Skeletal Muscle Pathology
Muscle biopsy often contributes significantly to the evaluation of patients with neuromuscular disease. Knowledge of the fundamentals of muscle biopsy pathology is useful to promote understanding of the pathogenesis of many types of neuromuscular disorders and assists the non-pathologist clinician to understand reports that he or she receives for the muscle biopsies from his or her patients. Knowledge of the basic foundation of muscle biopsy also helps the clinician to understand in what situations a muscle biopsy would be expected to be helpful in assessment of the patient with neuromuscular disease and to be familiar with the types of information that it can provide.
This article is intended to provide an introduction to the pathology of skeletal muscle biopsy and present the pathological features characteristic of certain disorders; this will not present instruction on the subtleties of advanced muscle biopsy diagnosis. This article first presents and contrasts neurogenic and general myopathic features on muscle biopsy. The remainder of this article addresses the key clinical characteristics and pathologic findings on muscle biopsy of selected examples of disorders from 4 different categories of muscle disease: immune-mediated (inflammatory) myopathies, muscular dystrophies, metabolic myopathies, and congenital myopathies. There are occasional examples of the pathology of other disorders that are in the differential diagnosis of some of these entities in order to illustrate their contrasting pathologic features.
Two other articles are companions for this article. The article Skeletal Muscle – Structure and Histology provides a review of normal skeletal muscle histology and ultrastructure, including the histologic appearance of normal muscle with some of the various stains that are used for the processing of muscle biopsies. The article Muscle Biopsy and Clinical and Laboratory Features of Neuromuscular Disease provides information about the procedure of muscle biopsy and background about the general features of the clinical presentations of neuromuscular disorders.
Interpretation of a muscle biopsy can be a challenging task. This process can be difficult because few individual histologic findings are specifically diagnostic of a single disorder. Most muscle biopsies exhibit a constellation of pathologic findings that must be synthesized to arrive at a diagnosis. The muscle pathologist must analyze and interpret the histopathologic features within the individual clinical context to arrive at a diagnostic formulation that makes sense for a given patient.
Here is an example to illustrate the lack of specificity of histopathologic findings and the importance of clinical information for interpretation of a muscle biopsy: A biopsy might exhibit myofibers that contain clear vacuoles on hematoxylin and eosin (H&E) sections. Similar vacuoles can be observed in a variety of settings, including glycogen storage disease, colchicine toxic myopathy, critical care myopathy, the periodic paralyses, and technical artifact, among others. The pathologist uses a variety of strategies to decide which is the most likely cause of the vacuoles in a given case and to determine whether additional special studies are indicated. The simplest and most cost-effective first step is to know which disorders might be reasonable considerations for a specific patient.
Many biopsy samples show numerous pathological findings in varying degrees, each of which is consistent with an assortment of diagnoses. The pathologist must judge the clinical significance of each finding, decide if and how it fits with the other findings in the specimen, and determine what light to cast on the biopsy result to best fit the patient’s presentation. This means that the physicians who submit the biopsy must provide reasonably detailed clinical information. Simply writing, “R/O polymyositis” or “weakness”, or worse, “muscle weakness” (we would not be concerned about weakness of character here, so using the term muscle weakness in this context seems oddly redundant) does not provide the pathologist with any useful clinical information and is a disservice to the patient. The clinical information you provide is not just a bureaucratic requirement and it is not for the benefit of the pathologist; it is for the patient.
Here is the clinical information that must accompany a muscle biopsy to make it possible for the pathologist to fully interpret the histopathologic findings and to determine if special studies are indicated, and if so, which ones would be relevant to a specific individual. It can be stated concisely in a few short phrases or lists or can be submittted in the form of a preexisting clinical note that contains this information:
Skeletal muscle can show neurogenic changes in disorders that affect any part of motor neurons, including diseases of the anterior horn cell (eg, motor neuron disease), motor neuropathy, peripheral neuropathy, and disorders that affect the intramuscular nerve twigs. One of the common tasks in evaluating muscle biopsies is to provide assistance in determining whether the patient has neuropathy or myopathy. (See the “Clinical and Laboratory Features of Neuromuscular Disease” section of Muscle Biopsy and Clinical and Laboratory Features of Neuromuscular Disease for a discussion of this issue.)
Neurogenic disorders have the following characteristics on muscle biopsy:
Angulated atrophic myofibers
These atrophic myofibers may stain intensely with the NADH stain
These atrophic myofibers may stain intensely with the nonspecific esterase stain
These characteristic features of neurogenic atrophy seen on muscle biopsy are discussed and illustrated below:
The image below shows an example of neurogenic fiber-type grouping using myosin heavy chain immunohistochemistry:
When all of these findings are present and no other abnormalities are found in the specimen, the diagnosis of neurogenic atrophy with evidence of denervation and reinnervation is straightforward. Often, the biopsy shows a combination of neurogenic and myopathic findings (see Muscle Biopsy in Myopathy, below). These additional myopathic features may represent myopathy that is secondary to the neuropathic process, which are referred to as pseudomyopathic features, or a separate unrelated primary myopathic process. The pathologist can often surmise the correct interpretation based on clinical findings and the balance of the pathologic features, but the truth cannot usually be determined with certainty based upon the histological features alone. Knowledge of the pertinent clinical and laboratory features can often eliminate the uncertainty and lead to a definitive biopsy diagnosis.
Many biopsy samples with inflammation also demonstrate evidence of neurogenic change. A few possible mechanisms account for neurogenic change in the setting of an inflammatory disorder: (1) myogenic denervation, in which the sick muscle fibers lose their innervation; (2) innocent bystander mechanism, in which the inflammatory process overruns and entraps the intramuscular nerve twigs, resulting in denervation; and (3) separate concurrent inflammation of peripheral nerves. An unrelated neurogenic disorder is also possible.
A broad spectrum of pathologic findings can occur in myopathic disorders. Each individual finding is usually nonspecific and can be found in a variety of pathologic processes. A single finding can have many connotations, and the pathologist must always use knowledge of the clinical context to interpret the diagnostic significance of the individual findings. The constellation of pathologic findings considered within a given clinical setting leads to the diagnosis.
