Citations

AbstractIntroduction/AimsImmune‐mediated necrotizing myopathy (IMNM) is an immune‐mediated myopathy typically presenting with progressive subacute weakness and characteristic, but nonspecific, myopathological findings. Atypical cases however can mimic other inherited or acquired myopathies, depriving patients of treatment. We describe a cohort of such patients.MethodsWe retrospectively identified IMNM patients who either previously carried a diagnosis of an inherited myopathy established on clinicopathological grounds or whose muscle biopsies displayed atypical features suggestive of a different myopathy.ResultsAmong 131 IMNM patients, seven previously unreported patients (5%) met one of the above criteria. Three patients were diagnosed with limb‐girdle muscular dystrophy on the basis of a chronic progressive course of weakness and family history of myopathy or cardiomyopathy. The other four patients displayed atypical histological features (two prominent mitochondrial abnormalities, one myofibrillar pathology, and one granulomatous inflammation). Immunostaining of biopsies from 12 additional IMNM patients did not identify myofibrillar pathology. The patient with granulomatous inflammation was known to have pulmonary sarcoidosis. Genetic testing for inherited myopathies was unrevealing. Antibodies against 3‐hydroxy‐3‐methylglutaryl‐CoA reductase or signal recognition particle were identified in 5 and 1 patients, respectively. Four patients presented with slowly progressive weakness over 3–13 y, while weakness was subacute over ≤6 mo in three patients. All patients responded to immunomodulatory therapy.DiscussionAtypical clinical and histological features can occur in IMNM patients, causing delays in diagnosis and treatment. Clinicians should, therefore, consider IMNM in the differential diagnosis of unexplained proximal myopathies in spite of atypical clinical and myopathological findings.

Abstract Objective To evaluate survival and associated comorbidities in inclusion body myositis (IBM) in a population-based, case-control study. Methods We utilized the expanded Rochester Epidemiology Project medical records-linkage system, including 27 counties in Minnesota and Wisconsin, to identify patients with IBM, other inflammatory myopathies (IIM), and age/sex-matched population-controls. We compared the frequency of various comorbidities and survival among groups. Results We identified 50 IBM patients, 65 IIM controls and 294 population controls. Dysphagia was most common in IBM (64%) patients. The frequency of neurodegenerative disorders (dementia/parkinsonism) and solid cancers was not different between groups. Rheumatoid arthritis was the most common rheumatic disease in all groups. A total of 36% of IBM patients had a peripheral neuropathy, 6% had Sjögren’s syndrome and 10% had a haematologic malignancy. T-cell large granular lymphocytic leukaemia was only observed in the IBM group. None of the IBM patients had hepatitis B or C, or HIV. IBM patients were 2.7 times more likely to have peripheral neuropathy, 6.2 times more likely to have Sjögren’s syndrome and 3.9 times more likely to have a haematologic malignancy than population controls. IBM was associated with increased mortality, with a 10-year survival of 36% from index, compared with 67% in IIM and 59% in population controls. Respiratory failure or pneumonia (44%) was the most common cause of death. Conclusions IBM is associated with lower survival, and higher frequency of peripheral neuropathy, Sjögren’s syndrome and haematologic malignancies than the general population. Close monitoring of IBM-related complications is warranted.

Abstract Introduction/Aims Intracellular congophilic inclusions within muscle fibers, although nonspecific, are one of the pathological hallmarks of sporadic inclusion body myositis (sIBM). Extracellular amyloid deposits in muscle, on the other hand, are the canonical findings of amyloid myopathies, which occur with or without systemic amyloidosis. Methods We reviewed the muscle biopsy database (1998–2020) to identify sIBM patients with extracellular amyloid deposits. Clinical and laboratory data were reviewed. Results We identified five sIBM patients (three clinicopathologically defined and two clinically defined) with extracellular amyloid deposits in muscle. Mean age at diagnosis was 74.8 y (range, 68–84 y). All patients had a typical sIBM pattern of weakness without associated sensory or autonomic symptoms. None had electrophysiological evidence of peripheral neuropathy. Only one patient had a monoclonal gammopathy (immunoglobulin M‐lambda, IgM‐λ) with normal bone marrow biopsy. This patient with monoclonal gammopathy and three other patients underwent abdominal fat pad aspirate and were negative for amyloid. Cardiac evaluation was unrevealing in the four patients tested. Three patients without monoclonal gammopathy had normal transthyretin gene sequencing and inconclusive mass spectrometry‐based analysis. The patient with monoclonal gammopathy died of pneumosepsis 5 y after diagnosis and autopsy revealed multi‐organ transthyretin amyloidosis. Discussion Detection of extracellular amyloid deposition in muscle should trigger an aggressive search for systemic amyloidosis independently from other associated myopathological abnormalities. Amyloid subtyping is crucial for early therapy and mortality prevention. An isolated monoclonal gammopathy should not halt a search for non‐hematological causes of systemic amyloidosis.

