Preferential Atrophy

Type 1 fibers: Myotonic dystrophy (prominent), nemaline myopathy, centronuclear myopathy, congenital fiber type disproportion Type 2 (especially 2B) fibers: Disuse, corticosteroid excess (exogenous, endogenous)* CYTOARCHITECTURAL ABNORMALITIES

Type 1 fibers: Target fibers, central cores (central core disease), rod bodies (nemaline myopathy), motichondrial abnormalities Type 2 fibers: Tubular aggregates

*Type fiber atrophy, especially if limited to type 2B fibers, is a nonspecific finding most frequently indicating disuse.

bodies (nemaline myopathy), which originate from Z disc material, appear reddish purple in the modified Gomori trichrome stain. Because a small number of muscle fibers in muscular dystrophy and polymyositis have been noted to contain these structures, 9 a diagnosis of nemaline myopathy requires the presence of numerous rod bodies in many muscle fibers. As previously noted, the modified Gomori trichrome stain is also useful in the identification of mitochondria and the tubular system of muscle. This stain readily identifies subsarcolemmal collections of mitochondria, termed ragged-red fibers, as well as sarcoplasmic reticulum-derived collections, termed tubular aggregates. Both of these abnormalities stain red. Because tubular aggregates are also highlighted by the NADH-TR reaction, but not by the succinate dehydrogenase reaction, they are easily differentiated from mitochondrial aggregates. Although these structures are frequently seen with hyperkalemic periodic paralysis, they are not diagnostically specific for this condition. Rimmed vacuoles have blue margins with hematoxylin and eosin and red margins with the modified Gomori trichrome stain. They are seen in association with inclusion body myopathy, oculopharyngeal muscular dystrophy, distal myopathy, and denervated muscle.

Regarding the two other specimens, the glutaraldehyde-fixed specimen is embedded in plastic for electron microscopy (discussed later), whereas the formalin-fixed specimen is embedded in paraffin for light microscopy. Paraffin sections, which are routinely stained with hematoxylin and eosin (viewed in polarized light) and trichrome (viewed in bright field optics), can serve several purposes. ^ Longitudinally oriented sections permit the identification of cross-striation loss, inflammatory infiltrates, and blood vessel wall changes, and can also serve as backup material.

Specialized Studies. Immunocytochemical techniques utilize commercially prepared antibodies to identify absent or abnormal proteins (e.g., dystrophin, laminin, complement cascade components) and to characterize cell types (e.g., lymphocyte subclasses), among other functions. For example, antibodies against dystrophin can confirm the diagnosis of Duchenne muscular dystrophy when blood tests are uninformative; antibodies against cell markers can demonstrate immune deposits distinctive of dermatomyositis; and antibodies against the membrane attack complex can identify cells targeted for destruction by the immune system. Enzyme histochemistry permits the biochemical analysis of muscle homogenates for specific enzymes (e.g.,

phosphofructokinase) and electron microscopy is available when ultrastructural examination of the tissue specimen (e.g., diagnosis of congenital myopathies, inclusion body myopathy, mitochondrial inclusions, tubular aggregates, and others) is required.

Moreover, some histopathological changes are pathognomonic of a particular disorder. In general, the more specialized the study, the more likely its results will have pathog- nomonic significance (e.g., immunocytochemical studies [dystrophin], electron microscopy [inclusion body myopathy, congenital myopathies with pathognomonic ultrastructural features], and enzyme histochemistry studies for specific enzymes). In addition, certain morphological features, such as atrophy, are indicative of an underlying muscle disorder. For example, perifascicular atrophy, in which the muscle fibers near the edges of the fascicle are atrophied, is the hallmark of dermatomyositis, whereas panfascicular atrophy is indicative of Werdnig-Hoffmann disease.

DIFFERENTIATING MYOPATHIC AND NEUROGENIC CHANGES

The histopathological features observed in skeletal muscle biopsies can be subdivided into two pathological processes--those due to interruption of innervation (i.e., neuropathic changes) and those due to dysfunction of the muscle fiber itself (i.e., myopathic changes). Because nerve and muscle pathophysiologies dictate the observed changes, a brief overview of this topic initiates this subsection. As previously discussed, the functional unit of movement is the motor unit. This structure consists of a single lower motor neuron, its peripherally directed axon, and all of the muscle fibers it innervates. With lower motor neuron and motor axon disorders, because the affected axons undergo wallerian degeneration, the muscle fibers of an entire motor unit are denervated. Denervated muscle fibers undergo several changes, including downregulation of contractile element synthesis and contractile element resorption, both of which permit their survival, albeit in an atrophied state. If these muscle fibers are not reinnervated within approximately 20 months, they will be replaced by connective tissue. With incomplete nerve lesions, the uninvolved motor axons can sprout collaterals to the denervated muscle fibers, thereby "adopting" them. This process increases the number of muscle fibers innervated by the adopting lower motor neuron. With myopathic disorders, random muscle fiber loss occurs, rather than loss of whole motor unit territories. However, collateral sprouting may still occur with a myopathy. When a portion of a muscle fiber is degenerated (i.e., segmental necrosis), the muscle fiber functions as two separate fibers, the portion with the motor endplate (i.e., the innervated fiber) and the portion without it (i.e., the denervated fiber). Because the regenerative capacity of muscle is considerable, the denervated portion can be adopted by collateral sprouting. Also, precursor cells (satellite cells) proliferate and fuse with each other to regenerate the destroyed portion of the muscle. Muscle fibers that are not reinnervated undergo degeneration, a process associated with extensive collagen deposition and fatty infiltration.

