Infectious agents associated with myopathies

Several infectious agents can cause chronic or acute myopathy. Most current investigations into possible infectious causes of the idiopathic inflammatory myopathies have focused on retroviruses, including HIV and human T-cell leukemia-lymphoma virus type I. In both cases, viruses likely do not directly infect muscle fibers but instead induce an immunologically mediated myositis. Other interest has focused on enteroviruses as potential etiologic agents of idiopathic inflammatory myopathy, but their relationship to human myositis is less clear. In addition to chronic muscle disease, several infectious agents can cause acute myositis, including pyomyositis, which is being recognized in temperate climates with increasing frequency, and rhabdomyolysis.     

Evaluation and treatment of speech and swallowing disorders associated with myopathies

Dysphagia, or disordered swallowing, can be demonstrated at any time over the course of many myopathies. Ability to swallow may be impaired because of weakness, inflammation, or dysfunction of the oropharyngeal, laryngeal, and esophageal musculature. Dysphagia may occur during the progression of disease regardless of whether the patient is properly treated. The presentation of signs of dysphagia can vary among patients because of differing patterns of weakness or incoordination of the facial muscles, lips, tongue, palate, pharyngeal constrictors, or smooth and striated muscles of the esophagus. Although the literature has focused on problems in the esophagus, scant attention has been paid to the oropharynx, which is often equally affected. Studies suggest that surgical myotomy and botulinum toxin injection may provide benefits for some patients with esophageal dysfunction. Although the condition is pervasive, there is little information on the incidence of dysphagia in muscular disorders. Because a major complication of dysphagia is aspiration, any sign of swallowing impairment demands medical attention and treatment.     

Drugs recently associated with lupus syndromes

To assess the long-term outcome in patients with acute cholecystitis treated initially by percutaneous cholecystostomy, the authors reviewed the medical and radiology records of all such patients treated at their hospital from January 1990 to September 1993. Of the 50 patients, 29 had calculous and 21 had acalculous cholecystitis. In the group with calculous cholecystitis, 1 of the patients required no further treatment, 3 subsequently underwent percutaneous stone removal, 14 underwent elective cholecystectomy, 6 underwent emergency cholecystectomy and 5 died of the underlying condition shortly after cholecystostomy. In the group with acalculous cholecystitis, 12 of the patients needed no further treatment after a mean follow-up period of 12 months; 8 of these underwent follow-up ultrasound examination, which revealed gallbladder calculi in only 1 patient. Four patients underwent elective cholecystectomy, 1 underwent emergency cholecystectomy, and 4 died of the underlying condition shortly after cholecystostomy. Over the long term, 23 (79%) of the 29 patients with calculous cholecystitis underwent surgery or removal of calculi. In the other group surgery was required in only 5 (24%) of the 21 patients. The authors conclude that percutaneous cholecystostomy is a useful temporizing measure, which allows patients with calculous cholecystitis to undergo elective cholecystectomy. In most cases of acalculous cholecystitis the procedure is curative, obviating the need for cholecystectomy.     

Expression of Fas antigen is not associated with apoptosis in human myopathies

In mammals, macrophages are multifunctional cells. Apart from their scavenger role in the clearance of non-self materials such as microorganisms and altered-self materials such as apoptotic cells, senescent erythrocytes, immune complexes, and inflammatory products, they play a crucial role in the regulation of both innate and acquired immunity. Whereas the former activity is based on phagocytosis and intracellular degradation, the latter activity largely depends on the production and secretion of a panel of regulatory molecules such as cytokines, chemokines, and nitrogen oxide (NO). Depletion of macrophages and blocking of phagocytosis form important approaches to study the role of these cells in various host defense mechanisms. Moreover, the efficacy of drug- and gene-targeting, based on the application of particulate carrier devices, can be improved in this way. However, compounds originally described as efficacious blockers of phagocytosis simultaneously activate their production of cytokines and NO. Moreover, elimination, blocking, as well as activation of macrophages are all dependent on the concentration of such compounds. When administered in vivo, they will reach some macrophages in a high and others in a low concentration. As a consequence, the former cells may be eliminated or blocked, whereas the latter are activated by the same treatment. In this review, the various methods for suppression of macrophage functions are compared and requirements for the development of new, selective, and organ-specific macrophage-suppressing devices are discussed.     

