Severe Muscle Symptoms Research Articles

Nelarabine-induced rhabdomyolysis in a patient with T-cell acute lymphoblastic leukemia: a case report

BackgroundNelarabine is an antineoplastic purine analog used for the treatment of refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL). The most prominent side effect of nelarabine are neurotoxicity and hematologic disorder, which are considered dose-limiting factors. Although clinical studies have reported myopathy due to nelarabine, actual detailed outcomes were not well-known initial approval. The incidence of nelarabine induced rhabdomyolysis has been reported at 2% in study in children. Cases of rhabdomyolysis have been reported in adults from medical facilities in the United Sates with renal dysfunction or severe muscle symptoms after administration of multiple courses of nelarabine. In this report, we discuss a case of rhabdomyolysis diagnosed after a single course of nelarabine. In this case, creatine kinase (CK) level was elevated in grade 4, without renal dysfunction and severe muscle symptoms.Case presentationA 46-year-old man from Japan was diagnosed with T-ALL and received a hematopoietic stem cell transplantation in first remission. However, the disease relapsed 6 months after transplantation. Nelarabine was selected as the next-line chemotherapeutic agent. The patient received 1500 mg/m2 of nelarabine on day 1 followed by a dose on days 3 and 5. CK levels, which were baseline before treatment, increased to grade 4 (18,620 IU/L) on the 8th day of treatment. He was diagnosed as rhabdomyolysis due to nelarabine with little possibility of other factors. He complained only of mild pain in his upper extremities and no other symptoms were noticed. The patient was managed with hydration. The pain lasted approximately 7 days, but there were no sequelae secondary to the rhabdomyolysis. Because of the elevation of CK in grade 4, we avoided re-administration.ConclusionIn the patient administrated nelarabine, CK level was elevated in grade 4, without other symptoms of rhabdomyolysis. The results suggest that CK may be elevated at the onset of rhabdomyolysis caused by nelarabine, even in the absence of other symptoms. Therefore, it was suggested that monitoring CK during nelarabine administration is important for detecting rhabdomyolysis before it becomes severe. We consider that CK should be monitored even in absence of symptoms.

The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs.

Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. A series of 200 double-blinded N-of-1 trials. Participants were recruited from 50 general practices in England and Wales. Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms. Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo. The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful. A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods. Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial. We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications. This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations. Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials

ObjectiveTo establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins.DesignSeries of randomised, placebo controlled n-of-1 trials.SettingPrimary care across 50 sites...

Activation of the interferon type I response rather than autophagy contributes to myogenesis inhibition in congenital DM1 myoblasts

Congenital myotonic dystrophy type 1 (CDM1) is characterized by severe symptoms that affect patients from birth, with 40% mortality in the neonatal period and impaired skeletal muscle development. In this paper, we examined the relationship between autophagy and abnormal myogenic differentiation of CDM1 myoblasts. We investigated these pathological features at both ultrastructural and molecular levels, utilizing two CDM1 foetal myoblasts, CDM13 and CDM15, with 1800 and 3200 repeats, respectively. The congenital nature of these CDM1 myoblasts was confirmed by the high methylation level at the DMPK locus. Our results indicated that abnormal autophagy was independent of myogenic differentiation, as CDM13 myoblasts differentiated as well as control myoblasts but underwent autophagy like CDM15, displaying impaired differentiation. miRNA expression profiles revealed that CDM15 myoblasts failed to upregulate the complex network of myo-miRNAs under MYOD and MEF2A control, while this network was upregulated in CDM13 myoblasts. Interestingly, the abnormal differentiation of CDM15 myoblasts was associated with cellular stress accompanied by the induction of the interferon type 1 pathway (innate immune response). Indeed, inhibition of the interferon (IFN) type I pathway restores myogenic differentiation of CDM15 myoblasts, suggesting that the inappropriate activation of the innate immune response might contribute to impaired myogenic differentiation and severe muscle symptoms observed in some CDM1 patients. These findings open up the possibility of new therapeutic approaches to treat CDM1.

Statin-Associated Muscle Symptoms: SAM

Abstract Statins are efficient lipid lowering drugs for treatment of dyslipidemia, one of the main risk factors for atherosclerosis, and have the benefits of preventing cardiovascular diseases. Although they are considered to be safe, frequently prescribed and well tolerated, statin associated muscle symptoms are the most common undesirable effects caused of statin discontinuation. From the observational studies, this undesirable effect rate from using statin to muscle was at 10% to 15% of total treated patients, ranging from mild myalgia, myopathy to more severe muscle symptoms with significant creatine kinase (CK) elevations. The most severe pattern of Statin-Associated Muscle symptom (SAM) is “rhabdomyolysis” which may result in acute renal failure, disseminated intravascular coagulation and death. This article aims to review the epidemiology, the mechanism of action, and the differentiate of statin-associated muscle symptoms. The exact pathophysiology of SAM is not fully described. The healthcare professional team must have the role to evaluate and diagnose the symptom whether it relates to statin drug or not. Surrounded factors should have been considered both patient factors (age, genetics, co-morbidities) and factors of drug (statin characteristics, metabolism). Management options for SAM include statin switching (to low dose or more hydrophilic), hold or discontinuation and/or need for additional therapy. Furthermore, the benefits and risks for taking statin drugs should be considered together with the appropriate treatment plan for each patient. Keywords : statin, statin-associated muscle symptom, creatine kinase, myalgia, myopathy, management of SAM

Skeletal muscle morphology, protein synthesis, and gene expression in Ehlers-Danlos syndrome.

