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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.

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.

Summary Background There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178 ) has also been completed, but will be reported separately. Findings Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. Funding Orion Corporation.

Background Before the role of shear wave elastography (SWE) and B mode ultrasound (US) in the diagnosis of different forms of idiopathic inflammatory myopathies (IIM) can be investigated, normative data is required. This study aimed to describe and then compare normative SWE and B mode ultrasound metrics of muscles in healthy controls and patients with IIM. Methods Twenty nine healthy adult controls and 10 IIM patients (5 with inclusion body myositis and 5 with necrotising autoimmune myopathy) underwent a full clinical examination, laboratory investigations, SWE and US measurements of selected proximal and distal limb muscles. Shear wave speed (SWS) and multiple US domains [echogenicity, fascial thickness, muscle bulk and power Doppler (PD)] were measured in both groups. Results In healthy controls (n = 29; mean age 46.60 ± 16.10; 44.8 % female), age was inversely correlated with SWS at the deltoid (stretch) (Rs. -0.40, p = 0.030) and PD score at the deltoid (rest) (Rs. -0.40, P = 0.032). Those ≥ 50 years old had a lower SWS at the deltoid (stretch) compared to the Conclusions Our findings suggest there is scope for US techniques to be useful for diagnostic screening of affected muscles in patients with IIM, especially in those with suspected inclusion body myositis or necrotising autoimmune myopathy. We provide normative data for future studies into SWE and US techniques in skeletal muscle. The differences between IIM patients and controls warrant further study in a broader IIM patient cohort.

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R-2) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R-2) of 0.027 (P value = 4.6 x 10(-8)), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS. Refereed/Peer-reviewed

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...

Dysphagia in inclusion body myositis (IBM) is common and associated with increased mortality and morbidity due to aspiration pneumonia, malnutrition and dehydration. There is currently no consensus on treatment of dysphagia in IBM and outcomes are variable depending on timing of intervention, patient preference and available expertise. There is a paucity of research exploring the pathophysiology of dysphagia in IBM and appropriate investigations. Increased knowledge of the aetiopathogenesis is likely to change the approach to treatment as well as improve the quality of life for patients. This review explores the epidemiology and pathophysiology of dysphagia in IBM and the currently available treatment strategies.

An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.

Neurological disorders are a leading cause of disease burden worldwide, placing a heavy demand on health systems. This study evaluated the impacts and cost savings of a community-based nursing service providing supported discharge for neurological patients deemed high-risk for unplanned emergency department presentations and/or hospital readmissions. It focused on adult patients with stroke, epilepsy, migraine/headache or functional neurological disorders discharged from a Western Australian tertiary hospital. An observational design was used comprising prospective enrolment of patients receiving nurse-led supported discharge and follow-up (Neurocare), 21 August 2018 to 6 December 2019 (N = 81), and hospital administrative data, 1 February 2016 to 31 January 2018, for patients in previous care model (N = 740). Healthcare utilisation and annualised cost savings from reduced rehospitalisation and/or emergency department presentations within 28 days post discharge were compared. Neurocare patients' postdischarge functional and health-related quality of life outcomes, and perceived involvement in self-management and integrated care were surveyed. The hospital's total cost savings are A$101,639 per annum and A$275/patient/year with a return on investment of 2.01. There was no significant difference in hospital length of stay (LOS) between models, but older age was associated with longer length of hospital stay and a predictor for non-neurological readmissions. Neurocare patients showed improved functional status, less equipment and/or service needs, improved health-related quality of life. They felt involved in self-managing their condition with well-integrated postdischarge care. This nurse-led model of transitional care for neurology patients discharged from hospital produced cost savings and a positive return on investment compared with usual care. With service maturity, earlier supported hospital discharge and reduced LOS may follow. Patients' reduced service needs and improved functional status and health-related quality of life may positively impact healthcare utilisation. Future research should include larger patient samples and multiple sites.

Objective.To present and vote on a myositis modified patient-reported outcome core domain set in the life impact area at the Outcome Measures in Rheumatology (OMERACT) 2018.Methods.Based on results from international focus groups and Delphi surveys, a draft core set was developed.Results.Domains muscle symptoms, fatigue, level of physical activity, and pain reached ≥ 70% consensus and were mandatory to assess in all trials. Domains lung, joint, and skin symptoms were mandatory in specific circumstances. This core set was endorsed by > 85% at OMERACT 2018.Conclusion.We propose a life impact core set for patients with idiopathic inflammatory myopathies and will proceed with instrument selections.

