Myopathy proximal

C. Late complications include bone marrow suppression, particularly leukopenia and thrombocytopenia (4-5 days) and alopecia (2-3 weeks). Chronic colchicine therapy may produce myopathy (proximal muscle weakness and elevated creatinine kinase levels) and polyneuropathy. This has also occurred after acute poisoning. 

Central core disease (CCD) is an autosomal dominant, non-progressive myopathy characterized by hypotonia and proximal muscle weakness in infancy. CCD is named after detection of characteristic central cores that lack both mitochondria and oxidative enzyme... 

Various syndromes associated with hypereosinophilia involve skeletal muscle. There is a rare form of polymyositis which is characterized by this feature (defined as exceeding 1,500 eosinophils/mm for at least six months). Clinical presentation includes skin changes, heart and lung involvement, and peripheral neuropathy as well as proximal myopathy. The condition must be distinguished from trichinosis and other parasitic infections associated with hypereosinophilia. Muscle biopsy findings are interstitial and perivascular infiltrates in which eosinophils predominate but are accompanied by lymphocytes and plasma cells, and occasional muscle fiber necrosis. Fascitis may also be associated with hypereosinophilia (Shulman s syndrome). This condition is characterized by painful swelling of skin and soft tissues of trunk and extremities and weakness of limb muscles. Biopsy of muscle... 

Primary hyperparathyroidism occurs as a result of hyperplasia or the occurrence of adenoma. Secondary hyperparathyroidism may result from renal failure because of the associated phosphate retention, resistance to the metabolic actions of PTH, or impaired vitamin D metabolism. The last-mentioned factor is primarily responsible for the development of osteomalacia. Muscle symptoms are much more common in patients with osteomalacia than in primary hyperparathyroidism. Muscle biopsy has revealed disseminated atrophy, sometimes confined to type 2 fibers, but in other cases involving both fiber types. Clinical features of osteomalacic myopathy are proximal limb weakness and associated bone pain the condition responds well to treatment with vitamin D. 

Another condition due to mutations in the RYRl gene is central core disease. This is a rare myopathy presenting in infancy with hypotonia and proximal muscle weakness. Electron microscopy reveals an absence of mitochondria in the center of many type I (see below) muscle fibers. Damage to mitochondria induced by high intracellular levels of Ca secondary to abnormal functioning of RYRl appears to be responsible for the morphologic findings. 

Glutaric aciduria type II, which is a defect of P-oxida-tion, may affect muscle exclusively or in conjunction with other tissues. Glutaric aciduria type II, also termed multiple acyl-CoA dehydrogenase deficiency (Fig. 42-2), usually causes respiratory distress, hypoglycemia, hyperammonemia, systemic carnitine deficiency, nonketotic metabolic acidosis in the neonatal period and death within the first week. A few patients with onset in childhood or adult life showed lipid-storage myopathy, with weakness or premature fatigue [4]. Short-chain acyl-CoA deficiency (Fig. 42-2) was described in one woman with proximal limb weakness and exercise intolerance. Muscle biopsy showed marked accumulation of lipid droplets. Although... 

It is unclear whether the myopathy was a direct toxic effect of chlordecone on the muscle or whether the myopathy was a consequence of neuronal dysfunction. In addition, arthralgia in the proximal joints was reported by 4 of 23 workers with active symptoms of chlordecone intoxication (Taylor 1982, 1985). No cause for the joint pain could be determined. 

Myopathy and neuropathy Colchicine myoneuropathy appears to be a common cause of weakness in patients on standard therapy who have elevated plasma levels caused by altered renal function. It is often unrecognized and misdiagnosed as polymyositis or uremic neuropathy. Proximal weakness and elevated serum creatine kinase are generally present, and resolve in 3 to 4 weeks following drug withdrawal. Maiabsorption of vitamin B-f2- Colchicine induces reversible malabsorption of vitamin B-12, apparently by altering the function of ileal mucosa. 

Musculoskeletal - Skeletal muscle palsies, myopathy, or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes, and abnormal nerve conduction. 

Only a small amount of aluminum is absorbed, and is usually readily eliminated in the urine, unless renal function is impaired. Then absorbed Ap+ can contribute to osteoporosis, encephalopathy, and proximal myopathy. There is some concern that excess of aluminium may contribute to the development of Alzheimer s disease and other neurodegen-erative disorders. 

An 87-year-old man developed progressive proximal limb weakness 1 year after starting leuprolide therapy for prostate cancer (60). Electromyography showed a moderately severe non-inflammatory myopathy without evidence of fiber necrosis or associated biochemical changes. Within 6 months after stopping leuprolide he was able to resume his usual activities. 

Since the original 1988 report of hypothyroidism in patients with breast cancer receiving leukocyte-derived interferon alfa (498), numerous investigators have provided clear clinical and biological data on thyroid disorders induced by different forms of interferon in patients with various diseases (499,500-503). Two of these reports also mentioned associated adverse effects that developed concomitantly, namely myelosuppression and severe proximal myopathy (Hoffmann s syndrome). 

