Clinical manifestations

Presentation and course

Symptoms of systemic amyloidosis include neuropathy, myopathy, and cardiac or renal insufficiency; there is often multiple-organ involvement. Myopathy is a rare clinical manifestation in primary systemic amyloidosis and, to some extent, an underdiagnosed entity (31; 23; 13). Proximal weakness, muscle stiffness, pseudohypertrophy, and myalgia constitute the principal features.

The initial manifestation may predominantly consist of proximal muscle weakness. Other features due to amyloid deposition at different sites may develop later (14). Pseudohypertrophy, nodular lesions of muscles, and macroglossia are often lacking. This syndrome usually develops in cases with well-recognized generalized amyloidosis (41). Carr and colleagues described the first case in literature in a patient with symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition (from sural nerve and vastus lateralis muscle) (04).

The mean onset age of amyloid myopathy is 60 years. Ninety percent of patients report proximal weakness. This may be associated with macroglossia and muscle pseudohypertrophy in almost a third of the patients. Macroglossia sometimes precludes closure of the mouth; dysphagia and hoarseness may also occur. Dysphagia is present in 25% of patients (39; 42; 05). The clinical importance of macroglossia in a patient with dyspnea and cardiomyopathy is highlighted in a case report (15).

The most prominent findings are abnormal firmness and pseudohypertrophy of the musculature and palpable tumors within muscles (29; 57; 40). Muscle weakness caused by amyloid myopathy has also been described in the absence of pseudohypertrophy. It can also manifest with diffuse muscle hypertrophy on general physical examination (54). The clinical picture then comprises proximal limb weakness with pronounced atrophy. As expected, with any proximal muscle weakness, patients have difficulty raising the arms overhead or climbing stairs (19). Weakness of the neck flexors, as well as shoulder and thigh muscles with atrophy, is also common (24; 57; 40).

Muscle claudication is rare but has been recognized in patients with amyloid myopathy. It results from progressive vascular deposition of amyloid and leads to ischemia and obstruction of small vessels. These patients have been misdiagnosed as having giant cell arteritis and inappropriately treated with high-dose corticosteroids (57; 45).

The presence of amyloid myopathy with myeloma and lytic bone disease has been recognized. Santos and colleagues reported a patient with amyloidosis associated with multiple myeloma who showed clinical characteristics of pseudomyopathy (44). Amyloid myopathy involving the diaphragm and resulting in diaphragmatic failure requiring ventilatory support is also well recognized (52; 43; 01). Amyloidosis may cause adult-onset sensorimotor peripheral neuropathy. Unlike neuropathy secondary to amyloid deposition, myopathy is infrequently described (55).

Amyloid myopathy is frequently misdiagnosed as an inflammatory myopathy, especially polymyositis because of similarities in clinical, neurophysiological, and muscle biopsy findings. Both can show similar inflammatory infiltrates on muscle biopsy, especially when only the hematoxylin-eosin stain is used (27; 17; 20; 09; 32). Spuler and colleagues found that routine use of Congo red-stained sections increased the frequency of a diagnosis of amyloid myopathy almost 10-fold.

Failure to recognize amyloid myopathy precludes patients from potentially life-prolonging treatment. Congo red staining and immunohistochemical analysis of tissue could prevent misdiagnosis (27). In middle-aged or elderly patients with proximal limb weakness, the diagnosis of amyloid myopathy should be considered (19).

Tanabe and colleagues reported an autopsy-proven case of systemic secondary amyloid A (AA) amyloidosis with muscle amyloid angiopathy, possibly induced by psoriasis vulgaris (53).

Prognosis and complications

Likelihood of survival with this disease remains poor, with a median survival rate of 1 to 2 years. Congestive heart failure and nephrotic syndrome are predominant causes of death. Without early therapy, however, the disease has a dismal prognosis (21). A case report from Ohtsuka and colleagues emphasized the fact that when amyloidosis is suspected and there is evidence of muscle injury, a muscle biopsy should be performed (36).

Clinical vignette

A 71-year-old woman with a history of primary systemic amyloidosis noted worsening fatigue, claudication, and weakness in her legs more than arms and hands over the past 2 years. Neurologic examination revealed symmetrical proximal limb weakness in lower and upper extremities with preserved tendon reflexes. Examination showed no other abnormalities. EMG study revealed myopathic findings and CK values were borderline elevated. Bone marrow biopsy revealed an IgG kappa monoclonal gammopathy. MRI of the thighs revealed increased T2 signal of subcutaneous fat and tissue between muscle groups with only minimal signal intensity alteration of muscle. Muscle biopsy revealed characteristic apple-green birefringent amyloid deposits surrounding individual muscle fibers in Congo red-stained sections. Electron microscopy demonstrated amyloid filaments in close apposition to muscle fibers exhibiting excessive corrugations of the sarcolemmal membrane. Treatment included prednisone 60 mg daily and cyclophosphamide 150 mg daily with improvement of symptoms.

