Patients with hyperthyroidism tend to develop muscle involvement more frequently after the age of 40. The likelihood of developing weakness, but not its degree, is correlated with the duration of the hyperthyroid state.

Approximately two-thirds of patients with hyperthyroid myopathy report proximal weakness that usually begins several weeks to several months after the onset of hyperthyroidism. Hip flexors and quadriceps may be predominantly affected. The remainder has distal as well as proximal muscle involvement. Bulbar and respiratory muscle dysfunction occurs rarely. Weakness is sometimes the sole manifestation of the endocrinopathy. Myalgias may occur. Deep tendon reflexes are normal or increased, an unusual finding in a myopathic disorder. Paresthesias, due to coexisting polyneuropathy, may be present.

Laboratory testing usually shows a normal serum CK level; electromyography sometimes reveals "myopathic" motor unit potentials, but fibrillation potential activity is usually absent. Pathologic changes are typically nonspecific.

Treatment involves returning the patient to euthyroidism. Patients generally improve fully within four months.

Hypothyroid myopathy — Muscle disease is a common complication of congenital and adult-onset hypothyroidism. Hypothyroid myopathy is briefly reviewed here and is discussed in greater detail separately. (See "Hypothyroid myopathy".)

Patients with hypothyroidism frequently complain of weakness with or without cramps and myalgias. Patients of all ages and either sex may be affected, but hypothyroidism and therefore hypothyroid myopathy is more common in women. Weakness may be an initial symptom of hypothyroidism, or it may occur years into the course of the endocrinopathy.

Myopathic weakness in congenital hypothyroidism occurs in association with other manifestations of cretinism, is accompanied by prominent muscle hypertrophy, and responds to thyroid replacement. (See "Hypothyroid myopathy", section on 'Congenital hypothyroidism'.)

In adults, the severity of muscle disease can range from asymptomatic elevation of serum creatine kinase (CK) to disabling muscle weakness. In addition to proximal muscle weakness, neurologic findings include sluggish or hung-up reflexes, myoedema (expansion of muscle following direct percussion), and, rarely, an increase in muscle bulk. In chronic hypothyroid myopathy, the triad of muscle hypertrophy, weakness, and CK elevation may occur. Rhabdomyolysis has been reported but occurs rarely. Myopathy attributed to hypothyroidism induced by the immune checkpoint inhibitor nivolumab was also reported [34]. (See "Hypothyroid myopathy", section on 'Clinical and laboratory manifestations'.)

The presence of typical myopathic symptoms in the setting of hypothyroidism is sufficient to make the diagnosis. Electromyography is normal or shows myopathic changes. Muscle biopsy, if performed to exclude other conditions, shows nonspecific changes and only mild, if any, inflammation. (See "Hypothyroid myopathy", section on 'Diagnosis'.)

Thyroid replacement usually leads to resolution of laboratory abnormalities and symptoms over a few to several weeks. Weakness may recover more slowly, over several months, and, in severely affected patients, may persist even longer. Pathologic changes in muscle may also persist after clinical recovery occurs. (See "Hypothyroid myopathy", section on 'Treatment and prognosis'.)

MYOPATHIES ASSOCIATED WITH MALABSORPTION

Osteomalacic myopathy and celiac sprue — Myopathy is common in osteomalacia, and proximal-predominant weakness is the initial symptom in approximately 30 percent of cases [35]. Patients often have pain, which may be partly of myopathic and partly of bone origin.

Celiac sprue can present with osteomalacic myopathy [36,37]. Although neuropathies with or without ataxia are more common accompaniments of sprue, myopathy can be the primary neuromuscular presentation [38]. Histopathologic features may include muscle inflammation, suggesting an autoimmune component.

Patients who develop malabsorption after gastric bypass can also develop vitamin D deficiency [39,40]. (See "Epidemiology and etiology of osteomalacia" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Bariatric surgery: Postoperative nutritional management".)