Histological Features Associated with Neuropathic Processes. Histological features associated with neuropathic processes include angular atrophic fibers, group atrophy, fiber type grouping, target fibers, nuclear bags, and the presence of minimal interstitial fibrosis. [a) Of these features, the most typical attribute is atrophy, a process resulting in the appearance of small angulated (in cross section) muscle fibers, not selective for fiber types, scattered throughout the specimen. The atrophy also causes the intensity of staining to increase; thus, the denervated fibers appear darker (e.g., nonspecific esterase). Normally, the intermixing of muscle fiber types produces a random checkerboard pattern when skeletal muscle tissue is stained using fiber type-specific techniques. Because collateral sprouting increases the number of muscle fibers innervated by the adopting lower motor neurons and, as previously discussed, converts them to its own histochemical type, fiber type grouping occurs. For this reason the normal checkerboard staining pattern of muscle fibers diminishes. As denervation continues, assuming reinnervation keeps pace, larger and larger groups of contiguous fibers of the same histochemical type are observed (the sine qua non of reinnervation). Atrophy of these groups produces grouped atrophy, the hallmark of chronic denervation. The extreme version of grouped atrophy is panfascicular atrophy, a feature indicative of Werdnig-Hoffmann disease. Fiber type grouping must be distinguished from fiber type predominance (discussed earlier).

Histological Features Associated with Myopathic Processes. Primary disorders of muscle may affect solely the sarcolemma, a single region (segment) of the muscle fiber, or the entire muscle fiber. Thus, the histological features observed vary with the particular myopathic process. Features considered to be indicative of a myopathic process include rounded fibers, central nucleation, muscle fiber size variability, fiber splitting, segmental necrosis, muscle fiber necrosis (degeneration), cellular inflammation, myophagocytosis, regeneration (i.e., basophilic fibers), an increase in connective tissue elements, and structural abnormalities (e.g., vacuoles [glycogen, lipid], ragged-red fibers [mitochondrial myopathies], granulomas [sarcoid], and microorganisms [toxoplasmosis, trichinosis], as well as those structural changes associated with various congenital myopathies [e.g., rod bodies, central cores]). [8] Centrally located nuclei may be observed in up to 3 percent of normal muscle tissue specimens, but when present in a higher percentage, this indicates an underlying myopathy. This finding is especially prominent in the muscle fibers of patients with myotonic dystrophy (see Ch.a.pie.L3.6 ). In fact, when internal nuclei appear in most of the muscle fibers of the sample, this diagnosis is strongly implicated. However, when a single central or paracentral nucleus appears in essentially every myocyte, the diagnosis of centronuclear myopathy is indicated. The combination of atrophy and hypertrophy contributes to the wide variability of muscle fiber size. Because muscle fiber splitting normally occurs near myotendinous junctions, muscle biopsies from this region may appear myopathic and, consequently, sampling in this region is discouraged. When viewed in cross section, connective tissue septae, often with adjacent nuclei, are seen traversing the affected (i.e., split) muscle fibers. When muscle fiber necrosis destroys only a portion of the myocyte, the term segmental necrosis is applied. In this situation, proliferating satellite cells may regenerate the de

stroyed segment, thereby reinnervating the portion lacking a motor endplate. Features of regeneration include basophilic sarcoplasm (due to the rich ribonucleic acid content) and large nuclei with prominent nucleoli. However, when reinnervation occurs by collateral sprouting, small foci of fiber type grouping may be observed. Hence, small patches of fiber type grouping should not be considered synonymous with a neuropathic process. Inflammatory cell collections may have a perivascular distribution (e.g., collagen vascular disorder, dermatomyositis) or be most pronounced intracellularly (e.g., facioscapulohumeral dystrophy). With dystrophic myopathies, the thin connective tissue layers separating individual muscle fibers thicken and the muscle fibers may undergo considerable fibrosis. Regarding disease tempo, muscle fiber necrosis, basophilia, and myophagocytosis are features typical of an active myopathic process, whereas muscle fiber splitting is more characteristic of a chronic myopathy. [11i

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Biopsy of the peripheral nerve has somewhat limited use. It is generally performed in suspected neuromuscular diseases in order to aid in the distinction between segmental demyelination and axonal degeneration, particularly when the clinical evaluation, laboratory studies, and electrophysiological examinations are nondiagnostic or contradictory. Nerve biopsy may also be useful in the diagnosis of a number of specific disorders with characteristic findings that may involve a peripheral nerve such as amyloidosis, vasculitis, sarcoidosis, and some neoplasms. y Diagnostic nerve biopsy is generally restricted to a relatively expendable sensory nerve such as the sural, although portions of peripheral motor nerve twigs may be available for examination as part of muscle biopsy. Because of the limited amount of nervous system tissue available for examination and the relatively limited repertoire of pathological findings, peripheral nerve biopsy has a high chance of being noninformative unless the procedure is performed to answer a specific question in the context of the other clinical and electrophysiological findings.

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