This review introduces/refreshes some basic histopathologic methods and findings of skeletal muscle biopsies with emphasis on those diseases commonly encountered in a rheumatologist’s practice. The 3 general areas of myopathology discussed are metabolic myopathies, toxic myopathies, and inflammatory myopathies. The authors, neuropathologists, hope to provide in this article what they think are some commonalities and disease-specific methods in their pathologic workup as well as a practical approach to the collaboration that pathologists undertake with their rheumatology colleagues to come to a working diagnosis.
Introduction to muscle biopsy and basic histopathologic changes in skeletal muscle
This review introduces/refreshes some basic histopathologic methods and findings of skeletal muscle biopsies with emphasis on those diseases commonly encountered in a rheumatologist’s practice. The 3 general areas of myopathology discussed are metabolic myopathies, toxic myopathies, and inflammatory myopathies. Although there is considerable overlap in the patient populations with muscle-based illness for the rheumatologist and neurologist, the rheumatologist is more likely to encounter patients with these 3 classes of myopathy.
The authors, neuropathologists, hope to provide in this article what they think are some commonalities and disease-specific methods in their pathologic workup as well as a practical approach to the collaboration that pathologists undertake with their rheumatology colleagues to come to a working diagnosis. Neonatal, pediatric, dystrophic, and neuropathic myopathies are beyond the scope of this article. Also, much of the basic biochemistry, genetics, clinical presentations, and therapy for muscle diseases are more thoroughly covered in other disease-specific reviews.
Biopsy of the skeletal muscle is an important diagnostic study for many muscle diseases and in some cases is still the gold standard. However, this technique is often appropriately held in reserve to be done after a full noninvasive workup has been completed. Although not usually debilitating to patients, biopsy procedures can be painful and carry the standard risks of postsurgical infection and discomfort. Many of the cases that the surgical neuropathologist worked up in the last century by histologic methods are now diagnosed without a biopsy by molecular diagnostic laboratories using blood samples. However, many muscle diseases treated by rheumatologists still need some combination of histopathologic, biochemical, and genetic work up on the muscle tissue itself. Despite the diagnostic tools available today, the diverse and subtle clinical presentations of patients make muscle diseases some of the most challenging conditions to diagnose in medicine.
Biopsy Considerations
Several factors come into play when rheumatologists decide to pursue a muscle biopsy in the diagnostic workup. First, is the institution/practice set up to handle this kind of surgery and these complex specimens? The rheumatologist should talk to the pathologist before considering the biopsy. If they do not handle these specimens regularly, it is essential that the patient be referred to the nearest institution with a neuropathologist on staff to have the biopsy performed there. If this is not a possibility, the biopsy can be done remotely and the sample sent by courier (not mailed) on ice in a saline-moistened gauze wrap to the neuropathologist, provided the sample can be delivered within an hour or two maximum. However, this step is not optimal, and communication/coordination before the surgery with the on-site pathologist and the off-site neuropathologist is essential. Regardless of where the biopsy is done, liquid nitrogen should be available in the operating room (OR)/procedure room to rapidly freeze a portion of the muscle immediately at the time of resection. This flash frozen tissue is used for biochemical and genetic analyses, as indicated.
The next factor is who will do the biopsy. Different physicians in different institutions/practices perform this fairly minor surgery. With training, any physician can perform this surgery, and many rheumatologists and neurologists handle these cases for their patients, a real preference by the pathologists because rheumatologists and neurologists can generally be in better communication about what should be technically done with the specimens at the time of surgery and in conveying the findings. If the patient is referred for the biopsy to a general surgeon, there should be communication between the rheumatologist, the surgeon, and the pathologist to coordinate logistics. Which muscle to biopsy is an important consideration—a muscle that is clinically affected but not in end-stage should be chosen. Magnetic resonance imaging is gaining popularity to help distinguish muscle groups with inflammation ; however, clinical judgment is still needed. The surgeon should be in contact with the pathologist to discuss how many samples are needed for the case and to arrange for the liquid nitrogen to be on-hand in the OR. Having a pathology assistant or technician come to the OR to manage the specimens can be helpful.
