Neuromuscular Centre Research Articles

Usefulness of subcutaneous immunoglobulin therapy in the management of myasthenia gravis: a retrospective cohort study.

IntroductionTo describe the efficacy of subcutaneous immunoglobulin (SCIg) in patients with myasthenia gravis (MG).MethodsThis was a retrospective study conducted in the neuromuscular referral center of Bordeaux (between January 1, 2014 and March 31, 2021) with MG patients treated with SCIg. The main outcome was SCIg efficacy assessed by the before and after SCIg Myasthenia Gravis Foundation of America (MGFA) clinical classification, the duration of hospitalization and the number of days of orotracheal intubation (OTI).ResultsSixteen patients were included in the study (11 females; 5 males). Nine patients were still treated with SCIg at the end of the study (March 31, 2021) and then underwent prospective follow-up. The average age of the patients was 56.1 (19–83) years. The median duration of MG at onset of SCIg was 37.4 months. Eight patients (50%) remained stable (4 in stage MGFA-IV and 4 in MGFA-III). Eight patients (50%) improved: 3 from MGFA-IV to MGFA-III, 1 from MGFA-IV to MGFA-II, 1 from MGFA-IV to MGFA-I, 2 from MGFA-III to MGFA-II and 1 from MGFA-III to MGFA-I (no patient worsened). The duration of disease progression did not appear to affect the response to SCIg therapy. The number of hospital days per month was significantly reduced after SCIg compared to before, and the number of days in intensive care unit and the number of days of OTI were also reduced. Only minor adverse effects were noted, and 80% of patients were in favor of continuing SCIg.ConclusionsSCIg is a well-tolerated and useful treatment in MG, offering interesting perspectives in the management of MG patients. However, further large-scale prospective studies are needed to confirm these results.

Expanding the clinicopathological-genetic spectrum of glycogen storage disease type IXd by a Chinese neuromuscular center.

BackgroundGlycogen storage disease (GSDs) is characterized by abnormally inherited glycogen metabolism. GSD IXd, which is caused by mutations in the PHKA1 gene, is an X-linked rare disease with mild myopathic symptoms. To date, only 13 patients with GSD IXd have been reported. In this study, we aimed to expand the clinicopathological-genetic spectrum of GSD IXd at a neuromuscular center in China.MethodsData on patients diagnosed with GSD IXd at our neuromuscular center were collected retrospectively. Clinical features, electrophysiology, muscle pathology, and genetic information were analyzed.ResultsBetween 2015 and 2021, three patients were diagnosed with GSD IXd based on clinical manifestations, pathological findings, and genetic testing. One patient presented with mitochondrial myopathy. All patients exhibited muscle weakness and elevated levels of creatine kinase. Electromyography-detected myopathic changes were found in two patients, whereas one patient refused to undergo this examination. Pathological examinations in all patients revealed subsarcolemmal accumulation of glycogen under PAS staining. All patients had mutations in the PHKA1 gene and the patient with mitochondrial myopathy also had a mutation in the MT-TL1 gene.ConclusionOur study expands the clinicogenotype and phenotype of GSD IXd in a Chinese population. Our study also expands the known mutation spectrum for GSD IXd, contributing to a better characterization and understanding of this ultrarare neuromuscular disorder.

Update on dermatomyositis.