Abstract Despite recent advances in the understanding of inherited muscle and neuromuscular junction diseases, as well as the advent of a wide range of genetic tests, patients continue to face delays in diagnosis of sometimes treatable disorders. These guidelines outline an approach to genetic testing in such disorders. Initially, a patient's phenotype is evaluated to identify myopathies requiring directed testing, including myotonic dystrophies, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, mitochondrial myopathies, dystrophinopathies, and oculopharyngodistal myopathy. Initial investigation in the remaining patients is generally a comprehensive gene panel by next‐generation sequencing. Broad panels have a higher diagnostic yield and can be cost‐effective. Due to extensive phenotypic overlap and treatment implications, genes responsible for congenital myasthenic syndromes should be included when evaluating myopathy patients. For patients whose initial genetic testing is negative or inconclusive, phenotypic re‐evaluation is warranted, along with consideration of genes and variants not included initially, as well as their acquired mimickers.

Abstract Amyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases, pathologically characterized by extracellular amyloid fibrils producing congophillic amorphous deposits in organs and tissues, which may lead to severe organ dysfunction and mortality. Clinical presentations vary and are often nonspecific, depending on what organs or tissues are affected. In systemic amyloidosis, the peripheral nervous system is commonly affected, whereas the skeletal muscles are only rarely involved. Immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin (ATTRv) amyloidosis are the most frequent types of systemic amyloidosis involving the neuromuscular system. Localized amyloidosis can occur in skeletal muscle, so‐called isolated amyloid myopathy. Amyloid neuropathy typically involves small myelinated and unmyelinated sensory and autonomic nerve fibers early in the course of the disease, followed by large myelinated fiber sensory and motor deficits. The relentlessly progressive nature with motor, painful sensory and severe autonomic dysfunction, profound weight loss, and systemic features are distinct characteristics of amyloid neuropathy. Amyloid myopathy presentation differs between systemic amyloidosis and isolated amyloid myopathy. Long‐standing symptoms, distal predominant myopathy, markedly elevated creatine kinase level, and lack of peripheral neuropathy or systemic features are highly suggestive of isolated amyloid myopathy. In ATTR and AL amyloidosis, early treatment correlates with favorable outcomes. Therefore, awareness of these disorders and active screening for amyloidosis in patients with neuropathy or myopathy are crucial in detecting these patients in the everyday practice of neuromuscular medicine. Herein, we review the clinical manifestations of neuromuscular amyloidosis and provide a diagnostic approach to this disorder.

AbstractBackgroundAnti‐cytosolic 5′‐nucleotidase 1A (cN1A) antibodies are commonly detected in patients with sporadic inclusion body myositis (sIBM). However, their pathogenic role has not been established. Moreover, efforts toward identifying sIBM distinct clinicopathologic characteristics associated with these antibodies have yielded conflicting results.MethodsWe first searched for patients, seen in our clinics, tested for anti‐cN1A antibodies between December 2015 and December 2019. We identified 92 patients who were diagnosed with sIBM, according to the 2011 ENMC or Griggs et al criteria. Thereafter, we reviewed and compared the clinical and investigational findings of these patients in relation to their antibody status.ResultsAnti‐cN1A antibodies were present in 47/92 (51%) patients with sIBM. Comparison of seropositive and seronegative cohorts yielded no significant difference in clinical features, including facial weakness, oropharyngeal and respiratory involvement, or disease severity. The antibody titer did not correlate with the clinical phenotype, CK value, or presence of myotonic discharges on EMG. Anti‐cN1A antibody positive patients appeared to have more frequent auto‐aggressive inflammation on muscle biopsy but not as an isolated myopathological feature.ConclusionsOur study showed that anti‐cN1A antibody positive and negative sIBM patients have similar clinical features and disease severity. Anti‐cN1A antibodies in our sIBM cohort did not correlate with any studied clinical or laboratory parameter and, therefore, were of limited value in the patient's assessment.