Biological basis

Etiology and pathogenesis

Plasma cell dyscrasia or multiple myeloma is associated with amyloid myopathy in the majority of patients (12; 02; 08). The mechanisms by which the amyloid deposits weaken the skeletal muscles remain unclear.

The clinical phenotype and muscle histology are well known, but the pathophysiological mechanisms remain poorly understood. Amyloid denotes a waxy, amorphous, and eosinophilic material. Amyloidosis can involve multiple organs, including kidney, heart, skin, joints, peripheral nerve, and skeletal muscle. The most common form of amyloidosis in the United States is termed “light chain amyloidosis,” which results from deposition of monoclonal antibody light chains. Of the three types of systemic amyloidosis, primary systemic amyloidosis is the type that most often involves skeletal muscle. Amyloid is generally not deposited in muscle in the secondary type (amyloid A protein) and can occasionally be seen in transthyretin (familial) forms of amyloidosis (22; 04). Pinto and colleagues have shown that myopathy can be the early manifestation of wild-type ATTR amyloidosis and can either appear earlier than the peripheral neuropathy or occur after liver transplant in hereditary ATTR amyloidosis (38).

Amyloid is mostly deposited in connective tissue; that is, around the basal lamina of blood vessels, in nodules, or between parenchymal cells. This distribution is seen in nerve, skeletal muscle, and heart muscle (07; 50; 41). The skeletal muscle is also infiltrated as a rule in patients with amyloid polyneuropathy (11). The deposits arise without obvious cause or from monoclonal serum proteins in a plasma cell dyscrasia. The cause of organ damage or skeletal muscle dysfunction in amyloidosis is unclear but is most likely due to the direct toxic effects of amyloid. Other hypotheses include mechanical interference of muscle function by amyloid, ischemic atrophy of muscle caused by accumulation of amyloid in vessels, or amyloid accumulating within or on the sarcolemmal membrane and interfering with electrical conduction along the muscle fiber (10; 21).

Amyloid deposition has been recognized histopathologically as causing compression atrophy of muscle fibers and ischemic atrophy owing to extreme narrowing of capillaries when muscle pseudohypertrophy is not present (41). One of the possible pathophysiological mechanisms in amyloid myopathy is mechanical disruption of the sarcolemma by the abutting amyloid fibrils (23).

The pathological features of progressive amyloid myopathy associated with primary systemic amyloidosis are distinct from the intracellular amyloid deposits characteristic of sporadic inclusion body myositis and inherited inclusion body myopathy (33). Inclusion body myositis is an inflammatory myopathy characterized pathologically by rimmed vacuoles and the accumulation of amyloid-related proteins (18). The frequency of the diagnosis of amyloid myopathy increased 10-fold with the use of fluorescent Congo red stain as a routine procedure in assessing muscle biopsy specimens (51). Congo red-stained sections revealed infiltration of blood vessel walls and endomysium with amyloid protein as well as an unusual pattern of pathologic changes to muscle fibers. Congo red-stained sections of muscle biopsy viewed under fluorescent or polarized optics, and serum or urine protein immunoelectrophoresis, play an important role in the evaluation of myopathy (05). Neurologic manifestations of amyloidosis may precede involvement of other organs by several years; therefore, recognizing amyloid neuropathy and myopathy is essential as we have effective therapies for light chain (AL) and transthyretin (ATTR) neuropathy (34).

Anoctaminopathy-5 and dysferlinopathy were recognized as causes of isolated amyloid myopathy. Isolated amyloid myopathy accounts for almost a quarter of patients with amyloid myopathy, predominantly due to anoctaminopathy-5 (25).

Epidemiology

Epidemiology is discussed in the clinical manifestations.

Prevention

No clear literature on prevention exists, but early diagnosis is essential for further management.

Differential diagnosis

Confusing conditions

Amyloid myopathy should be included in the differential diagnosis when proximal limb muscle weakness without pseudohypertrophy develops in middle-aged or elderly patients. In such cases, a search for plasma cell dyscrasia should be made (21). In addition, this entity should be given consideration with finger flexor weakness, especially when there is an absence of histopathological evidence of inclusion body myositis (35).

The differential diagnosis for an adult presenting with acquired proximal muscle weakness is broad and includes inflammatory myopathies, drug- and toxin-induced myopathies, infectious myopathies, endocrine myopathies, muscular dystrophies, anterior horn cell disease (progressive muscular atrophy), and the Lambert-Eaton myasthenic syndrome (06).

