A case of acute quadriplegic myopathy]

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.     

Apoptotic features accompany acute quadriplegic myopathy

OBJECTIVE: To investigate the role of apoptosis in acute quadriplegic myopathy. BACKGROUND: Acute quadriplegic myopathy is a muscular disease characterized by diffuse flaccid weakness occurring in patients with severe systemic illness and exposure to corticosteroids or neuroblocking agents. Myofiber atrophy and thick filament loss are the distinguishing pathologic features on muscle biopsy. Increased calpains expression and lysosomal and nonlysosomal proteolytic pathways have been claimed as possible pathogenic factors. Nevertheless, the mechanisms leading to myofiber atrophy and thick filament loss need further investigation. PATIENTS AND METHODS: The expression of ubiquitin and proapoptotic proteases as well as DNA fragmentation in muscle biopsies from three patients with acute quadriplegic myopathy were studied. RESULTS: All patients exhibited an important overexpression of caspases, calpain, cathepsin B, and ubiquitin, and the presence of numerous apoptotic nuclei in over 70% of myofibers. CONCLUSIONS: These data suggest that apoptosis mediated by proteolytic proteases may play a role in the pathogenesis of acute quadriplegic myopathy.     

Direct muscle stimulation in acute quadriplegic myopathy

We have previously found that muscle is electrically inexcitable in severe acute quadriplegic myopathy (AQM). In contrast, muscle retains normal electrical excitability in peripheral neuropathy. To study the relationship between muscle electrical excitability and all types of flaccid weakness occurring in the intensive care unit, we identified 14 critically ill, weak patients and measured the amplitude of compound muscle action potentials (CMAPs) obtained with direct muscle stimulation (dmCMAP) and with nerve stimulation (neCMAP). In 11 of 14 patients dmCMAP amplitudes were reduced and the ratio of the neCMAP amplitude to the dmCMAP amplitude (nerve/muscle ratio) was indicative of loss of muscle electrical excitability. In 2 other patients, the nerve/muscle ratio indicated neuropathy. Direct muscle stimulation may allow differentiation of AQM from neuropathy even in comatose or encephalopathic critically ill patients. AQM may be more common than has previously been appreciated. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 665–673, 1997.     

Analysis of muscle proteins in acute quadriplegic myopathy

We investigated the changes of muscle proteins in acute quadriplegic myopathy (AQM) using immunohistochemistry and stoichiometry. Cases of AQM were observed in which it was difficult to type muscle fibers with adenosine triphosphatase staining in biopsied muscle. Well-defined typing of these cases was possible by performing immunofluorescent staining using slow and fast skeletal troponin I (TnI) antibodies. By this means, small angular fibers were shown to be fast skeletal muscle, and myosin was absent from these muscle fibers. Actin and tropomyosin were maintained. Muscle protein ratios were determined by stoichiometry following sodium dodecyl sulfate-polyacrylamide gel electrophoresis of AQM myofibril specimens from four subjects. The myosin heavy chain/actin ratio was significantly decreased compared with a normal control group and other neuromuscular diseases. These pathologic findings returned to normal during recovery from AQM. Thus, myosin selectively decreases, whereas actin and regulatory proteins located above it are maintained during AQM.     

Pindolol-induced rhabdomyolysis in sarcoid myopathy

A 72-year-old man suddenly developed severe muscle weakness following the treatment with pindolol (Calvisken) for three days. Neurological examination on admission disclosed marked proximal muscle weakness with absent deep tendon reflexes. Laboratory data showed significant increase of serum CK, aldolase and myoglobin. Electromyography revealed both neurogenic and myogenic changes in all muscle tested. Skeletal muscle CT showed patchy low density areas in muscles of thigh and leg, especially in the hamstrings. Femoral muscle biopsy demonstrated a granulomatous nodule with multinucleated giant cells in the degenerated muscle fibers showing small-grouped atrophy. By Mb-PAP staining, Mb-negative fibers were randomly distributed among normally stained ones. Leu 1, 3a, 4, HLA-DR positive cells were found adjacent to the granuloma by immunoperoxidase staining. After immediate withdrawal of pindolol and treatment with steroid, he recovered muscle strength and enzyme activities were normalized in a week. Beta blockers have been known to induce muscle cramps or pain and moderate elevation of serum muscle enzymes. However, severe muscle weakness with highly elevated enzyme activities leading to rhabdomyolysis as noticed in the present case was rarely reported in the literature. Underlying sarcoid myopathy might be suspected to exaggerate this unusual case of pindolol-induced rhabdomyolysis. A careful use of pindolol is emphasized.     

