Round 22: Myopathy Presenting in the Context of Interstitial Lung Disease

by Alan Baer, MD

Division of Rheumatology
Johns Hopkins University School of Medicine

Release Date: January 19, 2010
Expiration Date: January 1, 2011

Dr. Baer has no significant financial interest or relationships to disclose.

For CME credit,TAKE POST-TEST & EVALUATION 

Objective

Given an adult patient with myositis, the learner will be able to distinguish among the various types of inflammatory myopathies and recognize diseases that mimic polymyositis.

Introduction

Idiopathic Inflammatory Myopathies (IIM)

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired muscle diseases in which muscle injury results from inflammation, usually as a result of an autoimmune reaction. IIM may have their onset in either childhood or during adult life.  Their annual incidence is 5 to 10 new cases per million. IIM may occur in association with a systemic inflammatory rheumatic disease, such as scleroderma or lupus, or with an underlying malignancy.

The IIM are still classified using diagnostic criteria for polymyositis and dermatomyositis published in 1975 by Bohan and Peter (New Engl J Med. 1975;292:344). These criteria include: 1) symmetrical weakness of limb-girdle muscles and anterior neck flexors; 2) biopsy evidence of muscle fiber necrosis, phagocytosis, regeneration, perifascicular atrophy, fiber size variation, and an inflammatory infiltrate, often perivascular; 3) elevation of serum skeletal muscle enzymes; 4) electromyographic evidence of myopathy (short duration, short amplitude muscle potentials,  insertional irritability); and 5) a typical skin rash of dermatomyositis  A definite disease of polymyositis is established with the fulfillment of four criteria while a definite diagnosis of dermatomyositis is established by the presence of the characteristic rash in addition to three other criteria.

Figure 1

Figure 1. Cutaneous features of dermatomyositis. The Gottron’s rash of dermatomyositis is characterized by erythema and scaling over the dorsal aspect of the PIP and MCP joints (left panel). Nailfold capillary telangiectasia (right panel) can be seen in dermatomyositis, but are not specific to this disease.

Bohan and Peter distinguished five subtypes of inflammatory myopathies: polymyositis (PM), dermatomyositis (DM), DM or PM associated with malignancy, childhood DM or PM associated with vasculitis, and PM or DM with an associated collagen-vascular disease.

The need for new classification criteria for the IIM

New classification criteria for the IIM are needed to accommodate our improved understanding of these diseases. These criteria would have to account for the following observations over the past 30 years. First, inclusion-body myositis (IBM) is now recognized as a distinct subset of these diseases.  Second, there are histopathologic features that are relatively specific for certain forms of IIM.  Third, myositis-specific antibodies (MSA) define disease subsets and predict prognosis and response to therapy.  Fourth, improved diagnostic tools now exist that distinguish certain muscular dystrophies and metabolic myopathies from the IIM.

Case Reports

Case 1

Presentation. A 59-year-old man began to note difficulty climbing up stairs or getting out of a chair three years earlier. His wife commented that his quadriceps muscles seemed to be withering away. One year earlier he began to fall because his legs “gave out” and he noticed some difficulty with swallowing. Upon presentation, he had wasting of the quadriceps and biceps muscles (Figure 2) with preservation of the deltoid muscle bulk. He was unable to rise from a chair without using his arms, and the strength in his biceps, quadriceps and tibialis anterior muscles was 4– out of 5.  The patient was on atorvastatin for hyperlipidemia.

Figure 2

Figure 2: Photographs of patient described in Case 1. Note the atrophy of the quadriceps (left panel) and biceps (right panel) muscles.

The patient’s creatine phosphokinase (CK) was moderately elevated, prompting his primary care physician to discontinue his atorvastatin therapy. However, the patient remained weak and his repeat CK was 902 four months after discontinuing atorvastatin. Biopsies of the biceps and quadriceps muscles showed a non-specific chronic inflammatory myopathy (Figure 3). A specific diagnosis could not be made. Accordingly, the muscle biopsy was repeated, this time from the deltoid muscle. That muscle was less severely affected by the myopathic process but demonstrated characteristic inclusion bodies.  With electron microscopy, ultrastructural changes typical of inclusion body myositis were demonstrated, including 15 to 18 nanometer tubulofilamentous inclusions and membranous whorls.

