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Introduction/Aims: Motor neuron disease (MND) is a progressive neurodegenerative condition with a limited life expectancy. There is very little data on mortality and its associated factors beyond 30 days following gastrostomy. We explored the demographic, clinical, and nutritional predictors for early mortality at 30, 90, and 180 days following gastrostomy in these patients. Methods: This was a retrospective study involving 94 MND patients in Western Australia who underwent gastrostomy between 2015 and 2021. Patients were divided into two groups based on mortality at 30, 90, and 180 days post‐gastrostomy. T‐test (or Mann–Whitney), chi‐square test and Fisher's exact test were used for detecting between‐group differences in various factors. Multivariable logistic regression was used to identify factors associated with post‐gastrostomy mortality at 90 and 180 days. Results: No mortality was attributable to gastrostomy‐related complications. Lower forced vital capacity (FVC) (p =.039) and greater weight loss (%) (p =.022) from diagnosis to gastrostomy were observed in those who died within 30 days post‐gastrostomy. Older age (p =.022), male sex (p =.041), lower FVC (p =.04), requiring but not tolerating noninvasive ventilation (p =.035), and greater weight loss (%) (p =.012) were independent predictors of 90‐day post‐gastrostomy mortality. However, only older age (p =.01) and greater weight loss (p =.009) were predictors of mortality at 180 days post‐gastrostomy. Discussion: Our data indicated that mortality at 90 and 180 days was influenced by the weight loss (%) from diagnosis to gastrostomy, highlighting the importance of nutritional care in the MND population. Gastrostomy placement prior to substantial weight loss may reduce the risk of weight loss‐associated mortality and warrants further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic inflammatory myopathies (known as 'myositis') are a group of rare sporadic inflammatory muscle disorders that significantly impact function and quality of life. There are no standardised approaches in the use of assistive technologies in myositis. This study was initiated to investigate current use and perceived value of assistive technology (AT) by people with myositis. Methods: A cross‐sectional online questionnaire (Qualtrics) was designed to capture information regarding AT use and perceived value and demographic information from people with myositis across Australia. The questionnaire was distributed via the Myositis Association of Australia and specialist myositis clinics. Participants were asked to identify which AT items they owned and how frequently the item was used and to rate the 'usefulness' of those items. Information was also collected on participants' engagement with health professionals regarding assistive technologies. Consumer and community involvement: Consumer involvement via the Myositis Research Consumer Panel identified a knowledge gap regarding AT. The questionnaire was designed with consumer input and review. Results: One hundred two people (102) with myositis completed the questionnaire. One hundred (100) participants owned at least one AT device, with a median of 12.5 items and a maximum of 65 items. The most used devices were associated with toileting, personal care and mobility. Participants rated AT devices relating to environmental support, sleeping, seating and body support as most useful. There was a positive correlation between disease duration and number of devices used (r2 = 0.248, p = 0.012). Majority of participants (75.5%) were interested in talking to health professionals about AT; however, only 50% had done so. Conclusion: AT device usage is high among people with myositis, with most items deemed to be useful. Greater occupational therapy input into recommendations and potential funding options may improve knowledge and access to AT. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Enteral feeding via gastrostomy is a key intervention to prevent significant weight loss in Motor Neuron Disease (MND). The aim of this study was to explore demographic, clinical, and nutritional factors associated with survival time in MND patients with gastrostomy. Methods: The retrospective study analyzed 94 MND patients (n = 58 bulbar‐onset and n = 36 limb‐onset) who underwent gastrostomy between 2015 and 2021. The primary outcome was the survival time from gastrostomy insertion to death. Independent variables of interest explored were: age at gastrostomy insertion, disease onset type, known genetic cause, use of riluzole, non‐invasive ventilation (NIV) use, forced vital capacity prior to gastrostomy, weight loss from diagnosis to gastrostomy insertion, and body mass index (BMI) at the time of gastrostomy insertion. Results: The median survival time from gastrostomy to death was 357 days (± 29.3, 95%CI: 299.5, 414.5). Kaplan–Meier method and log‐rank test revealed patients with lower body mass index <18.5 kg/m2 at the time of gastrostomy insertion (p =.023) had shorter survival. Cox proportional hazards model with multivariable adjustment revealed that older age (p =.008), and greater weight loss from diagnosis to gastrostomy (p =.003) were associated with shorter survival time post gastrostomy. Limb onset (p =.023), NIV use not being required (p =.008) and daily NIV use when required and tolerated (p =.033) were associated with longer survival. Discussion: Preventing or minimizing weight loss from MND diagnosis and encouraging NIV use when clinically indicated are modifiable factors that may prolong the survival of MND patients with gastrostomy. [ABSTRACT FROM AUTHOR]

