The neuromuscular and multisystem features of RYR1-related malignant hyperthermia and rhabdomyolysis: A study protocol.

INTRODUCTION: Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise healthy individuals with variants in RYR1. However, recent studies have demonstrated a clinical and histopathological continuum between patients with RYR1-related congenital myopathies and those with ERM or MH susceptibility. Furthermore, animal studies have shown non-neuromuscular features such as a mild bleeding disorder and an immunological gain-of-function associated with MH/ERM related RYR1 variants raising important questions for further research. Awareness of the neuromuscular disease spectrum and potential multisystem involvement in RYR1-related MH and ERM is essential to optimize the diagnostic work-up, improve counselling and and future treatment strategies for patients affected by these conditions. This study will examine in detail the nature and severity of continuous disease manifestations and their effect on daily life in patients with RYR1-related MH and ERM. METHODS: The study protocol consists of four parts; an online questionnaire study, a clinical observational study, muscle imaging, and specific immunological studies. Patients with RYR1-related MH susceptibility and ERM will be included. The imaging, immunological and clinical studies will have a cross-sectional design, while the questionnaire study will be performed three times during a year to assess disease impact, daily living activities, fatigue and pain. The imaging study consists of muscle ultrasound and whole-body magnetic resonance imaging studies. For the immunological studies, peripheral mononuclear blood cells will be isolated for in vitro stimulation with toll-like receptor ligands, to examine the role of the immune system in the pathophysiology of RYR1-related MH and ERM. DISCUSSION: This study will increase knowledge of the full spectrum of neuromuscular and multisystem features of RYR1-related MH and ERM and will establish a well-characterized baseline cohort for future studies on RYR1-related disorders. The results of this study are expected to improve recognition of RYR1-related symptoms, counselling and a more personalized approach to patients affected by these conditions. Furthermore, results will create new insights in the role of the immune system in the pathophysiology of MH and ERM. TRIAL REGISTRATION: This study was pre-registered at ClinicalTrials.gov (ID: NCT04610619).

Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study.

BACKGROUND: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness. METHODS: LAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient's age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed. DISCUSSION: Our study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up. CONCLUSION: Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD. TRIAL REGISTRATION: This study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017-3911) and is registered at ClinicalTrial.gov ( NCT04478981 ).

Complete resolution of a hamstring intramuscular tendon injury on MRI is not necessary for a clinically successful return to play.

BACKGROUND: Clinical decision-making around intramuscular tendon injuries of the hamstrings is a controversial topic in sports medicine. For this injury, MRI at return to play (RTP) might improve RTP decision-making; however, no studies have investigated this. OBJECTIVE: Our objectives were to describe MRI characteristics at RTP, to evaluate healing and to examine the association of MRI characteristics at RTP with reinjury for clinically recovered hamstring intramuscular tendon injuries. METHODS: We included 41 athletes with hamstring intramuscular tendon injuries and an MRI at baseline and RTP. For both MRIs, we used a standardised scoring form that included intramuscular tendon injury characteristics. We recorded reinjuries during 1-year follow-up. RESULTS: At RTP, 56% of the intramuscular tendons showed a partial or complete thickness tendon discontinuity. Regarding healing from injury to RTP, 18 of 34 (44% overall) partial-thickness tendon discontinuities became continuous and 6 out of 7 (15% overall) complete thickness tendon discontinuities became partial-thickness tendon discontinuities. Waviness decreased from 61% to 12%, and 88% of tendons became thickened. We recorded eight (20%) reinjuries within 1 year. Intramuscular tendon characteristics at RTP between participants with or without a reinjury were similar. CONCLUSION: Complete resolution of an intramuscular tendon injury on MRI is not necessary for clinically successful RTP. From injury to RTP, the intramuscular tendon displayed signs of healing. Intramuscular tendon characteristics of those with or without a reinjury were similar.

Acrophyseal growth arrest in a long-term survivor of acute lymphoblastic leukemia.

Growth arrest at the secondary growth plate, also known as the acrophysis, is a rare phenomenon with only very few known published case reports. We report on a case of formation of ghost secondary ossification centers at the acrophyses of the knee joint in a 14-year-old female, who survived early childhood acute lymphoblastic leukemia. The patient suffered from severe side effects from both disease and subsequent treatment strategies with a 10-month immobilization period as a consequence at the age of 3 years. The ghost secondary ossification centers were encountered on radiographs and MRI 10 years later, when she presented for evaluation of chronic pain in her left knee related to sports activities, due to a meniscal cyst. Awareness of this phenomenon is nevertheless important, because it seems that endochondral bone growth recovery at the acrophyses might be different from recovery in physes, because we found no concomitant sequelae of growth arrest in the metaphyses.

Classification criteria for diffuse idiopathic skeletal hyperostosis: a lack of consensus.

Objectives: DISH is a condition characterized by flowing ossifications of the spine with or without ossifications of entheses elsewhere in the body. Studies on the prevalence and pathogenesis of DISH use a variety of partly overlapping combinations of classification criteria, making meaningful comparisons across the literature difficult. The aim of this study was to systematically summarize the available criteria to support the development of a more uniform set of diagnostic/classification criteria. Methods: A search was performed in Pubmed, Embase, Cochrane Library and Web of Science using the term DISH and its synonyms. Articles were included when two independent observers agreed that the articles proposed a new set of classification criteria for DISH. All retrieved articles were evaluated for methodological quality, and the presented criteria were extracted. Results: A total of 24 articles met the inclusion criteria. In all articles, spinal hyperostosis was required for the diagnosis of DISH. Peripheral, extraspinal manifestations were included as a (co-)requirement for the diagnosis DISH in five articles. Most discrepancies revolved around the threshold for the number of vertebral bodies affected and to defining different developmental phases of DISH. More than half of the retrieved articles described a dichotomous set of criteria and did not consider the progressive character of DISH. Conclusion: This systematic review summarizes the available different classification criteria for DISH, which highlights the lack of consensus on the diagnosis of (early) DISH. Consensus criteria, including consecutive phases of new bone formation that characterize DISH, can be developed based upon established diagnostic/classification criteria.

The prognostic value of vascular diameter measurements on routine chest computed tomography in patients not referred for cardiovascular indications.

OBJECTIVES: The aim of the study was to investigate whether diameter measurements of the thoracic aorta and the heart can be used as prognostic markers for future cardiovascular disease. METHODS: Following a case-cohort design, a total of 10,410 patients undergoing chest computed tomography were followed up for a mean period of 17 months. The ones with a cardiovascular indication were excluded. Diameter measurements were evaluated with Cox proportional hazard analysis. RESULTS: Five hundred fifteen incident cardiovascular events occurred during follow-up. The heart (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03-1.06) and ascending thoracic (HR, 1.002; 95% CI, 1.001-1.004) diameter showed an exponential prognostic effect beyond a threshold diameter of, respectively, 11 and 30 mm; the descending aortic diameter (HR, 1.04; 95% CI, 1.01-1.13) and cardiothoracic ratio (HR, 1.06; 95% CI, 1.04-1.08) showed linear prognostic effects beyond, respectively, 25 and 0.45 mm. CONCLUSION: Intrathoracic diameter measurements can be used as markers to predict cardiovascular events in patients not referred for that disease outcome.