The pathologic findings that typify neurogenic change in muscle have been discussed in the preceding section. Below are some findings that are characteristic of myopathic processes, including the following:
Myofiber necrosis (see the image below)
Myophagocytosis (see the following image)
Regeneration (see the image below)
Rounded, atrophic fibers (see the following image)
Myofiber hypertrophy and splitting (see the image below)
Increase in internal nuclei: Myofiber nuclei are normally located at the periphery of the cell; it is abnormal when greater than 3% of the myofibers in a specimen exhibit internal nuclei (see the following image).
Endomyisal fibrosis (see the image below)
Numerous other ancillary findings can be found in myopathic muscle biopsy samples. Additional histologic myopathic findings include the following:
Nuclear chains (see the following image)
Moth-eaten fibers (see the image below)
Ring fibers (see the following image)
Whorled fibers (see the image below)
Vacuoles (see the following image)
Inclusions (see the 2 images below)
Inflammation (see the following 3 images)
Some histologic findings mimic abnormalities but are actually normal features of skeletal muscle structure. For example, near the myotendinous junction, the muscle fibers appear fragmented, exhibit increased variability of fiber size, and have an increase in number of internal nuclei (see the image below). The myofibers near the myotendinous insertion in normal muscle can also contain nemaline rods (see “Nemaline myopathy” in the Congenital Myopathies and Tubular Aggregate Myopathy section). The pathologist must be vigilant not to misinterpret these normal findings.
Five important groups of disorders that can be diagnosed by muscle biopsy include the following:
Myositis and immune-mediated myopathies
Glycogen storage diseases (metabolic myopathies)
Mitochondrial myopathies (metabolic myopathies)
The clinical features and pathology of these myopathies are reviewed by diagnostic category in the following sections.
The term myositis is nonspecific and refers to inflammatory disease of muscle, encompassing both infectious and noninfectious inflammatory disorders, and includes some immune-mediated disorders that exhibit little to no inflammation on muscle biopsy. Infectious myositis occurs from direct infection of skeletal muscle by organisms from any category, including bacteria, viruses, protozoans (eg, Toxoplasma gondii) and metazoans (eg, the nematode Trichinella spiralis or the cestode Taenia solium). See the end of this section for an image of a muscle with trichinosis.
A postinfectious inflammatory myopathy can occur, in which the organism might no longer be present or may never have been present in the muscle, and the inflammatory disorder in this case can be the result of an autoimmune response to the infection.
In daily practice, the term myositis is often applied to three disorders that are often considered to be the major idiopathic inflammatory myopathies that are included in the discussion below; however, it is more appropriate to avoid the nonspecific designation myositis in favor of more specific and meaningful terminology. This field is in flux and there are multiple current classifications, each with its own group of advocates. A listing of some of immune-mediated myopathic disorders is presented in the image below. The terms immune-mediated myopathy, autoimmune myopathy, and inflammatory myopathy will be used interchangeably in this section, although technically they are not identical in meaning. Good reviews of the clinical and pathologic features and some current nosologies of inflammatory myopathies exist; reading of these references will highlight the issues of controversy in this area of medicine. [1, 2, 3, 4, 5]
The most common reason for performing a muscle biopsy is to address the diagnostic consideration of immune-mediated myopathy. The three major immune-mediated (or inflammatory myopathies) that have been recognized for the last few to several decades are polymyositis, dermatomyositis, and sporadic inclusion body myositis (to be referred to here as IBM). It is not certain whether IBM will always remain in this category or if it will be moved into the category of degenerative diseases of muscle (it will probably always straddle both categories); for now, it is considered in this section of this article. A fourth category of immune-mediated myopathy, that of immune-mediated necrotizing myopathy, is now recognized as a significant category among the autoimmune myopathies.
The usual clinical presentation of individuals with polymyositis and dermatomyositis is a subacute course of progressive weakness affecting proximal muscle groups, occasionally with myalgia, an elevated creatine kinase (CK) level, and myopathic and irritative findings on electromyography (EMG). Many patients have serum autoantibodies, [3, 5] many of which are associated with specific clinical syndromes; the specific autoantibodies are taking on increasing importance in the classification of the inflammatory myopathies. Patients with dermatomyositis usually have characteristic cutaneous findings, such as a periocular heliotrope rash, Gottron papules on the extensor surfaces of the hands and fingers over the joints, or certain other skin changes.
Dermatomyositis in adults can be a paraneoplastic syndrome  ; therefore, some testing for malignancy is necessary when an adult patient has this disorder. Dermatomyositis can develop before, concurrently with, or following the diagnosis of a neoplasm, usually within 2 years either before or after. The risk of malignancy in a specific individual with dermatomyositis is associated with which autoantibody is present; some autoantibodies are associated with a high risk of malignancy and others with a low risk. Polymyositis can also be a paraneoplastic syndrome, but the association of polymyositis with cancer is weaker than that of dermatomyositis.
The clinical presentation of immune-mediated necrotizing myopathy (IMNM) varies depending upon the underlying cause. In one form of this disorder that can be associated with anti-signal recognition particle (anti-SRP) antibodies, individuals typically present with a rapidly progressive proximal myopathy. One form of IMNM is associated with treatment with the statin medications that are hydroxy-methyl-glutaryl coenzyme A reductase (HMGCR) inhibitors. Affected individuals present with a subacute progressive proximal myopathy. Progression continues despite discontinuation of the statin medication. Many of the individuals with statin-associated IMNM have HMGCR autoantibodies. There are also non-immune myopathies that are associated with treatment of statin medications; these are not discussed here.
The following are the key diagnostic pathologic features of polymyositis:
Endomysial inflammation (see the images below): The inflammatory infiltrates in polymyositis are predominantly endomysial, and they are enriched with T-lymphocytes, particularly T-suppressor/cytotoxic (CD8) lymphocytes.
