Multiple-pulse stimulation and dantrolene in malignant hyperthermia

A potentially fatal condition, yet preventable, malignant hyperthermia (MH) lacks a satisfactory noninvasive diagnostic test. Studying the effects of intravenous dantrolene (3 mg/kg) on electrically stimulated skeletal muscle, we found that this approach does not conclusively distinguish between normal humans and those susceptible to malignant hyperthermia but nonetheless yielded important information about the action of dantrolene in man and in MH. Supramaximal single- and multiple-pulse stimulation of the common peroneal nerve produced stable torque responses of the dorsiflexor muscles (monitored in vivo), which dantrolene suppressed. With the multiple-pulse stimulation (5-6 pulses) this torque suppression was significantly less in MH-susceptible subjects than in control subjects. This distinction, also observed in MH swine, confirms this animal as a good model for human MH. That dantrolene's effect in MH can be more completely reversed with high frequency stimulation is intriguing; presumably, excitation-contraction coupling differs in MH and normal muscle.     

Screening test for malignant hyperthermia in patients with persistent hyperCKemia: A pilot study

Introduction: Persistently elevated serum creatine kinase (CK) is frequently associated with predisposition to malignant hyperthermia (MH). We investigated whether a minimally invasive metabolic test is suitable to diagnose MH susceptibility among patients with hyperCKemia. Methods: Thirty‐nine participants were included: 10 were MH susceptible (MHS); 21 MH were non‐susceptible (MHN); and 8 had MHN with persistent hyperCKemia >500 U/L. Microdialysis probes were inserted into the vastus lateralis muscle, and halothane or caffeine was injected via an attached microtubing catheter. Lactate concentrations in dialysis samples were measured spectrophotometrically. Results: Baseline lactate did not differ between the groups. After local application of halothane or caffeine, a significant lactate increase was detected only in the MHS group. Conclusions: Test results were not influenced by hyperCKemia. To avoid risks and complications of a surgical muscle biopsy this microdialysis test might be a useful screening tool for MH susceptibility among patients with persistent CK elevation. Muscle Nerve 47: 677–681, 2013     

Concurrence of malignant hyperthermia and congenital abnormalities

Two children about to undergo corrective surgery were required to be investigated for malignant hyperthermia (MH). These investigations arose out of concern by the anesthetist who had obtained a history of unexplained pyrexial reactions to anaesthetic in other members of the family. Because over the years we have encountered several children with multiple congenital abnormalities who have been found to be susceptible to MH, we stressed the advisability of biopsying not only the patient but also the patient's parents. Positive responses for MH were obtained in the patients and in one of the parents on each occasion. The hypothesis of intrauterine MH with its pharmacogenetic propensity for heat production is considered as a possible etiological factor which may cause abnormalities of a congenital nature.     

Emery-Dreifuss肌营养不良症的临床、病理特征及emerin蛋白、STA基因的表达(附1例报告)

目的研究Emery-Dreifuss肌营养不良症（EDMD）的临床、病理特征及emerin蛋白、STA基因的表达。方法回顾性分析1例EDMD患者的临床资料及STA基因检测结果。结果本例患者儿童期发病,进行性四肢肌肉无力、萎缩,早期关节挛缩和心脏受累;血肌酶仅轻度增高;病理检查肌肉肌纤维大小不等,纤维变圆,部分被脂肪取代;脊髓前角细胞正常,腓肠神经无改变,除外神经源性肌萎缩;横纹肌与心肌emerin蛋白消失;STA基因无突变。结论EDMD是肌营养不良的特殊类型,发病早期出现关节挛缩和心脏受累;肌核膜emerin蛋白缺失;散发性EDMD的STA基因无突变。     

Emery-Dreifuss muscular dystrophy with unusual features

Two families with Emery-Dreifuss muscular dystrophy (EMD) are described. Several unusual features for EMD are emphasized. One of the patients had severe neuromuscular disability with inability to walk during early childhood. This patient also had mild bifacial paresis. His brothers had the typical slow progression of EMD. In some of the patients, muscle weakness distribution was more widespread than has usually been reported, with prominent involvement of finger extensors. It is suggested that there is a wide phenotypic spectrum in EMD. In both families, the disease segregated with markers spanning the EMD locus in Xq28. © 1993 John Wiley & Sons, Inc.     