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.

Objective To investigate the content validity of several patient-reported outcome measures (PROMs) in patients with idiopathic inflammatory myopathies (IIM). Methods Seven individual PROM instruments were selected by the Outcome Measures in Rheumatology (OMERACT) Myositis Working Group relating to the following domains: pain, fatigue, physical function and physical activity. Twenty patients from the Johns Hopkins Myositis Center were selected for one-on-one face-to-face or phone interviews for cognitive interviewing of individual PROMs to assess comprehension and content validity. Additionally, patients were asked if they thought muscle symptoms, an area originally identified in qualitative studies, were encapsulated by the other four domains. Results The majority of patients (>70%) felt that each of the instruments was clear, easy to read and understand, and could be used for assessment of its domain. Two-thirds (66%) of patients felt that ‘muscle symptoms’ were captured by the other domains. Conclusions We provided evidence to support adequate content validity for several PROMs. Further research is needed to determine whether ‘muscle symptoms’ warrant a separate domain.

(Ashton C, Banham N, Needham M. Acute spontaneous spinal cord infarction: Utilisation of hyperbaric oxygen treatment, cerebrospinal fluid drainage and pentoxifylline. Diving and Hyperbaric Medicine. 2020 December 20;50(4):325–331. doi: 10.28920/dhm50.4.325-331. PMID: 33325011.) Introduction: Spinal cord infarction (SCI) is a potentially devastating disorder presenting with an acute anterior spinal artery syndrome, accounting for an estimated 1% of stroke presentations. Aetiologies include aortic surgical complications, systemic hypotension, fibrocartilaginous embolism and vascular malformations. Diagnosis is clinical combined with restriction on diffusion-weighted magnetic resonance imaging (MRI). There are no treatment guidelines for non-perioperative cases although there is limited literature regarding potential therapies, including hyperbaric oxygen treatment (HBOT) and cerebrospinal fluid (CSF) drainage. We describe 13 cases of acute SCI, five receiving HBOT, and three also receiving pentoxifylline and drainage of lumbar CSF. Methods: Data for all patients with MRI-proven SCI at Fiona Stanley Hospital from 2014–2019 were reviewed. Results: Thirteen patients, median age 57 years (31–74), 54% female, were identified. Aetiologies: two fibrocartilaginous emboli; seven likely atherosclerotic; two thromboembolic; two cryptogenic. All presented with flaccid paraplegia except one with Brown-Sequard syndrome. Levels ranged from C4 to T11. Five patients received HBOT within a median time of 40 hours from symptom onset, with an average 15 treatments (10−20). Three of these received triple therapy (HBOT, pentoxifylline, CSF drainage) and had median Medical Research Council manual muscle testing power of 5, median modified Rankin Score (mRS) of 1 and American Spinal Injury Association (ASIA) score of D on discharge, compared with 2 power, mRS 3.5 and ASIA B in those who did not. Conclusions: SCI can be severely disabling. Triple therapy with pentoxifylline, CSF drainage and HBOT may reduce disability and further prospective trials are required.

We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands sample (area under the curve, AUC = 0.65, CI95% = [0.62–0.68], p = 8.3 × 10−22). The maximum AUC achieved was 0.69 (CI95% = [0.66–0.71], p = 4.3 × 10−34) when cell-type proportion was included in the predictor.

Background: Sporadic Inclusion Body Myositis (sIBM) is a rare and slowly progressive debilitating muscle disease with symptoms generally developing≥50 years of age. Objective: To conduct a systematic review and meta-analysis of the prevalence of sIBM literature, including a methodological quality assessment of the selected papers. Methods: A systematic search of Medline, Embase, Cochrane Database of Systematic Reviews and major Myositis and Neurological conferences was conducted. Articles reporting prevalence and published in English up to March 2017 were assessed for methodology quality using the Loney quality assessment, Downs & Black score, and the Methodological Evaluation of Observational Research checklists. Meta-analyses using random effects were completed on both general population and≥50 years prevalence estimates. Results: 315 articles were retrieved and data were extracted from 10 relevant studies. One study was subsequently excluded due to methodological issues. The meta-prevalence estimate from 9 papers was 24.8/1,000,000 (95% CI: 20.0–29.6). The methodological quality results were consistent across assessment tools with four articles scoring 4 or 5 out of 8 in the Loney assessment. The meta-prevalence of these four articles was 45.6/ 1,000,000 (95% CI: 35.9–55.2). Conclusion: There was high variability in reported sIBM prevalence estimates and the quality of the studies conducted. Existing evidence suggests an increase of prevalence estimates over time, which may be explained by growing disease awareness, improvements in diagnostic criteria and study methodologies. Further high quality studies are needed to understand if prevalence varies across geographies or ethnicities.