Invasion of (or an attack on) nonnecrotic myofibers by autoaggressive lymphocytes (see the following images): This is a key diagnostic finding in which T cells attack intact myofibers, and it is believed to be the pathologic correlate of the main factor in the etiopathogenesis of polymyositis. [7, 8, 9] This represents the fundamental distinction between inflammation that can occur as a secondary phenomenon and inflammation that is the primary pathologic process. In the former case (eg, muscular dystrophy), inflammation is usually found associated with fibers that are already degenerating. In polymyositis, inflammation can be found associated with healthy, intact fibers.
The expression of major histocompatibility complex (MHC) class I antigen or human leukocyte antigen (HLA) class ABC (or class I) antigen on the surface of intact (nonnecrotic or nonregenerating) myofibers occurs in all inflammatory myopathies and is not specific for polymyositis (see the image below). This up-regulation of HLA class I expression on nonnecrotic myofiber surfaces is not entirely specific for inflammatory myopathies and can be found in some muscular dystrophies. Degenerating and regenerating myofibers in any disorder often have HLA class I upregulation, so one must consider only the intact myofibers when interpreting this stain.
The following pathologic features are also often found in polymyositis, but they are not diagnostically specific and can be found in a variety of myopathic disorders:
Myofiber necrosis (see the image below)
Myophagocytosis (see the following image): This is the removal of the dead cellular elements by macrophages.
Internal nuclei (see the image below): An increase in internal nuclei is a nonspecific myopathic finding.
Myofiber atrophy: Myopathic atrophic fibers are generally of both myofiber types and rounded in contour. In some patients with polymyositis, the atrophy affects primarily type 2 myofibers. In patients with inflammatory myopathies, type 2 myofiber atrophy can also be the result of treatment with steroids.
Regeneration (see the following image)
Endomysial fibrosis: This is a feature of chronic polymyositis.
The distribution of the pathology in polymyositis can be patchy, so it is possible for a patient who has this disorder to have a normal muscle biopsy, and this does not completely exclude the diagnosis. Magnetic resonance imaging of the muscle reportedly assists in selection of a muscle to biopsy to increase the likelihood of a positive biopsy. As in all of medicine, neuromuscular diagnosis is a synthesis of clinical, laboratory, and biopsy features, and physicians must use judgment in interpreting the clinical significance of each individual result.
Pathologic findings in dermatomyositis can sometimes bear a superficial resemblance to polymyositis, but some important distinguishing features are present. In many patients, the pathology of dermatomyositis is strikingly unique.
The following are pathologic features that are characteristic of dermatomyositis:
Chronic inflammation (see the image below): The infiltrates are most often concentrated in a perimysial perivascular distribution. More B-lymphocytes and T-helper (CD4) lymphocytes are present than in polymyositis. If the histologic features are otherwise characteristic, the diagnosis is made regardless of the exact cell types within an individual infiltrate in a single case, so if typing the lymphocytes is not expected to contribute to the diagnosis, it is not performed. Some cases of dermatomyositis do not exhibit inflammation.
Perifascicular atrophy (see the following image): This type of myofiber atrophy affects the fibers at the periphery of the fascicle and is believed to be a product of muscle ischemia at the capillary level. It is found somewhat more often in juvenile dermatomyositis, but is frequently also observed in the adult variant of this disorder. Although perifascicular atrophy is not absolutely specific for dermatomyositis, it is found only in a small number of other disease processes.
Myofiber necrosis and/or regeneration: This can occur in a perifascicular distribution.
Complement deposition in microvessel walls (see the image below): The deposition of the membrane attack complex of complement (C5b-9) is found in the walls of the microvessels early in the disease process, even before other pathologic findings are present. This immune attack on vessel walls, with an immunologic cascade involving humoral immunity, may be the pathogenetic mechanism of dermatomyositis, according to the pioneering research of Andrew Engel and his colleagues.  Treatment with steroids may promptly eliminate this finding.
Tubuloreticular inclusions (TRIs) in endothelial cells (see the following image): This finding is seen only at the ultrastructural level and is usually no longer present after treatment.
HLA class I antigen expression on the surfaces of myofibers (see the image below)
Inclusion body myositis (IBM) is the most common idiopathic inflammatory myopathy in patients older than 50 years. In contrast to polymyositis and dermatomyositis, which affect more women than men, IBM more often affects men, with a male-to-female ratio of 1.5:1. The clinical course of IBM is typically more indolent than polymyositis or dermatomyositis. It is not unusual for a person to have severe muscle atrophy at the time of presentation for medical care. This indicates that the disorder has been present for some time before the individual seeks medical evaluation. Distal muscle involvement, particularly with weakness of finger flexors, is a common feature of IBM, but it is unusual in other inflammatory myopathies. IBM is often resistant to therapy, although some patients do respond to immunomodulatory therapies.
IBM is the inflammatory counterpart of a group of disorders known as inclusion body myopathies, which includes a variety of inherited myopathies, some with characteristic, distinctive clinical presentations (eg, quadriceps-sparing myopathy). These myopathies share many of the pathologic findings of IBM. However, the hereditary forms of IBM (HIBM) are not inflammatory myopathies, and they do not typically exhibit evidence of mitochondrial abnormalities, whereas mitochondrial abnormalities are commonly seen in inclusion body myositis. A succinct review of inclusion body myositis by Needham and Mastaglia summarizes the key clinical, histologic, pathogenetic, and treatment issues.  A more recent reference that includes a brief discussion of clinical trials for inclusion body myositis is written by Dimachkie and Barohn. 
The following are pathologic features of IBM:
Chronic inflammation: The inflammatory process is similar to that of polymyositis, with an endomysial location of the inflammation and infiltrates that are enriched in CD8 lymphocytes, which are cytotoxic/suppressor T-lymphocytes.
Invasion of nonnecrotic myofibers by autoaggressive lymphocytes (see the following image)
Myofiber hypertrophy (see the image below): Hypertrophy in a myositis biopsy should prompt a consideration of the possibility of IBM
Atrophy: Some of the atrophic fibers in IBM share features with those of neurogenic atrophy.
Rimmed vacuoles (see the following image): These appear on hematoxylin and eosin (H&E) sections as ovoid sarcoplasmic vacuoles lined by blue granular material. The granular material is red with the trichrome stain.