This review summarizes and comments on current knowledge in dermatomyositis. The 2018 European Neuromuscular Centre classification of dermatomyositis has been challenging by the discovery of clinicopathological features associated with dermatomyositis-specific antibody (DMSA) that were not incorporated in the original criteria. These features include but may not be limited to the presence of perifascicular necrosis in anti-Mi-2 dermatomyositis; presence of diffuse nonperifascicular sarcoplasmic myxovirus resistance protein A expression in anti-MDA5 dermatomyositis; and dermatomyositis sine dermatitis in anti-NXP-2 dermatomyositis. Variations and subclassifications within the same DMSA subtypes are observed: anti-MDA5 dermatomyositis is clinically subcategorized into good, intermediate, and poor prognostic subgroups; concurrent anti-CCAR1 and anti-TIF1-γ positivity identify anti-TIF1-γ-positive patient with a lower risk for cancer-associated myositis. Owing to distinct IFN1-signaling pathway activation in dermatomyositis, JAK-STAT inhibitor - the pathway-targeted therapy, have been studied with promising results in refractory dermatomyositis and some new-onset dermatomyositis. In addition, the potential serum biomarkers for IFN1 pathway activation are being investigated for their performance in monitoring the disease activity and the efficacy of the treatment. DMSA, evidence of prominent IFN1 pathway activation, and risk/severity-associated biomarkers would likely play major roles in future dermatomyositis classification, disease monitoring, and treatment decision.

The Location of Disease-Causing DES Variants Determines the Severity of Phenotype and the Morphology of Sarcoplasmic Aggregates.

Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes.

A genetic basis is identified in 74% cases of paediatric hyperCKaemia without weakness presenting to a tertiary paediatric neuromuscular centre

Paediatric hyperCKaemia without weakness presents a clinical conundrum. Invasive investigations with low diagnostic yields, including muscle biopsy, may be considered unjustifiable. Improved access to genome-wide genetic testing has shifted first-line investigations towards genetic studies in neuromuscular disease. This research aims to provide an evidence-based diagnostic approach to paediatric hyperCKaemia without weakness, a current gap in the literature. We identified 47 individuals (10-months to 16-years-old; 34 males, 13 females) from 43 families presenting with hyperCKaemia on two or more occasions, without weakness, from The Children's Hospital at Westmead Neuromuscular Clinic Database. Clinical features, investigations and outcomes were analysed via retrospective chart review. Genetic testing has been performed in 34/43. Genetic variants explaining hyperCKaemia were identified in 25/34 (74%) using multiplex ligation-dependent probe amplification, massive parallel sequencing, single gene testing and exome sequencing. Pathogenic/likely pathogenic variants were identified in 19 neuromuscular disease genes and six metabolic myopathy genes. Individuals with metabolic diagnoses had higher peak creatine kinase levels that sometimes normalized. Conversely, creatine kinase levels remained persistently elevated those with neuromuscular diagnoses. In summary, a genetic cause is found in most paediatric patients with hyperCKaemia without weakness informing clinical management and counselling. Thus, we propose a diagnostic algorithm for this cohort.

Newborn Screening for Spinal Muscular Atrophy in New York State: Clinical Outcomes From the First 3 Years.

Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel in July 2018 largely on the basis of the availability and efficacy of newly approved disease-modifying therapies. New York State (NYS) started universal newborn screening for SMA in October 2018. The authors report the findings from the first 3 years of screening. Statewide neonatal screening was conducted using DNA extracted from dried blood spots using a real-time quantitative PCR assay. Retrospective follow-up data were collected from 9 referral centers across the state on 34 infants. In the first 3 years since statewide implementation, nearly 650,000 infants have been screened for SMA. Thirty-four babies screened positive and were referred to a neuromuscular specialty care center. The incidence remains lower than previously predicted. The majority (94%), including all infants with 2-3 copies of survival motor neuron (SMN) 2, have received treatment. Among treated infants, the overwhelming majority (94%; 30/32) have received gene replacement. All infants in this cohort with 3 copies of SMN2 are clinically asymptomatic posttreatment based on early clinical follow-up data. Infants with 2 copies of SMN2 are more variable in their outcomes. Electrodiagnostic outcomes data obtained from a subgroup of patients (n = 11) demonstrated either improvement or no change in compound muscle action potential (CMAP) amplitude at last clinical follow-up compared with pretreatment baseline. Most infants were treated before 6 weeks of age (median = 34.5 days of life; range 11-180 days). Delays and barriers to treatment identified by treating clinicians followed 2 broad themes: medical and nonmedical. Medical delays most commonly reported were the presence of AAV9 antibodies and elevated troponin I levels. Nonmedical barriers included delays in obtaining insurance and insurance policies regarding specific treatment modalities. The findings from the NYS cohort of newborn screen-identified infants are consistent with other reports of improved outcomes from early diagnosis and treatment. Additional biomarkers of motor neuron health including EMG can potentially be helpful in detecting preclinical decline.