Pompe Disease is a spectrum disorder with an evolving phenotype in which diagnostic delay is common. Contributing factors include the rarity of the disorder, its wide clinical spectrum, signs and symptoms that overlap with those of other neuromuscular disorders, variable diagnostic approaches, lack of awareness of the clinical manifestations and difficulties in completing the diagnostic inventory. International updates and recommendations have been published providing diagnostic guidelines and management criteria. However, questions remain in the Australian setting. A panel (two neurologists, one clinical geneticist) reviewed the literature, examined clinical questions of relevance to the Australian setting, and developed a framework for the guidance. A wider panel, comprising the initial panel plus eight additional members, critiqued the framework and contributed clinical guidance within the scope of their respective areas of clinical expertise. The resultant expert consensus recommendations build on currently available data to propose an appropriate management framework incorporating the diagnosis, classification, therapeutic approach, multidisciplinary care, and on-going monitoring of patients with Pompe Disease in the Australian setting. It is hoped that diagnostic delay can be reduced with appropriate recourse to evidence-based insights and practical advice on diagnosis and management tailored to the Australian setting.

Inclusion Body Myositis (IBM) is the most common acquired myopathy in older individuals with more than two thirds of patients experiencing impaired swallowing. There are currently no standardized exercise therapies to improve or sustain swallowing despite good evidence for exercise therapy in limb muscles. Reduced upper esophageal sphincter opening is a common abnormality associated with dysphagia in IBM. This pilot study recruited IBM patients with abnormal upper esophageal sphincter function and dysphagia into an exercise program. It was hypothesized that regular practice using the Expiratory Muscle Strength Trainer (EMST) device would improve hyolaryngeal movement by strengthening suprahyoid musculature and facilitate opening of the upper esophageal sphincter thereby improving swallowing and quality of life. Overall, IBM patients who used the EMST device demonstrated no improvement in swallowing function. Consistent with that result, there was also no change in measures of quality of life. However, further studies are needed to elucidate whether it has a preventative role in the development or progression of dysphagia in IBM as there is a suggestion that patients with a shorter duration of disease may have had some benefit. This research provides pilot data and recommendations that will guide future studies on exercise therapy and swallowing in this area.

Introduction: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of muscle diseases that carry a significant morbidity and mortality risk. The utilization of imaging in the diagnostic pathway of IIM is therefore important to obtain early diagnosis and even monitor patients over time. Areas covered: Magnetic resonance imaging (MRI) has been the main imaging modality used to detect myositis but limitations include cost and accessibility, leading to delays in time to scan, and patient contraindications. This has led to the exploration of other imaging techniques to diagnose and monitor response to therapy. This article is based primarily on a literature search via PubMed using Boolean terms ‘myositis’ and the various imaging modalities. Expert opinion: Imaging is sensitive to pathology in IIM and may contribute to the diagnostic process. Learning how specific imaging features can distinguish different forms of IIM may allow more rapid diagnosis of myositis subtype and treatment planning, and to monitor disease activity particularly in patients who respond poorly to treatment. However, more work is needed to investigate the validity and relative utility of these imaging modalities.