Myophosphorylase B deficiency and malignant hyperthermia

A 6-year-old boy was examined with the dual purpose of establishing whether he had malignant hyperthermia (MH) and to investigate his complaint of excessive muscle fatiguability. In the course of such investigations, McArdle's disease was diagnosed, and the patient was also identified as an MH-positive reactor.     

Benign muscular dystrophy with contractures: a new syndrome?

Three patients are described with muscular dystrophy and contractures. Although this disorder bears similarities to Emery-Dreifuss disease and variants previously described, absence of cardiomyopathy is a distinguishing feature. Electrodiagnostic testing and muscle biopsy are consistent with a myopathy. An autosomal dominant pattern of inheritance is suspected, but the possibility of a Y-to-Y transmission cannot be completely excluded.     

Pathological findings in 165 patients explored for malignant hyperthermia susceptibility

The pathological findings in 165 patients explored for malignant hyperthermia (MH) susceptibility are reported. The first group of 120 subjects were patients investigated for MH. These patients had suffered an attack of MH under anaesthetic or were members of families in which a subject had died of MH. In vitro contracture tests revealed 25 malignant hyperthermia susceptible (MHS) subjects, with positive contracture tests for halothane and caffeine, 5 malignant hyperthermia subjects with reaction to caffeine only (MHC), 3 malignant hyperthermia subjects with reaction to halothane only (MHH) and 87 malignant hyperthermia negative (MHN) subjects with normal contracture tests. The second group of 45 subjects had exertional heat stroke. In vitro contracture tests performed at least 3 months after the exertional heat stroke revealed 11 MHS, 6 MHC, 2 MHH subjects and 26 MHN. In both groups, whatever the in vitro contracture test results, pathological findings were heterogeneous and revealed various changes: rhabdomyolysis, mitochondrial myopathy, denervation, type II atrophy, AMPase deficiency, non-specific findings or normal features. Central core myopathy was only observed in the first subgroup and was the only disease significantly associated with MH. In contrast to previous reports, this study demonstrates the absence of a specific malignant hyperthermia or exertional heat stroke myopathy. Furthermore, the discovery of MHS subjects among the EHS group of patients highlights the need for systematic exploration of all these patients.     

Dominantly inherited malignant hyperthermia (MH) in the King-Denborough syndrome.

A 14-year-old boy, an only child, with the phenotypical dysmorphic features of the King-Denborough Syndrome developed a severe hyperthermic episode during anesthesia which responded to the administration of sodium dantrolene. As adequate metabolic studies were not available at the time of the crisis he was referred for confirmation of the malignant hyperthermia (MH) status. Muscle tension studies confirmed the presence of MH. The patient's mother and father were subsequently tested and the mother was found to be MH positive, the father MH negative.     

Ca(2+)-ATPase and Na(+)-K(+)-ATPase content in skeletal muscle from malignant hyperthermia patients.

The purpose of this study was to determine the concentration of Ca(2+)-ATPase and Na(+)-K(+)-ATPase in biopsies from vastus lateralis muscle of 24 patients, who underwent a diagnostic contracture test for susceptibility to malignant hyperthermia (MH). Ca(2+)-ATPase was quantified as the Ca(2+)-dependent 32P incorporation in whole muscle homogenates. Na(+)-K(+)-ATPase was quantified as the [3H]ouabain-binding capacity in intact muscle samples. These methods avoid isolation of membranes, a procedure that may influence the results due to interindividual variation in recovery. The results show that both enzymes can be determined in (frozen) muscle biopsies weighing 50 mg. Neither the concentration of Ca(2+)-ATPase nor that of Na(+)-K(+)-ATPase differed in biopsies from subjects diagnosed as susceptible (MHS) or nonsusceptible (MHN) to MH. Our data support the view that changes in the concentration of Ca(2+)-ATPase and/or Na(+)-K(+)-ATPase do not play a primary role in the pathogenesis of MH.     