Clinicopathological-genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre.

Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. The aim of this study was to characterize the clinical, physiological, pathohistological and genetic features of nine unrelated Chinese patients with CMS from a single neuromuscular centre. A total of nine patients aged from neonates to 34 years were enrolled who exhibited initial symptoms. Physical examinations revealed that all patients exhibited muscle weakness. Muscle biopsies demonstrated multiple myopathological changes, including increased fibre size variation, myofibrillar network disarray, necrosis, myofiber grouping, regeneration, fibre atrophy and angular fibres. Genetic testing revealed six different mutated genes, including AGRN (2/9), CHRNE (1/9), GFPT1 (1/9), GMPPB (1/9), PLEC (3/9) and SCN4A (1/9). In addition, patients exhibited differential responses to pharmacological treatment. Prompt utilization of genetic testing will identify novel variants and expand our understanding of the phenotype of this rare syndrome. Our findings contribute to the clinical, pathohistological and genetic spectrum of congenital myasthenic syndrome in China.

Epidemiology, Survival, and Clinical Characteristics of Inclusion Body Myositis.

ObjectiveWe performed a population‐based study on inclusion body myositis with the primary aims to define the prevalence, survival rate, and incidence, and to investigate the symptom profiles associated with disease duration and sex over a 33‐year period.MethodsPatients diagnosed between 1985 and 2017 in Region Västra Götaland, Sweden, were identified according to the European Neuromuscular Centre diagnostic criteria from 2011.ResultsWe identified 128 patients, 89 men and 39 women, with the strict clinicopathological definition of inclusion body myositis. The prevalence was 32 per million inhabitants, 19 per million women and 45 per million men, by December 31, 2017. Mean incidence was 2.5 per million inhabitants and year. Mean age at symptom onset was 64.4 years with quadriceps weakness being the most common presenting symptom followed by finger flexor weakness. Dysphagia was a common presenting symptom being more frequent in women (23%) than men (10%) and was during the disease course reported in 74% of men and 84% of women. Seventy‐three patients were deceased, with a mean survival of 14 years from symptom onset. Survival rates from both diagnosis date and symptom onset were decreased compared to the matched population.Twenty‐one percent of the patients had an additional autoimmune disease. A cross‐sectional analysis of autoantibodies in 50 patients and 28 matched controls showed autoantibodies to cytosolic 5′‐nucleotidase 1A in 40% of the patients and 3.6% of controls.InterpretationInclusion body myositis is an autoimmune disease with decreased survival rate and with marked sex differences in both prevalence and clinical manifestations. ANN NEUROL 2022;92:201–212

Patient preference for virtual versus in-person visits in neuromuscular clinical practice.

Introduction/AimsIt is unknown if patients with neuromuscular diseases prefer in‐person or virtual telemedicine visits. We studied patient opinions and preference on virtual versus in‐person visits, and the factors influencing such preferences.MethodsTelephone surveys, consisting of 11 questions, of patients from 10 neuromuscular centers were completed.ResultsFive hundred and twenty surveys were completed. Twenty‐six percent of respondents preferred virtual visits, while 50% preferred in‐person visits. Sixty‐four percent reported physical interaction as “very important.” For receiving a new diagnosis, 55% preferred in‐person vs 35% reporting no preference. Forty percent were concerned about a lack of physical examination vs 20% who were concerned about evaluating vital signs. Eighty four percent reported virtual visits were sufficiently private. Sixty eight percent did not consider expenses a factor in their preference. Although 92% were comfortable with virtual communication technology, 55% preferred video communications, and 19% preferred phone calls. Visit preference was not significantly associated with gender, diagnosis, disease severity, or symptom management. Patients who were concerned about a lack of physical exam or assessment of vitals had significantly higher odds of selecting in‐person visits than no preference.DiscussionAlthough neither technology, privacy, nor finance burdened patients in our study, more patients preferred in‐person visits than virtual visits and 40% were concerned about a lack of physical examination. Interactions that occur with in‐person encounters had high importance for patients, reflecting differences in the perception of the patient‐physician relationship between virtual and in‐person visits.