Patients typically have malabsorption with hypovitaminosis D, secondary hyperparathyroidism, and, eventually, bony abnormalities (pseudofractures). An elevation in serum alkaline phosphatase is a clue to diagnosis. The 25-dihydroxyvitamin D3 level is low, but 1,25-dihydroxyvitamin D3 may be normal if there is increased renal conversion of vitamin D to the dihydroxy form in the setting of hypophosphatemia and elevated parathyroid hormone (PTH) [41,42]. The serum creatine kinase (CK) level is usually normal. Electromyography findings may be normal or may show some mild "myopathic" motor unit potential changes without fibrillation potentials.

Histopathologic findings are nonspecific but may include type 2 muscle fiber atrophy [42].

It is important to identify the underlying cause of osteomalacia so that the disorder can be corrected. Vitamin D and calcium supplementation are typically beneficial over a period of months [37]. (See "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults".)

Vitamin E deficiency — Vitamin E is fat soluble and can be depleted in malabsorption states. Patients with celiac sprue and patients who have undergone gastric bypass surgery may be especially at risk. (See "Overview of vitamin E", section on 'Deficiency' and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Bariatric surgery: Postoperative nutritional management".)

Neurologic complications of vitamin E deficiency include ataxia and peripheral neuropathy, but also myoclonus, dementia, epilepsy, and myopathy. In particular, a vacuolar myopathy with inflammation can be a consequence, although it is uncommon. Serum CK may be normal [43].

Vitamin E supplementation and a gluten-free diet benefit celiac sprue patients who have vitamin E deficiency with neuropathy and myopathy. The myopathic component improves over a few months, and histologic improvement on muscle biopsy has also been reported [43]. (See "Management of celiac disease in adults".)

HYPOKALEMIC MYOPATHY — A vacuolar myopathy occurs in patients with repeated bouts of hypokalemic periodic paralysis.

Paralysis from severe hypokalemia can also occur in some clinical settings, including chronic diarrhea, renal tubular acidosis, primary aldosteronism, and alcoholism. Certain drug and substance intoxications, from licorice, cola, and clay, for example, can also trigger this phenomenon [44-47].

Weakness associated with hypokalemia can develop over hours to days, and usually affects proximal muscles. It may be associated with cramping. Rarely, the diaphragm, cranial, or posterior cervical muscles are affected [48]. Tendon reflexes may be diminished, and cardiac arrhythmias can also occur.

Muscle membrane may become unexcitable and, eventually, myofiber vacuolation and necrosis can occur. The CK may be normal or slightly elevated. Electromyography may show "myopathic" motor unit potentials, which may be accompanied by fibrillation potentials.

Administration of potassium is the appropriate treatment. Depending on the acuity and severity, intravenous verses oral replacement should be considered. Improvement begins over an hour or two, but patients with severe weakness may take weeks to improve.

MYOPATHY ASSOCIATED WITH CRITICAL ILLNESS — Neuromuscular weakness related to critical illness is reviewed here briefly and discussed in detail elsewhere. (See "Neuromuscular weakness related to critical illness".)

In the setting of critical illness, the most common causes of neuromuscular weakness are critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of the two. Risk factors include sepsis, multiorgan failure, and the systemic inflammatory response syndrome. The use of intravenous glucocorticoids is another possible risk factor for CIM.

Typical features of CIM and CIP include symmetric, flaccid limb weakness, which is usually worse in proximal compared with distal muscles. Extraocular muscles are relatively spared, and facial muscles are usually but not always spared. The diagnosis is suspected in patients who develop flaccid muscle weakness and ventilatory failure after the onset of critical illness. In the appropriate setting, the diagnosis is confirmed when other, unrelated causes of weakness are excluded or deemed unlikely.

Treatment of both CIM and CIP is directed toward aggressive management of medical conditions, avoidance of additional complications such as venous thrombosis, and rehabilitation. Minimizing sedation and early mobilization of critically ill patients may help to prevent or mitigate neuromuscular weakness.

Many patients who survive critical illness experience prolonged impairment in cognition, mental health, and physical function, known as post-intensive care syndrome (PICS). Neuromuscular weakness related to critical illness is often a significant aspect of this syndrome. In survivors of CIP with mild or moderate nerve injury, recovery of muscle strength generally occurs over weeks to months. Patients with severe CIP may remain quadriplegic. Patients with CIM tend to have better outcomes than those with CIP.

