Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

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.

Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants.

Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.

Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review.

BACKGROUND: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. METHODS: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. RESULTS: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. CONCLUSIONS: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.

Intraoperative Presentation of Malignant Hyperthermia (Confirmed by RYR1 Gene Mutation, c.7522C>T; p.R2508C) Leads to Diagnosis of King-Denborough Syndrome in a Child With Hypotonia and Dysmorphic Features: A Case Report.

We present the novel case report of a child with hypotonia and dysmorphic features who developed malignant hyperthermia (MH) intraoperatively. Neurology workup revealed the presence of a known causative ryanodine receptor (RYR1) mutation for MH, c.7522C>T; p.R2508C. Furthermore, the neurology workup diagnosed the child with King-Denborough syndrome (KDS). This particular mutation has never been documented in a patient with KDS. Atypical presentation of MH is more likely in patients with RYR1-related myopathy. A high index of suspicion for MH in children with myopathy is important. The MH hotline was helpful in the management of this patient when it was called after the initial dose of dantrolene. A neurology consult was essential for the diagnosis of KDS and future care.

Long term oral Dantrolene Improved Muscular Symptoms in a Malignant Hyperthermia Susceptible Individual.

This case report describes a female with p.Lys4876Arg amino acid change in the ryanodine receptor type 1 (RYR1) and a sibling who died of malignant hyperthermia (MH) during anesthesia. After her diagnosis as MH susceptible, this patient was administered low-dose dantrolene daily for greater than 25 years for treatment of chronic muscle spasm and pain in her lower extremities and back limiting sleep. Her creatine phosphokinase (CPK) was as high as 2390 IU/L during labor and 900 IU at rest. With 25 mg dantrolene daily, muscle cramps were eliminated, and sleep was improved. Gait instability was noted with dantrolene in the morning, but not when taken at bedtime. There was no evidence of liver injury. This case suggests that low dose dantrolene by mouth could be considered for the treatment of chronic muscle pain in individuals with MH susceptibility.

MALIGNANT HYPERTHERMIA--AN UPDATE FOR PERIOPERATIVE NURSES.

This article is a summary of the "Updates on Malignant Hyperthermia" presentation given at the 2015 ORNAC National Conference in Edmonton. It presents the facts known about malignant hyperthermia (MH) including definition, anesthetic and non-anesthetic triggers for MH, signs and symptoms, and treatment of MH. It also discusses the care of an MH susceptible patient while undergoing an elective surgery.

Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.