POS1342 DEPLETION OF KLRG1+ T CELLS IN A FIRST-IN-HUMAN CLINICAL TRIAL OF ABC008 IN INCLUSION BODY MYOSITIS (IBM)

BackgroundInclusion body myositis (IBM), a relentlessly progressive autoimmune skeletal muscle disease, has no effective available pharmacological therapy. A prominent feature of IBM on microscopy is highly differentiated effector CD8+ cytotoxic T (Tc) cells invading non-necrotic myofibers [1]. These Tc cells, known to be relatively resistant to apoptosis, express markers including killer cell lectin-like receptor G1 (KLRG1) [2]. ABC008, a first-in-class humanized, afucosylated monoclonal antibody (mAb) specific for KLRG1, selectively depletes these highly differentiated Tc cells while sparing other blood cell populations, e.g., naïve, central memory, and regulatory T cells and B cells. ABC008 has been designed to treat diseases mediated by these Tc cells, including IBM and T-cell large granular lymphocytic leukemia (T-LGLL). IBM and rheumatoid arthritis overlap clinically with T-LGLL and share similar expansions of large granular lymphocytes (LGLs), which also express KLRG1. We report here our preliminary data from our ongoing trial of ABC008 in IBM (NCT04659031).ObjectivesEvaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of ABC008 administered subcutaneously (SC) in adults with IBM.MethodsIn this first-in-human, open-label, single ascending dose trial with 3 + 3 design evaluating ABC008 SC, eligible participants must have clinicopathologically defined, clinically defined, or probable IBM according to the European Neuromuscular Centre 2011 research diagnostic criteria [3] and an IBM Functional Rating Scale (IBMFRS) score ≤38. Four dose cohorts are planned: ABC008 0.1, 0.5, 2.0, and 5.0 mg/kg. PD, PK, safety, and disease severity assessments are performed pre-dose (Day 0) and during the 6-month follow-up period.ResultsFive of the 6 (83.3%) participants were male with baseline mean age = 65.7 years, mean IBM disease duration = 6.8 years, and mean IBMFRS score = 27.5 (Table 1). Each received a single dose of ABC008 SC: Cohorts 1 (C1) and 2 (C2) received 0.1 and 0.5 mg/kg and have completed 168 and 56 days of follow-up, respectively.Table 1.Baseline DemographicsBaseline CharacteristicsABC008 SC Treatment GroupsCohort 10.1 mg/kg SC (n=3)Cohort 20.5 mg/kg SC (n=3)ABC008 Overall (N=6)Age (years), mean ± SD64.0 ± 11.3667.3 ± 6.6665.7 ± 8.52Male sex, n (%)3 (100)2 (66.7)5 (83.3)Caucasian3 (100)3 (100)6 (100)Body Mass Index (kg/m2)28.5 ± 3.5828.3 ± 4.2528.4 ± 3.52Disease Duration (years), mean ± SD9.7 ± 5.973.9 ± 4.486.8 ± 5.70IBMFRS score, mean ± SD30.0 ± 4.0825.0 ± 6.1627.5 ± 5.80Abbreviations: IBMFRS, Inclusion Body Myositis Functional Rating Scale; n or N, number; SC, subcutaneous; SD, standard deviation.Maximum depletion of CD8+KLRG1+ cells for C1 and C2 ranged from 46-96% and 98-99%, respectively (Figure 1A), with depletion evident by the next assessment on Day 1. Recovery in C1 began at Day 84 with Day 168 depletion at 29-71%. Other hematologic parameters generally were stable (e.g., T regulatory and B cells). CD8+CD57+ LGLs, mostly KLRG1+, were also depleted (Figure 1B). Preliminary PK showed that ABC008 SC displays a long absorption phase and slow clearance properties typical of mAb therapies. No severe adverse events (AEs) or discontinuations due to AEs have been reported. One unrelated serious AE of fall with muscle tear in a C1 participant with a prior history of falls occurred.Figure 1.Key pharmacodynamic parameters in Study ABC008-IBM-101. Baseline and change (A) of KLRG1+CD8+ T cells and (B) CD8+CD57+ large granular lymphocytes (LGLs). C1 and C2 are Cohorts 1 and 2; P1, P2, and P3 are Participants 1, 2, and 3.ConclusionIn study participants with IBM, single SC doses of 0.1 and 0.5 mg/kg of ABC008 resulted in the depletion of CD8+KLRG1+ cells and CD8+CD57+ LGLs with clear evidence of a dose response for KLRG1+ T cell depletion and no apparent safety signals. Based on these results, a study evaluating ABC008 for the treatment of T-LGLL is planned.