Once the specimens are obtained, what tests need to be performed on them? The pathologist in most cases performs some standard processing and then works with the clinical team to come up with additional studies based on the clinical suspicions and initial histopathologic findings. Most muscle biopsy specimens have a portion fixed in buffered formalin for standard hematoxylin-eosin (H&E) histologic analysis, a portion fixed in glutaraldehyde for possible electron microscopic (EM) analysis, a portion frozen in a controlled manner for frozen section histochemical stainings, and one or more pieces flash frozen in liquid nitrogen for biochemical/genetic analyses. Specialized testing for many biochemical/genetic analyses often needs specimens to be sent out to one of a few reference laboratories that can perform the testing.
General Histopathology of Neuropathic, Myopathic, and Inflammatory Causes
Although the goal of the pathologist is to define as specifically as possible the pathologic diagnosis of the surgical specimen, with muscle biopsies, sometimes, the best one can do is categorizing them as most likely because of 1 of the following 3 causes: (1) myopathic in which the pathogenesis involves an intrinsic skeletal muscle disease that could be caused by genetic alterations, metabolic dysfunction, or toxic insult; (2) neuropathic (also called neurogenic), in which the observed muscle changes are caused by motor neuron injury/degeneration; or (3) inflammatory in which the change is caused by systemic immune system dysfunction or intrinsic muscle disease eliciting an inflammatory response. The cause of the disease dictates how the muscle will respond acutely and chronically and what will be the findings on histologic examination.
Neuropathic changes to muscle are brought about by deinnervation and sometimes reinnervation of myocytes by motor neurons. This change could occur with vasculitis that injures the motor neuron or a neurodegenerative process such as amyotrophic lateral sclerosis. The normal cross section of a myocyte is generally round or slightly polygonal, and there is minimal variation in fiber size in the tissue. Deinnervation causes myofibers to atrophy and have more sharp acute angles on cross section ( Fig. 1 A). Another common change in neuropathic myopathies is fiber type grouping into type I and type II fibers rather than the normal fairly even distribution of fibers or the so-called checkerboard pattern, which is highlighted best by ATPase histochemical stain on frozen section (see Fig. 1 B). Finally, target fibers can be seen on frozen sections stained with NADH, which show clearing of the central portion of the myocyte.
Myopathic changes are more varied than those of neuropathic changes. There can also be marked variation in myofiber size and shape with both severe atrophy and hypertrophy of fibers, but usually, the fibers maintain more rounded contours. In long-standing processes, fibrosis is often seen between the individual myocytes. Degenerating and regenerating myofibers that take on a bluish color with H&E stain can often be seen in myopathic processes. Because these fibers are degenerating, lymphocytes and macrophages can be seen around and within the fiber as it breaks down, although infiltrates are usually minimal. Congenital myopathies and dystrophies that involve derangement of structural proteins of the cytoskeleton or extracellular matrix are examples in this category of myopathic change. Metabolic and toxic myopathies are also in this category and described in subsequent sections.
Inflammatory myopathic changes as a result of intrinsic muscle disease or systemic inflammatory conditions display variable types and amounts of immune cell infiltrates and myocyte injury. Some diseases smolder and display chronic inflammatory changes, whereas others run rampant through the affected muscle with acute inflammation and myocyte damage.
Metabolic myopathies
Metabolic myopathies comprise a large group of maladies that span all age groups and have diverse causes that generally alter the intermediary metabolic biochemistry of myocytes. Many of these diseases can affect other tissues, especially those of the central nervous system. Diseases with a prominent muscle pathologic condition tend to have disruption in lipid or glycogen metabolism or mitochondrial functions such as oxidative phosphorylation. Defects in nearly every component of the lipid or carbohydrate metabolic pathways have been described in the literature.
Mitochondrial Myopathies
These disorders are the most common of the metabolic myopathies with highly variable severity affecting both young and old. Mutations or other genetic alterations in either mitochondrial or nuclear genes can lead to enzyme deficiencies and mitochondrial structural alterations that can be determined with biochemical testing and light and ultrastructural microscopy, respectively. Given the variable genes involved, the genetics is complex, and these diseases can be sporadic or familial following either Mendelian or non-Mendelian maternal transmission when mitochondrial gene alterations are involved. With multiple organ involvement common, several syndromes such as Kearns-Sayre syndrome; Leigh syndrome; mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS); and myoclonic epilepsy, ragged red fibers (MERRF) have been recognized for sometime and the gene mutations involved have been identified more recently.