Objective.Patient-reported outcome measures (PROM) that incorporate the patient perspective have not been well established in idiopathic inflammatory myopathies (IIM). As part of our goal to develop IIM-specific PROM, the Outcome Measures in Rheumatology (OMERACT) Myositis special interest group sought to determine which aspects of disease and its effects are important to patients and healthcare providers (HCP).Methods.Based on a prior qualitative content analysis of focus groups, an initial list of 24 candidate domains was constructed. We subsequently conducted an international survey to identify the importance of each of the 24 domains to be assessed in clinical research. Patients with IIM, their caregivers, and HCP treating IIM completed the survey.Results.In this survey, a total of 638 respondents completed the survey, consisting of 510 patients, 101 HCP, and 27 caregivers from 48 countries. Overall, patients were more likely to rank “fatigue,” “cognitive impact,” and “difficulty sleeping” higher compared with HCP, who ranked “joint symptoms,” “lung symptoms,” and “dysphagia” higher. Both patients and providers rated muscle symptoms as their top domain. In general, patients from different countries were in agreement on which domains were most important. One notable exception was that patients from Sweden and the Netherlands ranked lung symptoms significantly higher compared to other countries including the United States and Australia (mean weighted rankings of 2.86 and 2.04 vs 0.76 and 0.80, respectively; p < 0.0001).Conclusion.Substantial differences exist in how IIM is perceived by patients compared to HCP, with different domains prioritized. In contrast, patients’ ratings across the world were largely similar.

Background: There is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years. Objective: Based on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians’ views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients. Methods: Thirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated and presented in the second questionnaire to seek elaboration and identify consensus. Results: All 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population. Conclusions: In the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies.

Sporadic inclusion body myositis is the most frequent acquired myopathy of middle and later life and is distinguished from other inflammatory myopathies by its selective pattern of muscle involvement and slowly progressive course, and by the combination of inflammatory and degenerative muscle pathology and multi-protein deposits in muscle tissue. This review summarises the findings of recent studies that provide a more complete picture of the clinical phenotype and natural history of the disease and its global prevalence and genetic predisposition. Current diagnostic criteria, including the role of electrophysiological and muscle imaging studies and the recently identified anti-5'-nucleotidase (anti-cN1A) antibody in diagnosis are also discussed as well as current trends in the treatment of the disease.

CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes remains uncertain. We identified a de novo missense variant in CHD7 in a family presenting with musculoskeletal abnormalities as the main manifestation of CHD7-related disease, representing a new phenotype. The proband presented with prominent scapulae, mild shoulder girdle weakness and only subtle dysmorphic features. Investigation revealed hypoplasia of the trapezius and sternocleidomastoid muscles and semicircular canal defects, but he did not fulfill diagnostic criteria for CHARGE syndrome. Although the shoulders are often sloping and anteverted in CHARGE syndrome, the underlying neuromuscular cause has never been investigated. This report expands the phenotypes associated with CHD7 mutations to include a musculoskeletal presentation, with hypoplasia of the shoulder and neck muscles. CHD7 should be considered in patients presenting in childhood with stable scapular winging, particularly if accompanied by dysmorphic features and balance difficulties.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a well-recognised disorder, first fully characterised in 2007. The long-term sequelae reported thus far include relapses with typical, as well as partial aspects of the well-defined neuropsychiatric syndrome. Rarely, isolated atypical symptoms (diplopia, ataxia and tremor) have been reported as relapse phenomenon. We report a case of a patient with a remote history of likely anti-NMDAR encephalitis with the longest follow-up reported in the literature to date (22 years). The relapse presentation was of a purely upper motor neuron syndrome with a primary lateral sclerosis-like picture.

Until recently, the treatment of immune-mediated inflammatory myopathies has largely been empirical with glucocorticoids, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin. However, a proportion of patients are only partially responsive to these therapies, and there has been a need to consider alternative treatment approaches. In particular, patients with inclusion body myositis are resistant to conventional immunotherapies or show only a transient response, and remain a major challenge. With increasing recognition of the different subtypes of immune-mediated inflammatory myopathies, and improved understanding of their pathogenesis, more targeted treatments are now being trialled. The overall approach to treatment, and novel therapies targeting B cells, T cells, and specific cytokines are discussed in this review.

Relatively little is known about frequency and extent of respiratory problems in sporadic inclusion body myositis (IBM). To address this issue a study of peripheral muscle and respiratory function and related symptoms was performed in a cohort with biopsy-proven IBM. Dyspnoea, daytime sleepiness, dysphagia, spirometry, respiratory muscle strength, arterial blood gas tensions and ventilation during sleep were assessed. Sixteen patients were studied (10 males; age 68.1±9.9years; disease duration 11.9±5.0years; body mass index 28.5±4.0kg/m(2)). Four reported excessive daytime sleepiness; 8 had at least mild dysphagia; forced vital capacity was

Sickle cell disease can present with neurological manifestations. One such presentation is with posterior reversible leukoencephalopathy also known as reversible posterior leukoencephalopathy. The condition is classically described as reversible over time; it commonly presents with oedematous changes involving the white matter of the occipital and parietal regions. Only a few patients with the association between sickle cell disease and posterior reversible leukoencephalopathy have been described in the adult literature. We present two patients from our institutions to emphasise the association between the two conditions and summarise the published cases in the literature.