Clinicopathologic Profiles of Sporadic Late-Onset Nemaline Myopathy: Practical Importance of Anti-α-Actinin Immunostaining.

Background and ObjectivesSporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort.MethodsWe performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc–associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5).ResultsMost of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti–α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti–α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti–α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant.DiscussionSLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti–α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.

Clinical and pathological features of immune-mediated necrotising myopathies in a single-centre muscle biopsy cohort.

ObjectiveImmune-mediated necrotising myopathy (IMNM) is a subset of idiopathic inflammatory myopathies (IIM) characterized by significantly elevated creatine kinase level, muscle weakness and predominant muscle fibre necrosis in muscle biopsy. This study aimed to investigate the clinical and pathological characteristics of patients with IMNM in a single-centre muscle biopsy cohort.MethodsA total of 860 patients who had muscle biopsy reports in our centre from May 2008 to December 2017 were enrolled in this study. IMNM was diagnosed according to the 2018 European Neuromuscular Centre (ENMC) clinicopathological diagnostic criteria for IMNM.ResultsThe muscle biopsy cohort consisted of 531 patients with IIM (61.7%), 253 patients with non-IIM (29.4%), and 76 undiagnosed patients (8.8%). IIM cases were classified as IMNM (68[7.9%]), dermatomyositis (346[40.2%]), anti-synthetase syndrome (82[9.5%]), polymyositis (32[3.7%]), and sporadic inclusion body myositis (3[0.3%]). Limb girdle muscular dystrophy (LGMD) 2B and lipid storage myopathy (LSM) are the two most common non-IIM disorders in our muscle biopsy cohort. IMNM patients had a higher onset age (41.57 ± 14.45 vs 21.66 ± 7.86 and 24.56 ± 10.78, p < .0001), shorter duration (21.79 ± 26.01 vs 66.69 ± 67.67 and 24.56 ± 10.78, p < .0001), and more frequent dysphagia (35.3% vs. 3.4 and 6.3%, p = .001) than LGMD 2B and LSM patients. Muscle biopsy from IMNM showed more frequent muscle fibre necrosis (95.6% vs 72.4 and 56.3%, p < .0001), overexpression of major histocompatibility complex-I on sarcolemma (83.8% vs 37.9 and 12.9%, p < .0001), and CD4+ T cell endomysia infiltration (89.7% vs 53.6 and 50%, p < .0001) compared with those from LGMD 2B and LSM patients.ConclusionsIt is easy to distinguish IMNM from other IIM subtypes according to clinical symptoms and myositis specific antibodies profiles. However, distinguishing IMNM from disorders clinically similar to non-IIM needs combined clinical, serological and pathological features.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12891-022-05372-z.