Objective: Inclusion body myositis (IBM) is a progressive late‐onset muscle disease characterised by preferential weakness of quadriceps femoris and finger flexors, with elusive causes involving immune, degenerative, genetic and age‐related factors. Overlapping with normal muscle ageing makes diagnosis and prognosis problematic. Methods: We characterised peripheral blood leucocytes in 81 IBM patients and 45 healthy controls using flow cytometry. Using a random forest classifier, we identified immune changes in IBM compared to HC. K‐means clustering and the random forest one‐versus‐rest model classified patients into three immunophenotypic clusters. Functional outcome measures including mTUG, 2MWT, IBM‐FRS, EAT‐10, knee extension and grip strength were assessed across clusters. Results: The random forest model achieved a 94% AUC ROC with 82.76% specificity and 100% sensitivity. Significant differences were found in IBM patients, including increased CD8+ T‐bet+ cells, CD4+ T cells skewed towards a Th1 phenotype and altered γδ T cell repertoire with a reduced proportion of Vγ9+Vδ2+ cells. IBM patients formed three clusters: (i) activated and inflammatory CD8+ and CD4+ T‐cell profile and the highest proportion of anti‐cN1A‐positive patients in cluster 1; (ii) limited inflammation in cluster 2; (iii) highly differentiated, pro‐inflammatory T‐cell profile in cluster 3. Additionally, no significant differences in patients' age and gender were detected between immunophenotype clusters; however, worsening trends were detected with several functional outcomes. Conclusion: These findings unveil distinct immune profiles in IBM, shedding light on underlying pathological mechanisms for potential immunoregulatory therapeutic development. [ABSTRACT FROM AUTHOR]

Background: Anti–3‐hydroxy‐3‐methylglutaryl CoA reductase (HMGCR) antibodies are associated with a subtype of immune‐mediated necrotising myopathy (IMNM). Aims: To determine clinical associations of anti‐HMGCR antibodies for anti‐HMGCR–associated IMNM (HMGCR‐IMNM) among a cohort of patients in Western Australia and to determine whether serial HMGCR antibody levels parallel disease activity. Methods: Adult patients with positive anti‐HMGCR antibodies detected by enzyme‐linked immunosorbent assay between January 2015 and November 2019 were included. Symptoms, examination findings, imaging findings and blood test results were reviewed retrospectively using patient records and laboratory database results. Results: Among 26 patients with positive anti‐HMGCR antibodies, 23 were diagnosed with HMGCR‐IMNM representing a positive predictive value (PPV) of 88%. Myopathy was frequently severe at diagnosis with limb weakness graded as Medical Research Council score 3 or below in 78% of patients, bulbar muscle weakness in 39% and an average creatine kinase (CK) at diagnosis of 7986 U/L. The majority (83%) required at least two therapies to maintain remission, 48% had at least one flare of disease and 57% did not achieve CK normalisation. Correlation between CK and anti‐HMGCR antibody level at diagnosis was low (r = 0.04). Anti‐HMGCR antibodies fell with treatment in 10 of 12 patients, but remained persistently positive in 83% of patients. Conclusions: The PPV of anti‐HMGCR antibodies for HMGCR‐IMNM in this Western Australian cohort is 88%. Patients typically present with proximal limb weakness, dysphagia and markedly elevated CK, and, despite multiagent immunosuppression, a significant number of patients have evidence of persistent biochemical myositis. Anti‐HMGCR antibodies did not correlate with CK levels at diagnosis. [ABSTRACT FROM AUTHOR]