Figure 3

Figure 3: Muscle biopsy histopathology from Case 1. Simultaneous biopsies of the biceps (upper left panel) and quadriceps (upper right panel) were initially performed. There are many necrotic and some regenerating fibers as well as interstitial fibrosis. There is a scant, but definite inflammatory infiltrate. Primary inflammation, with invasion of the muscle fibers by inflammatory cells, is not seen. A repeat biopsy from the deltoid muscle (bottom panels) showed characteristic changes of IBM, not evident on the initial biopsies. Inclusion bodies are evident on the H&E stain (lower left) and on the frozen section with the modified trichrome stain (lower right).

The clinical phenotype of this patient was characteristic of inclusion body myositis, yet biopsies from two separate muscles performed at the same time did not show the characteristic pathology. A third biopsy from a muscle less severely affected secured the diagnosis.

Inclusion-body myositis accounts for a significant proportion of cases of refractory polymyositis in older patients. It affects predominantly men over the age of 50 and is characterized by insidious yet progressive proximal and distal muscle weakness and atrophy. There is a predilection for involvement of the forearm flexor and quadriceps muscles. Foot drop is common and dysphagia may occur. CPK levels are normal or only minimally elevated. Mixed myopathic and “neurogenic” features are present on electromyography.  The disease is typically resistant to immunosuppressive therapy.

The histopathology of IBM is notable for the presence of necrotic and regenerating muscle fibers.  There is an endomysial mononuclear cell infiltrate comprised of cytotoxic CD8 T-cells that are invading non-necrotic fibers, often in association with MHC class I antigen expression by otherwise morphologically healthy fibers. These characteristic features can also be seen in polymyositis. However, IBM is distinguished by the presence of rimmed vacuoles. Using special stains, one can see amyloid deposits or inclusions containing ubiquitin within the muscle fibers.  COX-negative and ragged red fibers may also be present.  By electron microscopy, characteristic filamentous inclusions and mitochondrial abnormalities are seen.

The pathogenesis of IBM likely includes autoimmune as well as degenerative pathways. Patients with IBM demonstrate clonal expansion of CD8+ T cells in their muscle and blood and upregulation of MHC class I antigens on the sarcolemma. There is abnormal accumulation of amyloid ß, amyloid precursor protein, phosphorylated tau, ubiquitin, and other proteins in the muscle, indicative of a degenerative process akin to Alzheimer’s dementia. There is also a clear genetic component—the association of inclusion-body myositis with HLA-DR3 is one of the strongest HLA associations.  Seventy-five percent of patients with this disease have the HLA-DR3 allele, and there is also a strong association with the ancestral 8.1 haplotype, which also is associated with type 1 diabetes, myasthenia gravis, and Graves disease.

In summary, IBM is the most common form of the IIM in persons over the age of 50. There is a distinctive pattern of muscle involvement, but the initial biopsy may not show the characteristic features.  It is thus often misdiagnosed as polymyositis and proves in time to be refractory to treatment. The case presented here demonstrates the occasional need to obtain multiple muscle biopsies in order to demonstrate the characteristic pathology.

Can one differentiate and classify the IIM based on specific histopathologic features?
The histopathologic features of dermatomyositis include an inflammatory exudate that is predominantly perivascular and perimysial and to a lesser extent endomysial. Perifascicular atrophy is a characteristic feature. There is also an angiopathy, evidenced by endothelial hyperplasia in intramuscular blood vessels, the presence of the membrane attack complex in blood vessels, diminished capillary density, and perivascular infiltrates, composed primarily of B cells (Arahata and Engel, Ann Neurol 16:193, 1984; Dalakas and Hohlfeld, Lancet 362:971, 2003). The histopathologic features of polymyositis include a predominantly endomysial and focal inflammatory exudate with CD8-positive T cells that are infiltrating non-necrotic fibers (“primary inflammation”). MHC class-I is expressed by non-necrotic fibers. (Arahata and Engel. Ann Neurol. 1984;16:193)

The histopathologic features of dermatomyositis, polymyositis, and inclusion body myositis are compared in the table below.

