Neuromuscular Notes: When to Order a Muscle Biopsy

Muscle biopsies, although used less commonly nowadays than in the past, remain an important diagnostic tool in the workup of individuals with suspected neuromuscular disorders. A muscle biopsy may be helpful in the evaluation of an individual with objective muscular weakness and other features supportive of a myopathy, such as elevated serum creatine kinase (CK) levels, myopathic electrodiagnostic findings, or abnormal muscle imaging study results. Not every individual suspected of having a myopathy requires a muscle biopsy, as a diagnosis can often be made with less invasive testing.¹ In this article, indications to obtain a muscle biopsy are discussed, organized by the suspected disease process (Table). Specific details of muscle biopsy acquisition, processing, and interpretation of histopathology are outside the scope of this article.

Inflammatory Myopathies

One of the primary indications for a muscle biopsy is in the workup of an individual with a suspected inflammatory myopathy or myositis. Diagnostic criteria, such as the Bohan and Peter criteria^2,3 and the European League Against Rheumatism/American College of Rheumatology criteria,⁴ include muscle biopsy evidence of myositis as a core diagnostic feature, with supportive histopathologic findings including muscle fiber necrosis, inflammatory infiltrate, perifascicular atrophy, and rimmed vacuoles. With the discovery of various autoantibodies and their clinical correlation with myositis, people who are found to have myositis-specific antibodies with an appropriate phenotype may not require a muscle biopsy for accurate diagnosis. The diagnostic yield of these antibodies is approximately 65% to 70%.⁵ For example, current diagnostic algorithms rely on a muscle biopsy to support a definitive diagnosis of inclusion body myositis (IBM). However, in the presence of serum autoantibodies against NT5C1A (eg, anti-NT5C1A, anti-cytosolic 5’-nucleotidase IA) in an individual with a typical IBM clinical phenotype, a clinical diagnosis of IBM can be made and a muscle biopsy may not be necessary. When there is a clinical suspicion for myositis and myositis-specific antibodies return negative, obtaining a muscle biopsy is an appropriate next diagnostic step. In the case of rapidly progressive weakness and suspected myositis, a muscle biopsy can be obtained early in the diagnostic process to facilitate diagnosis and the prompt initiation of therapeutic management, as serologic studies often take several weeks to return. Certain histopathologic findings not only confirm the diagnosis of myositis but also further refine the particular subtype. This has potential implications on the need for additional surveillance studies, such as malignancy screening in people found to have seronegative immune-mediated necrotizing myopathy given the strong association with this subtype of myositis and cancer.⁶

Toxic Myopathies

Many medications and other agents are myotoxic by various pathogenic mechanisms. The diagnosis of a toxic myopathy can be challenging because of variability in onset and heterogenous clinical features. Certain myotoxic medications are associated with distinct histopathologic features that can support the diagnosis. Necrotizing myopathy is classically seen in both toxic statin myopathy and statin-induced immune-mediated necrotizing myopathy. Inflammatory myopathy may be caused by several different agents, most notably the immune checkpoint inhibitors used in the treatment of a variety of malignancies. Amiodarone, chloroquine, and hydroxychloroquine are associated with an amphiphilic myopathy with associated autophagic vacuoles; characteristic curvilinear structures with the vacuoles may be seen on electron microscopy in hydroxychloroquine myopathy. Colchicine is associated with an antimicrotubular myopathy that also demonstrates vacuoles on muscle biopsy. Various antiretroviral agents may cause a mitochondrial myopathy with histopathologic findings of ragged-red fibers, COX-negative fibers, and increased lipid accumulation.⁷

