Naddaf, Elie

AbstractIntroductions/AimsInclusion body myositis (IBM) typically presents with progressive weakness preferentially involving finger flexors and quadriceps. Atypical presentations have been less commonly reported. Here, we aim to describe the clinical characteristics and long‐term outcomes of IBM patients with atypical presentations.MethodsWe retrospectively searched the Mayo Clinic medical records to identify IBM patients with atypical disease onset, seen between 2015 and 2020.ResultsWe identified 357 IBM patients, of whom 50 (14%) had an atypical presentation. Thirty‐eight patients were diagnosed with IBM because they fulfilled one of the European Neuromuscular Center diagnostic categories at a later stage, 10 had all IBM histopathological features, and 2 were diagnosed on the basis of clinical and laboratory data. The most common presentation was dysphagia (50%), followed by asymptomatic hyperCKemia (24%; CK, creatine kinase), then foot drop (12%). 6% of patients presented with proximal arm weakness, 4% with axial weakness and 4% with facial diplegia. Median time from symptom onset to diagnosis was 9 y. Median age at diagnosis was 70.5 y. 16% of patients needed a walking aid. When tested, 86.5% of patients had impaired swallowing and 56% had elevated cytosolic nucleotidase‐1A antibodies. Only 1/26 patients who received immunotherapy had minimal improvement. Upon follow‐up, most patients had generalization of their weakness with a decline in their strength summated score of 0.082/mo.DiscussionA significant proportion of IBM patients may have an atypical presentation. Recognition of such heterogeneity could improve early diagnosis, prevent unnecessary immunotherapy, and provide insight for future diagnostic criteria development and clinical trials.

Peripheral neuropathies are a recognized complication of labor in the post-partum period. Herein, we describe an uncommon presentation of sciatic mononeuropathy due to ischiofemoral impingement during labor. A 29-year-old, gravida 4 para 2, female presented post-partum with acute left lower limb paresthesia and left foot drop, following spontaneous vaginal delivery of twins. Neurological examination demonstrated no activation of the left sciatic-innervated muscles and sensory loss in the same distribution. Electromyography (EMG) demonstrated an acute complete left sciatic mononeuropathy. MRI of the lumbosacral plexus and sciatic nerve showed a narrowed quadratus femoris space with mild edema of the muscle, consistent with ischiofemoral impingement syndrome. In addition, there was flattening of the sciatic nerve as it passed through the ischiofemoral space. She was treated conservatively, and at 7-month follow-up, there was marked improvement in muscle strength with ongoing sensory impairment. Repeat EMG demonstrated reinnervation in all sciatic-innervated muscles. This case highlights the risk of a sciatic mononeuropathy secondary to ischiofemoral impingement in the peripartum setting. Future studies are needed to determine if women with a narrow ischiofemoral space at baseline are at increased risk for peripheral nerve injury during labor.

AbstractObjectivesTo investigate immune-mediated necrotizing myopathy (IMNM) association with cancer and its clinical implications.MethodsIMNM cases were identified 1 January 2000 to 31 December 2020 matching sex and age controls (4:1).ResultsA total of 152 patients with IMNM were identified and among serologically tested, 60% (83/140) were HMGCR-IgG+, 14% (20/140) were SRP-IgG+ and 26% (37/140) were seronegative. Cancer rates were not significantly different between serological subgroups; 18.1% (15/83) HMGCR-IgG+, 25% (5/20) SRP-IgG+ and 30% (11/37) seronegative (P = 0.34). Cancer screening was performed within 12 months from IMNM diagnosis in 88% (134/152) (whole-body CT plus FDG-PET CT in 53, CT alone in 72 and FDG-PET alone in 9). FDG-PET/CT was positive in 73% (25/34) of cancers. Increasing age was the only risk associated with cancer (P = 0.02). The odds of developing cancer at ±3 or ±5 years from IMNM diagnosis was not higher than controls (OR = 0.49; CI: 0.325–0.76). Lifetime IMNM diagnosis of cancer was less compared with controls (OR = 0.5 CI: 0.33–0.78, P = 0.002). Most patients responded to treatment (137/147, P < 0.001). Death and treatment response did not significantly differ between cancer [23% (8/34); 88% (29/33)] and non-cancer patients [19% (23/118); 92% (108/118)]. In total, 13% (20/152) of patients died during follow-up compared with 14% (41/290) of medicine and 16% (46/290) of neurology controls (P = 0.8). Seropositives had greater life expectancy than seronegatives (P = 0.01).ConclusionsGreater cancer risk is not observed in IMNM vs controls. Cancer screening in IMNM should be individualized based on age-personal and family history, including consideration of FDG-PET/CT. Immune-treatment response did not differ with cancer.