A case of glycogen storage myopathy with acute heart failure

A case of 25-year-old woman with glycogen storage myopathy is reported here. She was hospitalized for acute heart failure after alcohol drinking. The electrocardiogram on admission showed marked ST elevation. Laboratory data showed elevated levels of serum myogenic enzymes but no rise in cardiomyogenic enzyme: CK 3862 IU/l CK-MB 35 IU/l, LDH 427 IU/l, GOT 203 IU/l. After several days, she recovered from acute heart failure and could walk without supporting. ST elevation in ECG and elevated myogenic enzymes were also normalized. The occurrence of acute myocardial infarction was ruled out because a coronary angiogram and 99 Tcm scintigram were normal. Physical examination revealed proximal muscular weakness and mental retardation (WAIS, total 72). Venous lactate response was normal after semi-ischemic forearm exercise. PAS staining of muscle specimen showed an excess deposit of glycogen. Ragged-red fibers were not seen on Gomori-trichrome stain. By electron microscopy, a large amount of glycogen particles were demonstrated in the subsarcolemma, but there were no abnormal mitochondrial changes. Biochemical analysis showed accumulation of glycogen in muscles: 28.7 mg/g muscle (normal 11.4 +/- 4.2 mg/g muscle). The activities of enzyme in the pathway of glycogen and glycogenosis (alpha-glucosidase, amylo-1,6-glucosidase, phosphorylase a, phosphorylase kinase, phosphofructokinase, etc.) were within normal limits. The spectrum of glycogen iodine complex was normal. Our case was different from any type of muscle glycogen storage disease previously reported. The etiology of an excess of glycogen deposit in muscles is unknown.     

Proximal myotonic myopathy

Three Swedish patients with proximal muscle weakness, myotonia and lack of CTG expansion on genetical analysis are presented. Clinical neurological and neurophysiological examination and muscle biopsy were performed. There was an indication of autosomal dominant inheritance in 2 of the 3 patients. The main symptoms and clinical findings in the 3 patients were weakness of the proximal muscles, myotonia, muscle stiffness, muscle pain and muscle atrophy. Neurophysiological examination showed myotonic bursts and muscle biopsy snowed a variation of fibre sizes, an increased number of muscle fibres with centralized nuclei and scattered atrophic muscle fibres. Laboratory data showed elevated CK, GT and LD in 1 patient. Before genetical analysis was performed, all 3 patients had been diagnosed as atypical cases of myotonic dystrophy. However, the symptoms, clinical signs, laboratory data, electrophysiological and muscle biopsy findings were compatible with proximal myotonic myopathy (PROMM).     

Unusual course of nemaline myopathy

A boy with onset features common for a moderate form of congenital nemaline myopathy, after some years developed scapulo-humeral syndrome. Extra- and intrafusal muscle fibers overloaded with rods and indicating focal degenerative changes were seen in the first biopsy. The biopsy was later repeated and revealed an improvement in muscle architecture with a dramatically decreased number of rods. This transformation suggests that rods, as well as Z-line streaming, might be a reversible anomaly of Z-discs.     

Congenital myopathy without specific features (minimal change myopathy)

A case of Congenital myopathy without specific features was reported. The main clinical findings were generalized muscle weakness and delayed developmental milestones. Histological and histochemical examination on the biopsied muscles demonstrated minimal nonspecific changes, mild variation in fiber size without structure and enzyme abnormality. No prominent necrotic changes were found and Ulrich and Fukuyama type of congenital myopathy were excluded. The abnormal muscle pathology was assumed to have resulted from delayed muscle fiber growth due to defective neural influence.     