Phenotypical variability and atypical presentations in a French cohort of Andersen-Tawil syndrome.

Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized. A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted. Thirty-five patients from 27 unrelated families carrying 17 different missense KCNJ2 mutations (four novel mutations) and a heterozygous KCNJ2 duplication are reported. The typical triad was observed in 42.9% of patients. Cardiac abnormalities were observed in 65.7%: 56.5% asymptomatic and 39.1% requiring antiarrhythmic drugs. 71.4% of patients exhibited dysmorphic features. Muscle symptoms were reported in 85.7%, amongst whom 13.3% had no cardiopathy and 33.3% no dysmorphic features. Periodic paralysis was present in 80% and was significantly more frequent in men. Common triggers were exercise, immobility and carbohydrate-rich diet. Ictal serum potassium concentrations were low in 53.6%. Of the 35 patients, 45.7% had permanent weakness affecting proximal muscles, which was mild and stable or slowly progressive over several decades. Four patients presented with exercise-induced pain and myalgia attacks. Diagnostic delay was 14.4±9.5years. ENMG long-exercise test performed in 25 patients (71.4%) showed in all a decremental response up to 40%. Muscle biopsy performed in 12 patients revealed tubular aggregates in six patients (associated in two of them with vacuolar lesions), dystrophic features in one patient and non-specific myopathic features in one patient; it was normal in four patients. Recognition of atypical features (exercise-induced pain or myalgia and permanent weakness) along with any of the elements of the triad should arouse suspicion. The ENMG long-exercise test has a high diagnostic yield and should be performed. Early diagnosis is of utmost importance to improve disease prognosis.

Hereditary myopathies in Mexican population: experience from a tertiary neuromuscular center. (P16-13.004)

Hereditary myopathies in Mexican population: experience from a tertiary neuromuscular center. (P16-13.004)

A deep learning tool without muscle-by-muscle grading to differentiate myositis from facio-scapulo-humeral dystrophy using MRI

PurposeThe purpose of this study was to assess the capabilities of a deep learning (DL) tool to discriminate between type 1 facioscapulo-humeral dystrophy (FSHD1) and myositis using whole-body muscle magnetic resonance imaging (MRI) examination without the need for visual grading of muscle signal changes. Materials and methodsA total of 40 patients who underwent whole-body MRI examination that included T1-weighted and STIR sequences were included. There were 19 patients with proven FSHD1 (9 men, 10 women; mean age, 47.7 ± 18.0 [SD] years; age range: 20–72 years) and 21 patients with myositis fulfilling European Neuromuscular Centre criteria and European League Against Rheumatism and American College of Rheumatology criteria (11 men, 10 women; mean age, 59.3 ± 17.0 [SD]; age range: 19–78 years). Based on thigh, calf, and shoulder sections a supervised training of a neural network was performed and its diagnostic performance was studied using a 5-fold cross validation method and compared to the results obtained by two radiologists specialized in musculoskeletal imaging. ResultsThe DL tool was able to differentiate FSHD1 from myositis with a correct classification percentage respectively of 69 % (95% CI: 39–99), 75% (95% CI: 48–100) and 77% (95% CI: 60–94) when thigh only, thigh and calf or the thigh, calf, and shoulder MR images were analyzed. The percentages of correct classification of the two radiologists for these later MR images were 38/40 (95%) and 35/40 (87.5%), respectively; with no differences with DL tool correct classification (P = 0.41 and P > 0.99, respectively). Among the seven patients who were misclassified by the radiologists, the DL tool correctly classified six of them. ConclusionA DL tool was developed to discriminate between FSHD1 and myositis using whole-body MRI with performances equivalent to those achieved by two radiologists. This study provides a proof of concept of the effectiveness of a DL approach to distinguish between two myopathies using MRI with a small amount of data, and no prior muscle signal changes grading.

