Clinical Approach to Muscle Diseases

Carlayne E. Jackson, M.D.

Disclosures

Semin Neurol. 2008;28(2):228-240. 

In This Article

The Muscle Biopsy

If the clinical features and/or electrodiagnostic features suggest the possibility of a myopathy, a muscle biopsy may be an appropriate test to confirm the diagnosis. However, many forms of hereditary muscle disorders can now be diagnosed with molecular genetic testing, thereby eliminating the need for performing a muscle biopsy in every patient. Similar to the use of electro-physiological studies, biopsy results must be interpreted in the light of the clinical history and other laboratory studies. It is also important to recognize that pathological changes may be focal, both between muscles and within a given muscle. This is particularly true for all of the inflammatory myopathies.

A muscle specimen can be obtained through either an open or closed (needle or punch) biopsy procedure. The advantage of a needle or punch biopsy is that it is minimally invasive, is cosmetically more appealing, and multiple specimens can be obtained. The disadvantage of the closed biopsy procedure is that not all laboratories have the expertise to adequately process the muscle tissue acquired with this approach for all the necessary studies. Selection of the appropriate muscle to biopsy is critical. Muscles that are severely weak (MRC grade 3 or less) should be not be biopsied because the results are likely to show only evidence of “end-stage” muscle. In addition, muscles that have recently been studied by needle EMG should be avoided due to the possibility of artifacts created by needle insertion. Biopsies should generally be taken from muscles that demonstrate MRC grade 4 strength. For practical purposes, in the upper extremities, the muscles of choice are either the biceps or deltoid; in the lower extremities, the best choice is the vastus lateralis. The gastrocnemius should be avoided because its tendon insertion extends throughout the muscle and inadvertent sampling of a myotendinous junction may cause difficulty with interpretation. Occasionally, an imaging procedure such as muscle ultrasound, computed tomography, or MRI can be used to guide selection of the appropriate muscle to biopsy.

Muscle biopsy specimens can be studied through histological, histochemical, immunocytochemical, biochemical, electron microscopic, or genetic techniques ( Table 20 ).[21,22] In most instances, light microscopic observations of frozen muscle tissue specimens are sufficient to make a pathological diagnosis. Typical myopathic abnormalities include central nuclei, both small and large hypertrophic round fibers, split fibers, and degenerating and regenerating fibers. Inflammatory myopathies are characterized by the presence of mono-nuclear inflammatory cells in the endomysial and perimysial connective tissue between fibers, and occasionally around blood vessels. In addition, in dermatomyositis, atrophy of fibers located on the periphery of a muscle fascicle, perifascicular atrophy, is a common finding. Chronic myopathies frequently show evidence of increased connective tissue and fat.

For general histology, hematoxylin and eosin (H&E) and modified Gomori trichrome are the most useful. The latter is particularly helpful in identifying ragged-red fibers, which might suggest a mitochondrial disorder. In addition to these standard stains, other histochemical reactions can be used to gain additional information ( Table 20 ). The myosin adenosine triphosphatase (ATPase) stains (alkaline - pH 9.4 and acidic pH 4.3 and 4.6) allow a thorough evaluation of histochemistry fiber types. Type 1 fibers (slow-twitch, fatigue-resistant, oxidative metabolism) stain lightly at alkaline and darkly at acidic pHs. Type 2 fibers (fast-twitch, fatigue-prone, glycolytic metabolism) stain darkly at alkaline and lightly at acidic pHs. Normally, there is a random distribution of the two fiber types, and there are generally twice as many type 2 as type 1 fibers. In several myopathies, there is a nonspecific type 1 fiber predominance. Oxidative enzyme stains (nicotinamide adenine dinucleotide [NADH] dehydrogenase, succinate dehydrogenase, cytochromec oxidase) are useful for identifying myofibrillar and mitochondrial abnormalities. Periodic acid-Schiff (PAS) stains can be helpful in identifying glycogen storage diseases, and oil red O stains may assist with the diagnosis of a lipid storage disease. Acid and alkaline phosphatase reactions can highlight necrotic and regenerating fibers, respectively. Qualitative biochemical enzymes stains can be performed for myophosphorylase (McArdle's disease), phosphofructokinase (PFK) deficiency, and myoadenylate deaminase (MAD) deficiency. Amyloid deposition can be assayed with Congo red or crystal violet staining. Finally, immunohistochemical techniques can stain for muscle proteins that are deficient in some muscular dystrophies (e.g., dystrophin in Duchenne's and Becker's dystrophies) or for products that are increased in certain inflammatory myopathies such as the membrane attack complex in dermatomyositis.

Electron microscopy (EM) evaluates the ultra-structural components of muscle fibers and is not required in the majority of myopathies to make a pathological diagnosis. Electron microscopy is important, however, in the diagnosis of some congenital myopathies and mitochondrial disorders. Findings detected only by EM are seldom of clinical importance.

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