Eosinophilic inclusions (see the following images): These inclusions are dense and red (eosinophilic) on H&E sections, they can be cytoplasmic or nuclear, and they may be found within rimmed vacuoles. These inclusions can stain positive with a Congo red stain for amyloid and with stains for amyloid precursor protein, ubiquitin, and TDP-43, which are proteins typically associated with neurodegenerative disease.
Tubulofilamentous inclusions (see the image below): These are the ultrastructural counterparts of the eosinophilic inclusions observed by light microscopy.
HLA class I expression on the surface of myofibers (see the following image)
Myofiber degeneration, myophagocytosis, internal nuclei, endomysial fibrosis (see the following 2 images). Patients with IBM commonly seek medical care at a relatively late stage in the disease process, so the biopsies often demonstrate severe loss of muscle mass with prominent fibrosis and even adipose replacement of the muscle.
Ragged red fibers (see the image below), indicative of mitochondrial alterations are commonly found in IBM.
There are some muscle biopsies that show randomly distributed necrotic and/or regenerating myofibers and widespread myofiber labeling with the HLA class I immunohistochemistry preparation, but little to no inflammation. These biopsy findings are consistent with the diagnostic entity of immune-mediated necrotizing myopathy (IMNM).
Some patients with IMNM present with a fairly rapidly evolving myopathy with severe weakness. They tend to have exceedingly high CK levels, often greater than 20,000 IU/L (normal CK levels are usually less than 200 IU/L). Some of these patients have autoantibodies in their serologic studies, often to anti–signal recognition particle (anti-SRP). The presence of these autoantibodies is the strongest evidence that this disorder is an immune-mediated disease. Anti-SRP IMNM is relatively resistant to therapy.
Some patients with IMNM have a history of therapy for hypercholesterolemia with HMG-CoA reductase inhibitors and are found to have HMG-CoA reductase antibodies in their serum. [13, 14, 15] IMNM is not the only type of myopathy that can develop in patients treated with statin medications; a discussion of this area is beyond the scope of this article. The next three images are from a case of IMNM.
An occasional eosinophil can often be seen in necrotizing and inflammatory myopathies. When many eosinophils are present, begin to search for a specific etiology of the myopathy, such as trichinosis (see the first image below) or drug reaction (see the second image below).
The image below shows a larva of the nematode, Trichinella spiralis, in skeletal muscle:
A muscular dystrophy is a potentially hereditary disease characterized by progressive degeneration of muscle. Many such diseases exist. The old nomenclature was somewhat random and comprised Duchenne, Becker, and various other eponymous dystrophies and dystrophies named for the distribution of affected muscle groups (such as oculopharyngeal muscular dystrophy or scapuloperoneal muscular dystrophy), all subclassified by their modes of inheritance.
The etiology of many of these disorders and a more pathogenetic classification is evolving. Duchenne and Becker dystrophies are now classified as dystrophinopathies, because they are caused by mutations in the gene for the protein dystrophin. Similarly, abnormalities of other structural proteins of skeletal muscle are being discovered, such that, instead of simply using the generic term limb-girdle muscular dystrophy, disorders due to abnormalities of membrane proteins, such as sarcoglycans, dystroglycans, dysferlin, and others, are recognized. Abnormalities of proteins of the nucleus, cytoskeletal proteins and the basal lamina external to the sarcolemma (plasma membrane of the skeletal muscle cell) are also responsible for some forms of muscular dystrophy. 
Some congenital muscular dystrophies are caused by mutations in genes that are responsible for glycosylation of alpha-dystroglycan, a membrane protein.  These latter disorders belong to yet another category of disorders that has been recognized, that of muscular dystrophies that result from abnormalities of genes for proteins involved in the posttranslational modification of membrane proteins, rather than from defects that alter the primary amino acid sequence of membrane or cytoskeletal proteins.
As steady progress is made in determining the genetic basis of many muscular dystrophies, in many cases muscle biopsy sometimes replaced by genetic testing and is becoming less important as a diagnostic tool for these disorders. However, muscle biopsy is still required for many muscular dystrophies, in which the biopsy can identify a myopathic disorder as dystrophic rather than another category of myopathy. Immunohistochemistry for specific muscular dystrophy proteins can often narrow the diagnostic possibilities and limit the number of genetic tests needed in an individual case.  Specific and directed biochemical or genetic testing can then be performed for definitive diagnosis.
For patients with classic presentations of dystrophinopathies with characteristic clinical features of either Duchenne or Becker muscular dystrophy, the diagnosis can be made by genetic testing of blood samples, so muscle biopsy is not usually necessary in these cases. In certain cases of other types of muscular dystrophies with characteristic clinical presentations, genetic testing can also bypass the need for muscle biopsy for definitive diagnosis.
For patients with nonclassic presentations and no family history of a dystrophinopathy, such as a limb-girdle dystrophy presenting in adulthood that is ultimately diagnosed as a dystrophinopathy or a woman who presents with a myopathic clinical syndrome and is eventually found to be a manifesting carrier of a dystrophin gene mutation, muscle biopsy is often a necessary first step to arrive at a diagnosis. For patients with nonspecific clinical features of myopathy that, in some cases, will finally be diagnosed as a specific dystrophy, muscle biopsy is still an important diagnostic tool.
Most of the pathologic findings in the routine histologic sections of skeletal muscle in the muscular dystrophies are nonspecific myopathic findings (see the following series of images).
Occasional features are somewhat characteristic of certain dystrophies, such as hypercontracted fibers in Duchenne muscular dystrophy (see the section about Duchenne muscular dystrophy, below, or the separate article Dystrophinopathies) or nuclear clumps in the muscle biopsies from some patients with limb-girdle muscular dystrophy (see Limb-Girdle Muscular Dystrophy). The skeletal muscles of certain patients with oculopharyngeal dystrophy (see the image below) contain rimmed vacuoles and eosinophilic inclusions similar to inclusion body myositis (IBM).