Differential difficulties exist in diagnosing the disorder, and familial amyloid polyneuropathy directly mimics the disease. Clinically, pseudohypertrophy is easy to recognize, and the differential diagnosis is narrow. The atrophic form of amyloidosis is much harder to recognize as such, and these patients should proceed directly to muscle biopsy for confirmation of a diagnosis because amyloidosis is often omitted from the differential diagnosis.

Diagnostic workup

Diagnostic tools include analysis of serum and urine, electromyography, imaging, and histological investigation of appropriate tissue.

A monoclonal protein is often found by immunoelectrophoresis of serum and urine. An important clue to the recognition of this disease, particularly when pseudohypertrophy is not present, is the demonstration of a monoclonal gammopathy in serum or urine. Immunoelectrophoresis or immunofixation should be considered mandatory in the evaluation of a patient with myopathy. Immunoelectrophoresis of serum and urine should be a routine diagnostic test during the evaluation of myopathy of unknown cause.

Skeletal amyloidosis has been evaluated by CT, MRI, technetium-99m methylene diphosphonate, and technetium 99m-pyrophosphate (19; 56; 58). The MR appearance of amyloid myopathy differs from that of other neuromuscular conditions in the minimal changes found in muscle. The MRI in amyloid myopathy has a striking abnormality with marked reticulation of the subcutaneous fat (31). Unique findings on the MRI can alert the clinician to the diagnosis of amyloidosis prior to the muscle biopsy (17). Quantitative turnover studies can measure the total body burden of amyloid and can show whether amyloid deposits are being mobilized after chemotherapy (16).

The utility of MRI has significantly increased to target affected muscles for biopsy as well as to assess disease activity (31). It has been hypothesized that the high calcium content of amyloid deposits that binds the serum amyloid P component also binds the radionuclide. Scintigraphic studies with radioiodinated serum amyloid P component have been used to evaluate amyloid deposits in vivo. The use of MRI for the evaluation of inflammatory myopathies and neuromuscular disorders has become increasingly common, especially in cases of polymyositis (17; 30). Conventional MRI sequences do not appear to be sensitive for the detection of amyloid deposition; however, MRI can be helpful in displaying hypertrophy of adductor magnus and reticular STIR hyperintensity (54).

None of the procedures are diagnostic, and biopsy is still required to confirm the diagnosis. Invasive techniques can be less or more invasive based on the type used. Less invasive techniques include rectal biopsy or subcutaneous fat aspirate. Muscle biopsy is essential in the diagnostic evaluation of possible polymyositis because metabolic abnormalities, muscular dystrophies, drug-induced changes, inclusion-body myopathy, dermatomyositis, and amyloid myopathies can be overlooked.

In one of the series, the prevalence rate of amyloid myopathy in muscle biopsy specimens was low. Most of the muscles showed neurogenic features histologically. All concomitant sural nerve biopsy specimens contained amyloid, and most showed a predominance of axonopathic changes. When suspecting amyloid myopathy, Congo red staining and an immunohistochemistry or immunofluorescence assay should be performed. In middle-aged patients with progressive myopathy or muscle pain of unclear cause, amyloid should be considered with muscle biopsy as the definite test (39; 30).

Acquired and hereditary amyloidosis can be definitively distinguished from one another only by immunohistochemical staining or molecular genetic testing (48).

Management

The recognition of amyloid myopathy is important because clinical symptoms may respond to chemotherapy (49). Manoli and colleagues in 2013 and Pinto and colleagues 2021 highlighted the importance of early diagnosis and therapy for this treatable cause of chronic myopathy with muscle hypertrophy (28; 37). Amyloid myopathy may be responsive to chemotherapy with melphalan and prednisone (47). Given the poor prognosis associated with this disorder, it seems that a trial of chemotherapy would be reasonable in all patients. Melphalan and prednisone treatment for at least 1 year has resulted in increased survival rates. There have also been reports of benefit from high-dose chemotherapy followed by peripheral blood stem cell transplantation (46). Ghosh and associates emphasized the importance of improved prognosis in patients on chemotherapy with cyclophosphamide, dexamethasone, and bortezomib (15). Carr and colleagues used diflunisal, an oral transthyretin (TTR) stabilizing agent, for their patient (04). Bumma and colleagues at the Ohio State University highlighted the importance of a multi-disciplinary clinic in amyloidosis care (03).

Special considerations

Pregnancy

Pregnancy is not a major concern as amyloid myopathy primarily affects the middle-aged population.