Genetic Workup for Charcot-Marie-Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years.

Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.

Peripheral polyneuropathy from electrodiagnostic tests: a 10-year etiology and neurophysiology overview.

Polyneuropathies are characterized by a symmetrical impairment of the peripheral nervous system, resulting in sensory, motor and/or autonomic deficits. Due to the heterogeneity of causes, an etiological diagnosis for polyneuropathy is challenging. The aim of this study was to determine the main causes of polyneuropathy confirmed by electrodiagnostic (EDX) tests in a tertiary service and its neurophysiological aspects. This observational cross-sectional study from a neuromuscular disorders center included individuals whose electrodiagnostic tests performed between 2008 and 2017 confirmed a diagnosis of polyneuropathy. Through analysis of medical records, polyneuropathies were classified according to etiology and neurophysiological aspect. Of the 380 included patients, 59.5% were male, with a median age of 43 years. The main etiologies were: inflammatory (23.7%), hereditary (18.9%), idiopathic (13.7%), multifactorial (11.1%), and diabetes (10.8%). The main electrophysiological patterns were axonal sensorimotor polyneuropathy (36.1%) and "demyelinating and axonal" sensorimotor polyneuropathy (27.9%). Axonal patterns showed greater etiological heterogeneity, with a predominance of idiopathic and multifactorial polyneuropathy, while demyelinating and "demyelinating and axonal" polyneuropathies had a significantly fewer etiologies, with a predominance of hereditary and inflammatory polyneuropathies. The main causes of polyneuropathy confirmed by EDX test in this study were those that presented a severe, atypical and/or rapidly progressing pattern. Other causes were hereditary and those that defy clinical reasoning, such as multiple risk factors; some polyneuropathies did not have a specific etiology. EDX tests are useful for etiological diagnosis of rare polyneuropathies, because neurophysiological patterns are correlated with specific etiologies.

Incidence and prevalence of immune-mediated necrotizing myopathy in adults in Olmsted County, Minnesota.

AbstractIntroduction/AimsImmune‐mediated necrotizing myopathy (IMNM) is considered a rare subtype of the immune‐mediated myopathies, but its incidence and prevalence are unknown. In this study we aimed to determine the incidence and prevalence of IMNM among adults in Olmsted County, Minnesota.MethodsWe identified adult patients with IMNM, as defined by the 2016 European Neuromuscular Centre diagnostic criteria, among residents of Olmsted County, Minnesota over a 20‐year period.ResultsSeven patients fulfilled the inclusion criteria. Six patients were tested for IMNM antibodies: four were anti–3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) positive, one was anti–signal recognition particle positive, and one was seronegative. The incidence of IMNM during 2010‐2019 was 8.3 per million person‐years. The prevalence of IMNM in 2010 was 1.85 per 100 000 people at least 50 years of age. Median age at symptom onset was 64 (range, 52‐86) years and median time from symptom onset to diagnosis was 3 (range, &lt;1 to 156) months. Statin use among anti‐HMGCR IMNM patients, but not the entire IMNM cohort, was higher than in controls (P = .024). Two IMNM patients developed cancers. The incidence of malignancy in IMNM was not higher than that of the general population. Treatment outcome was favorable in all patients except for one patient with delayed treatment and another with insufficient therapy. Among three deceased patients, one died of cancer and another died of IMNM‐related cardiorespiratory complications.DiscussionIMNM is a rare disease. Its prevalence is one tenth that of inclusion‐body myositis in Olmsted County, Minnesota. IMNM patients in our cohort were not at higher risk for developing cancer.