Genetic Myopathies

A muscle biopsy has historically been part of the diagnostic evaluation of individuals with suspected genetic myopathies. Histopathologic findings in many genetic myopathies demonstrate nonspecific changes consistent with a muscular dystrophy; however, the presence of certain features may be helpful in the diagnosis of some specific genetic myopathies, including various congenital myopathies, vacuolar myopathies, metabolic myopathies, mitochondrial myopathies, and the myofibrillar myopathies. Certain genetic myopathies may be associated with an inflammatory infiltrate, notably calpainopathy, dysferlinopathy, and facioscapulohumeral dystrophy. With advances in the identification of molecular defects and availability of relatively low-cost genetic panels, many clinicians now obtain genetic testing before considering a muscle biopsy. With this clinical approach, the identification of pathogenic genetic variants can lead to a specific diagnosis through noninvasive testing. However, muscle biopsy remains a valuable tool in individuals with a suspected genetic myopathy and unremarkable genetic testing, or as a means to clarify the significance of variants of uncertain significance. In the case of a suspected mitochondrial myopathy, obtaining muscle tissue for histopathologic analysis, biochemical testing, and genetic testing can support and further refine the diagnosis.

Vasculitis

A nerve biopsy is necessary for a definite diagnosis of vasculitis, although the sensitivity of a nerve biopsy is estimated to be only 50% due to the “patchy” nature of the disease in which not all features of the disease are seen. Obtaining a muscle biopsy simultaneously with a nerve biopsy in individuals with suspected vasculitis increases diagnostic yield by an additional 15%.⁸ The muscle chosen for biopsy is generally in close proximity to the nerve of interest, such as the peroneus brevis with superficial peroneal nerve biopsies or the gastrocnemius with sural nerve biopsies.

Muscle Biopsy Site Selection

When a muscle biopsy is determined to be of diagnostic value, determining which muscle to biopsy is an important consideration. In general, a muscle with Medical Research Council grade 4 is used. Muscles with full motor power may not demonstrate specific histopathologic changes, and muscles that are too weak often demonstrate end-stage changes such as fibrofatty replacement that may mask the defining histopathologic features of specific disease processes. Needle EMG and muscle MRI may be helpful in determining muscle biopsy site selection. Obtaining a biopsy from muscles that demonstrate myopathic changes with fibrillation potentials or positive sharp waves on EMG increases the diagnostic yield.⁹ In most myopathies, there is sufficient symmetry to allow the biopsy to be obtained from the corresponding contralateral muscle to avoid potential artifact secondary to the needle EMG. Likewise, imaging evidence of edema or inflammation can guide muscle biopsy site selection in conditions that may be multifocal, such as in inflammatory myopathies. In addition, the muscle biopsy technique or surgeon’s experience may influence the muscle biopsy site selection.

Muscle biopsies are obtained either through an open approach or a needle biopsy. An open muscle biopsy is more invasive, although direct visualization of the muscle tissue helps ensure that a proper specimen is obtained and myotendinous junctions are avoided, and a larger tissue sample is obtained, which may be required for biochemical studies. Larger tissue samples are thought to increase the diagnostic yield in patchy or multifocal disease processes, such as myositis.¹ Proponents of the needle biopsy technique believe that an appropriate sample can be procured and the same diagnostic conclusion can generally be reached with this simpler technique.¹⁰

Select Low-Yield Clinical Scenarios

Muscle biopsies are considered to be of low yield in individuals presenting with myalgias or mild elevations in serum CK levels (ie, less than 5 times the upper limit of normal), particularly in the absence of other objective features such as weakness, myopathic findings on EMG, or abnormal muscle imaging studies.¹ In the setting of acute rhabdomyolysis, a muscle biopsy is often uninformative, as the biopsy typically demonstrates widespread muscle fiber necrosis regardless of the cause (eg, exertional, traumatic, toxic, genetic). If there is clinical concern for an underlying myopathy as the predisposing factor for the episode of rhabdomyolysis, it is preferable to wait a minimum of 6 weeks before obtaining a muscle biopsy.¹¹

Conclusion

The acquisition of muscle biopsies has declined in recent years in the wake of advances in serologic and genetic diagnosis. However, muscle biopsy remains an important diagnostic tool in the evaluation of individuals with suspected acquired or genetic myopathies, and to increase the diagnostic yield in the setting of vasculitis.