Table 1: Histopathology of the IIM*

Dermatomyositis Polymyositis Inclusion body myositis
Inflammatory infiltrates Perivascular, perifascicular and perimysial Endomysial, perimysial, and perivascular Endomysial
Distinctive features Perifascicular atrophy
Decreased capillary density
CD8+ T lymphocytic invasion of non-necrotic fibers CD8+ T lymphocytic invasion of non-necrotic fibers
Rimmed vacuoles
Amyloid deposits
Immuno-histochemistry Membrane attack complex deposition in vessel walls MHC-1 expression on surface of most muscle fibers MHC-1 expression on surface of most muscle fibers

*Adapted from Dalakas and Hohlfeld, Lancet 362:971, 2003

Immunopathogenesis of IIM. The pathogenesis of dermatomyositis is thought to be mediated by a humoral autoimmune response. Autoantibodies directed against the endothelium are hypothesized to produce an angiopathy and resultant ischemic myofiber injury in the perifascicular area.  In contrast, polymyositis is thought to derive from cytotoxic T-cell mediated myofiber injury.

New findings are challenging these paradigms concerning the immunopathogenesis of dermatomyositis and polymyositis. In dermatomyositis, an autoantibody to an endothelial antigen has not been identified. A distinctive interferon signature is evident in gene expression studies of dermatomyositis patients, suggesting T-cell involvement. Finally, the perifascicular area is not preferentially susceptible to ischemia and thus, perifascicular atrophy may have an etiology other than vascular injury. In polymyositis, there is a high expression of immunoglobulin genes, arguing for a role of the humoral immune response it its immunopathogenesis. Plasma cells and myeloid dendritic cells are evident in polymyositis muscle specimens.

Greenberg et al have recently published a series of findings that support new concepts in the immunopathogenesis of dermatomyositis (Neurology. 2007;69:2008–19). Dendritic cells were found in the muscle of patients with dermatomyositis. They have either a plasmacytoid or a dendritic cell morphology. Those in the perimysial area have plasmacytoid characteristics and are high producers of interferon; those with dendritic cell morphology are present in endomysial areas and do not produce interferon but are capable of antigen processing.  The expression of myxovirus resistance protein is strongly induced by interferon, and this interferon-induced protein is clustered in the perifascicular area. Greenberg et al have thus questioned whether the perifascicular atrophy might in fact have a different origin then ischemia.  This high-expression of interferon in the perifascicular area suggests that there may be some other mechanism responsible for the perifascicular atrophy.

Histopathologic features of a myositis cohort.

In a recent retrospective analysis of muscle biopsies from a large cohort of myositis patients, the frequency of various histopathologic subtypes was documented (Neurology 61:316, 2003). The cohort consisted of 165 patients with myositis.  The study was restricted to myositis patients who were 16 years or older at diagnosis and who had a subacute onset of symmetric proximal muscle weakness. Inclusion body myositis and other neuromuscular disorders diagnosed at presentation or during subsequent follow-up were excluded from the study. One hundred and eleven patients were re-examined after a follow-up period of at least one year. The types of myositis were defined as follows:

  • Polymositis (definite)
    • Serum CK more than 2 times elevated
    • Mononuclear cells surrounding and preferably invading individual non-necrotic muscle fibers in the endomysium
  • Dermatomyositis (definite)
    • Typical skin abnormalities or perifascicular muscle atrophy
  • Unspecified myositis
    • Perimysial/perivascular mononuclear cell infiltrate without involvement of endomysium
    • No perifascicular atrophy or rash of DM
  • Possible myositis
    • Serum CK more than 2 times elevated
    • Necrotizing myopathy, but no or only minimal mononuclear cell infiltrates

The frequency of these 4 types of myositis is shown in Table 2 below.