MYOPATHIES IN RHEUMATIC DISEASES — Muscle weakness and inflammation are characteristic features of inflammatory myopathies. In addition, skeletal muscle can be affected by polymyalgia rheumatica (PMR), vasculitis, or amyloidosis.

Amyloid myopathy — Amyloid myopathy is rare, but it may be underdiagnosed unless muscle biopsy specimens are routinely evaluated by Congo red stain with fluorescence optics [49,50]. It occurs most often in the setting of systemic amyloidosis, but approximately one-quarter of cases may occur in isolation (ie, isolated amyloid myopathy) [51].

Patients with amyloid myopathy usually have proximal weakness and an elevated serum CK level. Less than half of patients have dysphagia, myalgias, or enlarged muscles with or without macroglossia [52]. Relatively uncommon features include distal weakness, muscle atrophy, focal axial myopathy [53], respiratory dysfunction, claudication, and exercise intolerance with or without rhabdomyolysis [51,54].

Systemic features may include bruising, diarrhea, autonomic neuropathy, renal and cardiac dysfunction, and arthropathy [49,55]. Magnetic resonance imaging (MRI) may identify distinctive reticulation of the subcutaneous fat [55,56]. (See "Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis".)

The mean or median age at diagnosis is 60 to 67 years, but there is a wide range, and patients with isolated amyloid myopathy tend to be younger [51]. The mean time to diagnosis is 22 months, reflecting the difficulty in recognition [52,54]. The clinical, laboratory, and electrodiagnostic features may mimic an inflammatory myopathy. Patients with immunoglobulin light chain (AL) amyloid myopathy may have elevated cardiac troponin T levels, even in the absence of other features of cardiac disease [52].

Nerve conduction studies may reveal low peroneal or tibial motor amplitudes [57]. Needle examination features include short-duration motor unit potentials in all cases, and long-duration motor unit potentials mainly in distal muscles in a minority [49,57]. At least half exhibit fibrillation potentials [49,57]. Complex repetitive or myotonic discharges are uncommonly encountered [57]. There may be evidence of a coexisting axonal sensorimotor polyneuropathy or mononeuropathy such as carpal tunnel syndrome.

Pathologically, there is amyloid deposition around small blood vessels, encasement of muscle fibers by amyloid, and mild muscle fiber necrosis and regeneration (picture 1). Mild signs of denervation atrophy may be present, and inflammatory infiltrates are uncommon [49,54].

Most patients with amyloid myopathy have AL amyloidosis with or without multiple myeloma (see "Monoclonal immunoglobulin deposition disease"). Tissue biopsy should be used to confirm the diagnosis in all cases of amyloidosis. (See "Overview of amyloidosis", section on 'Diagnosis' and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

Some patients with amyloid myopathy have familial amyloidosis with mutations in gelsolin [49] and transthyretin [58,59]. Transthyretin gene mutations are typically associated with distal weakness and polyneuropathy [58], and age of onset may be earlier in familial forms (see "Genetic factors in the amyloid diseases"). Isolated amyloid myopathy may be the initial presentation of systemic amyloidosis [60] but most often is associated with limb-girdle muscular dystrophy types LGMD R12 (anoctamin 5-related) or LGMD R2 (dysferlin-related) [51]. (See "Limb-girdle muscular dystrophy", section on 'Anoctaminopathies' and "Limb-girdle muscular dystrophy", section on 'Dysferlinopathies'.)

The prognosis is poor for most forms of amyloidosis, but treatments for transthyretin amyloid are now available (see "Overview of amyloidosis", section on 'Treatment'). A minority of AL amyloidosis patients treated with alkylating agents, usually melphalan, respond [55], and mean survival is 22 months [54]. The role of more aggressive immunotherapies and stem cell transplant in treating amyloid myopathy is undetermined [54]. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Inflammatory myopathies

●Dermatomyositis and polymyositis – These myopathies may occur in the setting of systemic connective tissue diseases, and less often in association with malignancy. These disorders are discussed separately. (See "Pathogenesis of inflammatory myopathies" and "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Malignancy in dermatomyositis and polymyositis".)

●Inclusion body myositis – This disorder occasionally occurs in patients with Sjögren's disease. This disorder is also discussed separately. (See "Clinical manifestations and diagnosis of inclusion body myositis" and "Management of inclusion body myositis".)