Nemaline rod myopathy: a rare form of myopathy

Nemaline rod myopathy (NM) is a rare form of congenital myopathy characterized by slowly progressive or nonprogressive muscle weakness and pathognomonic rod-like structures within the muscle fibers. To the best of our knowledge, this is first documentation of the clinicopathological features of this rare entity from India. All cases of NM diagnosed in our laboratory were retrieved. Clinical and pathological features were reviewed. During a period of 1.5 years (Jan 2004 to June 2005), we received 750 muscle biopsies for various reasons. Of which, 15 were diagnosed as congenital myopathies and four as nemaline rod myopathies. Thus, NM comprises 0.53% of all muscle diseases and 22.6% of all congenital myopathies. All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness. Both males and females were equally affected. The CPK levels were normal and EMG was myopathic. Microscopic examination revealed minimal changes but characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods. NM, although a rare form of congenital myopathies, should be suspected in children who present with generalized hypotonia, repeated chest infections and slowly progressive muscle weakness. This report highlights the importance of histochemistry and ultrastructural examination in the diagnosis of this entity, in the absence of the availability of methodology for genetic studies.     

Nonspecific congenital myopathy (minimal change myopathy): a case report

A 28-month-old male with generalized hypotonia and muscle weakness, a myopathic face, skeletal dysmorphism and delayed motor milestones from birth is reported. He gradually developed the ability of sitting and rolling over, but could not stand without support until 28 months. There was no intellectual impairment or seizures. Deep tendon reflexes were absent. The serum CK value, peripheral nerve conduction velocity and EMG were within normal limits. A muscle biopsy specimen showed mild variation in fiber size, and an increased number of type 2C fibers on histochemical examination, but no apparent abnormalities on electron microscopy. The baby was tentatively diagnosed as having minimal change myopathy or nonspecific congenital myopathy which is thought to be one of the congenital nonprogressive myopathies.     

Reversible emetine-induced myopathy with ECG abnormalities: a toxic myopathy

Summary A young anorexic woman is described with a history of progressive muscle weakness following chronic ingestion of syrup of ipecac that was used in an attempt at weight control. Electrocardiogram (ECG) showed T-wave inversion in all leads and prolongation of the Q-T interval. Electromyography was abnormal. Muscle biopsy revealed a randomized, generalized, predominantly type-2 fibre atrophy and structural alterations in oxidative enzyme stains, such as targetoid and motheaten fibres. A few necrotic cells were actively phagocytosed. Electron microscopy revealed severe sarcomeric abnormalities with Z-line streaming, myofibrillar disorganization and increased lysosomal activity. After discontinuation of ipecac syrup, the patient noted a gradual improvement in her condition. The ECG became normal. Emetine and related drug-induced myopathies are uncommon but are of experimental interest because of their effects on mitochondria and the light they shed on autophagic mechanisms in muscle.Read in part before the 9th International Meeting on Neuromuscular Diseases, Marseille, 17 September 1988     

Constitutive activation of MAPK cascade in acute quadriplegic myopathy

Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)-beta/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-beta receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-beta pathway in myofibers. The acute stimulation of the TGF-beta/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients.     

Lipid storage myopathy in Kearns-Sayre syndrome

A 7-year-old girl had external ophthalmoplegia, limb weakness, short stature, hearing loss, pigmentary degeneration of the retina, and increased CSF protein content. Muscle biopsy revealed vacuolar myopathy with accumulation of lipids. Electronmicroscopy showed abnormalities of shape, size, and internal structure of muscle mitochondria. Muscle activity of palmitoyl-CoA synthetase was decreased, and the content of lipids was increased. Serum and muscle carnitine levels were normal, as were muscle carnitine palmitoyltransferase and carnitine acetyltransferase.     

Distal myopathy

A family with distal myopathy with early onset of the disease and autosomal dominant inheritance is reported. In EMG examination and in the histological examination of muscle features of nervous system involvement were found besides primarily muscular lesions. The character of the pathological changes in the muscles is discussed.     

Sodium channel inactivation in an animal model of acute quadriplegic myopathy.