IntroductionElectrodiagnostic evaluation is crucial in establishing the diagnosis of motor neuron disease (MND) and excluding other pathologies. It is recommended that sensory nerve conduction studies (NCS) include the ulnar and sural nerves, and generally accepted that sensory nerves are normal in MND. There are however previous reports in the literature documenting variable sensory abnormalities in patients with MND. We sought to determine the frequency of unexplained sensory abnormalities seen on NCS in patients with MND.MethodsMedical records of patients attending our tertiary MND clinic over a 2 year period were reviewed. We identified 92 patients with a clinical diagnosis of MND for whom electrodiagnostic studies were available to review. Sensory abnormalities in patients without a clear underlying aetiology (eg. compressive neuropathies, diabetes) were considered unexplained.ResultsUnexplained sensory abnormalities were detected in at least one nerve in 18/92 (20%) patients. In 17 of those 18 patients, the ulnar sensory response was abnormal. 12 of 18 patients demonstrated abnormalities in 2 or more sensory nerves. Sensory abnormalities were present in 4 of 37 (10.8%) patients with bulbar onset MND and 14 of 55 (25.4%) patients with limb onset MND. Sensory symptoms were infrequently reported and did not correlate with abnormalities found on NCS.ConclusionsUnexplained sensory nerve action potential abnormalities are not uncommon in MND, with ulnar sensory responses the most frequently affected. These findings raise the possibility of sensory nerve pathology in patients with MND and suggest that the presence of unexplained sensory abnormalities should not exclude a diagnosis of MND.

IntroductionSpinal cord infarction is a potentially devastating disorder commonly presenting with anterior spinal artery syndrome developing over minutes to hours, accounting for an estimated 1% of stroke presentations. Aetiologies range from aortic surgical complications, systemic hypotension and other rare causes including fibrocartilaginous embolism and vascular malformations. Diagnosis is clinical combined with restriction on diffusion-weighted MRI. There are no specific treatment guidelines. The evidence for hyperbaric oxygen therapy (HBOT) in acute spinal infarction is mixed. This case series describes ten cases of acute spinal infarction at Fiona Stanley Hospital (FSH), half of which received HBOT.MethodsData for all MRI-proven spinal cord infarctions at FSH between 2014 and 2018 were reviewed.ResultsTen patients, median age 55years (31–74), 60% male. Aetiologies: three fibrocartilaginous emboli, five likely atheroembolic disease, one antiphospholipid syndrome, one cryptogenic. Sixty percent presented with flaccid paraplegia ranging from levels C4 to T11. Five patients received HBOT within a median time of 31 hours from symptom onset, with average 15 treatments. Three patients received triple therapy of HBOT, pentoxyfiline and high-volume lumbar-puncture drainages and had median MRC muscle power of 5- on discharge, compared with 2+ power in those who did not. Nine required inpatient rehabilitation, of average eight weeks’ duration, with median disability at discharge of 3 on the Modified Rankin Scale.ConclusionSpinal infarctions can be severely disabling. Fibrocartilaginous embolism may be more common than previously thought. More research is needed on the role of acute triple therapy with pentoxyfiline, spinal drains and HBOT given the marked difference in this case series.

Patients with muscle disorders can present a diagnostic challenge to physicians because of the different ways they can present and the large number of different underlying causes. Recognition of the 'myopathic phenotype' coupled with investigations usually including electrodiagnostic and histological investigations have been essential for diagnosing the underlying cause of a myopathy. Despite these standard investigations, some patients can remain undiagnosed. New tests including more specific antibody tests for immune-mediated myopathies and the introduction of next-generation sequencing promise to revolutionise diagnostic approaches for immune and inherited myopathies, but clinical expertise remains essential to choose the most appropriate tests and interpret the results. The aim of this review is to provide an overview of the different presentations to the neuromuscular clinic and the latest investigations that can be helpful in the diagnosis of muscle disorders.