●Necrotizing myopathy – This may occur in several settings, including in association with 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and signal recognition particle (SRP) antibodies, as a paraneoplastic disorder or rarely with the use of certain drugs (eg, checkpoint inhibitor immunotherapy, statins). (See "Toxicities associated with immune checkpoint inhibitors", section on 'Rheumatologic and musculoskeletal' and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Acute necrotizing myopathy'.)

●Viral infection and myopathy

•HIV myopathy can be a presenting manifestation of HIV infection or can occur in the later stages of infection. (See "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Differential diagnosis'.)

•Myopathy may accompany other viral disorders including coronavirus disease 2019 (COVID-19). (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neuromuscular syndromes'.)

Polymyalgia rheumatica — Patients with PMR typically are over 50 years of age and have bilateral aching and stiffness in proximal muscles, hips, neck, or torso. The stiffness is usually noted in the morning. It is often difficult to determine whether there is proximal muscle weakness because the examination is limited by pain. The pain usually worsens with activity. Imaging studies suggest inflammation in synovial tissues. Systemic features are common, including anorexia, weight loss, and fatigue (see "Clinical manifestations and diagnosis of polymyalgia rheumatica"). The RS3PE (Remitting, Symmetric, Seronegative [for rheumatoid arthritis] Synovitis with Pitting Edema) syndrome may be considered a variant of PMR when it responds to low-dose prednisone. It may also be associated with neoplastic disorders or other rheumatic diseases. These patients may also present with "weakness" due to pain. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)

In addition, some patients with PMR develop giant cell arteritis of the head and neck, potentially leading to headache, jaw claudication, anterior ischemic optic neuropathy, aortic aneurysm, cranial neuropathy, and even brachial plexopathy and stroke. (See "Clinical manifestations of giant cell arteritis".)

Typically, elevations in Westergren erythrocyte sedimentation rate (ESR; >40 mm/hour) and C-reactive protein are present. The serum creatine kinase (CK) level is normal. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)

Electromyography is also normal. Muscle histopathology is either normal or reveals atrophy of type 2 muscle fibers [61,62]. Microvascularization of muscle has also been reported [63].

There is usually a dramatic improvement with low doses of prednisone. (See "Treatment of polymyalgia rheumatica".)

Skeletal muscle vasculitis — Skeletal muscle vasculitis typically occurs in association with either systemic vasculitis or isolated peripheral nervous system vasculitis. In either group, an associated vasculitic neuropathy is often the major peripheral nervous system clinical manifestation.

●Clinical features – Approximately 55 percent or more of patients with vasculitis affecting skeletal muscle have substantial myalgias and some degree of weakness. They may also exhibit weight loss and fever, and some (approximately 20 percent in one series) will have paresthesias due to an associated peripheral neuropathy [64]. Patients with systemic vasculitides may also have fever, arthralgias, and involvement of other organ systems.

In polyarteritis nodosa, vascular occlusions and aneurysmal dilatations can affect digits and intra-abdominal organs. Skeletal muscle MRI with contrast may show small, fluffy enhancing lesions centered on blood vessels in addition to signal changes of muscle edema [65]. Other systemic vasculitides that may involve skeletal muscle include eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), granulomatosis with polyangiitis, hypersensitivity vasculitis, and microscopic polyarteritis [66-68]. (See "Overview of and approach to the vasculitides in adults".)

Occasionally, patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma, HIV infection, and Sjögren's disease can develop skeletal muscle vasculitis, often in conjunction with a vasculitic peripheral neuropathy. MRI may reveal increased signal on slow tau inversion recovery (STIR) sequences in affected muscles [69]. (See "Clinical manifestations and diagnosis of vasculitic neuropathies".)

Giant cell arteritis is only rarely associated with skeletal muscle vasculitis [70]. (See "Clinical manifestations of giant cell arteritis".)

In patients with skeletal muscle vasculitis, the ESR is often, but not always, elevated [64]. Anemia and leukocytosis may be present. Other laboratory findings may reflect the presence of an underlying systemic disorder, such as anti-DNA antibodies in systemic lupus erythematosus, and antineutrophilic cytoplasmic bodies in patients with granulomatosis with polyangiitis and EGPA. Patients with polyarteritis nodosa may have associated hepatitis C or B virus infections.

