The Clinicopathological Distinction between Immune-Mediated Necrotizing Myopathy and Limb–Girdle Muscular Dystrophy R2: Key Points to Prevent Misdiagnosis

Abstract

Background: Limb–girdle muscular dystrophy R2 (LGMD R2) is most frequently misdiagnosed as immune-mediated necrotizing myopathy (IMNM). This study aimed to compare the clinicopathological data of IMNM and LGMD R2 to find distinguishing features. Methods: We retrospectively reassessed the medical data of patients with IMNM (n = 41) and LGMD R2 (n = 8) treated at Tongji Hospital from January 2017 to December 2021. Results: In our cohort, patients with LGMD R2 had a longer interval of onset to first visit, mild muscle weakness with late upper limb involvement, less myalgia, no cervical muscle weakness or dysphagia, no extramuscular organs affected except cardiac involvement, and lack of various autoantibodies, such as antinuclear antibodies. These features were completely reversed in IMNM. Moreover, thigh MRIs showed that muscle edema prominently affecting the adductor magnus was a characteristic of IMNM, while extensive fatty replacement was more common in LGMD R2 (p = 0.0086). Necrotic myofibers presented in both entities (p = 0.1693), while features such as ring/whorled and splitting myofibers were more often found in LGMD R2 (p = 0.0112 and p < 0.0001, respectively). Conversely, sarcoplasmic p62 expression was more pronounced in IMNM (p < 0.05). There were 4 of 8 (50%) patients with LGMD R2 initially considered as seronegative IMNM, and therefore unnecessarily treated with immunosuppressive drugs. Insufficient recognition of the early clinical, imaging, and histopathological features of LGMD R2 is the main reason for misdiagnosis. Conclusions: These findings may help clinicians differentiate seronegative IMNM and LGMD R2, reducing early misdiagnosis and mismanagement. Particularly, prominent adductor magnus edema on MRI and abundant p62 staining seem to be good markers for IMNM, while the presence of splitting myofibers is a crucial clue to early hereditary myopathy, including LGMD R2.

Machine learning-based radiomics to differentiate immune-mediated necrotizing myopathy from limb-girdle muscular dystrophy R2 using MRI

“…The radiomics features in each model were from calf, thigh and “calf + thigh” images, respectively. The difference in the distribution and severity of muscular fatty infiltration and atrophy between LGMDR2 and IMNM can be clearly shown in the T1-weighted sequence ( 5 ). Water-only images, including the water signal without fat interference, can exhibit edema of muscle and muscular fascia ( 18 ).…”

“…Previous studies on using the Mercuri scale based on the T1-weighted sequence to identify the different patterns of myopathies suggested that this visual scoring could be advantageous in conveniently applied in clinical practice, especially in primary care hospitals ( 8 , 31 ). Some studies reported selectively involved pattern characterization of muscles evaluated by the Mercuri scale in LGMDR2 and IMNM patients ( 8 , 9 ) and compared the distributions and characteristics of intramuscular fatty infiltration of lower limbs between these two diseases ( 5 ). However, different muscular disorders may have various patterns and degrees of muscular fatty infiltration, edema or atrophy ( 7 ).…”

“…Perhaps this is because some patients with LGMDR2 were not at the early stages of the disease, while calf muscles were involved by fatty infiltration and acute muscle edema in thigh muscles were partial relief. Yang et al reported that patients with LGMDR2 had a longer interval of onset to first visit than patients with IMNM ( 5 ). Besides, some residual fat signal in water-only images may result in mistaking the fat signal for an edema signal ( Figure 2 ), making it difficult to rely on muscle edema to identify the two diseases, which could explain the lower AUC of the water-only model in this study.…”

“…Moreover, its primary clinical manifestation is rapidly progressive muscle weakness ( 3 ). In recent years, many researchers noticed that LGMDR2 most frequently mimics IMNM because they both have onset in adulthood and have similar clinicopathological features, including progressive proximal muscle weakness, elevated creatine kinase (CK) and scattered myonecrosis or inflammatory infiltrates on a muscle biopsy, which leads quickly to clinical misdiagnosis ( 4 , 5 ). Nevertheless, they differ in their management.…”

“…Muscle MRI is capable of clearly demonstrating muscle edema, atrophy or fat replacement, becoming an indispensable tool for diagnosing myopathies, and therefore it contributes to researching the particular pattern of muscle involvement in various muscle diseases ( 7 – 9 ). Although previous studies have compared characteristic muscle MRI performance in LGMDs-and IIM-patients ( 5 , 10 , 11 ), the similarity and complexity of these patterns pose great challenges for radiological diagnosis. Mercuri et al ( 12 ) published the Mercuri scale that has been frequently used to grade intramuscular fatty infiltration based on conventional T1-weighted sequence, but the method depends on the human visual system, which is subjective and does not enable quantification.…”