Valosin‐containing protein (VCP)‐associated multisystem proteinopathy (MSP) is a rare genetic disorder with abnormalities in the autophagy pathway leading to various combinations of myopathy, bone diseases, and neurodegeneration. Ninety percent of patients with VCP‐associated MSP have myopathy, but there is no consensus‐based guideline. The goal of this working group was to develop a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe. As an initiative by Cure VCP Disease Inc., a patient advocacy organization, an online survey was initially conducted to identify the practice gaps in VCP myopathy. All prior published literature on VCP myopathy was reviewed to better understand the different aspects of management of VCP myopathy, and several working group sessions were conducted involving international experts to develop this provisional recommendation. VCP myopathy has a heterogeneous clinical phenotype and should be considered in patients with limb‐girdle muscular dystrophy phenotype, or any myopathy with an autosomal dominant pattern of inheritance. Genetic testing is the only definitive way to diagnose VCP myopathy, and single‐variant testing in the case of a known familial VCP variant, or multi‐gene panel sequencing in undifferentiated cases can be considered. Muscle biopsy is important in cases of diagnostic uncertainty or lack of a definitive pathogenic genetic variant since rimmed vacuoles (present in ~40% cases) are considered a hallmark of VCP myopathy. Electrodiagnostic studies and magnetic resonance imaging can also help rule out disease mimics. Standardized management of VCP myopathy will optimize patient care and help future research initiatives. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS‐R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression. Methods: Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross‐sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS‐R score; (ii) Medical Research Council (MRC) score; and (iii) forced vital capacity and sniff nasal inspiratory pressure. Results: Fast‐progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS‐R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS‐R (P =.002) and MRC (P =.002) scores over 40 weeks. Baseline BMI <25 was also associated with faster reduction of ALSFRS‐R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression. Discussion: Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: Sporadic Inclusion Body Myositis (IBM) is an inflammatory muscle disease affecting individuals over the age of 45, leading to progressive muscle wasting, disability and loss of independence. Histologically, IBM is characterised by immune changes including myofibres expressing major histocompatibility complex molecules and invaded by CD8+ T cells and macrophages, and by degenerative changes including protein aggregates organised in inclusion bodies, rimmed vacuoles and mitochondrial abnormalities. There is currently no cure, and regular exercise is currently the only recognised treatment effective at limiting muscle weakening, atrophy and loss of function. Testosterone exerts anti‐inflammatory effects, inhibiting effector T‐cell differentiation and pro‐inflammatory cytokine production. Methods: We conducted a double‐blind, placebo‐controlled, cross‐over trial in men with IBM, to assess whether a personalised progressive exercise training combined with application of testosterone, reduced the inflammatory immune response associated with this disease over and above exercise alone. To assess intervention efficacy, we immunophenotyped blood immune cells by flow cytometry, and measured serum cytokines and chemokines by Luminex immunoassay. Results: Testosterone supplementation resulted in modest yet significant count reduction in the classical monocyte subset as well as eosinophils. Testosterone‐independent immunoregulatory effects attributed to exercise included altered proportions of some monocyte, T‐ and B‐cell subsets, and reduced IL‐12, IL‐17, TNF‐α, MIP‐1β and sICAM‐1 in spite of interindividual variability. Conclusion: Overall, our findings indicate anti‐inflammatory effects of exercise training in IBM patients, whilst concomitant testosterone supplementation provides some additional changes. Further studies combining testosterone and exercise would be worthwhile in larger cohorts and longer testosterone administration periods. [ABSTRACT FROM AUTHOR]