The specific diagnosis of muscular dystrophies can be confirmed in many cases by special immunohistochemical stains for specific proteins that are abnormal or deficient in these disorders. Many of these disorders are uncommon, so this testing is only available in a limited number of specialized centers, and it is necessary to send the muscle biopsy to a laboratory that is prepared to perform these studies, if they are indicated. If the immunohistochemistry findings point to a certain disorder, the muscle specimen might be sent to a facility that can perform biochemical analysis for the protein or direct genetic testing. More often, in these cases, a sample of blood from the affected individual can be submitted to a laboratory that performs genetic testing for confirmation of the immunohistochemistry results and final definitive diagnosis.
Some muscular dystrophies cannot be specifically diagnosed by immunohistochemistry, for reasons that are beyond the scope of this article.
Examples of muscle biopsies from patients with the two dystrophinopathies, Duchenne and Becker muscular dystrophies, and congenital muscular dystrophy (CMD) due to laminin alpha-2 deficiency are presented below to illustrate the pathology of muscular dystrophies.
Duchenne muscular dystrophy (DMD) is the most common and most severe of all muscular dystrophies, occurring with a frequency of 1 case in 3500 – 5,000 live male births. This condition is caused by a mutation on the X-chromosome in the gene for the protein dystrophin, resulting in an absence of the protein. Dystrophin is a structural protein that is normally located on the inner aspect of the sarcolemma (muscle plasma membrane). The gene for dystrophin is large, with approximately 2 million base pairs. Because of the size of this gene, spontaneous mutations are common, and one-third of patients with DMD do not have a family history of the disease.
The children (boys) are generally healthy until approximately age 3 years, when they develop problems with gait. In the early juvenile years, when normal development proceeds with a steep upward curve in increasing strength, many children with DMD appear to stabilize for a short time, but after that, they experience an inexorably progressive course. Without treatment, all patients are wheelchair bound by age 12 years, and most die in the second decade of life. With steroid therapy, many patients remain ambulatory until age 15 or 16 years, and survival can be prolonged well into the third decade of life. There are other therapies for Duchenne muscular dystrophy, some current, some in clinical trials and some for the future. [19, 20]
Muscle biopsy sections from young patients with DMD illustrate the following characteristic, but nonspecific pathologic findings:
Endomysial and perimysial fibrosis (see the image below)
Increased variability of myofiber size caused by the presence of both atrophy and hypertrophy with fiber splitting (see the following image)
Myofiber necrosis (see the image below)
Increased internal nuclei
Opaque fibers (see the following image): These are characteristic of DMD, although they can be found in other disorders and can be a technical effect. Opaque fibers are enlarged, densely eosinophilic fibers that are hypercontracted. Their presence in DMD caused investigators to postulate that membrane defects might be present in DMD, which were later demonstrated, and this finding eventually led to the discovery of the cause of DMD. [21, 22] In DMD, the lack of dystrophin leads to membrane instability, which is responsible for the cascade of cellular events that causes cycles of necrosis, regeneration, and progressive fibrosis of the muscle.
The specific diagnosis of DMD on muscle biopsy relies on special immunohistochemical studies, most often for the N -terminal, mid-rod, and C -terminal regions of dystrophin. Some laboratories use other sets of anti-dystrophin antibodies. In control skeletal muscle, these studies reveal linear labeling of the periphery of the myofibers, consistent with the regular periodic subsarcolemmal localization of dystrophin (see the first image below). In a patient with DMD (see the second image below), all 3 antibodies demonstrate absence of labeling of all but an occasional myofiber.
The rare myofibers that do label with antidystrophin antibody can produce dystrophin because of a second mutation in the dystrophin gene that restores the reading frame and allows for production of this protein. The observation that occasional myofibers in patients with DMD can produce dystrophin serves as the basis for some efforts to develop novel therapeutic interventions for this disorder (see the previous image, which shows labeling for dystrophin in a single myofiber, whereas all of the other myofibers do not produce dystrophin).
It is also possible to perform immunohistochemistry for a protein that is homologous to dystrophin, utrophin, which in postnatal life is normally limited to the neuromuscular junction. In patients with dystrophinopathies, utrophin expression is increased, and it can be detected in the sarcolemma by immunohistochemistry (see the image below).
Becker muscular dystrophy (BMD), a disease similar to DMD but with a later onset and a course characterized by a slower progression, is also caused by mutations of the dystrophin gene. In BMD, the mutations lead to production of abnormal dystrophin, occasionally in decreased quantities in comparison with normal skeletal muscle and in contrast to the absence of dystrophin in DMD. The term Becker muscular dystrophy should ultimately be replaced by the term dystrophinopathy with a designation of what part of the dystrophin molecule is affected in a given case.
The course of BMD, as the term is commonly used in clinical practice, is more variable than that of DMD, which is stereotypical. Although BMD originally meant a progressive proximal myopathy presenting in young school-age boys, currently clinicians will use the term for an individual of any age who presents with a muscular dystrophy and is found to have abnormal dystrophin. In BMD, the severity of the disease generally correlates with the portion of the dystrophin molecule affected. The C -terminal end of dystrophin is linked to β-dystroglycan of the transmembrane glycoprotein complex that is linked to alpha-dystroglycan, which is, in turn, anchored to the external basal lamina of the myofiber. If the C -terminal region of the dystrophin molecule is absent, the patient experiences a severe course. In general, if the patient has a mutation affecting the mid-rod domain the course is less severe and more indolent. In the setting of a mutation affecting the N -terminal end of the dystrophin molecule, which is linked to cytoskeletal actin, the clinical course is often intermediate between the other two types.