Several histologic hallmarks of mitochondrial myopathies (MMs) assist in making a preliminary diagnosis and are used in conjunction with the clinical picture and biochemical/genetic analyses to solidify a diagnosis. Mitochondria are numerous and diffusely arrayed within normal myocytes. In most MMs, ragged red fibers are readily seen and are so named, because on modified Gomori trichrome stain, the affected irregular myocytes stain reddish ( Fig. 2 A). The stain picks up accumulations of mitochondria, often in a subsarcolemmal localization. Additional stains that can be useful in the workup of MM include NADH and succinate dehydrogenase, which show increased staining in aggregates; cytochrome c oxidase (COX), which does not stain in some MMs; and lipid stains such as oil red O, which highlight increased lipid deposition. The burden of ragged red fibers is highly variable, and sometimes they are not picked up on small biopsies. Conversely, rare ragged red fibers can be seen normally in elderly patients or in patients taking some drugs such as zidovudine (AZT). So identification, although helpful, is not entirely sensitive or specific. Ultrastructural analysis by EM can be helpful. Alteration of sizes, shapes, and numbers of atypical mitochondria are found in affected fibers and suggest that the gene mutations involved could be altering the replication and structure of mitochondria in addition to key enzyme activities either directly or indirectly. Bizarre-appearing paracrystalline inclusions can sometimes be found within the mitochondria (see Fig. 2 B).
Glycogenoses
Glycogen is the main storage molecule for glucose in the body and found primarily in liver and muscle tissue. With defects in the biosynthetic and breakdown pathways of glycogen metabolism, the storage and/or breakdown to glucose is diminished when needed for energy. Therefore, muscle cramping and fatigue or persistent muscle weakness are the prevailing presentations of glycogenoses (also called glycogen storage diseases [GSDs]). Some of the more common types of glycogenoses include McArdle disease (myophosphorylase deficiency, GSD type V), Pompe disease (acid maltase deficiency, GSD type II), and Tarui disease (phosphofructokinase deficiency, GSD type VII). Many other less-common glycogenoses are also recognized with nomenclatures based on genetics and discovery dates. To date, 11 glycogenoses associated with myopathy are known.
A microscopic examination of muscle in glycogenoses can show very little pathology on H&E stain as in McArdle disease or can display abundant accumulation of glycogen in the so-called glycogen pools ( Fig. 3 ) of other glycogenoses. Communicating with the pathologist the clinical suspicion for GSD is essential so that nonstandard staining for activity of enzymes such as myophosphorylase or phosphofructokinase can be added to the battery of stains or so that tissue can be analyzed biochemically for enzyme activity. Periodic acid–Schiff staining with and without diastase helps to highlight glycogen stores. EM can also delineate glycogen and show increased lysosomes with glycogen in diseases such as Pompe disease. Mutation analyses are available for most glycogenoses and can be performed on either lymphocytes or muscles.
Fatty Acid Oxidation Defects
Fatty acid oxidation metabolism myopathies are another common class of metabolic myopathies characterized by lipid accumulations within the muscle. These disorders are caused by defects in enzymes in free fatty acid beta oxidation that prevent the appropriate transport of lipids across the mitochondrial membrane for energy use. Carnitine, which is biosynthesized from amino acids, plays a major role in this transport process. Deficiencies of carnitine either systemically or specifically in the muscle can occur because of inherited mutations or can be drug-induced (valproate therapy). Muscle biopsies often reveal vacuoles and increased lipid storage on oil red O staining. Carnitine palmityltransferase deficiencies of several types are also recognized often early in childhood with cramping and myoglobinuria, but can also manifest in adulthood. These patients generally do not show many histopathologic changes on biopsy and require genetic/biochemical enzyme analyses to make the diagnoses. Similarly, acyl-coenzyme A (CoA) dehydrogenase deficiencies show few, if any, histopathologic changes and must be screened for genetically/biochemically.
Myoadenylate Deaminase Deficiency
Myoadenylate deaminase converts AMP into ammonia and inosine monophosphate, which is important to driving ATP synthesis. The deficiency of this enzyme is common in the general population and often asymptomatic. However, increased stress and/or increased intolerance to exercise with cramping can occur in some affected individuals. Muscle biopsies show no abnormalities with commonly used stains. However, if myoadenylate deaminase histochemistry is performed, variable, but often complete, loss of staining will occur in these cases confirming the diagnosis.