Patients with Ehlers-Danlos syndrome (EDS) are known to have genetically impaired connective tissue and skeletal muscle symptoms in form of pain, fatigue, and cramps; however earlier studies have not been able to link these symptoms to morphological muscle changes. We obtained skeletal muscle biopsies in patients with classic EDS [cEDS; n = 5 (Denmark)+ 8 (The Netherlands)] and vascular EDS (vEDS; n = 3) and analyzed muscle fiber morphology and content (Western blotting and muscle fiber type/area distributions) and muscle mRNA expression and protein synthesis rate (RT-PCR and stable isotope technique). The cEDS patients did not differ from healthy controls (n = 7-11) with regard to muscle fiber type/area, myosin/α-actin ratio, muscle protein synthesis rate, or mRNA expression. In contrast, the vEDS patients demonstrated higher expression of matrix proteins compared with cEDS patients (fibronectin and MMP-2). The cEDS patients had surprisingly normal muscle morphology and protein synthesis, whereas vEDS patients demonstrated higher mRNA expression for extracellular matrix remodeling in skeletal musculature compared with cEDS patients.NEW & NOTEWORTHY This study is the first of its kind to systematically investigate muscle biopsies from Ehlers-Danlos patients, focusing on muscle structure and function. These patients suffer from severe muscle symptoms, but in our study they show surprisingly normal muscle findings, which points toward indirect muscle symptoms originating from the surrounding connective tissue. These findings have basal physiological importance and implications for future physiotherapeutic treatment options for these patients.

Severe muscle symptoms with lipid-lowering agents may be confused with neurogenic claudication associated with spinal canal stenosis

Screening of the WHO global individual case safety report database (VigiBase) has recently identified case reports with HMG CoA reductase inhibitors and muscle symptoms co-reported with spinal stenosis. In some reports spinal stenosis appears to have been listed as a coincidental finding. To assess reports with sufficient information to ascertain if they suggested that there may have been diagnostic confusion between muscle symptoms attributable to HMG CoA reductase inhibitors with or without ezetimibe and symptoms of spinal stenosis. Reports were examined for patient demographics, past history, clinical and investigational findings, co-prescribed medicines and outcomes. Three case histories recorded details suggestive of diagnostic confusion between severe and disabling muscle symptoms affecting the lower limbs attributable to an HMG CoA reductase inhibitor with and without ezetimbe and symptoms of neurogenic claudication due to spinal stenosis. The statins were not discontinued promptly leading to prolonged morbidity. Serum creatine kinase levels (CK) were normal in two patients and not recorded for the third. The reports include two safety issues, firstly the need to consider HMG CoA reductase inhibitors as a cause of severe lower limb muscle symptoms even in the presence of spinal stenosis and normal CK levels and the second, the need to measure serum creatine kinase when these symptoms occur to detect progression of myopathy and potentially serious outcomes.

Statin-induced myopathy: a review and update

Introduction: Statin-induced myopathy is an important cause of statin intolerance and the most common cause of statin discontinuation. Observational studies estimate that 10 – 15% of statin users develop statin-related muscle side effects ranging from mild myalgia to more severe muscle symptoms with significant CPK elevations.Areas covered: This article reviews the epidemiology, clinical features, risk factors and mechanisms of statin-induced myopathy and provides an evidence-based algorithm for managing patients with statin myopathy.Expert opinion: There are multiple risk factors for statin-induced myopathy that are both patient-related (age, genetics, co-morbidities) and drug-related (statin metabolism via the CYP system, drug–drug interactions and statin drug transport). Management options for statin-intolerant patients include statin switching, especially to low-dose, non-daily doses of long-acting statins, such as rosuvastatin and atorvastatin, and other non-statin lipid-lowering agents, such as ezetimibe and colesevelam, and possibly red yeast rice. In conclusion, statin-induced myopathy is a significant clinical problem that contributes considerably to statin therapy discontinuation. However, there exist multiple and effective management options for statin intolerant patients.