The electrodiagnostic examination with myopathies

The values and limitations of the electrodiagnostic examination in assessing patients with possible myopathies are discussed. Limitations include: (1) no findings are specific for muscle disease; (2) the particular changes may be quite diverse; (3) myopathies of different etiologies may have the same presentation, whereas the same myopathy may have different presentations at different times; (4) a specific myopathy cannot be diagnosed; and (5) the ability to diagnose myopathy may be seriously compromised by the presence of certain disorders. Benefits include: (1) widespread muscle sampling; (2) help in determining most appropriate muscle for biopsy; (3) ascertaining, to some extent, the type of myopathy present, depending on the particular findings; (4) distinguishing entities often confused clinically with myopathies; (5) recognizing abnormalities (e.g., myotonic discharges) otherwise undetectable. Both the clinical and electrodiagnostic presentations of myopathies are discussed. Regarding the latter, the potential or actual changes seen with each component of the electrodiagnostic assessment (nerve conduction studies, late responses, repetitive stimulation studies, needle electrode examination, quantitative electromyographic studies) is reviewed.     

Apoptosis and myopathies

Recently a new type of cell death, apoptosis, was reported in the biological and many other fields. In an attempt to determine whether the Fas-Fas-ligand mediated apoptosis operates in the pathologic process of human myopathies, we examined the expression of Fas antigen, the synthesis of Fas-ligand mRNA, and the presence of chromosomal DNA fragmentation in the muscles from patients with various human muscle disorders. The Fas antigen of a whole molecule that can transduces the apoptotic signal into the cytoplasm was expressed on the muscle fibers of patients with various muscle wasting diseases. Its expression on muscle fibers was not disease specific, and the frequency of it becomes high according to the extent of the alteration of the muscle pathology. However, there was no evidence of operating the apoptotic process, that is no DNA fragmentation by TUNEL method. Furthermore, no Fas-ligand synthesis was detected in the diseased muscle tissue by RT-PCR method. Our data suggest that the expression of Fas antigen on muscle fibers in diseased muscles might be related to unknown biological functions other than "apoptosis" in the process of muscle fiber injury.     

Oral toxicity in mice of algal toxins from the diarrheic shellfish toxin (DST) complex and associated toxins

Mussel samples from four locations along the Norweigian coast were extracted by methods for diarrheic shellfish toxins (DST) and tested by chemical and biological methods, including histopathology. All samples had previously been found to be highly toxic in mice, with symptoms indicating the presence of non-diarrheagenic toxins in the mouse bioassay. Chemical analysis revealed that the DST okadaic acid (OA) and dinophysistoxin-1 (DTX1) were present each one in one sample, but only a minor part of the total toxicity could be attributed to these toxions. In the other two samples, OA and DTX1 were absent. Incubation of the mussel extracts from all four samples with freshly prepared hepatocytes indicated the presence of unknown toxin(s) which may not be classified within the DST complex. Purified mussel samples were given to baby mice both via intraperitoneal (i.p.) injections and by oral intubation. Oral toxicity was about 25-50 times lower than toxicity obtained by i.p. injections, a result in accordance with acute toxic properties of many toxins. Risk assessment of the unknown toxin(s) requires chemical identification, but the preliminary results obtained indicate a large margin of safety, based on the large amounts of mussel extracts necessary to yield toxic effects in the intestine and liver in experimental animals upon oral exposure versus human intake.     

Fascicular block and skeletal myopathies

Ecg investigation of skeletal myopathies showed in the approximate half of cases mono- and bifascicular blocks (left anterior, left posterior, RBBB). In view of the possibility of development of complete AV-block, whose prognosis will not be the best, cardiological observation is recommended for life.     