Table 2: Clinical and Laboratory Features of Myositis Subsets at ≥ 1 year of Follow-Up

Isolated*

+CTD*

+Malignancy*

MSA any Jo-1 Mi-2
PM

4

0

0

2/8 0/8 1/7
DM

48

4

7

22/42 9/42 12/36
Unspecified myositis

25

36

4

13/35† 9/35 4/30
Possible myositis

27

3

2

8/23 2/23 3/22

*number at follow-up
†among CTD patients: 4/14
MSA = myositis-specific antibody

Note the rarity of polymyositis as defined by these histopathologic criteria alone. The unspecified myositis group was the largest. These patients often had an associated connective tissue disease.  Malignancies were most commonly associated with dermatomyositis, a finding that supports earlier observations.  The myositis-specific antibodies tended to cluster in the dermatomyositis or the unspecified myositis patient groups.

In another cohort of IIM in 59 adult patients (excluding IBM), the specificity of histopathologic features that traditionally define PM (focal invasion of non-necrotic fibers) and DM (perifascicular atrophy) was detailed (Arthritis Rheum 54:1687, 2006).

Table 3: Specific Histopathologic Features in a Cohort of Adult IIM

Focal invasion of non-necrotic fiber (%)

Perifascicular atrophy
(%)

All IIM, excluding IBM

22

33

Adult PM

37

0

Anti-Jo-1 PM

0

100

Adult DM

0

100

Anti-SRP myopathy

0

0

The focal invasion of non-necrotic fibers was present in only 37% of the PM patients and none of the Jo-1 PM patients. Perifascicular atrophy was evident in all of the patients with DM and anti-Jo-1 PM. Thus, PM and DM cannot be defined strictly on histopathologic features alone.

Histopathology of the IIM: Conclusions

  • Polymyositis is the least common form of IIM if defined by rigorous histopathologic criteria
  • The presence of an associated connective tissue disease and/or MSA correlates strongly with non-specific patterns of muscle inflammation.
  • Many IIM patients have a non-specific pattern of muscle histopathology.
  • The pathogenesis of DM and PM need further exploration.

Case 2.

A 35-year-old African-American woman started noticing fatigue, night sweat and severe muscle weakness in the Fall of 2006. Her CPK levels climbed to as high as 21,000 with no rash, arthritis or pulmonary symptoms. She was started on high-dose prednisone and had a quadriceps muscle biopsy shortly after (Figure 4).

Figure 4

Figure 4. Histopathology of initial muscle biopsy from Case 2. There are a number of necrotic and regenerating fibers, but no inflammatory infiltrate.

The muscle biopsy was interpreted as a necrotizing myopathy without any evidence of primary inflammation. Subsequently, she developed progressive weakness despite aggressive therapy with corticosteroids, intravenous immunoglobulin and methotrexate.  Within 3 months, she was confined to a wheelchair, and 10 months later, she was in respiratory failure and had to undergo tracheostomy to facilitate respiratory support. Treatment with plasmapheresis and rituximab resulted in modest improvement.  Repeat MRI with fat-suppressed imaging showed dramatic signal in both the shoulder girdle and in the thigh muscles, indicative of muscle edema and/or inflammation (Figure 5). Biopsies of the quadriceps and gastrocnemius were obtained (Figure 6).

Figure 5

Figure 5. MR imaging with fat-suppression of Case 2. Note the increased signal in the shoulder girdle and thigh musculature.

Figure 6

Figure 6. Histopathology of second muscle biopsy from Case 2. The quadriceps muscle biopsy showed a number of atrophic fibers, large areas of necrosis, a marked increase in interstitial fibrosis, but again no inflammatory infiltrate.  On the trichrome stain (right panel), the only muscle is stained red. Connective tissue has largely replaced the muscle.

Initial testing for SRP antibodies at a commercial reference laboratory had been negative, but when tested by Dr. Livia Casciola-Rosen in our division laboratories, the sample was positive for anti-signal recognition particle antibodies.