Abstract Delayed diagnosis of immune-mediated necrotizing myopathy leads to increased morbidity. Patients with the chronic course without 3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG or signal recognition particle-IgG are often challenging to diagnose. Immunotherapy response can also be difficult to assess. We created a statistical model to assist immune-mediated necrotizing myopathy diagnosis. Electrical myotonia versus fibrillations were reviewed as biomarkers for immunotherapy treatment response. Identified were 119 immune-mediated necrotizing myopathy cases and 938 other myopathy patients. Inclusion criteria included all having electrophysiological evaluations, muscle biopsies showing inflammatory/necrotizing myopathies, comprehensively recorded neurological examinations, and creatine kinase values. Electrical myotonia was recorded in 56% (67/119) of retrospective and 67% (20/30) of our validation immune-mediated necrotizing myopathy cohorts, and significantly (P < 0.001) favoured immune-mediated necrotizing myopathy over other myopathies: sporadic inclusion body myositis (odds ratio = 4.78); dermatomyositis (odds ratio = 10.61); non-specific inflammatory myopathies (odds ratio = 8.46); limb-girdle muscular dystrophies (odds ratio = 5.34) or mitochondrial myopathies (odds ratio = 14.17). Electrical myotonia occurred in immune-mediated necrotizing myopathy seropositive (3-hydroxy-3-methylglutaryl-coenzyme-A reductase-IgG 70%, 37/53; signal recognition particle-IgG 29%, 5/17) and seronegative (51%, 25/49). Multivariate regression analysis of 20 variables identified 8 (including electrical myotonia) in combination accurately predicted immune-mediated necrotizing myopathy (97.1% area-under-curve). The model was validated in a separate cohort of 30 immune-mediated necrotizing myopathy cases. Delayed diagnosis of cases with electrical myotonia occurred in 24% (16/67, mean 8 months; range 0–194). Half (8/19) had a chronic course and were seronegative, with high model prediction (>86%) at the first visit. Inherited myopathies were commonly first suspected in them. Follow-up evaluation in patients with electrical myotonia on immunotherapy was available in 19 (median 21 months, range 2–124) which reduced from 36% (58/162) of muscles to 7% (8/121; P < 0.001). Reduced myotonia correlated with immunotherapy response in 64% (9/14) as well as with median creatine kinase reduction of 1779 U/l (range 401–9238, P < 0.001). Modelling clinical features with electrical myotonia is especially helpful in immune-mediated necrotizing myopathy diagnostic suspicion among chronic indolent and seronegative cases. Electrical myotonia favours immune-mediated necrotizing myopathy diagnosis and can serve as an adjuvant immunotherapy biomarker.

Abstract Immune checkpoint inhibitors have revolutionized the landscape of cancer treatment. Alongside their many advantages, they elicit immune-related adverse events, including myopathy, which potentially result in substantial morbidity if not recognized and treated promptly. Current knowledge of immune checkpoint inhibitor-associated myopathy is limited. We conducted a 5-year retrospective study of patients with immune checkpoint inhibitor-associated myopathy. Clinical features, survival and ancillary test findings were analysed and compared with those of immune-mediated necrotizing myopathy patients without immune checkpoint inhibitor exposure seen during the same time period. We identified 24 patients with immune checkpoint inhibitor-associated myopathy (median age 69 years; range 28–86) and 38 patients with immune-mediated necrotizing myopathy. Ocular involvement occurred in 9/24 patients with immune checkpoint inhibitor exposure, without electrodiagnostic evidence of neuromuscular transmission defect, and in none of the immune-mediated necrotizing myopathy patients (P < 0.001). Myocarditis occurred in eight immune checkpoint inhibitor-associated myopathy patients and in none of the immune-mediated necrotizing myopathy patients (P < 0.001). Median creatine kinase was 686 IU/l in the immune checkpoint inhibitor cohort (seven with normal creatine kinase) compared to 6456 IU/l in immune-mediated necrotizing myopathy cohort (P < 0.001). Lymphopenia was observed in 18 and 7 patients with and without immune checkpoint inhibitor exposure, respectively (P < 0.001). Myopathological findings were similar between patients with and without immune checkpoint inhibitor exposure, consisting of necrotic fibres with no or subtle inflammation. Necrotic fibres however arranged in clusters in 10/11 immune checkpoint inhibitor-associated myopathy patients but in none of the immune checkpoint inhibitor-naïve patients (P < 0.001). Despite the lower creatine kinase levels in immune checkpoint inhibitor-exposed patients, the number of necrotic fibres was similar in both groups. Immune checkpoint inhibitor-associated myopathy patients had a higher frequency of mitochondrial abnormalities and less number of regenerating fibres than immune-mediated necrotizing myopathy patients (P < 0.001). Anti-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle antibodies were absent in patients with immune checkpoint inhibitor exposure but positive in two-thirds of immune checkpoint inhibitor-naïve patients. Most patients with immune checkpoint inhibitor-associated myopathy responded favourably to immunomodulatory treatments, but four died from myopathy-related complications and one from myocarditis. Intubated patients had significantly shorter survival compared to non-intubated patients (median survival of 22 days; P = 0.004). In summary, immune checkpoint inhibitor-associated myopathy is a distinct, treatable immune-mediated myopathy with common ocular involvement, frequent lymphopenia and necrotizing histopathology, which contrary to immune-mediated necrotizing myopathy, is featured by clusters of necrotic fibres and not accompanied by anti-hydroxy-3-methylglutaryl-CoA reductase or signal recognition particle antibodies. Normal or mildly elevated creatine kinase level does not exclude the diagnosis.