Idiopathic inflammatory myopathies
Inflammatory myopathies are classically divided into infectious and idiopathic (ie, noninfectious) etiologies. The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare disorders that include dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (sIBM). The dominant clinical manifestation of the IIMs is skeletal muscle weakness. IIMs are distinguished from each other based on clinical signs and symptoms, laboratory and serologic tests, electromyography, and histopathologic findings. On muscle biopsy, all the 3 IIMs share the histologic feature of an inflammatory cell infiltrate. The pattern and composition of the infiltrate and identification of salient histologic features unique to each of the IIMs helps differentiate among them. This section summarizes the main histopathologic findings that characterize the IIMs. The clinical features and underlying pathogenic mechanisms of IIMs are briefly discussed in this article but are extensively reviewed elsewhere.
DM
The most common IIM is DM. DM is a multisystem disorder of adults and children that presents with muscle weakness, cutaneous disease, and systemic features. The skeletal muscle weakness is classically proximal, symmetric, and progressive over weeks to months. Cutaneous involvement of DM occurs early in the disease, even preceding muscle weakness, and includes heliotrope rash and Gottron papules. Heliotrope rash is a symmetric violaceous eruption of the periorbital skin that may be associated with scaling, desquamation, and/or massive periorbital edema. Gottron papules are elevated erythematous papules frequently with telangiectasia found over bony prominences, especially knuckles. Other cutaneous findings include photosensitivity, periungual telangiectasia, and poikiloderma of the anterior part of the neck and chest (V sign) and upper part of the back and shoulders (shawl sign). Systemic manifestations include arthralgias, dyspnea secondary to pulmonary disease, conduction defects and arrhythmias due to cardiac involvement, and dysphasia secondary to involvement of pharyngeal and/or upper esophageal skeletal muscles. DM can also be seen in association with systemic sclerosis and mixed connective tissue disease. Patients with DM also have an increased risk of various malignancies, including ovarian, gastrointestinal, pulmonary, and breast carcinomas and non-Hodgkin lymphoma.
Laboratory studies reveal that serum creatine kinase (CK) levels can be normal or elevated (up to 50-fold). Serologic testing often reveals the presence of myositis-associated autoantibodies (MAAs) and/or myositis-specific antibodies (MSAs). MAAs are associated not only with myositis but also with various connective tissue disorders and include anti-U1-ribonucleoprotein, anti-Ro (SS-A), and anti-PM/scleroderma antibodies. MSAs are primarily associated with myositis. Antibodies against histidyl-transfer RNA (tRNA)-synthetase (anti–Jo-1) are the most common MSAs and identify a clinical subgroup (anti-synthase syndrome) that combines myositis, interstitial lung disease, nonerosive arthritis, fever, and Raynaud phenomenon. Other MSAs include various anti–aminoacyl-tRNA synthetases, anti–Mi-2, and anti–signal recognition particle.
The myopathologic hallmark of DM is perifascicular myofiber atrophy characterized by abnormal small fibers at the periphery of muscle fascicles (ie, bundles of muscle fibers) ( Fig. 4 A). Myofibers adjacent to perimysial connective tissue are preferentially affected, whereas myofibers bordering other fascicles are less affected. Perifascicular myofibers can also undergo necrosis, degeneration, and regeneration characterized by basophilic sarcoplasm and increased numbers of internalized myonuclei. Microinfarcts characterized by wedge-shaped areas of necrosis are rarely found. Severely affected fibers can become vacuolated and may become partially reactive or nonreactive to histochemical stains (ghost fibers). Myopathic changes are typically multifocal and can vary in severity in different regions of the same muscle biopsy. Histochemical stains for ATPase reveal that both type I and II fibers are affected. NADH activity is increased in the affected muscle fibers. Immunohistochemical stains for major histocompatibility complex (MHC) class I reveals abnormal upregulation of MHC class I in the sarcolemma of perifascicular myofibers.