BACKGROUND: AMRA (adverse metabolic or muscular reaction to anesthesia) reports submitted to The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States from 1987 to 2006 revealed a 2.7% cardiac arrest and a 1.4% death rate for 291 malignant hyperthermia (MH) events. We analyzed 6 years of recent data to update MH cardiac arrest and death rates, summarized characteristics associated with cardiac arrest and death, and documented differences between early and recent cohorts of patients in the MH Registry. We also tested whether the available data supported the hypothesis that risk of dying from an episode of MH is increased in patients with inadequate temperature monitoring. METHODS: We included U.S. or Canadian reports of adverse events after administration of at least 1 anesthetic drug, received between January 1, 2007, and December 31, 2012, with an MH clinical grading scale rank of "very likely MH" or "almost certain MH." We excluded reports that, after review, were judged to be due to pathologic conditions other than MH. We analyzed patient demographics, family and patient anesthetic history, anesthetic management including temperature monitoring, initial dantrolene dose, use of cardiopulmonary resuscitation, MH complications, survival, and reported molecular genetic DNA analysis of RYR1 and CACNA1S. A one-sided Cochran-Armitage test for proportions evaluated associations between mode of monitoring and mortality. We used Miettinen and Nurminen's method for assessing the relative risk of dying according to monitoring method. We used the P value of the slope to evaluate the relationship between duration of anesthetic exposure before dantrolene administration and peak temperature. We calculated the relative risk of death in this cohort compared with our previous cohort by using the Miettinen and Nurminen method adjusted for 4 comparisons. RESULTS: Of 189 AMRA reports, 84 met our inclusion criteria. These included 7 (8.3%) cardiac arrests, no successful resuscitations, and 8 (9.5%) deaths. Of the 8 patients who died, 7 underwent elective surgeries considered low to intermediate risk. The average age of patients who died was 31.4 ± 16.9 years. Five were healthy preoperatively. Three of the 8 patients had unrevealed MH family history. Four of 8 anesthetics were performed in freestanding facilities. In those who died, 3 MH-causative RYR1 mutations and 3 RYR1 variants likely to have been pathogenic were found in the 6 patients in whom RYR1 was examined. Compared to core temperature monitoring, the relative risk of dying with no temperature monitoring was 13.8 (lower limit 2.1). Compared to core temperature monitoring, the relative risk of dying with skin temperature monitoring was 9.7 (1.5). Temperature monitoring mode best distinguished patients who lived from those who died. End-tidal CO2 was the worst physiologic measure to distinguish patients who lived from those who died. Longer anesthetic exposures before dantrolene were associated with higher peak temperatures (P = 0.00056). Compared with the early cohort, the recent cohort had a higher percentage of MH deaths (4/291 vs 8/84; relative risk = 6.9; 95% confidence interval, 1.7-28; P = 0.0043 after adjustment for 4 comparisons). CONCLUSIONS: Despite a thorough understanding of the management of MH and the availability of a specific antidote, the risk of dying from an MH episode remains unacceptably high. To increase the chance of successful MH treatment, the American Society of Anesthesiologists and Malignant Hyperthermia Association of the U.S. monitoring standards should be altered to require core temperature monitoring for all general anesthetics lasting 30 minutes or longer.

Anesthetic drugs and onset of malignant hyperthermia.

BACKGROUND: The time between the beginning of anesthetic administration and recognition of the first sign of malignant hyperthermia (MH) (MH onset time) could differ among anesthetic drugs. METHODS: We examined the time of the first signs of suspected MH, anesthetic drugs administered, subject age, and year of event in Adverse Metabolic/Musculoskeletal Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Inclusion criteria were judgment by the reporting clinician that the event was possible or fulminant MH, documentation of the time when anesthetic administration began, and the time when the first MH sign was noted. Descriptive statistics, Kruskal-Wallis analysis, and nonparametric correlation were used to assess the difference in MH onset times under different conditions. RESULTS: Four hundred seventy-seven cases met inclusion criteria; 58.5% were possible MH and 41.5% fulminant MH. Inhaled anesthetic and succinylcholine were given in 53.9% of cases, inhaled anesthetic only in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in 7 MH cases. In 394 patients exposed to only 1 of the 4 inhaled anesthetics, without regard for subject age, MH onset time was shorter in the presence of halothane than any of the other anesthetics and shorter after succinylcholine in all anesthetics. If succinylcholine was not given, MH onset was shorter during sevoflurane anesthesia than during desflurane or isoflurane. In 322 cases, 1 rather than multiple first signs of MH were reported with masseter spasm as the earliest MH sign. In 339 cases in which masseter spasm was not reported, there was no difference in MH onset time with or without succinylcholine. In 146 cases in which masseter spasm was not reported and succinylcholine was not given, MH onset was shorter during halothane anesthesia, than during exposure to desflurane, or isoflurane. MH onset time during sevoflurane was shorter than during desflurane or isoflurane. MH was reported later in the course of anesthesia after 1998, when halothane and succinylcholine were less often reported. MH occurred after succinylcholine administration in the absence of inhaled anesthetics. We could not separate an effect of age from that of other variables. CONCLUSION: The onset of MH has been observed later during desflurane and isoflurane anesthesia than during exposure to sevoflurane. Since 1998, MH signs have more often appeared later, in the second or third hour of anesthesia, than they did before 1998.

Unexpected MH deaths without exposure to inhalation anesthetics in pediatric patients.

Children, later found to have ryanodine receptor type one variants (RYR1), died without exposure to inhalation anesthetics. Family members with the same RYR1 variants had contracture tests consistent with susceptibility to malignant hyperthermia or in vitro testing showed increased sensitivity to RYR1 agonist.

Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.

BACKGROUND: Mutations in the ryanodine receptor type 1 gene (RYR1) that encodes the skeletal muscle-specific intracellular calcium (Ca(2+)) release channel are a cause of malignant hyperthermia (MH). In this study, we examined RYR1 mutations in a large number of North American MH-susceptible (MHS) subjects without prior genetic diagnosis. METHODS: RYR1 was examined in 120 unrelated MHS subjects from the United States in a tiered manner. The α-1 subunit of the dihydropyridine receptor gene (CACNA1S) was screened for 4 variants in subjects in whom no abnormality was found in ≥ 100 exons of RYR1. RESULTS: Ten known causative MH mutations were found in 26 subjects. Variants of uncertain significance in RYR1 were found in 36 subjects, 16 of which are novel. Novel variants in both RYR1 and CACNA1S were found in the 1 subject who died of MH. Two RYR1 variants were found in 4 subjects. Variants of uncertain significance were found outside and inside the hotspots of RYR1. Maximal contractures in the caffeine-halothane contracture test were greater in those who had a known MH mutation or variant of uncertain significance in RYR1 than in those who did not. CONCLUSIONS: The identification of novel RYR1 variants and previously observed RYR1 variants of uncertain significance in independent MHS families is necessary for demonstrating the significance of these variants for MH susceptibility and supports the need for functional studies of these variants. Continued reporting of the clinical phenotypes of MH is necessary for interpretation of genetic findings, especially because the pathogenicity of most of these genetic variants associated with MHS remains to be elucidated.

Case report: Death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old.

A healthy 6-year-old boy developed lower extremity rigidity, trismus, and fever after playing in a splash pool. On arrival in the emergency department, he appeared to be seizing. An endotracheal tube was emergently placed using succinylcholine. Cardiac arrest followed. He could not be resuscitated. Postmortem genetic analysis found a novel RYR1 variant. Family testing revealed the same variant in his father who also had muscle contracture testing diagnostic for susceptibility to malignant hyperthermia and central core disease diagnosed histologically. Because there was no exposure to volatile anesthetics before the onset of symptoms, this is a case of "awake" malignant hyperthermia worsened by succinylcholine.

Special article: Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities.

CLINICAL PROBLEM: Volatile anesthetics and/or succinylcholine may trigger a potentially lethal malignant hyperthermia (MH) event requiring critical care crisis management. If the MH triggering anesthetic is given in an ambulatory surgical center (ASC), then the patient will need to be transferred to a receiving hospital. Before May 2010, there was no clinical guide regarding the development of a specific transfer plan for MH patients in an ASC. MECHANISM BY WHICH THE STATEMENT WAS GENERATED: A consensual process lasting 18 months among 13 representatives of the Malignant Hyperthermia Association of the United States, the Ambulatory Surgery Foundation, the Society for Ambulatory Anesthesia, the Society for Academic Emergency Medicine, and the National Association of Emergency Medical Technicians led to the creation of this guide. EVIDENCE FOR THE STATEMENT: Most of the guide is based on the clinical experience and scientific expertise of the 13 representatives. The list of representatives appears in Appendix 1. The recommendation that IV dantrolene should be initiated pending transfer is also supported by clinical research demonstrating that the likelihood of significant MH complications doubles for every 30-minute delay in dantrolene administration (Anesth Analg 2010;110:498-507). STATEMENT: This guide includes a list of potential clinical problems and therapeutic interventions to assist each ASC in the development of its own unique MH transfer plan. Points to consider include receiving health care facility capabilities, indicators of patient stability and necessary report data, transport team considerations and capabilities, implementation of transfer decisions, and coordination of communication among the ASC, the receiving hospital, and the transport team. See Appendix 2 for the guide.

Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families.