AbstractObjectiveTo define the proteomic profile of sporadic late‐onset nemaline myopathy (SLONM) and explore its pathogenesis.MethodsWe performed mass spectrometry on laser‐dissected frozen muscle samples from five patients with SLONM, three of whom with an associated monoclonal protein (MP), and four controls, to determine the proteomic profile of SLONM. Furthermore, we assessed the role of the MP by evaluating the expression of the immunoglobulin light chain variable regions (IGVL).ResultsThere were 294 differentially expressed proteins: 272 upregulated and 22 downregulated. Among the top 100 upregulated proteins, the most common categories were: nuclear or nucleic acid metabolism (24%), extracellular matrix and basal lamina (17%), immune response (13%), and actin dynamics (8%). Downregulated proteins consisted mostly of contractile proteins. Among upregulated proteins, there were 65 with a role related to the immune system, including eight proteins involved in major histocompatibility complex 1 (MHC1) and antigen processing, 15 in MHCII complex and phagocytosis, and 23 in B and/or T‐cell function. Among nine upregulated immunoglobulin proteins, there were two IGVL genes. However, these were also detected in SLONM cases without an MP, with no evidence of clonally dominant immunoglobulin deposition. In muscle sections from SLONM patients, nemaline rods tended to accumulate in atrophic fibers with marked rarefaction of the myofibrils. Increased MHC1 reactivity was present in fibers containing nemaline rods as well as adjacent nonatrophic fibers.ConclusionOur findings suggest that aberrant immune activation is present in SLONM, but do not support a direct causal relationship between the MP and SLONM.

AbstractIntroduction/AimsThe full spectrum of the clinical phenotype of facioscapulohumeral muscular dystrophy (FSHD), beyond skeletal muscle weakness, remains poorly characterized. In this study, we describe systemic manifestations and symptom burden in a large series of FSHD patients.MethodsWe performed a retrospective chart review of FSHD patients seen at our institution between 2000 and 2017. We reviewed patients' responses to a comprehensive review of symptoms and the results of diagnostic testing for sensorineural hearing loss, cardiac disease, dysphagia, ocular abnormalities, and respiratory insufficiency. We assessed the association between disease manifestations and age of onset, genetic profile, and disease duration.ResultsWe identified 87 patients with FSHD. The most common reported symptoms included pain (71%), difficulty sleeping (41%), headaches (27%), and altered mood (24%). When tested, 7 of 16 (44%) patients had sensorineural hearing loss, 20 of 60 (33%) had cardiac arrhythmias or conduction defects, 17 of 45 (38%) had echocardiogram abnormalities, 12 of 25 (48%) had reduced forced vital capacity, and 4 of 10 (40%) had oropharyngeal dysphagia. However, patients with these abnormalities represented 8%, 23%, 20%, 14%, and 5% of total number of patients, respectively, as uniform screening was lacking. Ocular pathology attributable to FSHD was not detected.DiscussionFSHD demonstrates a broad clinical phenotype. Increased vigilance among neurologists to screen for systemic manifestations of the disease is warranted. More uniform screening and future population‐based studies are needed to compare findings in FSHD patients with the general population.

AbstractSkeletal muscle‐related symptoms are common in both acute coronavirus disease (Covid)‐19 and post‐acute sequelae of Covid‐19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post‐viral fatigue syndrome. Patients with severe Covid‐19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid‐19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post‐intensive care unit (ICU) syndrome and ICU‐acquired weakness and likely explain a substantial part of Covid‐19‐acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS‐CoV)‐2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS‐CoV‐2‐specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid‐19 and PASC.

Abstract Objective To determine whether histopathological, electromyographic and laboratory markers correlate with clinical measures in inclusion body myositis (IBM). Methods We reviewed our electronic medical records to identify patients with IBM according to European Neuromuscular Center (ENMC) 2011 criteria, seen between 2015 and 2020. We only included patients who had a muscle biopsy and needle electromyography (EMG) performed on the same muscle (opposite or same side). We used a detailed grading system [0 (normal) to 4 (severe)] to score histopathological and EMG findings. Clinical severity was assessed by the modified Rankin scale (mRS), muscle strength sum score (SSS), quadriceps strength and severity of dysphagia on swallow evaluation. Serum markers of interest were creatine kinase level and cN-1A antibodies. Results We included 50 IBM patients, with a median age of 69 years; 64% were males. Median disease duration at diagnosis was 51 months. On muscle biopsy, endomysial inflammation mainly correlated with dysphagia, and inversely correlated with mRS. Vacuoles and congophilic inclusions did not correlate with any of the clinical measures. On EMG, the shortness of motor un it potential (MUP) duration correlated with all clinical measures. Myotonic discharges, and not fibrillation potentials, correlated with the severity of inflammation. Serum markers did not have a statistically significant correlation with any of the clinical measures. Conclusions Dysphagia was the main clinical feature of IBM correlating with endomysial inflammation. Otherwise, inclusion body myositis clinical measures had limited correlation with histopathological features in this study. The shortness of MUP duration correlated with all clinical measures.

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.