Emerging treatments in myopathies

Outstanding improvement has been made in the molecular understanding of several muscle diseases with the application of molecular biological techniques to the investigation of human disorders. The identification of genetic mutations has improved considerably the diagnostic approach to muscular dystrophies, mitochondrial myopathies and ion channel disorders. Important results have been achieved in the field of inflammatory myopathies. With a few exceptions, therapies available are nonspecific and rarely represent a cure for the disease. Molecular medicine offers an opportunity to design new therapeutic strategies based on the pathogenic mechanisms underlying each disease.     

Antimyosin scintigraphy compared with magnetic resonance imaging in inflammatory myopathies

OBJECTIVE: To compare indium In 111 altumomab pentetate-labeled antimyosin scintigraphy with magnetic resonance imaging (MRI) in the diagnosis and follow-up of patients with myositis. DESIGN AND METHODS: Sixteen patients with polymyositis and 1 patient with dermatomyositis, all verified with biopsy samples, were examined during diagnostic evaluation with antimyosin antibody scintigraphy and low-field MRI of the thighs and calves using T1- and T2-weighted sequences. Both examinations were repeated 6 to 22 months after therapeutic intervention with antiinflammatory drugs. The performance of the 2 methods for the assessment of the severity of muscle inflammation was evaluated using comparison with clinical examination and the serum creatine kinase level. RESULTS: At diagnosis all patients had increased uptake of antimyosin antibody in the thighs and/or calves. In T2-weighted MRI images, increased signal intensity changes reflecting intramuscular edema and inflammation were seen in all patients in at least 1 muscle group in the thighs or calves. After anti-inflammatory drug therapy, the mean uptake of antibody and the mean signal intensity changes in T2-weighted MRI had decreased. However, in T1-weighted MRI the signal intensity changes reflecting intramuscular fatty degeneration were more pronounced in the follow-up study. The level of serum creatine kinase had decreased markedly by the second examination except in 1 patient who also had more accumulation of antibody in the calves after than before treatment. The clinical condition improved in 8 patients and remained unchanged in 9 patients. CONCLUSIONS: Antimyosin scintigraphy and T2-weighted MRI are feasible tools for the detection and follow-up of lesions in patients with myositis. Scintigraphy findings correlate with serum creatine kinase activity and seem to reflect disease activity better than T2-weighted MRI changes, whereas secondary degenerative intramuscular lesions are only detectable using T1-weighted MRI.     

Mitochondrial myopathies: genetic mechanisms

Maintenance electroconvulsive therapy (M-ECT) has been used to control schizophrenic patients for more than 50 years. In spite of this, there has been no prospective study made of this treatment. Most of the available information comprises naturalistic studies or case reports. As a result many unanswered questions concerning M-ECT remain, including its therapeutic efficacy. This pilot study was done prospectively on 11 schizophrenic patients suffering acute exacerbations, in order to determine the merits of M-ECT. After acute treatment, using only ECT, in 16 patients, 11 were able to pass the 3-week-stabilization-period. They were identified as ECT responders and enrolled into the M-ECT study. M-ECT was started one week after the last treatment in the stabilization period using a tapering regimen, fixed interval schedule, beginning with weekly intervals for 1 month (4 treatments), then biweekly intervals for 2 months (4 treatments) and with monthly intervals thereafter. No neuroleptic drugs were used. Benzodiazepines were the only medications prescribed to control agitation on a prn basis. The duration of the study was one year. Bilateral ECT was used throughout the study. Global Assessment of Functioning (GAF), Brief Psychiatric Rating Scale (BPRS) and the Thai Mental State Exam (TMSE) were used to measure the outcome. A total of 8 patients completed the study or stayed until relapse and 3 dropped out. At the 6-month-evaluation there were no relapses. After this, however, 5 patients suffered relapses. Only 3 could complete the one year study. There were no serious side effects. This study indicates that M-ECT may have a role in the maintenance of some schizophrenic patients. Further studies are needed to determine the optimum frequency and the role of concurrent neuroleptic use.     