BACKGROUND: Mutations in the type 1 ryanodine receptor gene (RYR1) result in malignant hyperthermia, a pharmacogenetic disorder typically triggered by administration of anesthetics. However, cases of sudden death during exertion, heat challenge, and febrile illness in the absence of triggering drugs have been reported. The underlying causes of such drug-free fatal "awake" episodes are unknown. METHODS: De novo R3983C variant in RYR1 was identified in two unrelated children who experienced fatal, nonanesthetic awake episodes associated with febrile illness and heat stress. One of the children also had a second novel, maternally inherited D4505H variant located on a separate haplotype. Effects of all possible heterotypic expression conditions on RYR1 sensitivity to caffeine-induced Ca release were determined in expressing RYR1-null myotubes. RESULTS: Compared with wild-type RYR1 alone (EC50 = 2.85 ± 0.49 mM), average (± SEM) caffeine sensitivity of Ca release was modestly increased after coexpression with either R3983C (EC50 = 2.00 ± 0.39 mM) or D4505H (EC50 = 1.64 ± 0.24 mM). Remarkably, coexpression of wild-type RYR1 with the double mutant in cis (R3983C-D4505H) produced a significantly stronger sensitization of caffeine-induced Ca release (EC50 = 0.64 ± 0.17 mM) compared with that observed after coexpression of the two variants on separate subunits (EC50 = 1.53 ± 0.18 mM). CONCLUSIONS: The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ∼2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.

Special article: Future directions in malignant hyperthermia research and patient care.

Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle disorders, the Malignant Hyperthermia Association of the United States (MHAUS) recently sponsored a scientific conference at which an interdisciplinary group of experts gathered to share new information and ideas. In this Special Article, we highlight key concepts and theories presented at the conference along with exciting new trends and challenges in MH research and patient care.

Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States.

BACKGROUND: Dantrolene is the only specific treatment for malignant hyperthermia (MH), a genetic disorder in which life-threatening temperature increase has been induced by inhalation anesthetics and succinylcholine. Because MH presents with nonspecific signs and delay of treatment can be fatal, dantrolene may be given as soon as MH is suspected. We report the complications associated with dantrolene administration as documented in AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports submitted to the North American Malignant Hyperthermia Registry. METHODS: AMRA reports were analyzed for differences between subjects with and without complications attributed to dantrolene. Documentation of dantrolene dose and subject weight were inclusion criteria. Because some reported complications were likely due to factors other than dantrolene, a reduced set of cases was also defined. We used χ(2) and Mann-Whitney tests. Logistic regression was applied to describe factors associated with increased risk of complications. RESULTS: In the full dataset of 368 subjects, the most frequent complications associated with dantrolene were muscle weakness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%), and respiratory failure (3.8%). Logistic regression described a 29% increase in risk of any complication when the total dantrolene dose was doubled, a 144% increase in risk when fluid administration was part of treatment, an 83% decrease in risk in the presence of neurosurgery, and a 74% decrease in risk in the presence of oral surgery. In the dataset reduced by removal of some serious complications that were judged likely to have been due to preexisting disease or the MH event, there were 349 subjects. The most frequent complications associated with dantrolene were muscle weakness (14.6%), phlebitis (9.2%), and gastrointestinal upset (4.3%). In this reduced dataset, logistic regression described a 25% increase in risk of any complication when the total dantrolene dose was doubled, a 572% increase in risk in the presence of obstetric or gynecologic surgery, a 56% decrease in risk if furosemide was given, and no relationship with fluid administration or other types of surgery. CONCLUSIONS: Complications after dantrolene are common, but rarely life threatening. Unidentified factors in the surgical environment are associated with changes in the risk of complications. Fluid management, as part of the treatment of MH, has an important association with the risk of complications after dantrolene administration and should be monitored closely.

What happens when things go wrong?

When a patient is injured or dies during anesthesia care, both the family of the patient and the health care providers suffer. The family needs to know what happened. The family can benefit from personal contact with the involved physicians. Apology to the injured is very important. The health care providers must report adverse events. Systematic review of adverse events can provide improved patient safety. Mechanisms exist to support the health care providers recovering from these potentially devastating experiences, but useful support is often not immediately available.