Experience of using gene replacement therapy with Zolgensma® (onasemnogene abeparvovec) in real clinical practice in Russia

Objective: to analyze the safety and evaluate the effectiveness of therapy with onasemnogene abeparvovec in patients with spinal muscular atrophy in real clinical practice based on the experience of using the drug in the neuromuscular center of Research Clinical Pediatric Institute of Pirogov Russian National Research Medical University.Materials and methods. Patients with spinal muscular atrophy received therapy with onasemnogene abeparvovec based on the prescription of the drug according to vital indications by a council of physicians of Federal institutions (the availability of the drug was carried out within the framework of the MAP Program (global program of managed access MAP to AVXS-101 for eligible patients in countries, where it is not approved by regulatory authorities (NCT03955679), through funding from the charitable foundations, as well as through funding from the state fund “Circle of Kindness”. The drug tolerance was assessed and the analysis of side effects after drug administration was based on the criteria for adverse events (General criteria Adverse Event Terminology (CTCAE) v. 5.0) Patient motor function was assessed prior to treatment initiation and every 3–6 months after therapy using the Philadelphia Pediatric Hospital’s CHOP INTEND scale, total motor development based on Hammersmith Hospital Neurological Assessment Scale in Young Children, Part 2 (HINE-2), and the acquisition of new motor skills.Results. 41 children aged 5 to 47 months (weighing no more than 21 kg) received therapy with onasemnogene abeparvovec in the period from April 2020 to December 2021. Adverse events (hyperthermia, decreased appetite, nausea, vomiting) were registered in all patients with different degree of severity. Elevated levels of transaminases greater than 2 times the upper limit of the normal range were observed in 32 patients (78 %), thrombocytopenia in 9 patients (22 %). 15 patients (36 %) required a dose adjustment of corticosteroids.17 patients underwent assessment of motor scales after 6 months, 10 children were assessed after a year. The average improvement on the HINE-2 scale was 3.3 / 4.4 points, respectively. The average improvement on the CHOP INTEND Scale was 7.1 / 9.4 points after 6 / 12 months of therapy.Conclusion. The efficacy and safety of onasemnogene abeparvovec have been demonstrated in real clinical practice in the treatment of spinal muscular atrophy for children in different age groups with a body weight of no more than 21 kg.

Best Practices for the Orthopaedic Care of Children with Spinal Muscular Atrophy: A Consensus Statement from the European Neuromuscular Centre Standard of Care Orthopaedic Working Group

Purpose: Spinal muscular atrophy (SMA) is a genetic disease resulting in orthopaedic problems that warrant intervention. Recent genetic therapies appear to improve the natural course of this disease, prompting care providers to rethink treatment strategies. Insufficient high-quality evidence exists to guide optimal intervention in this new landscape. To address this, the European Neuromuscular Centre (ENMC) tasked an orthopaedic subgroup to update previous recommendations. Materials and Methods: A consensus statement on orthopaedic treatment of patients with SMA undergoing genetic therapy was sought via Delphi method. After review of the orthopaedic literature, three iterative surveys were administered from 2015-2016 to worldwide experts in orthopaedic care of children with SMA. Surveys identified important topics for optimal management, solicited responses regarding management and evaluation of identified topics, and clarified decision-making strategies and indications for evaluation and management, respectively. In light of new evidence of the long-term effects of gene therapy on SMA patients, an additional review of literature was used to contextualize the consensus recommendations. Results: Thirteen experts on orthopaedic management of SMA identified treatment of spine deformity, hip instability, and joint contractures as issues of importance. Experts recommended instrumentation in spinal deformity for major curves greater than 50 degrees, while monitoring pain, respiratory function, kyphosis, pelvic obliquity, functional status, trunk imbalance, and rib deformity. Preferential use of magnetically controlled growth constructs and performance of final fusion with skipped levels to accommodate intrathecal access were also endorsed. Additionally, experts advocated for surgical correction of hip instability and/or contractures that cause pain or functional impairment. Conclusions: Practice guidelines for management of scoliosis, hip instability and joint contractures were created to aid clinical decision-making in the era of genetic therapy.