We previously demonstrated that muscle fibers become unable to fire action potentials in both patients and an animal model of acute quadriplegic myopathy (AQM). In the animal model, skeletal muscle is denervated in rats treated with high-dose corticosteroids (steroid-denervated; SD), and muscle fibers become inexcitable despite resting potentials and membrane resistances similar to those of control denervated fibers that remain excitable. We show here that unexcitability of SD fibers is due to increased inactivation of sodium channels at the resting potential of affected fibers. A hyperpolarizing shift in the voltage dependence of inactivation in combination with the depolarization of the resting potential induced by denervation results in inexcitability. Our findings suggest that paralysis in the animal model of AQM is the result of an abnormality in the voltage dependence of sodium channel inactivation.     

Experimental ischemic myopathy

The acute and chronic morphological changes in ischemic rat solei and gastrocnemii produced by abdominal aortic ligation were studied with histochemical and electron microscopic techniques. By light microscopy, the fully developed lesions 4 days after aortic ligation consisted of grouped or scattered necrotic fibers undergoing phagocytosis as well as regenerating fibers. By electron microscopy, the earliest lesions seen 2 hr after aortic ligation, consisted of trilaminar plates in the intracristal space of mitochondria and muscle cell necrosis as evidenced by interruption of the plasma membrane and dissolution of the Z-discs. From 18 hr onward post ligation, prominent Z-disc streaming was also present. Regenerating fibers were numerous by 4 days post-ligation. Six and 12 weeks after aortic ligation prominent “type grouping” was the only significant alteration by histochemistry. An increase of the endomysial connective tissue was conspicuously absent.The ischemic lesions were much more severe in amount and degree in the solei than in the gastrocnemii. Sciatic nerve section, Achilles tenotomy and skeletal fixation of the ankles and knees prevented ischemic lesions as viewed with light microscope. A comparison of the experimental ischemic lesions to the lesions of early or late Duchenne dystrophy revealed significant dissimilarities, while muscle biopsies in childhood dermatomyositis share many ultrastructural features of experimental ischemic myopathy.     

Covert persistence of mdx mouse myopathy is revealed by acute and chronic effects of irradiation.

To compare muscle fiber loss in young and old mdx mice, we have blocked regeneration in one leg with a high dose (18 Gy) of X-rays administered at two ages; 16 days, just prior to the onset of the myopathy, and 15 weeks, when the myopathy is considered to be quiescent. Mice were examined 4 days after irradiation to look for acute effects, or after 6 weeks to look for cumulative effects. Tibial length, muscle weight, muscle fiber size, fiber number and histological changes were recorded. Signs of acute damage to muscle fibers, leakage of Procion Orange dye into fibers and loss of creatine kinase from the fibers were also examined. Irradiation caused no acute or chronic damage to muscle fibers; on the contrary, in the youngest mdx mice, irradiation delayed the onset of the disease. However, in mdx but not in normal mice, there was a loss of muscle mass and fiber number in irradiated by comparison with the non-irradiated contra-lateral muscles. This loss, attributed to fiber necrosis in the absence of regeneration, was as great in animals irradiated at 15 weeks as in those irradiated at 16 days. Such persistence of muscle fiber necrosis contradicts the standard view of the mdx mouse and establishes it as a closer model of Duchenne muscular dystrophy than is generally appreciated.     

Osteomalacic myopathy

A 45-year-old woman reported the development of thigh pain followed within a year by proximal muscle weakness. Clinical findings included short stature, prominent kyphoscoliosis, proximal weakness, and brisk reflexes. Recognition of an increased level of serum alkaline phosphatase and hypophosphatemia led to the diagnosis of osteomalacia. Identification of iron deficiency anemia and hypocholesterolemia implicated previously unrecognized gluten-sensitive enteropathy with associated vitamin D malabsorption as the cause of the osteomalacia. Adherence to a gluten-free diet and treatment with vitamin D₂ resulted in weight gain, resolution of pain, and improvement in strength within 3 months. Painful proximal weakness and hyperreflexia may be the initial and primary manifestations of osteomalacia, a readily treatable cause of muscle and bone disease. © 1994 John Wiley & Sons, Inc.