●Pathology – Histopathologically, vasculitis is identified by the presence of fibrinoid necrosis of the vessel wall in conjunction with transmural inflammation. There may be vascular occlusion in a minority [64]. In all types of systemic vasculitis, macrophages and lymphocytes of various types are commonly noted.

In polyarteritis nodosa, neutrophils may be seen within the inflammatory infiltrate, and, with EGPA, eosinophils are common. Giant cells are typically seen in the region of the internal elastic membrane in giant cell arteritis, and they are sometimes seen in other systemic vasculitides. With hypersensitivity vasculitis and vasculitis affecting small blood vessels, fibrinoid necrosis may not be evident, but there should be a transmural inflammatory infiltrate with nuclear debris.

The vast majority of muscle specimens also reveal evidence of neurogenic atrophy. Regenerating and degenerating muscle fibers are also seen in approximately 40 percent of biopsy specimens [64].

●Treatment – Treatment depends upon the cause of vasculitis. The treatments are addressed in the individual sections regarding these disorders. (See "Overview of the management of vasculitis in adults".)

In isolated peripheral nervous system vasculitis, treatment with glucocorticoids alone is a consideration, but often cyclophosphamide will be necessary. (See "Treatment and prognosis of nonsystemic vasculitic neuropathy".)

In a retrospective series that excluded vasculitis associated with inflammatory myopathic conditions, such as polymyositis or dermatomyositis, 33 patients with skeletal muscle vasculitis underwent glucocorticoid therapy, and 19 received additional immunosuppressants [64]. At least 17 (52 percent) improved with combined glucocorticoid and immunosuppressive therapy. Some were lost to follow-up and five died.

SUMMARY

●Endocrine diseases are generally associated with hormonally mediated systemic alterations in metabolism. Muscle may become affected at any time during the course of several endocrinopathies. The diagnosis of such a myopathy may be more difficult if it is the presenting manifestation of the endocrinopathy. The range of endocrine disorders associated with myopathy includes the following conditions (see 'Endocrine myopathies' above):

•Adrenal insufficiency (see 'Adrenal insufficiency' above)

•Cushing syndrome (see 'Cushing syndrome' above)

•Diabetes (see 'Diabetic muscle infarction' above)

•Hyperaldosteronism (see 'Hyperaldosteronism with myopathy' above)

•Hyperparathyroidism (see 'Hyperparathyroid myopathy' above)

•Hyperthyroidism (see 'Hyperthyroid myopathy' above)

•Hypothyroidism (see 'Hypothyroid myopathy' above)

●Myopathy is common in osteomalacia. Celiac sprue can present with osteomalacic myopathy. It is important to identify the underlying cause of osteomalacia so that the disorder can be corrected. Vitamin E is fat soluble and can be depleted in malabsorption states; a vacuolar myopathy with inflammation can be a consequence, although it is uncommon. (See 'Myopathies associated with malabsorption' above.)

●A vacuolar myopathy occurs in patients with repeated bouts of hypokalemic periodic paralysis. Paralysis from severe hypokalemia can also occur in some clinical settings, including chronic diarrhea, renal tubular acidosis, primary aldosteronism, alcoholism, and certain drug and substance intoxications. (See 'Hypokalemic myopathy' above.)

●In the setting of critical illness, the most common causes of neuromuscular weakness are critical illness myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of the two. Risk factors include sepsis, multiorgan failure, and the systemic inflammatory response syndrome. The use of intravenous glucocorticoids is another possible risk factor for CIM. Typical features of CIM and CIP include symmetric, flaccid limb weakness, which is usually worse in proximal compared with distal muscles. Extraocular muscles are relatively spared, and facial muscles are usually but not always spared. (See 'Myopathy associated with critical illness' above.)

●The idiopathic inflammatory myopathies dermatomyositis and polymyositis may occur in the setting of systemic connective tissue diseases. Occasionally, skeletal muscle can be affected by amyloidosis, polymyalgia rheumatica (PMR), or vasculitis. (See 'Myopathies in rheumatic diseases' above.)