This patient thus had SRP myopathy, a disease that tends to start in autumn. Quite typically, patients with SRP myopathy have severe proximal muscle weakness and atrophy at presentation, very high levels of serum CK and a rapidly progressive clinical course. Dysphagia is common. There is poor response to treatment. The histopathology is that of a necrotizing myopathy with minimal endomysial inflammation. Other features include prominent endomysial connective tissue and diffuse deposition of the membrane attack complex in the capillaries.

Myositis-specific and myositis-associated antibodies:

  • Myositis-Specific
    • Anti-synthetase
    • Anti-Mi-2
    • Anti-signal recognition particle (SRP)
  • Myositis-Associated
    • Anti-SS-A
    • anti-U1RNP
    • anti-PM/Scl
    • anti-Ku

The potential utility of the myositis-specific antibodies includes the definition of specific clinical subsets, differentiation of PM and DM from IBM, and the prediction of the presence of an underlying malignancy. Each of these is examined below. As seen in Table 4, myositis-specific antibodies do define clinical subsets of the IIM with distinct phenotypes.

Table 4: Myositis-Specific Antibodies Define Clinical Subsets of IIM

Autoantibody % Myositis patients Onset of disease Clinical correlates Response to therapy
Anti-synthetase 20-25 Acute, severe, often in Spring Symmetric polyarthritis
Interstitial lung disease
Fever
Mechanic’s hands
Raynaud’s
Moderate;
Myositis flare with tapering of therapy
Anti-signal recognition particle (SRP) <5 Very acute, often in Fall Cardiac involvement
Myalgias
Rapidly progressive
Poor
Anti-Mi-2 5-10 Acute Classic dermatomyositis with V and shawl signs, cuticular overgrowth Good

Antisynthetase antibodies are seen in both polymyositis and dermatomyositis as well as in myositis patients with overlap features of a connective tissue disease.  In contrast, Mi-2 defines a group of patients with DM while SRP defines a group of patients with PM (Medicine 85:111, 2006).

Myositis-specific antibodies are found less frequently in reported cases of IBM and cancer-associated myositis. Among 1233 reported patients with IBM, MSA were seen in 9% (table 5).  In contrast, the frequency of MSA in non-IBM muscle disease was 37%.

Table 5: Myositis-Specific Antibodies in Inclusion Body Myositis

Series # pts MSA in IBM MSA in non-IBM
O’Hanlon et al. Medicine. 2006;85:111.

603

0/47

199/556 (36%)

Brouwer, et al. Ann Rheum Dis. 2001;60:116.

417

7/38*

150/379 (40%)

Hengstman, et al. J Neurol. 2002;249:69.

125

3/28†

37/97 (38%)

Selva-O’Callaghan et al. Arthrit Care Res. 2006;55:791.

88

0/2

28/86 (33%)

TOTAL

1233

10/115 (9%)

414/1118 (37%)

Similarly, 13% of the patients with a cancer-associated malignancy have MSA in contrast to 37% of those with a non-cancer-associated myopathy (Table 6).

Table 6: Myositis-Specific Antibodies in Cancer-Associated Myositis (CAM)

Series # pts MSA in CAM MSA in non-CAM
Chinoy et al, 2007 282 3/16 92/266
Hengstman et al, 2002 97 1/3 38/94
Selva-O’Callaghan et al, 2006 86 2/8 26/78
O’Hanlon et al, 2006 556 4/51 195/505
TOTAL 842 10/78 (13%) 351/943 (37%)

MSA: summary

  • An important diagnostic tool for differentiating specific myositis subsets
  • Infrequent in IBM and cancer-associated myositis
  • Histopathologic correlates:
    • Jo-1 associated myositis
      • Perifascicular atrophy, fragmentation of perimysium; perimysial inflammation with macrophage (or ?DC) predominance
    • SRP myopathy
      • Necrotizing myopathy with scant inflammation
    • Mi-2 myopathy
      • Typical histopathology of dermatomyositis

Case 3.