Malignant hyperthermia of Duchenne muscular dystrophy: application of clinical grading scale and caffeine contracture of skinned muscle fibers]

Episodes of acute myoglobinuria or cardiac arrest were occasionally complicated in general anesthesia of patients with Duchenne or Becker muscular dystrophy (DMD/BMD). Whether these complications are malignant hyperthermia (MH) or not has several times been discussed. In the present study, we applied the clinical grading scale (CGS) of Larach and modified criteria of caffeine contracture test of the skinned fiber (sIVCT) to solve this problem. When the CGS was applied to reported MH-like episodes of DMD/BMD cases, 9 out of 20 cases were classed as almost certain or very likely MH. According to results of sIVCT in 11 patients with DMD/BMD, 5 patients were judged as MHS (MH-susceptible) and 3 as MHE (MH-equivocal). The diagnostic specificity of present MHS criteria was 100% for the fulminant MH. A possible "false positive" result in European IVCT has been discussed in relation to myopathy such as muscular dystrophy. When we applied our sIVCT to the muscle of mdx mouse, caffeine contracture was rather reduced compared to controls. Present study suggested that a true MH was complicated in some cases of DMD/BMD. In certain stage of muscular degeneration, patients with DMD/BMD become susceptible to MH, probably temporarily, but exact mechanism still awaits clarification.     

Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life-threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.     

Malignant hyperthermia-like reactions in Duchenne or Becker muscular dystrophy: review and hypothesis.

Adverse reactions to genral anesthesia, which partly resembled malignant hyperthermia (MH), were more frequent in muscular dystrophy than in controls. In the present study, 35 cases so far reported in Duchenne or Becker muscular dystrophy (DMD or BMD) were analyzed and their pathogenesis was discussed. Cardiac involvements were sole manifestations in 7 cases. In other 28 cases, the acute rhabdomyolysis was the most prevailing manifestation. About 60% of myolysis cases were associated with muscle contracture (rigidity) or other hypermetabolic signs such as hypercapnia, hyperthermia and metabolic acidosis. Cases with BMD were more hyperthermic than with DMD. These results suggest Ca ion-induced hypermetabolic reactions are also present in dystrophinopathy, which have been assumed as core syndromes of the classical (gene-defined) MH. However, question whether the abnormal Ca ion is from the extracellular or intracellular stores is still unclear. Circumstancial evidences suggest that the Ca-induced Ca release (CICR) mechanism might also be involved. Endogenous redox modulators such as nitric oxide or reactive oxygen species in the dystrophic muscle might contribute to the perturbed Ca ion homeostasis.     

Central core disease due to recessive mutations in RYR1 gene: Is it more common than described?

Central core disease (CCD) is an autosomal-dominant congenital myopathy, with muscle weakness and malignant hyperthermia (MH) susceptibility. We identified two of nine Brazilian CCD families carrying two mutations in the RYR1 gene. The heterozygous parents were clinically asymptomatic, and patients were mildly affected, differing from the few autosomal-recessive cases described previously. Recessive inheritance in CCD may therefore be more common than previously appreciated, which has important implications for genetic counseling and MH prevention in affected families.     

Clinical and muscle biopsy findings in malignant hyperthermia susceptibility

Patients (155) were investigated for malignant hyperthermia susceptibility (MHS), by in vitro testing of muscle taken from the vastus medialis muscle. Histopathological and histochemical investigation of muscle was also performed. Ultrastructural investigation was performed in 13 MHS patients; 90% of the patients replied to a questionnaire concerning present or previous neuromuscular symptoms. The majority of MHS and MH negative (MHN) patients had no or only minor histopathological and histochemical abnormalities. Core-targetoid fibres were the only potentially important abnormalities found in MHS patients. There were no differences in neuromuscular symptoms between MHS, MHN and control patients, and most patients in both the MHS and MHN group were normal on clinical examination.     