Below, the muscle biopsy illustrating BMD is from a 22-year-old man with a history of gradually progressive weakness that began in childhood. At age 22 years, he remained ambulatory but could no longer run. Muscle biopsy demonstrated the following:
Myofiber necrosis (see the following images): Mild, focal, chronic inflammation is associated with some necrotic fibers in this biopsy. The presence of inflammation might lead to a mistaken consideration of an inflammatory myopathy. In this patient, the clinical history strongly suggests dystrophy instead of inflammatory myopathy, which should prompt a pathologist to avoid hastily forming an erroneous conclusion. With dystrophy, the inflammation is often restricted to an association with necrotic fibers, whereas in myositis, it can usually be found elsewhere in the muscle; this key finding can sometimes help to distinguish the inflammation in a dystrophy from that of myositis. This assessment can be difficult, and exceptions to this guideline exist. In inflammatory myopathies, there should be widespread myofiber surface expression of human leukocyte antigen (HLA) class I antigen (see section about inflammatory myopathies, above), which in most dystrophies is limited to the actively necrotic or regenerating myofibers, so this study can also assist in distinguishing a dystrophy with inflammation from an inflammatory myopathy.
Increased variability of myofiber size with myofiber atrophy and hypertrophy (see the first image below) and myofiber splitting (see the second image below)
Myofiber regeneration (not shown here, but see regenerating myofiber in the section Muscle Biopsy in Myopathy, above)
Increase in internal nuclei (see the previous two images): In this patient, the increase in the percentage of myofibers with internal nuclei is mild.
The findings in this representative biopsy, above, are nonspecific and can be observed in most muscular dystrophies. The immunohistochemical findings lend specificity to the histologic diagnosis. In this case, staining for C -terminal and mid-rod portions of the dystrophin molecule is normal (see the first image below), but the muscle shows no staining with the antibody for the N -terminal region (see the second image below). This is highly consistent with the diagnosis of BMD, but this diagnosis should be confirmed by sending a sample of blood for genetic testing for a mutation in the gene for dystrophin. It might be possible to send a skeletal muscle specimen to a laboratory for Western blot analysis to confirm the immunohistochemistry result, but genetic testing on a sample of blood is currently more commonly performed and more widely available than analysis of the protein in muscle.
Extensive research has led to a detailed model of the structure of the myofiber membrane and has elucidated the components of the transmembrane glycoprotein complex. It contains several proteins known as sarcoglycans and others known as dystroglycans. Mutations of each of these proteins, as well as others not mentioned here, are now known to be responsible for many forms of muscular dystrophy. 
Congenital muscular dystrophy (CMD) is usually clinically evident from the neonatal period. Multiple disorders fall within this category. In one-third of affected patients, CMD is caused by an abnormality of laminin alpha-2, also known as merosin, which is a component of the basal lamina of skeletal muscle, located just external to the myofiber. Some forms of CMD are now known to be due to mutations that result in defective glycosylation of alpha-dystroglycan, a membrane protein to which laminin alpha-2 binds. 
Congenital muscular dystrophy is in the differential diagnosis of the floppy infant syndrome. An illustrative case is described below.
Muscle biopsy was performed in a 4-month-old floppy male infant who was a full-term infant with low Apgar scores. He had mild joint contractures and weakness of the upper extremities greater than that of his lower extremities. Electrodiagnostic studies showed early myopathic units and borderline nerve conduction velocities. Computed tomography (CT) scans and magnetic resonance images (MRIs) of the brain were reportedly normal.
This infant’s muscle biopsy (see the following images) shows a range of fiber sizes, instead of the normal fairly uniform size of myofibers.
Necrosis is absent, but occasional fibers exhibit minor nonspecific abnormalities on trichrome and nicotinamide adenine dinucleotide (NADH) stains. Immunohistochemical studies for dystrophin are normal (see the first image from this case, above), but no labeling occurs with an antibody to laminin alpha-2 (see the second image from this case, above). A control stain performed simultaneously on a normal muscle sample (see the third image from this case, above) demonstrates the normal pattern of staining for laminin alpha-2, demonstrating that the lack of staining observed in the case is specific for this case and not simply a technical failure of the staining procedure. The labeling that is present with antibodies to dystrophin, noted above, demonstrates that the lack of labeling of the case with laminin alpha-2antibody is specific and not just due to generalized loss of immunoreactivity of the specimen. Therefore, the diagnosis is CMD caused by deficiency of laminin alpha-2 (or merosin); this should be confirmed by genetic testing for the gene for this protein.
There are developmental brain abnormalities that are commonly found in laminin-deficient congenital muscular dystrophy, although they were not identified in the neuroimaging study of this patient.
A major clinical differential diagnostic consideration in this patient prior to muscle biopsy was Werdnig-Hoffmann disease, which is infantile spinal muscular atrophy, a motor neuron disease. At present, the best way to diagnose infantile spinal muscular atrophy is by genetic testing performed with a sample of blood. If the blood test is unrevealing, muscle biopsy can be performed.
In Werdnig-Hoffmann disease, as in CMD, muscle biopsy demonstrates a range of myofiber sizes. However, unlike CMD, in Werdnig-Hoffmann disease, the largest fibers (see the first image below) tend to cluster. In biopsy samples from patients with Werdnig-Hoffmann, the largest and smallest fibers are both type 1 myofibers (see the second image below); this finding does not occur in CMD. If immunohistochemistry for muscular dystrophy proteins were performed, it would be normal. An important caveat is that these changes in myofiber distribution are generally not present until the infant is several months old. Therefore, when possible, defer biopsy until the infant is age 6 months, or prepare the family for the possibility of the necessity to obtain a second biopsy if findings on the first are not specifically diagnostic. Because Werdnig-Hoffmann disease can currently be diagnosed by genetic testing, it is no longer common practice to obtain a muscle biopsy if this disorder is suspected.
Glycogenoses are inherited inborn errors of glycogen metabolism; 9 of these disorders affect skeletal muscle. The 2 most commonly encountered by muscle pathologists are type II glycogenosis (acid maltase or alpha glucosidase deficiency) and type V glycogenosis (myophosphorylase deficiency).
There are 2 types of clinical presentations of glycogen storage diseases, as follows:
The first type is characterized by symptoms of weakness and/or cramps during the anaerobic phase of exercise. This syndrome is due to defects in the enzymes required for mobilization of glycogen or abnormalities of glycolytic enzymes that for energy production from metabolism of glucose during exercise, particularly during anaerobic exercise.
The second type is characterized by a progressive proximal myopathy without significant exercise-induced symptoms. This syndrome is caused by defective enzymes involved in the glycogen synthetic pathway or for the metabolism of glycogen located in lysosomes that is not in the metabolic pathway for energy production during exercise.