A 62-year-old woman developed pain and swelling of her left knee with some erythema and warmth along the medial aspect of both knees. She had mild swelling in both hands and puffy eyelids.  A rheumatologist did not notice any definite synovitis, facial rash, or muscle weakness. She did have elevated CK and aldolase levels. Her ANA was positive. EMG showed an irritable myopathy, and a quadriceps muscle biopsy showed only a few scattered necrotic fibers.  However, she went on to develop progressive weakness of her shoulders and extensor muscles of her hands. She was placed on prednisone. Her CK improved, but did not return to normal. The prednisone was tapered off, and she was referred to the National Institutes of Health for further evaluation. There, she was noted to have a V-shaped erythematous rash on her anterior chest and erythema over her MCP and PIP joints. Manual muscle testing documented the following pattern of muscle weakness (10 point Kendall scale):

Right Left
Shoulder abduction 8 6
Shoulder elevation 10 10
Elbow flexion 6 6
Wrist flexion 6 8
Wrist extensors 6 1
Hip flexors 6 4
Hip extensors 4 6
Hip abductors 8 8
Knee flexors 10 10
Ankle dorsiflexors 10 9
Ankle plantar flexors 10 10

She had asymmetric weakness involving both the proximal and distal musculature, findings not expected in polymyositis.  MR imaging of the left upper extremity showed fatty infiltration of the muscle but also edema within the biceps muscle.

Figure 7

Figure 7. MR imaging of the left arm of Case 3. There is considerable fatty infiltration, but also edema within the biceps muscles as well as the other muscles of the forearm of the upper arm.

A repeat muscle biopsy from her biceps showed dramatically different findings than the biopsy that was done only 5 months earlier. She had extensive muscle fiber atrophy, interstitial fibrosis and prominent inflammatory infiltrate.

Figure 8

Figure 8. Muscle histopathology in Case 3. The initial quadriceps muscle biopsy (left panel) was normal with the exception of a few scattered necrotic fibers (not evident in this image). A second muscle biopsy 5 months later from the biceps showed extensive muscle fiber atrophy, interstitial fibrosis and a prominent inflammatory infiltrate

The impression was that she had inflammatory myopathy. She was treated with pulse methylprednisolone followed by daily prednisone, methotrexate, and later azathioprine, but did not have a substantial improvement in muscle strength.

After she transferred her care to Johns Hopkins, she underwent genetic testing for facioscapulohumeral muscular dystrophy (FSHD). This showed a deletion mutation on chromosome 4q35 and a mutant allele size of 35 kb (normal allele size ≥ 42 kb)

Facioscapulohumeral Dystrophy

  • Third most common muscular dystrophy
  • Slow and steadily progressive or relapsing course:
    • Facial→periscapular→humeral→truncal→leg weakness, often asymmetric
    • Spares bulbar, cardiac, and respiratory muscles
  • Presentation usually in second decade
  • Autosomal dominant, but up to 30% de novo cases
  • Deletions of tandem repeat (D4Z4) on chromosome 4q35
    • ≤ 12 repeats on one copy of 4q35 (normal ³15 repeats)

Certain features of “polymyositis” patients should prompt one to look for other potential causes for the myopathy:

  • Family history of same syndrome
  • Onset of muscle symptoms in childhood
  • Slowly progressive course measured in years
  • Marked muscle wasting at presentation
  • Scapular winging
  • Facial weakness
  • Early distal muscle weakness
  • Calf hypertrophy or atrophy
  • Clinical myotonia or myotonic discharges on EMG
  • CK level >100X

Muscular dystrophies that mimic adult polymyositis

Certain muscular dystrophies may mimic polymyositis, in part because they may show endomysial inflammation. These include certain dystrophinopathies, (including Becker’s and manifesting female carriers), limb-girdle muscular dystrophies (particularly dysferlinopathy and sarcoglycanopathies),  facioscapulohumeral muscular dystrophy, and proximal myotonic dystrophy type 2.

Diagnosis of the muscular dystrophies

Molecular diagnostic testing can now be used to secure a diagnosis in many patients with dystrophinopathies, FSHD and limb-girdle muscular dystrophies. Immunohistolochemistry can also be used to stain the sarcolemma for the dystrophin, dysferlin, and sarcoglycan proteins.

Case 4.