Objective To capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia. Methods Data were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death. Design Prospective observational cohort study. Participants 1834 patients with a diagnosis of ALS/MND were registered and followed in ALS/MND clinics between 2005 and 2015. Results 5 major clinical phenotypes were determined and included ALS bulbar onset, ALS cervical onset and ALS lumbar onset, flail arm and leg and primary lateral sclerosis (PLS). Of the 1834 registered patients, 1677 (90%) could be allocated a clinical phenotype. ALS bulbar onset had a significantly lower length of survival when compared with all other clinical phenotypes (p

Necrotising Autoimmune Myopathy (NAM) presents as a subacute proximal myopathy with high creatine kinase levels. It is associated with statin exposure, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibody, connective tissue diseases, signal recognition particle (SRP) antibody and malignancy. This case series presents our Western Australian NAM patient cohort: comparing the subgroup presentations, biopsy appearance and treatment outcomes. We retrospectively collected data on patients diagnosed with NAM at the Western Australian Neuroscience Research Institute between the years 2000 and 2015. We identified 20 patients with Necrotising Autoimmune Myopathy: 14 with anti-HMGCR antibodies; two with anti-SRP antibodies; three with connective tissue disease; two as yet unspecified. Median creatine kinase level was 6047units/L (range 1000–17000). The statin naive patients with HMGCR antibodies and patients with SRP antibodies were the most severely affected subgroups, with higher creatine kinase levels, and were more resistant to immunotherapy. Two or more immunotherapy agents were required in 90%; eight patients required IVIG and rituximab. Steroid weaning commonly precipitated relapses. Four patients had complete remission, and the remaining patients still require immunotherapy. Necrotising Autoimmune Myopathy is a potentially treatable myopathy, which can be precipitated by statin therapy and requires early, aggressive immunotherapy, usually requiring multiple steroid sparing agents for successful steroid weaning.

Objective: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes. Methods: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing. Results: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A > G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. Conclusion: We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects.

Cauda equina syndrome (CES) is an uncommon neurological condition resulting in the retention of urine in young women [1]. This is usually caused by the compression of the cauda equina, resulting in the dysfunction of the sacral and lumbar nerve roots in the vertebral canal [2]. Clinical diagnosis is based upon impairment of bladder, bowel, or sexual function and perianal or saddle numbness. An MRI scan confirms the level and the pathological diagnosis [3].

Background and Aims: There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes. Method: A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed. Patients were interviewed and examined by a single investigator, and had HLA typing and autoantibody studies. Results: Although the initial symptoms in the majority of cases were attributable to quadriceps weakness (79%), a proportion of patients presented due to finger weakness (12%), foot drop (7%) or dysphagia (1.8%). Although the majority had the classic combination of quadriceps and forearm muscle involvement, some patients had predominantly forearm weakness with sparing of the quadriceps, or severe involvement of the anterior tibial muscles. Asymmetrical involvement was common (82%), particularly of the forearm muscles, with the non-dominant side being more severely affected in most cases. Carriage of the HLA-DRB1*0301 (DR3) allele was associated with lower quadriceps muscle strength and a more rapid decline in strength. Conclusions: The findings emphasise the variability in the mode of presentation, patterns of muscle involvement and clinical course of sIBM in this population, and indicate that the HLA-DRB1*0301 (DR3) allele may influence the rate of progression as well as susceptibility to the disease.

Inclusion body myositis is the most common acquired muscle disease in older individuals, and its prevalence varies among countries and ethnic groups. The aetiology and pathogenesis of sporadic inclusion body myositis are still poorly understood; however genetic factors, ageing, and environmental triggers might all have a role. Unlike other inflammatory myopathies, sporadic inclusion body myositis causes slowly progressing muscular weakness and atrophy, it has a distinctive pattern of muscle involvement, and is unresponsive to conventional forms of immunotherapy. This review covers the clinical presentation, diagnosis, treatment, and the latest information on genetic susceptibility and pathogenesis of sporadic inclusion body myositis.

Statins can cause a necrotizing myopathy and hyperCKaemia which is reversible on cessation of the drug. What is less well known is a phenomenon whereby statins may induce a myopathy, which persists or may progress after stopping the drug. We investigated the muscle pathology in 8 such cases. All had myofibre necrosis but only 3 had an inflammatory infiltrate. In all cases there was diffuse or multifocal up-regulation of MHC-I expression even in non-necrotic fibres. Progressive improvement occurred in 7 cases after commencement of prednisolone and methotrexate, and in one case spontaneously. These observations suggest that statins may initiate an immune-mediated myopathy that persists after withdrawal of the drug and responds to immunosuppressive therapy. The mechanism of this myopathy is uncertain but may involve the induction by statins of an endoplasmic reticulum stress response with associated up-regulation of MHC-I expression and antigen presentation by muscle fibres.