DM is also characterized by an inflammatory infiltrate within the perimysium (ie, the connective tissue surrounding muscle fascicles) or in the perivascular space (see Fig. 4 B). The inflammatory infiltrate is composed primarily of CD20 + B cells, macrophages, and CD4 + T cells and plasmacytoid dendritic cells. The perimysial inflammatory infiltrate may focally extend into the endomysium at the periphery of fascicles, but invasion into individual myofibers is rarely seen. Intramuscular blood vessels may show vessel wall thickening, endothelial hyperplasia, vacuolization, and/or necrosis with loss of vessels in severe cases. Lumens of residual capillaries are frequently dilated. Decreased numbers of vessels can be detected with the lectin Ulex europaeus agglutinin I. Deposition of complement on the walls of intramuscular blood vessels can be detected with antibodies against C5b-9 complement membrane attack complex (MAC). Ultrastructural studies reveal swollen damaged capillary endothelial cells containing undulating tubules or tubuloreticular structures.
Most current models of muscle injury indicate that DM is a complement-mediated endomysial microvasculopathy. Complement activation is thought to be an early pathologic feature preceding inflammation and myofiber injury. Activation of the complement C3 leads to formation of MAC, the lytic component of the complement pathway. MAC deposits on intramuscular capillaries and lyses capillary endothelial cells with subsequent vessel necrosis and perivascular inflammation. Progressive intramuscular vascular injury leads to capillary depletion and myofiber hypoperfusion and ischemia. The fibers at the peripheral watershed region of the fascicle, where there is normally a reduced capillary density, are more sensitive to the microvascular insults. Cytokines and chemokines related to complement activation facilitate inflammatory cell recruitment to the perimysial and endomysial spaces. Although the exact mechanisms of complement activation are unknown, many have implicated, but have not yet identified, autoantibodies directed against vascular endothelial antigens. Other suggested models of DM indicate that plasmacytoid dendritic cells overproduce interferons, leading to overexpression of intracellular proteins that mediate capillary injury and perifascicular myofiber atrophy.
PM
PM is a disease of adults and shares many clinical features with DM. Patients with PM present with symmetric proximal muscle weakness usually more severe in the lower extremities than in the upper extremities. The weakness is progressive and develops over weeks to months. PM may also show extramuscular systemic manifestations, including interstitial lung disease, dysphagia, arthalgias, and cardiac arrhythmias. PM can be associated with various autoimmune diseases such as rheumatoid arthritis, lupus, or Sjögren syndrome. Similar to DM, PM is also associated with an increased risk of malignancy. The most important clinical finding that distinguishes PM from DM is the absence of the heliotrope rash, Gottron papules, and other cutaneous manifestations. Laboratory studies reveal that serum CK levels can be elevated up to 50-fold, and various autoantibodies may also be seen.
The myopathologic features that distinguish PM from DM are the absence of perifascicular atrophy and the presence of a multifocal endomysial inflammatory infiltrate composed primarily of lymphocytes and occasionally macrophages. The lymphocytes are CD8 + cytotoxic T suppressor cells that surround and invade intact, nonnecrotic, and morphologically normal-appearing myofibers ( Fig. 5 ). Immunohistochemical studies reveal that all myofibers (ie, those with and without lymphocytic invasion), show an increased expression of sarcolemmal MHC class I that persists even after administration of steroids. The diffuse MHC class I overexpression in PM differs from that in DM, which is confined to damaged perifascicular muscle fibers. Other nonspecific findings such as variation in muscle fiber size, increased number of internalized myonuclei, scattered myofiber necrosis and regeneration, and fibrosis may be present. EM confirms the histologic findings and does not reveal any specific ultrastructural markers for PM.
PM is traditionally viewed as a cell-mediated autoimmune process with a clonal population of autoaggressive CD8 + T cells that invade nonnecrotic muscle fibers overexpressing MCH class I. Normal muscle fibers do not express MHC class I. However, muscle in patients with PM shows widespread MHC class I overexpression, an early pathogenic feature that even precedes the inflammatory infiltrate. It is thought that MHC class I molecules act as antigen-presenting cells to autoaggressive clonal T cells. The T cells contain and release perforin and granulysin that induce myofiber lysis and necrosis. Upregulation of numerous cytokines including interleukins, tumor necrosis factor α, and interferon γ may not only have direct myocytotoxic effects but also promote chronic inflammation and fibrosis. Systemic retroviral infection has also been proposed to play a role in pathogenesis.
sIBM
sIBM is an inflammatory myopathy of patients older than 40 years and is the most common IIM presenting in adults older than 50 years. sIBM presents with an insidious onset of proximal, lower extremity weakness that develops over months to years. Unlike in DM and PM, the weakness in sIBM can be asymmetric, more frequently involves the upper extremities, and involves distal muscle groups such as those of the wrist and forearms. At least 40% of patients may complain of dysphagia secondary to involvement of esophageal and pharyngeal muscles. In contrast to DM and PM, interstitial lung disease in sIBM is rare and there is no association with myocarditis. Physical examination reveals a characteristic pattern of muscle atrophy involving the quadriceps and forearm flexor muscles. The serum CK level is frequently normal or only mildly elevated (<10-fold).
