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Brody disease is a rare myopathy characterized by exercise-induced muscle stiffness caused by mutations in the ATP2A1 gene. In the largest cohort of Brody patients to date, Molenaar et al. clarify the phenotype and diagnostic possibilities to help improve understanding and recognition of this distinct myopathy., Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

Malignant hyperthermia (MH) is a life-threatening hypermetabolic disorder triggered by volatile anesthetics and/or succinylcholine. We report a case of a 58-year-old patient with a type-A aortic dissection. After induction of general anesthesia, a hypermetabolic reaction was successfully treated by deep hypothermia using cardiopulmonary bypass. Dantrolene became available in theater after the hypermetabolism was already treated successfully by hypothermia. Because of a low suspicion of MH, dantrolene was not administered when it became available. The patient fully recovered, and MH susceptibility was confirmed. Cardiopulmonary bypass should be considered to treat MH in case dantrolene and conservative therapy are unavailable or insufficient.

Contains fulltext : 238097.pdf (Publisher’s version ) (Open Access) 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).

Neurologists are often asked for specific advice regarding patients with neuromuscular disease who require general anaesthesia. However, guidelines on specific neuromuscular disorders do not usually include specific guidelines or pragmatic advice regarding (regional and/or general) anaesthesia or procedural sedation. Furthermore, the medical literature on this subject is mostly limited to publications in anaesthesiology journals. We therefore summarise general recommendations and specific advice for anaesthesia in different neuromuscular disorders to provide a comprehensive and accessible overview of the knowledge on this topic essential for clinical neurologists. A preoperative multidisciplinary approach involving anaesthesiologists, cardiologists, chest physicians, surgeons and neurologists is crucial. Depolarising muscle relaxants (succinylcholine) should be avoided at all times. The dose of non-depolarising muscle relaxants must be reduced and their effect monitored. Patients with specific mutations in RYR1 (ryanodine receptor 1) and less frequently in CACNA1S (calcium channel, voltage-dependent, L type, alpha 1S subunit) and STAC3 (SH3 and cysteine rich domain 3) are at risk of developing a life-threatening malignant hyperthermia reaction.

Objective : Endonasal cocaine gauzes are applied during functional endoscopic sinus surgery (FESS) for their combined analgesic and decongestive properties. Seeking an alternative for cocaine, tetracaine/oxymetazoline, and ropivacaine/oxymetazoline were investigated for their efficacy and safety during FESS. Methods : Over 18 months a double-blinded randomised prospective intervention study was conducted. Ninety patients were allocated to 3 groups that received a blinded 5 ml solution containing cocaine 5 %, tetracaine 0.8 % plus oxymetazoline 0.02 % or ropivacaine 0.8% plus oxymetazoline 0.02 %. Two Ear Nose Throat surgeons participated and evaluated preprocedural decongestion, postoperative decongestion and haemostasis according to a numeric rating scale (NRS, 0 - 10). Postoperative pain scores (NRS) registered until discharge. Secondary outcomes were intraoperative blood loss, perioperative hemodynamics, postoperative bandage changes, morphine consumption, nausea and vomiting. Results : No significant difference was observed between groups for preprocedural decongestion (p = 0.72) and postoperative decongestion (p = 0.48) and haemostasis (p = 0.44). Mean postoperative pain scores were low (NRS 1.00, SD 1.15) without significant difference (p = 0.55). Conclusion : Based on the results of this study we can recommend tetracaine / oxymetazoline or ropivacaine / oxymetazoline as a safe and effective topical agent for FESS that can replace cocaine.

Background This study evaluated efficacy and safety of sugammadex 4 mg kg −1 for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CL CR ] −1 ) vs those with normal renal function (CL CR ≥80 ml min −1 ). Methods Sugammadex 4 mg kg −1 was administered at 1–2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T 4 /T 1 ) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within −1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed. Results The intent-to-treat group comprised 67 patients (renal n =35; control n =32). Median (95% CI) time from sugammadex to recovery to T 4 /T 1 ratio 0.9 was 3.1 (2.4–4.6) and 1.9 (1.6–2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6–2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg −1 ) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics. Conclusions Sugammadex 4 mg kg −1 provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex-rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population. Clinical trial registration NCT00702715.

Contains fulltext : 89451.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sugammadex is a selective relaxant binding agent designed to encapsulate the neuromuscular blocking agent, rocuronium. The sugammadex-rocuronium complex is eliminated by the kidneys. This trial investigated the pharmacokinetics (PKs) of sugammadex and rocuronium in patients with renal failure and healthy controls. METHODS: Fifteen ASA class II-III renal patients [creatinine clearance (CL(CR)) or =80 ml min(-1)) were included. After induction of anaesthesia, a single i.v. dose of rocuronium 0.6 mg kg(-1) was given, followed by a single i.v. dose of sugammadex 2.0 mg kg(-1) at reappearance of the second twitch of the train-of-four response. Plasma concentrations of rocuronium and sugammadex were estimated and PK variables determined using non-compartmental analyses. Percentages of sugammadex and rocuronium excreted in the urine were measured. RESULTS: PK data were obtained from 26 patients. Mean total plasma clearance (CL) of sugammadex was 5.5 ml min(-1) in renal patients and 95.2 ml min(-1) in controls (P