Effect of prior exercise on thermal sensitivity of malignant hyperthermia‐susceptible muscle

Malignant hyperthermia (MH) episodes may occur upon exposure to halogenated anesthetics, during resistance and endurance exercise, and in response to thermal stress. The purpose of this study was to investigate the effects of prior eccentric and concentric (i.e., wheel running) exercise on the thermal sensitivity of isolated MH‐susceptible mouse muscle (RyR1^Y522S/wt). Eccentric, but not concentric, exercise attenuated the thermal sensitivity of MH‐susceptible muscle. Muscle Nerve, 2010     

Light and electron microscopic studies on localization of myoglobin in skeletal muscle cells in neuromuscular diseases

The localizations of myoglobin in skeletal muscle cells of patients with Duchenne muscular dystrophy (DMD), myotonic dystrophy (MyD), and amyotrophic lateral sclerosis (ALS) were studied by immunohistochemistry and immunoelectron microscopy. In normal skeletal muscle cells, myoglobin was localized mainly in the I-band region. In degenerating muscle cells of patients with DMD and MyD, myoglobin was also demonstrated in the distended lumen of the internal membrane system and in the intermyofibrillar space, through which it seemed to pass into the extracellular space. No myoglobin was detected in opaque fibers or in some of small-sized fibers in DMD muscle. In patients with ALS the staining intensities of myoglobin varied in different muscle cells, but myoglobin was restricted to the I-band region in many muscle cells. These findings suggest that changes in the localization of myoglobin in skeletal muscle cell sensitively reflect the pathologic status of muscle cells.     

Duchenne muscular dystrophy: a study of wrist and hand function

The wrist and hands of 18 Duchenne muscular dystrophy (DMD) patients were assessed for abnormalities. The subjects were divided into three groups by age. Flexion and ulnar deviation contractures of the wrist began in the youngest age group, 8-14 years. Other abnormalities, present in all age groups, included extrinsic and intrinsic digital muscle shortness, boutonniere and swan neck deformities, and hyperextension of the digital interphalangeal joints. Pain found with passive proximal interphalangeal joint flexion has not been reported previously. This study supports the importance of early assessment of the wrist and hand in DMD and suggests intervention techniques to possibly retard the deforming process.     

Intellectual function in muscular dystrophies

Summary Intellectual function was studied in 28 boys with Duchenne dystrophy, 12 patients with facioscapulohumeral-type and 10 patients with limb-girdle-type muscular dystrophy. A definite relationship between intelligence level and the type of muscle disease was found. The more severe the genetic damage manifested by the rapidity of progression of muscular dystrophy the more definite the affection of the CNS manifesting as mental deficit. The factors influencing the level and structure of intelligence seem to exert their effect before the manifestation of muscle lesions.     

Malignant hyperthermia and neuromuscular disease.

Malignant hyperthermia (MH) is a rare clinical syndrome characterized by hypermetabolism and triggered by specific anesthetic agents. The mechanism of this abnormal reaction is due to uncontrolled calcium flux in the skeletal muscles resulting in a variable clinical syndrome of muscle rigidity, respiratory and metabolic acidosis, and elevation of temperature. The specific genetic defect underlying this condition has not been identified in humans, though in susceptible swine a mutation of the gene for the ryanodine receptor, a large protein which comprises the calcium channel in the sarcoplasmic reticulum, has been identified recently. Inheritance in humans appears to be autosomal dominant with variable penetrance. Patients with MH rarely have physical or laboratory signs of muscle disease. However, scattered case reports and investigations of individuals with known myopathies and other muscle related problems, such as acute rhabdomyolysis or idiopathic persistently elevated creatine kinase, suggest a possible association of MH with a variety of neuromuscular diseases and stress syndromes. This association is very strong in the case of central core disease (CCD) where it is supported by clinical and laboratory evidence, including the proximity of the CCD gene to the ryanodine receptor gene on chromosome 19. A variety of other diseases have been implicated and can be classified as possibly associated (King-Denborough syndrome, Duchenne muscular dystrophy) or unlikely to be associated (myotonia congenita, sudden infant death syndrome, limb girdle dystrophy, neuroleptic malignant syndrome, etc.).(ABSTRACT TRUNCATED AT 250 WORDS)