Similar to PM, sIBM is characterized by a prominent endomysial inflammatory infiltrate of CD8 + lymphocytes and macrophages between and around muscle fibers ( Fig. 6 A). Lymphocytes, at least focally, invade intact nonnecrotic myofibers. The pathologic feature that distinguishes sIBM from PM on routine light microscopy is the presence of irregularly shaped vacuoles within myofibers. Typically, the vacuolated fibers are not invaded by lymphocytes. Often the vacuoles appear empty, but some are lined by granular material (rimmed vacuoles) that is basophilic on H&E stain and red on Gomori trichrome stain. Myonuclei in IBM are enlarged and morphologically abnormal, with disrupted nuclear membranes, and rimmed vacuoles occasionally contain myonuclei. Studies have shown that rimmed vacuoles are lined by nuclear proteins (eg, emerin and lamin A/C) and are thought to be possibly derived from myonuclei breakdown and/or are autophagic with abnormal lysosomal functions. Ultrastructural studies reveal that vacuoles consist of multilaminated membranous structures; glycogen granules; dense bodies; and amorphous, granular, and fibrillar material. Although thought to be a distinguishing feature of sIBM, rimmed vacuoles are occasionally seen in PM, DM, and distal myopathies, later-onset type II glycogenosis, myofibrillar myopathies, oculopharyngeal muscular dystrophy, and denervated muscle.
Various multiprotein inclusion bodies may also be seen within myofibers. Round plaquelike amyloid eosinophilic inclusions can be found in the cytoplasm or nucleus of vacuolated myofibers. These inclusions can be visualized with a Congo red stain with polarized light as apple green birefringence or with Texas red fluorescence microscopy. The congophilic inclusions immunoreact with various related proteins, including ubiquitin, β-amyloid, and β-amyloid precursor protein among others. EM reveals amyloidlike fibrils that are 6 to 10 nm in diameter and are located in the cytoplasm.
A second type of myofiber inclusion, also congophilic, is recognized with immunostaining with SMI-31 antibodies that highlight linear squiggly aggregates and aggregates around/near rimmed vacuoles (see Fig. 6 B). Antibodies for SMI-31 recognize several proteins including neurofilaments, phosphorylated tau, microtubule-associated proteins 1B and 2, lamin intermediate filament, and possibly sequestosome 1. Although specific proteins recognized by SMI-31 antibodies in sIBM are unknown, many speculate that these inclusions represent abnormal aggregates of tau. Ultrastructural studies reveal that these inclusions correspond to clusters of filaments 15 to 21 nm in diameter that resemble accumulations of tau paired helical filaments in Alzheimer disease.
Recent studies have found abnormal accumulations of TAR DNA-binding protein (TDP)-43 in myofibers of sIBM. TDP-43 is a nucleic acid–binding protein normally found within myocyte nuclei. In sIBM muscle, TDP-43 redistributes from myonuclei into the sarcoplasm forming punctuate inclusions. TDP-43 inclusions may contain ubiquitin but do not appear to colocalize with SMI-31 or congophilic material. Redistribution of TDP-43 occurs much more frequently than other histologic markers of inclusion body myositis (IBM) (rimmed vacuoles, congophilic material, SMI-31 inclusions) and is a highly sensitive and specific feature for IBM. Although the exact role that TDP-43 plays in IBM in unknown, TDP-43 could potentially be a standard diagnostic marker for sIBM.