Clinical Trial; Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; OBJECTIVES To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. METHODS Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. RESULTS Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. CONCLUSIONS Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry. This study was funded by MSBase Foundation, a not-for-profit organisation. The MSBase Foundation receives financial support from Merck Serono, Biogen Idec, Novartis Pharma, Bayer Schering and Sanofi Aventis. The study was also funded by Multiple Sclerosis Research Australia and MSAngels. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Yes

Inclusion body myositis is the most common myopathy in patients over the age of 40 years encountered in neurological practice. Although it is usually sporadic, there is increasing awareness of the influence of genetic factors on disease susceptibility and clinical phenotype. The diagnosis is based on recognition of the distinctive pattern of muscle involvement and temporal profile of the disease, and the combination of inflammatory and myodegenerative changes and protein deposits in the muscle biopsy. The diagnostic importance of immunohistochemical staining for major histocompatibility complex I and II antigens, for the p62 protein, and of the recently identified anti-cN1A autoantibody in the serum, are discussed. The condition is generally poorly responsive to conventional immune therapies but there have been relatively few randomised controlled trials and most of these have been under-powered and of short duration. There is an urgent need for further well-designed multicentre trials of existing and novel therapies that may alter the natural history of the disease.

Objective: To use patient data to evaluate and construct diagnostic criteria for inclusion body myositis (IBM), a progressive disease of skeletal muscle. Methods: The literature was reviewed to identify all previously proposed IBM diagnostic criteria. These criteria were applied through medical records review to 200 patients diagnosed as having IBM and 171 patients diagnosed as having a muscle disease other than IBM by neuromuscular specialists at 2 institutions, and to a validating set of 66 additional patients with IBM from 2 other institutions. Machine learning techniques were used for unbiased construction of diagnostic criteria. Results: Twenty-four previously proposed IBM diagnostic categories were identified. Twelve categories all performed with high (≥97%) specificity but varied substantially in their sensitivities (11%–84%). The best performing category was European Neuromuscular Centre 2013 probable (sensitivity of 84%). Specialized pathologic features and newly introduced strength criteria (comparative knee extension/hip flexion strength) performed poorly. Unbiased data-directed analysis of 20 features in 371 patients resulted in construction of higher-performing data-derived diagnostic criteria (90% sensitivity and 96% specificity). Conclusions: Published expert consensus–derived IBM diagnostic categories have uniformly high specificity but wide-ranging sensitivities. High-performing IBM diagnostic category criteria can be developed directly from principled unbiased analysis of patient data. Classification of evidence: This study provides Class II evidence that published expert consensus–derived IBM diagnostic categories accurately distinguish IBM from other muscle disease with high specificity but wide-ranging sensitivities.

Previous studies have differed as to whether APOE epsilon4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the epsilon2 allele.

Herein, we present a case of a parkinsonism-hyperpyrexia syndrome (PHS) in a 58-year-old man with a 10-year history of Parkinson's disease. The patient presented with a 2-week history of fever and increasing confusion, in the context of a number of changes to his medication regimen. On presentation, he was noted to be febrile with autonomic instability, diaphoresis and marked rigidity. He was disoriented and responding to visual hallucinations. Investigations revealed an elevated creatine kinase and a provisional diagnosis of PHS was made. After the patient failed to respond during a 2-week period to supportive measures, electroconvulsive therapy (ECT) treatment was commenced. A good response to eight bilateral ECT treatments was achieved, with resolution of his confusional state and associated psychotic phenomena. We discuss the nosological and management issues associated with this case and discuss the role of ECT as a treatment modality in this condition.

Susac's syndrome is a microangiopathy of the retina, inner ear and brain manifesting as a triad of encephalopathy, hearing loss and branch retinal artery occlusion. The pathological mechanism is thought to be an immune-mediated small vessel vasculitis with some pathophysiological similarity to dermatomyositis. Awareness and early recognition of this syndrome is important as early treatment with immunosuppression can minimise cognitive, audiological and visual sequelae. We report a case of a 33-year-old woman who presented with the characteristic syndrome. She was treated with immunomodulatory therapy and remains well 2 years postpresentation with no new events.