Objectives Fracture of the upper femur is a common injury in the elderly. Several anesthetic techniques exist for surgery of traumatic hip fracture. The aim of this investigation was to study plasma concentrations and safety of 2 mg/kg bupivacaine in a femoral "3-in-1" nerve block in patients older than 80 years of age. Subjects and methods A 3-in-1 femoral nerve block, combined with a general anesthetic was used in 10 elderly patients aged over 80 years. They were undergoing emergency surgery for stabilization of their fractured femur. Bupivacaine plasma concentrations of radial artery blood samples were assessed over a 6-hour period after a femoral 3-in-1 injection of 2 mg/kg bupivacaine 0.375% with epinephrine (1:400,000). Results No toxic reactions to bupivacaine were seen. In 8 of the 10 patients per- and postoperative analgesia were adequate as a result of the nerve block. Patients experienced loss of sensation and analgesia for 26.6 +/- 4.6 hours (mean +/- SD). This was inversely related to the apparent steady state concentration of bupivacaine. The mean of the individual peak plasma concentrations of bupivacaine (C(max) was 0.74+/- 0.64 microg/ml. The highest plasma concentration was 1.83 microg/ml. Large variations in plasma concentrations were detected in these patients. Bupivacaine metabolites were not detected. Conclusions A femoral 3-in-1 nerve block, using 2 mg/kg bupivacaine with epinephrine, provides prolonged pain reliefwithout local anesthetic toxicity in elderly patients. It is a satisfactory supplementary analgesic technique for hip and knee surgery in the elderly.

Background Genome-wide expression profiles are altered during biological aging and can describe molecular regulation of tissue degeneration. Age-regulated mRNA expression trends from cross-sectional studies could describe how aging progresses. We developed a novel statistical methodology to identify age-regulated expression trends in cross-sectional datasets. Results We studied six cross-sectional RNA expression profiles from different human tissues. Our methodology, capable of overcoming technical and genetic background differences, identified an age-regulation in four of the tissues. For the identification of expression trends, five regression models were compared and the quadratic model was found as the most suitable for this study. After k-means clustering of the age-associated probes, expression trends were found to change at two major age-positions in brain cortex and in Vastus lateralis muscles. The first age-position was found to occur during the fifth decade and a later one during the eighth decade. In kidney cortex, however, only one age-position was identified correlating with a late age-position. Functional mapping of genes at each age-position suggests that calcium homeostasis and lipid metabolisms are initially affected and subsequently, in elderly mitochondria, apoptosis and hormonal signaling pathways are affected. Conclusions Our results suggest that age-associated temporal changes in human tissues progress at distinct age-positions, which differ between tissues and in their molecular composition.

Background Sevoflurane, a potent inhalational anaesthetic agent that is structurally similar to halothane, has some favourable characteristics, but may also be able to trigger malignant hyperthermia (MH) in susceptible patients. The diagnosis of malignant hyperthermia susceptibility relies on the in vitro contracture test on skeletal muscle. The present study was undertaken to investigate whether exposure to sevoflurane of muscles of malignant hyperthermia susceptible (MHS) patients would also cause an abnormal contracture. Methods Muscle fascicles obtained from three MHS patients, one malignant hyperthermia non-susceptible (MHN) patient, two control patients and one malignant hyperthermia equivocal (MHE) patient were exposed to sevoflurane instead of halothane in the in vitro contracture test, carried out according to the protocol of the European Malignant Hyperthermia Group. The muscle fascicles were surplus to diagnostic requirements. Sevoflurane concentrations in the testbath were measured using a headspace gas chromatographic technique. Results The kinetics of sevoflurane concentration in the testbath were similar to those of halothane. An in vitro contracture response of 2 mN or more was seen in all four MHS/MHE patients with sevoflurane but not in the three control/MHN patients. The magnitude of muscle contracture in the sevoflurane test was less than in the conventional halothane test at comparable testbath concentrations. Conclusions Sevoflurane can trigger an abnormal contracture in human muscle in vitro. This is indicative of malignant hyperthermia susceptibility. Exposure to sevoflurane should be avoided in patients thought to be susceptible to malignant hyperthermia.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset progressive muscle disorder caused by a poly-alanine expansion mutation in the Poly(A) Binding Protein Nuclear 1 (PABPN1). The molecular mechanisms that regulate disease onset and progression are largely unknown. In order to identify molecular pathways that are consistently associated with OPMD, we performed an integrated high-throughput transcriptome study in affected muscles of OPMD animal models and patients. The ubiquitin-proteasome system (UPS) was found to be the most consistently and significantly OPMD-deregulated pathway across species. We could correlate the association of the UPS OPMD-deregulated genes with stages of disease progression. The expression trend of a subset of these genes is age-associated and therefore, marks the late onset of the disease, and a second group with expression trends relating to disease-progression. We demonstrate a correlation between expression trends and entrapment into PABPN1 insoluble aggregates of OPMD-deregulated E3 ligases. We also show that manipulations of proteasome and immunoproteasome activity specifically affect the accumulation and aggregation of mutant PABPN1. We suggest that the natural decrease in proteasome expression and its activity during muscle aging contributes to the onset of the disease.