A 69-year-old woman recalls that when she used to run to catch a school bus as a child, her legs would become so tired she could not run further and had difficulty getting on the school bus.  She enjoyed a healthy adult life until 1/1998 when she was placed on a statin for her hyperlipidemia and developed severe myalgia and CK elevation. The CK elevation persisted after cessation of the statins, but she did not have definite muscle weakness when she was first seen.

A muscle biopsy showed a mild focal mononuclear cell infiltrate in the endomysium, some degenerating and regenerating fibers and phagocytosis. Prednisone did not help.  Methotrexate and leflunomide were later added without benefit, and she got progressively weaker over time, until she was unable to rise from the floor and had difficulty climbing stairs MR imaging of the right lower leg showed fatty atrophy with some muscle edema (Figure 10).

Figure 10

Figure 10. MR imaging of the right lower leg. There is some edema in the muscle fibers on the STIR images (left panel).  Extensive fatty atrophy was evident on the T1 images (right panel).

In 12/2006 a repeat muscle biopsy was performed (Figure 9).

Figure 9

Figure 9. Second muscle biopsy for Case 4. There is an inflammatory infiltrate around the muscle fibers (left panel). A necrotic fiber infiltrated by inflammatory cells is seen in the right panel. There was no evidence of primary inflammation (invasion of a non-necrotic muscle fiber by lymphocytes).

Figure 11

Figure 11. Subsarcolemmal vesicles are evident in the H&E stain of the muscle (left panel). There is intense staining of the subsarcolemmal material with PAS stain (right panel).

The histopathologic findings were indicative of abnormal glycogen accumulation. This was confirmed by a biochemical analysis of the muscle tissue, showing a significant increase in glycogen content. The low level of myophosphorylase activity established a diagnosis of McArdle’s disease.

Biochemical analysis.

Patient Control
Glycogen content (%) 4.8 0.94 ± 0.55
Myophosphorylase activity
(mmol/min/gm tissue)
0.5 30.4

Myophosphorylase deficiency (McArdle’s Disease)

Myophosphorylase deficiency (McArdle’s disease) is an autosomal recessive disease that usually presents with exercise intolerance, pain, stiffness or weakness of exercising muscles. The symptoms are mainly triggered by brief intense isometric exercise or less intense, but sustained exercise. Fixed weakness is more common with increasing age. McArdles’s disease is an example of a metabolic myopathy, a group of muscle diseases that have in common abnormalities in muscle energy metabolism that result in skeletal muscle dysfunction.

Diagnostic features of metabolic myopathies

  • Symptoms:
    • Exercise intolerance (muscle fatigue, pain and stiffness) is usually the chief complaint.
    • Intermittent myoglobinuria
    • Progressive fixed muscle weakness can occur.
  • Diagnostic testing
    • Elevated muscle enzymes
    • Elevated lactic acid in mitochondrial disorders
    • Ischemic forearm exercise test for certain glycogenoses
    • Mutation analysis for more common diseases

Key clinical features of the metabolic myopathies

  • Myophosphorylase deficiency (McArdle’s)
  • Muscle pain early in course of exercise, especially if intense
  • Can continue to exercise if lower exercise rate at onset of symptoms (second wind phenomenon)
  • Carnitine palmitoyltransferase II deficiency
  • Muscle pain and cramps during or following prolonged lower intensity exercise or fasting
  • Mitochondrial  myopathies
  • Fatigue and dyspnea during low levels of exercise

Summary: Diagnosis of the IIM

The Differential diagnosis of a myositis includes a variety of disorders. The choice of diagnostic testing will depend on one’s initial diagnostic impression. Elements of successful diagnosis include (1) an experienced msucle histopathologist; (2) in patients with refractory myositis, looking for clues that argue against the original diagnosis and repeating the muscle biopsy; and (3) consulting an expert.

Conclusions

  • Myology is an exciting and evolving field.
  • There are many different types of inflammatory myopathies.
  • A better understanding of these will lead to better therapies.

For CME credit,TAKE POST-TEST & EVALUATION 

Updated: August 16, 2012

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