PURPOSE OF REVIEW: Necrotizing autoimmune myopathy (NAM) is a relatively newly recognized subgroup of idiopathic inflammatory myopathies, which despite diverse causes, have the common histopathological features of myocyte necrosis without significant inflammation. Patients present with a subacute severe symmetrical proximal myopathy, associated with a markedly elevated creatine kinase level. These are most likely immune-mediated, as they respond to immunotherapy. The review aims to define this heterogeneous entity and summarize the salient clinical, laboratory, and muscle biopsy findings, in order to facilitate the diagnosis and treatment of this condition. RECENT FINDINGS: Statin-associated NAM has been linked with an antibody against the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein, which is up-regulated in regenerating fibres. This finding suggests that NAM is an antibody-mediated disease, and may explain the continuing progression of disease despite cessation of the statin. In addition it may provide a useful diagnostic test in the future, to help differentiate immune from nonimmune statin myopathies. SUMMARY: It is important to recognize and distinguish NAM from other causes of myocyte necrosis, because it has the potential of being amenable to treatment.

Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic disorders associated with proximal muscle weakness that begins after 2 years of age and dystrophic changes on muscle biopsy. The genetic cause of LGMD in Australia remains uncertain in approximately 40% of patients resulting in uncertainty about reproductive risks for patients and long term prognosis. We reviewed the clinical information in a large cohort of patients with LGMD who lacked a genetic diagnosis, usually after extensive previous investigations ( n = 50). We first screened patients for myotonic dystrophy type 2 and then performed whole exome sequencing (WES), analysing data using the ‘xBrowse’ web interface (Broad Institute). Testing for myotonic dystrophy type 2 (DM2) identified 2 families in our LGMD cohort. Using WES we identified likely pathogenic mutations in known myopathy genes in 20 families, often in genes not typically associated with LGMD. Two families were diagnosed with dominant LGMD, 9 families with recessive LGMD, 3 with mutations congenital muscular dystrophy genes, 3 with collagen myopathies, 2 with metabolic myopathies and 1 in ACTA1. In addition one family had a mutation CHD7, a gene usually associated with CHARGE syndrome. Our overall diagnostic success rate was 46% in our LGMD cohort of patients most of whom had been extensively investigated previously and who remained without a genetic diagnosis. The diversity of genetic causes that we identified supports the clinical observation of that LGMD is highly heterogeneous and shares clinical features with many other forms of myopathy. Our study emphasises the challenges that clinicians face making a genetic diagnosis in all families. Whole exome sequencing and similar next-generation sequencing are likely to be efficient and cost-effective methods for identifying the genetic basis of LGMD but clinicians must remember that some disorders in the differential diagnosis, such as DM2, are routinely missed by WES.

Sporadic inclusion body myositis (sIBM) usually occurs as an isolated condition, but it may occur in association with another autoimmune disorder such as Sjogren's syndrome. We reviewed sIBM cases with Sjogren's syndrome (sIBM/SS) from the Perth Inflammatory Myopathies Database to determine whether they are distinguishable from other sIBM cases. Six such cases were identified, representing 12% of all sIBM cases. Muscle biopsies confirmed the presence of an inflammatory myopathy with rimmed vacuoles and the characteristic muscle fibre inclusions of sIBM. Five of the six were females, contrasting with a 2:1 male preponderance in the rest of the sIBM cohort. The mean age-at-onset and the pattern of muscle weakness were similar in the two groups. Four out of five sIBM/SS patients treated with immune therapies had improvement in muscle strength lasting for 6–24 months, whereas only 27% of other sIBM patients improved. All 6 patients with sIBM/SS carried the HLA-DRB1*0301 allele, or its equivalent HLA-DR3 serological specificity, compared with 83% of other sIBM cases and all carried some or all of the major markers of the 8.1 MHC ancestral haplotype which is also associated with Sjogren's syndrome. Patients with sIBM/SS represent a subgroup of sIBM cases who are more likely to be female and carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype, and are more likely to respond to treatment. The association of sIBM and Sjogren's syndrome is likely to be due to a common genetic predisposition linked to the MHC and supports the notion that sIBM has an autoimmune basis.