Acute onset, atraumatic, bilateral diaphragm paralysis due to isolated bilateral phrenic neuropathy is uncommon. Respiratory physicians should be alert to this disorder because it is associated with considerable morbidity and diagnosis is often delayed. These case reports highlight important aspects of the presentation, investigations and management of this disorder. [ABSTRACT FROM AUTHOR]

This document provides consensus‐based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus‐based recommendations will continue to evolve, but current standards of care are summarised in this document. [ABSTRACT FROM AUTHOR]

Objective: Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro‐inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. Methods: Phase‐2, double‐blind, placebo‐controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin‐receptor p75 and quality of life. Results: A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS‐R score was not significantly different at week 36 (−1.12 [−3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least‐squares mean: (0.84 [−0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. Interpretation: Dimethyl fumarate, in combination with riluzole, was safe and well‐tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS. [ABSTRACT FROM AUTHOR]

Idiopathic inflammatory myopathy (IIM) is the umbrella term including dermatomyositis (DM), polymyositis (PM), overlap myositis (OM), sporadic inclusion body myositis (IBM) and necrotising autoimmune myopathy (NAM), also known as immune‐mediated necrotising myopathy. There is some debate as to whether PM exists as a discrete entity, or perhaps is an overly generalising term encompassing connective tissue disease associated myositis, or OM, and the previously poorly recognised NAM. As such, PM will not be covered in detail in this review. DM, OM and NAM all present similarly, with proximal weakness and elevated creatine kinase (CK) level. By contrast, IBM preferentially involves the long finger flexors and quadriceps, and presents with a normal or only mildly elevated CK. Developments in serological testing and imaging are shifting the diagnostic paradigm away from a reliance on histopathology. The therapeutic armamentarium for IIM continues to evolve, with intravenous immunoglobulin and rituximab proving to be successful for refractory disease. This review will provide a diagnostic algorithm for the clinician to help distinguish between IIM subtypes – with emphasis on clinical assessment, serology and imaging, as well as discussion of therapeutic options and escalation of immunotherapy. [ABSTRACT FROM AUTHOR]

The aim of this study is to determine whether primary over-expression of Aβ PP in skeletal muscle results in the development of features of inclusion body myositis ( IBM) in a new lineage of the MCK-Aβ PP transgenic mouse. Quantitative histological, immunohistochemical and western blotting studies were performed on muscles from 3 to 18 month old transgenic and wild-type C57 BL6/ SJL mice. Electron microscopy was also performed on muscle sections from selected animals. Although western blotting confirmed that there was over-expression of full length Aβ PP in transgenic mouse muscles, deposition of amyloid-β and fibrillar amyloid could not be demonstrated histochemically or with electron microscopy. Additionally, other changes typical of IBM such as rimmed vacuoles, cytochrome C oxidase-deficient fibres, upregulation of MHC antigens, lymphocytic inflammatory infiltration and T cell fibre invasion were absent. The most prominent finding in both transgenic and wild-type animals was the presence of tubular aggregates which was age-related and largely restricted to male animals. Expression of full length Aβ PP in this MCK-Aβ PP mouse lineage did not reach the levels required for immunodetection or deposition of amyloid-β as in the original transgenic strains, and was not associated with the development of pathological features of IBM. These negative results emphasise the potential pitfalls of re-deriving transgenic mouse strains in different laboratories. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Discussion Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes.Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005–2016), and age‐specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age‐specific incidence and log age of onset, with McFadden's R2 used to assess the goodness of fit of the model.In total, 2647 ALS patients were included, with mean disease‐onset age being 62.2 ± 12.1 years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6–5.6); cervical 2.7 (95% CI 2.3–3.0); lumbar 3.5 (95% CI 3.2–3.9); flail arm 4.7 (95% CI 3.9–5.5); flail leg 3.6 (95% CI 2.6–4.5); primary lateral sclerosis 2.7 (95% CI 1.8–3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R2 values were >0.4 for all phenotypes indicating excellent model fit.A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance. [ABSTRACT FROM AUTHOR]