Type II glycogenosis, which is due to deficiency of acid maltase (acid alpha-glucosidase), is the only glycogen storage disease that is also a lysosomal storage disease. This disorder has the following 3 basic clinical variants:
A severe, fatal, infantile form, also known as Pompe disease, affects multiple organs, including the heart, liver, kidneys, leukocytes, central nervous system, and skeletal muscle. Glycogen storage is demonstrated in most tissues in this disorder.
A juvenile variant presents with weakness affecting the muscles of proximal limbs.
In adult-onset acid maltase deficiency, weakness and fatigue occur and early progressive respiratory failure is typical.
The age of onset and severity of the clinical presentation are generally inversely correlated with the severity of the enzymatic deficiency; the infantile form is the most severe and usually associated with the lowest levels of residual enzyme activity.
The following are muscle biopsy findings in acid maltase deficiency:
Clear vacuoles on hematoxylin and eosin (H&E) sections, usually distributed throughout the affected myofibers (see the image below)
Periodic acid Schiff (PAS)–positive staining of these vacuoles, with disappearance of staining following digestion with diastase
Acid phosphatase stain, which demonstrates excessive staining for lysosomes (see the image below) that correspond to the vacuoles seen with the H&E stain
Intralysosomal storage of glycogen on electron micrography (EM) (see the following image)
Confirming the diagnosis of type II glycogenosis by biochemical assay of the activity of acid maltase from a special sample of skeletal muscle that has been obtained appropriately for this purpose or genetic confirmation of the diagnosis is necessary. If an optional additional fresh specimen, described in the technical section of the article Muscle Biopsy and Clinical and Laboratory Features of Neuromuscular Disease, it can be used for enzyme assay at a laboratory that performs this type of study. The assay can also be performed on cultured fibroblasts or on a sample of urine. It is also possible to identify the specific mutations responsible for producing the disease in an individual.
In type V glycogenosis (McArdle disease), due to deficiency of myophosphorylase, the abnormality is restricted to skeletal muscle. The classic presentation is the development of muscle cramps during the anaerobic phase of exercise and episodes of exercise-induced rhabdomyolysis (myofiber necrosis). Venous lactate levels fail to rise during an ischemic forearm exercise test; very few clinicians perform this test, at least partially due to a risk of inducing myofiber necrosis with this test.
The following are muscle biopsy findings in patients with myophosphorylase deficiency:
Clear vacuoles on H&E section, particularly in the subsarcolemmal location (see the following image)
PAS-positive staining of these vacuoles (see the first image below), with disappearance following digestion with diastase (see the second image below)
Storage of excessive amounts of free glycogen within myofibers on EM (see the following image)
Evidence of absence of myophosphorylase activity (see the first image below) on special histochemical staining, with normal activity in a simultaneous control specimen (see the second image below).
Mitochondrial myopathies are disorders with a broad spectrum of clinical presentations due to involvement of a variety of organ systems. These disorders affect organs that are highly dependent upon aerobic metabolism and therefore commonly affect the heart, skeletal muscle, eye, and brain. Renal and gastrointestinal involvement occurs in some cases. Many patients with disorders of mitochondrial function have basal elevation of serum lactate, because a block in oxidative phosphorylation causes slower turning of the Krebs cycle, which then results in decrease conversion of pyruvate to acetyl-CoA. The excess pyruvate that results is converted to lactate.
Numerous well-recognized clinical disorders are among this group of diseases, such as Kearns-Sayre syndrome, myoclonus epilepsy with ragged red fibers (MERRF), mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS), and Leber hereditary optic neuropathy (LHON). Many of these disorders present with a combination of central nervous system (CNS) disease and myopathy and are referred to as encephalomyopathies.
The common etiology underlying the mitochondrial disorders is the presence of mutations that affect mitochondrial function. In some of these disorders, the mutations are in the mitochondrial genome; in others, they are in the nuclear genes that encode mitochondrial proteins.
This is an extremely complex area because of the large variety of potential clinical presentations of these disorders. Many of the disorders can be due to multiple different mutations, and an individual mutation can cause more than one type of clinical disorder. Numerous excellent reviews address this complex topic and make it possible for clinicians to develop an approach to diagnosis. [24, 25, 26, 27]
Many of these fairly diverse disorders share a common finding on muscle biopsy: the ragged red fiber (RRF). A ragged red fiber is one with intense peripheral red staining with the Gomori trichrome stain. This red staining corresponds to aggregates of abnormal mitochondria. Ragged red fibers are not found in all mitochondrial disorders, so their absence does not exclude the presence of a mitochondrial disorder. Nonetheless, it is diagnostically important finding when they are present in a muscle biopsy from a patient with a clinical presentation that is suggestive of a mitochondrial disorder.
Ragged red fibers can occur as an age-related change in individuals age 50 years and older, so this finding in an older person must be interpreted with caution.
The following are characteristic pathologic findings in skeletal muscle in the mitochondrial myopathies:
On trichrome stain, ragged red fibers have a peripheral rim of red material caused by the subsarcolemmal aggregation of mitochondria (see the following image).
Dense peripheral staining for the activity of succinic dehydrogenase (SDH), which is a mitochondrial enzyme involved in the electron transfer chain, can be seen in myofibers corresponding to the ragged red fibers of the trichrome stain (see the blue fibers in the second image below). When visualized with the SDH stain, they are referred to as ragged blue fibers.
The presence of many fibers with absence of the activity of cytochrome oxidase (COX), which is complex IV of the respiratory chain enzymes, is a characteristic finding (see the following image).
Combined SDH/COX staining demonstrates that many of the COX-negative fibers are the ragged red fibers (see the image below).
Electron micrography shows both an increase in mitochondria and morphologically abnormal mitochondria (see the following images). Normal mitochondria can be seen in the electron micrographs in the article Muscle Biopsy and Clinical and Laboratory Features of Neuromuscular Disease
Identifying the specific biochemical and genetic abnormalities is possible in many patients with mitochondrial encephalomyopathies if an extra muscle specimen has been properly handled for this purpose.
