Inclusion body myositis. Hematoxylin & eosin stain (a) shows lymphocytic invasion into viable myofibers. Gomori trichrome stain (b) shows a myofiber with sarcoplasmic red rimmed vacuole. COX/SDH stain (c) shows abundant COX-deficient myofibers (blue). MHC1 immunostain (d) shows diffuse sarcolemmal and sarcoplasmic upregulation of MHC1. EM (e: low power; f: high power) shows a vacuole containing abundant myeloid debris (e), and bundles of tubulofilamentous inclusions with individual filament measuring about 20 nm in diameter (f)
Final Diagnosis
Sporadic Inclusion Body Myositis.
Patient Follow-up
The diagnosis of IBM was discussed with the patient. He underwent physical therapy and occupational therapy. He had slow progression of his limb weakness over 2 years. His glycemic control improved after adjusting medications by his endocrinologist. His distal sensory deficits were stable.
Discussion
Sporadic inclusion body myositis (sIBM) is a type of idiopathic inflammatory myopathies (IIM) which also include polymyositis (PM), dermatomyositis (DM), antisynthetase syndrome (ASS), and immune-mediated necrotizing myopathy (IMNM) [1–3]. It is distinguished from the other types by its clinical weakness pattern, muscle biopsy features, autoantibody association, and resistance to immunosuppressive therapy. It is currently viewed as an inflammatory and degenerative muscle disease [4, 5].
The prevalence of sIBM varies in different populations and ethnic groups, ranging from 46 to 117 per million [6–8]. It is the second most common type of IIM, accounting for 15.9% (73/460) of IIM in a Japanese cohort [9] and 29.6% (77/260) in a French cohort [10]. The disease mainly affects men over age 50 years with the mean age of symptom onset ranging from 61–68 years. About 20% of the patients had a symptom onset in their 40s in one study cohort [11]. One of the current diagnostic criteria for sIBM is age at onset >45 years [12]. Young sIBM is more commonly seen in patients with HIV or HTLV infection, and sIBM is overrepresented in HIV-infected patients [13, 14].
The symptom onset of sIBM is usually insidious, and the progression is slow. The disease preferentially affects knee extensors and finger flexors. But the other limb muscles can be affected at an advanced stage. The initial symptom in a majority of the patients is caused by thigh muscle weakness with difficulty getting out of a car or climbing stairs and knee buckling when walking [15]. During the disease course, patients commonly develop finger flexor weakness with difficulty bending fingers to make a fist, and anterior distal leg muscle (tibialis anterior) weakness with difficulty picking up feet and resultant falls. The limb weakness is often asymmetrical as seen in our case. Difficulty swallowing (dysphagia) is not uncommon, which can cause weight loss and aspiration pneumonia, a major cause of mortality in sIBM. Respiratory weakness is mild and often asymptomatic. In rare cases of sIBM, patients present with head drop. Examination often shows limb weakness with asymmetry, more severely affecting knee extensors and finger flexors. Weakness may also be detected in ankle dorsiflexors, hip flexors, and finger extensors. Proximal upper limb weakness is uncommon and relatively mild if present. At a late stage, quadriceps and forearm muscle atrophy is prominent. Serum CK can be normal or mildly elevated, no greater than 15 times the upper limit of normal; it is rarely above 2000 U/L. EMG frequently shows fibrillation potentials and/or positive sharp waves, and mixed small and large motor unit potentials in the affected limb muscles [16]. Due to the late onset of the disease, asymmetrical limb weakness, common co-existing spine spondylosis and diabetes mellitus, normal or mildly elevated CK, and mixed large and small motor units on EMG, sIBM is often initially misdiagnosed with radiculopathy, neuropathy, or even motor neuron disease. A correct diagnosis can be delayed by several years [15] as seen in our case.