The major population at risk for aluminum loading and toxicity consists of individuals with renal failure. In a study by Alfrey (1980), 82% of nondialyzed uremic patients and 100% of dialyzed uremic patients had an increased body burden of aluminum. The decreased renal function and loss of the ability to excrete aluminum, ingestion of aluminum compounds to lessen gastrointestinal absorption of phosphate, the aluminum present in the water used for dialysate, and the possible increase in gastrointestinal absorption of aluminum in uremic patients can result in elevated aluminum body burdens. The increased body burdens in uremic patients has been associated with dialysis encephalopathy (also referred to as dialysis dementia), skeletal toxicity (osteomalacia, bone pain, pathological fractures, and proximal myopathy), and hematopoietic toxicity (microcytic, hypochromic anemia). Pre-term infants may also be particularly sensitive to the toxicity of aluminum due to reduced renal capacity (Tsou et al. 1991)... 

In the past several clinical patterns have been described. The most important recognized clinical patterns or types of Al toxicity include two types of encephalopathy. Firstly, the classical dialysis dementia sometimes referred to as dialysis encephalopathy syndrome (DES) or dementia dialytica [24, 28, 37, 42, 70-74] and secondly, the acute or subacute Al encephalopathy [41]. There are also two types of bone disease - either osteomalacia with bone fractures and proximal myopathy or aplastic bone disease [41, 75, 76]. There is quite some confusion in the definitions of Al toxicity in the literature. Because there seems to be an obligatory lag phase of at least several days to weeks for symptoms to occur, acute Al encephalopathy, defined as a direct result of a single overdose, probably does not exist. Because of the long lag phase of several months to years necessary to develop the chronic dialysis encephalopathy and also because acute Al encephalopathy has an abrupt, sudden onset of symptoms one can understand why the term acute is used instead of the more descriptive subacute . The descriptions dialysis dementia [37, 42, 46, 73, 74] and dialysis encephalopathy [33-36, 38, 40, 41, 78] are also unfortunate because true dementia is rare in Al encephalopathy [73] and non-dialyzed patients can also develop these symptoms [78]. There are also many dialysis-related encephalopathy syndromes unrelated to Al. As an example,... 

The most common presenting symptoms are acute abdominal pain, tachycardia and dark urine. Neurological and psychological symptoms may also be present. Muscular weakness including a proximal myopathy of the arms is also common and can progress to quadraparesis, respiratory paralysis and arrest. 

Musculoskeletal. Proximal myopathy and tendon rupture may occur. Osteoporosis develops insidiously leading to fractures of vertebrae, ribs, femora and feet. Pain and restriction of movement may occur months in advance of radiographic changes. A biphosphonate, with or without vitamin D, is useful for prevention and treatment. Growth in children is impaired. A vascular necrosis of bone (femoral heads) is a serious complication (at higher doses) it appears to be due to restriction of blood flow through bone capillaries. 

A proximal myopathy has occasionally been reported in patients taking amiodarone (69) and there has been a report of an acute necrotizing myopathy (206). 

A 64-year-old woman with systemic lupus erythematosus took chloroquine for 7 years (cumulative dose 1000 g). She developed sjmcope, and the electrocardiogram showed complete heart block a permanent pacemaker was inserted. The next year she presented with biventricular cardiac failure, skin hyperpigmentation, proximal muscle weakness, and chloroquine retinopathy. Coronary angiography was normal. An echocardiogram showed a restrictive cardiomyopathy. A skeletal muscle biopsy was characteristic of chloroquine myopathy. Chloroquine was withdrawn and she improved rapidly with diuretic therapy. 

The combination of colchicine with ciclosporin increased the risk of myopathy. In a retrospective study of 221 renal transplant patients, five of 10 patients who took both drugs developed acute or chronic proximal myopathy, whereas none of the 30 controls matched for age, sex, transplant duration, ciclosporin use, and cumulative dose of glucocorticoids had similar symptoms (238). 

Among reports of myopathy in patients taking glucocorticoids, involvement of the respiratory muscles is often mentioned (235,236), possibly because this is particularly likely to have clinical consequences. Patients on mechanically assisted ventilation may be particularly at risk of myopathy (SEDA-18, 390). However, any muscle can be affected one often sees weakness and atrophy of the hip muscles and (in about half the cases) the shoulder muscles and the proximal muscles of the limbs. 

Two children developed a proximal myopathy and rhabdo-myolysis, which resolved on withdrawal of labetalol (11). 

Initially, most of the adverse effects seen with zidovudine use (in particular hematological effects) were attributed to interference with cellular DNA replication. However, DNA replication also occurs in mitochondria. Mitochondrial DNA encodes some of the enzymes used for oxidative phosphorylation. Only recently has it been hjrpothesized that inhibition of this pathway could lead to mitochondrial toxicity and be responsible for most of the toxicity seen with NRTIs, including polyneuropathy, myopathy, cardiomyopathy, steatosis, lactic acidosis, exocrine pancreas failure, bone marrow failure, and proximal tubular dysfunction (11). These adverse effects are also a compilation of the clinical features seen in several genetic mitochondrial cytopathies. 

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