The precise cause of sIBM is unknown. Similar to PM, sIBM is characterized by MCH class I–restricted CD8 + T cell endomysial inflammation. However, unlike the other IIMs, sIBM does not respond to anti-inflammatory drugs, suggesting that IBM is a multifactorial myopathy with both inflammatory and noninflammatory components. In addition to tau, amyloid, and TDP-43, discussed earlier, there are accumulations of proteins αβ-crystallin, apolipoprotein E, presenilin 1, and α-synuclein. These proteins are linked to various neurodegenerative diseases, suggesting that sIBM could be a myodegenerative process. Similar to other neurodegenerative disorders, accumulations of unfolded and misfolded multiprotein complexes likely contributes to the pathogenesis of IBM. In addition, abnormal accumulation of nitric oxide synthase and cellular protective enzymes (eg, superoxide dismutase) indicates an intracellular oxidative stress component, and the identification of ragged red and COX-negative fibers implicates mitochondrial abnormalities.
In a patient with clinical features of IBM, the diagnosis is confirmed by characteristic features on muscle biopsy (ie, rimmed vacuoles, SMI staining, congophilic inclusions, tubulofilaments on EM). Many characteristics of IBM may be difficult to identify or are absent in an affected muscle on initial muscle biopsy because of sampling error, and the results of these biopsies frequently provide a diagnosis of PM. Thus, when a clinician is confronted with a patient with PM refractory to immunosuppressive therapies or a patient with clinically suspected IBM with a prior biopsy suggesting PM, repeat muscle biopsies may be required for a definitive diagnosis.
Metabolic myopathies
Metabolic myopathies comprise a large group of maladies that span all age groups and have diverse causes that generally alter the intermediary metabolic biochemistry of myocytes. Many of these diseases can affect other tissues, especially those of the central nervous system. Diseases with a prominent muscle pathologic condition tend to have disruption in lipid or glycogen metabolism or mitochondrial functions such as oxidative phosphorylation. Defects in nearly every component of the lipid or carbohydrate metabolic pathways have been described in the literature.
Mitochondrial Myopathies
These disorders are the most common of the metabolic myopathies with highly variable severity affecting both young and old. Mutations or other genetic alterations in either mitochondrial or nuclear genes can lead to enzyme deficiencies and mitochondrial structural alterations that can be determined with biochemical testing and light and ultrastructural microscopy, respectively. Given the variable genes involved, the genetics is complex, and these diseases can be sporadic or familial following either Mendelian or non-Mendelian maternal transmission when mitochondrial gene alterations are involved. With multiple organ involvement common, several syndromes such as Kearns-Sayre syndrome; Leigh syndrome; mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS); and myoclonic epilepsy, ragged red fibers (MERRF) have been recognized for sometime and the gene mutations involved have been identified more recently.
Several histologic hallmarks of mitochondrial myopathies (MMs) assist in making a preliminary diagnosis and are used in conjunction with the clinical picture and biochemical/genetic analyses to solidify a diagnosis. Mitochondria are numerous and diffusely arrayed within normal myocytes. In most MMs, ragged red fibers are readily seen and are so named, because on modified Gomori trichrome stain, the affected irregular myocytes stain reddish ( Fig. 2 A). The stain picks up accumulations of mitochondria, often in a subsarcolemmal localization. Additional stains that can be useful in the workup of MM include NADH and succinate dehydrogenase, which show increased staining in aggregates; cytochrome c oxidase (COX), which does not stain in some MMs; and lipid stains such as oil red O, which highlight increased lipid deposition. The burden of ragged red fibers is highly variable, and sometimes they are not picked up on small biopsies. Conversely, rare ragged red fibers can be seen normally in elderly patients or in patients taking some drugs such as zidovudine (AZT). So identification, although helpful, is not entirely sensitive or specific. Ultrastructural analysis by EM can be helpful. Alteration of sizes, shapes, and numbers of atypical mitochondria are found in affected fibers and suggest that the gene mutations involved could be altering the replication and structure of mitochondria in addition to key enzyme activities either directly or indirectly. Bizarre-appearing paracrystalline inclusions can sometimes be found within the mitochondria (see Fig. 2 B).
Related posts:
Polymyositis, Dermatomyositis, and Autoimmune Necrotizing Myopathy: Clinical Features
Paraneoplastic Muscle Disease
Drugs Causing Muscle Disease
Muscular Dystrophies and Neurologic Diseases that Present as Myopathy
Imaging of Skeletal Muscle
Metabolic Myopathies: Clinical Features and Diagnostic Approach
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