Congenital myopathies are a diverse group of disorders with the common feature that each has its own characteristically distinctive morphologic-pathologic finding. Each congenital myopathy is named for these findings, as in the following:
In central core disease, the central region of many myofibers has abnormal structure.
In nemaline myopathy, the fibers contain aggregates of rodlike material seen on trichrome stain.
In centronuclear (or myotubular) myopathy, the main pathologic finding is centrally located nuclei in myofibers and fibers that appear immature.
In congenital fiber type disproportion, type 1 myofibers are small, and type 2 myofibers are of normal size.
Each individual congenital myopathy is probably actually a group of disorders with a common morphology on biopsy. Some have multiple characteristic clinical presentations, rates of progression, and modes of inheritance. Currently, the genetic and molecular bases of the defects are being identified, providing further evidence that they are heterogeneous disorders.
Nemaline myopathy is a disorder with both autosomal dominant and recessive modes of inheritance. A severe infantile form exists, and milder forms present later in life. Mutations in 5 different genes (so far) are associated with nemaline myopathy: α-actinin (chromosome 1q42), the nebulin gene (chromosome 22q2), α-tropomyosin 3, β-tropomyosin, and troponin-1. [28, 29, 30, 31] A form of nemaline myopathy is associated with human immunodeficiency virus (HIV) infection. Small numbers of nemaline rods are found relatively frequently in muscle biopsies, so their presence is not specifically diagnostic. They are a normal finding in myofibers located at the myotendinous insertion.
The biopsy presented below—from an 8-year-old boy with weakness since infancy, high arched oral palate, myopathic face with mild weakness of the proximal muscle groups of the extremities, and difficulty keeping up with his peers on the playground—demonstrates the characteristic findings of nemaline myopathy, as follows:
Hematoxylin and eosin (H&E) stain (see the following image) reveals a biopsy that appears normal except for a slight increase in internal nuclei.
Trichrome stain (see the first image below) shows the presence of inclusions in many fibers; on high power (see the second image below), these have a rodlike structure.
Myosin ATPase (see the following image) shows a predominance of type 1 myofibers.
Electron micrograph from a biopsy from a different individual with nemaline myopathy (see the image below) shows that the rods are dense fibrillar structures that extend from the Z bands.
Central core disease is another disorder that is actually a group of disorders. Many patients with central core disease are susceptible to malignant hyperthermia when certain anesthetics are administered. Some patients with central core disease possess mutations in a gene for the ryanodine receptor, which is a calcium channel in the sarcoplasmic reticulum. 
In central core disease, H&E section (see the first image below) shows many myofibers with faint central irregularities of staining. Myosin ATPase (see the second image below) demonstrates that many of the type 1 myofibers have central round areas that do not stain. These are the central cores. They also show absence of staining with the nicotinamide adenine dinucleotide tetrazolium reductase (NADH) stain, not illustrated here.
Tubular aggregate myopathy (TAM) is an unusual disorder that is not always classified as a congenital myopathy, but it has such a distinctive histopathologic picture that it is presented in this section. In a rare familial syndrome, affected patients have fluctuating weakness. Tubular aggregates also are found in association with patients with a variety of presentations or disorders, including: progressive proximal weakness, muscle cramps, diabetes mellitus, and alcoholism.
In tubular aggregate myopathy, inclusions are quite prominent, as demonstrated in the following:
H&E (see the image below): Many fibers have large, pale intracytoplasmic inclusions.
Periodic acid Schiff (PAS) (see the following image): These inclusions are PAS positive.
Fiber-typing stain (see the image below), in this case myosin ATPase: In some subgroups of this myopathy, inclusions are typically found only in type 2 myofibers, as illustrated here. This is highly unusual. In most disorders with inclusions that are fiber-type specific, the inclusions are usually found in type 1 myofibers.
NADH (see the following image): Inclusions are dark with this stain.
Succinic dehydrogenase (SDH) (see the image below): Tubular aggregate myopathy is the rare disorder in which inclusions are positive with the NADH stain but are negative for SDH. They are negative for the latter stain, because the tubular aggregates are composed of sarcoplasmic reticulum membrane. SDH is found exclusively in mitochondria.
Electron micrograph of tubular aggregates in cross-section (see the following image): Their tubular structure should be appreciated easily in this view.
Electron micrograph of tubular aggregates in slightly tangential longitudinal section: The image below demonstrates continuity of the tubules with the lateral sacs of the sarcoplasmic reticulum.
The intent of this article is to provide an introduction to the clinical and pathologic features of neuromuscular disease, focusing on myopathic disorders. For a detailed primer on the procedure of muscle biopsy and a discussion of the clinical issues that inform the decision to obtain a muscle biopsy, see the article Muscle Biopsy and Clinical and Laboratory Features of Neuromuscular Disease. For a review of normal muscle structure and interpretation of histologic features, see the article Skeletal Muscle – Structure and Histology
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Roberta J Seidman, MD Associate Professor of Clinical Pathology, Stony Brook University; Director of Neuropathology, Department of Pathology, Stony Brook University Medical Center
Roberta J Seidman, MD is a member of the following medical societies: American Academy of Neurology, Suffolk County Society of Pathologists, New York Association of Neuropathologists (The Neuroplex), American Association of Neuropathologists
Disclosure: Nothing to disclose.
Adekunle M Adesina, MD, PhD Professor, Medical Director, Section of Neuropathology, Director, Molecular Neuropathology Laboratory, Texas Children’s Hospital, Department of Pathology and Immunology, Baylor College of Medicine
Adekunle M Adesina, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Neuropathologists, College of American Pathologists, United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.
I would like to thank all of the clinicians and surgeons who allow me to share in the care of their patients with neuromuscular disorders, Karin Thompson and the other technologists whose conscientiousness and expertise in handling and processing the biopsies are essential to the successful evaluation of the patients, and Dr. Nancy Peress, who generously devoted years of her life to training me in neuropathology and subsequently working with me as a treasured colleague, advisor, and friend.
Skeletal Muscle Pathology
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