Dementing Disease in a Married Couple

To the Editor:—Dr. James Kvale1 has described a highly suspicious relationship between an episode with some of the characteristics of untreated organophosphate poisoning and onset, 12 months later, of Alzheimer's disease (or a very similar dementia) simultaneously in a married couple. Autopsy findings were consistent with a diagnosis of Alzheimer's disease. Donald Hunter, in his classic textbook, Diseases of Occupations,2 has meticulously described the case of a 28-year-old research chemist, one of three workers who became acutely ill in 1951 following exposure to mipafox (at that time an experimental organophosphate). The worker presented with vomiting and involuntary defecation, cramps in the legs, and generalized muscle weakness. She also had pinpoint pupils, muscle twitching, general muscle hypotonia, and diminished tendon reflexes. Both red cell and serum cholinesterase activity were severely diminished. The gastro-intestinal symptoms were controlled with frequent administration of atropine, of which she received a total of 54 mgm. After the onset of delirium and hallucinations, the atropine was discontinued, with total correction of her mental state. No cholinesterase reactivator was given by her primary care physician. Pralidoxime, newly discovered at that time by IB Wilson,3 is now routinely given, usually together with atropine. This treats the neuromuscular debility which, as in this patient, increases after 3 weeks. The patient's subsequent history under the care of Dr. Hunter was of slow progressive improvement of severe muscle symptoms over a period of 10 years. Her plasma cholinesterase took 3 months to return to normal. This patient is thus an example of treatment of the muscarinic features but not the nicotinic effects of the toxic agent. In spite of this, she had absolutely no loss of mental function except for delirium and hallucinations believed to be a result of heavy atropine dosage and resolving with its discontinuation. Indeed she went on to a PhD degree, and had two promotions, the second to Senior Lecturer in Biochemistry. However, as Dr. Kvale points out, there is now a suspicion that anticholinesterase poisoning may be an etiological factor in some patients with Parkinson's disease or Alzheimer's disease. The age-adjusted annual death rate for Alzheimer's disease in the United States rose from 0.4 per 100,000 in 1979 to 4.2 per 100,000 in 1987.4 The contamination of ground-water is an increasing problem which should concern us all. Pesticides are significant contaminants. It now seems that even where pollution is identified, efforts at correction are inadequate.5 Therefore, a high index of suspicion is necessary whenever the clinical circumstances are consistent with acute organophosphate poisoning and (of historical and etiological value) whenever a patient with apparent Alzheimer's disease is encountered who may have had subacute poisoning in the past.

Infectivity of influenza B virus in cultured human muscle.

Severe muscle symptoms, particularly in children, are frequently associated with influenza B virus infection. In this study we examined the effects of influenza B virus (Lee Strain) on cultured human muscle by light and electron microscopy (EM), immunofluorescence, hemadsorption and plaque assays. Muscle injury was also evaluated by the appearance of muscle-specific creatine kinase (CK) in the culture medium. By fluorescence immunocytochemistry viral antigen was demonstrated in muscle cell nuclei within 3 h postinoculation (p.i.) and in the cytoplasm at 6 h p.i. Membrane-associated viral antigen was seen at 16 h p.i., at which time budding influenza virus-like particles could be demonstrated by EM, both in myoblasts and multinucleated myotubes. At 16 h all cells were hemadsorption positive. Plaque assays showed peak virus production at 48 h (p.i.), at which time cytopathic effects (cell retraction, pycnosis and cytoplasmic vacuolization) were prominent and some cells detached from the substratum. Leakage of muscle-specific CK isozyme into the culture medium could be demonstrated as early as 6 h p.i. with peak enzyme activity around 40-48 h p.i. Cytopathic changes and virus production were observed both in myoblasts and myotubes indicating that both cell types are susceptible.

Leg blood flow and muscle metabolism in occlusive arterial disease of the leg before and after reconstructive surgery.

1. Leg blood flow, uptake of oxygen and glucose and release of lactate by the leg and changes in intramuscular concentrations of metabolites were studied at rest and during exercise of increasing work loads in thirteen patients with occlusive disease of the iliac or superficial femoral arteries. 2. Leg blood flow (dye-dilution technique) and oxygen uptake during exercise were low and levelled with increasing work load. Considerable increases were noted in muscle lactate concentration and in the net release of lactate from the exercising leg. Muscle content (needle-biopsy technique) of ATP and creatine phosphate decreased during exercise, with an almost complete depletion of creatine phosphate in three patients. The decrease in muscle glycogen during work did not differ significantly from that of control subjects. 3. Repeated exercise after reconstructive surgery showed a considerable improvement in physical working capacity. Leg blood flow and oxygen uptake during exercise were significantly higher than before surgery and increased linearly in relation to work intensity. The decrease in creatine phosphate and lactate concentration of the thigh muscle during exercise was less pronounced and the release of lactate was lower than before vascular reconstruction. 4. It is suggested that the onset of the severe muscle symptoms during exercise in patients with occlusive arterial disease of the leg may be related to a low concentration of ATP and creatine phosphate in the affected muscles.