Anti-NT5C1A autoantibody was identified in sIBM in 2011 [17–19]. It helps not only explore the pathogenesis but also facilitate the diagnosis of sIBM. The test for detecting this autoantibody in serum is commercially available. This autoantibody test showed over 70% sensitivity and over 90% specificity for diagnosing sIBM [18, 20, 21]. It is highly specific for sIBM and rarely present in polymyositis, dermatomyositis, non-immune neuromuscular diseases, or non-neuromuscular autoimmune diseases such as systemic lupus erythematosus and Sjogren’s syndrome [4]. The sensitivity and specificity of the test may vary due to different methods and cut-offs used by different laboratories. One study showed that female patients with sIBM were more likely to have a positive anti-NT5C1A autoantibody , and that sIBM patients with a positive anti-NT5C1A autoantibody were more likely to have dysphagia, facial weakness, respiratory muscle weakness, and severe leg weakness that requires assistive devices for ambulation [20]. The other studies did not find the association of this autoantibody with gender, age at onset, disease duration, weakness pattern, or prevalence of inflammation on muscle biopsy [18, 22]. It remains unclear whether the presence of this autoantibody influences muscle pathology, disease progression, or treatment response.
Muscle biopsy plays a key role in the diagnosis of sIBM, and the current diagnostic criteria for sIBM include both clinical and muscle biopsy features [12, 23]. Anti-NT5C1A autoantibody has not yet been incorporated into the diagnostic criteria. Muscle biopsy is particularly helpful at the early stage of the disease to avoid misdiagnosis or delay in making the correct diagnosis. We do see patients with isolated quadriceps weakness at the early stage of the disease, who subsequently develop finger flexor weakness after the muscle biopsy diagnosis of sIBM is made. It is important to select a muscle for biopsy to increase the diagnostic yield, as rimmed vacuoles, one of the key pathology features of sIBM, can be missed from muscle biopsies in 20% of patients with sIBM due to the sampling error [24]. The most commonly selected muscle for biopsy in sIBM is quadriceps. It should be noted that vastus lateralis and vastus medialis are affected sooner and greater than rectus femoris in sIBM, and rectus femoris can be relatively spared at the early stage of the disease [25]. Therefore, we usually biopsy vastus lateralis, and our biopsy yield is very high.
The characteristic features of sIBM on muscle biopsy include primary endomysial inflammation, mitochondrial abnormality, rimmed vacuoles and a background of chronic active myopathy. The inflammation is similar to polymyositis, dominated by T lymphocytes predominantly located in the endomysium that surround and invade viable myofibers, accompanied by diffuse MHC1 upregulation in myofibers. The mitochondria abnormality is reflected by the presence of substantially increased number of ragged red fibers on Gomori trichrome stain and COX-deficient fibers on COX or COX/SDH combined stains, far exceeding what is expected from the age related change. The vacuoles in sIBM contain red staining granules on Gomori trichrome and acid phosphatase stains, so called “red rimmed vacuoles ”. On EM, these red staining granules are composed of myeloid debris , also referred to as “myelinoid” or “lipidic” debris, due to their resemblance to myelin ovoids in peripheral nerve (Fig. 6.1e). The more characteristic inclusion is the tubulofilamentous inclusion, which is considered a form of amyloid and may show apple green bi-referengence on Congo red stain and bright fluorescence signal under fluorescence light through the red Rhodamine filter.
The diagnosis of sIBM is not difficult to make when all the diagnostic features are present on muscle biopsy. However, the presence of primary inflammation, MHC1 upregulation, and rimmed vacuoles are variable and may make the diagnosis challenging when absent. sIBM cases lacking rimmed vacuoles need to be differentiated from polymyositis with mitochondria abnormality and other inflammatory myopathies. In sIBM, the chronic myopathic changes (e.g. hypertrophied fibers, split fibers, interstitial fibrosis, and fatty tissue replacement) are usually much more prominent than in polymyositis. The presence of p62 and TDP43 positive protein aggregates in myofibers [26, 27] and a positive serum anti-NT5C1A antibody may help differentiate sIBM from polymyositis. The distinction is important as polymyositis with mitochondria abnormality may respond to methotrexate therapy [28].
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