Scorpion toxins and defensins

Advances in CT, MR imaging, and catheter angiography provide the radiologist and neurosurgeon with a variety of imaging options for screening, diagnosis, presurgical evaluation, and postoperative monitoring of patients with intracranial aneurysms. Noninvasive imaging techniques have not replaced conventional angiography for the comprehensive evaluation o aneurysms but are effective in screening patients suspected to have an unruptured aneurysm or for preoperative planning in emergency situations that preclude catheter angiography. CT, CT angiography, MR imaging, and MR angiography can all complement the information obtained with catheter angiography in presurgical planning, and the choice of supplemental studies should be individualized. Rotational and intraoperative angiography are problem-solving options used for selected cases at our institution. Continuous improvements in techniques for CT and MR angiography may someday reach the point where surgery can be undertaken on the basis on noninvasive imaging alone, with catheter angiography reserved for endovascular therapy planning and guidance.     

Microbial toxins

Microbial toxins represent major virulence determinants of pathogenic bacteria. Endotoxins are lipopolysaccharides of the gram-negative bacterial cell wall. They exert their action via deregulating host cell function and stimulating cytokine overproduction. Exotoxins are proteins that can conveniently be grouped into three major categories. The first are intracellularly active molecules, all of which have to date been identified as enzymes. The second are membrane-damaging molecules, most of which create transmembrane pores. The third are the superantigens that cross-link T cells with antigen-presenting cells, thus causing cytokine overproduction. Most pathogens elaborate several toxins that can synergize in their detrimental action. Research on microbial toxins has fundamentally advanced our understanding of the pathogenesis of bacterial infections in the past two decades.     

Genetics of the idiopathic inflammatory myopathies

Genetic predisposition to development of the idiopathic inflammatory myopathies is probably multifactorial. Major histocompatibility complex associations with these diseases provide the strongest evidence for a genetic component. In Caucasoids, haplotypes marked by B8/DR3 are associated with each of the clinical subgroups, except mixed connective tissue disease (DR4). The strongest associations are with inclusion body myositis, polymyositis in the presence of anti-Jo-1, and with antibodies to PM-Scl in overlap syndromes. The underlying mechanisms of these associations are probably different. Unique major histocompatibility complex associations are seen with other myositis-associated autoantibodies. The association can vary between racial groups as can the type of autoantibody produced within a disease subgroup, perhaps reflecting different T cell receptor repertoires or different inducing agents. The mapping of a gene for one form of hereditary inclusion body myositis to chromosome 9p1-q1 provides a lead for the investigation of sporadic inclusion body myositis, as does the expanding knowledge of genetic factors in Alzheimer's disease. The demonstration of deletions of mitochondrial DNA in the muscle of patients with inclusion body myositis raises the question of their role in the pathogenesis of the disease.     

Cell death and oxidative damage in inflammatory myopathies

AIMS: To evaluate the independent prognostic value of apoptotic versus proliferative fractions in a series of 92 patients with non-Hodgkin's lymphomas (NHL). METHODS AND RESULTS: Apoptotic fractions were quantified by use of the TdT (terminal deoxynucleotidyl-transferase)-mediated in-situ end-labelling technique (TUNEL), the percentage of positive cells constituting the apoptotic index (AI). Proliferative rate was expressed as percentage of Ki67 positive cells (Ki67 LI). Tissues were also stained for p53 protein with the DO-1 antibody. Patients were followed up until death (n = 33) or for an average of 63 months (n = 56). AI increased with malignancy grade and proliferative activity but was not related to location, cell of origin, clinical stage, bone marrow involvement and p53 expression. In multivariate analysis, overall survival was independently influenced by grade, stage, p53 LI and chemotherapy. The independent predictors of disease-free survival were Ki67 LI location and chemotherapy. AI turned out to be the only independent (negative) predictor of post-relapse survival. On the other hand, a low Ki67 LI increased the risk of relapse (logistic regression analysis) whereas a low p53 LI increased the probability of complete response. CONCLUSIONS: Our results suggest that the combined assessment of apoptotic fraction, proliferative rate and p53 expression may provide important prognostic information independent of other clinicopathological parameters in NHL.     

Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy

We used a standardized bicycle ergometry protocol with a stepwise increasing workload (30-100 W) to evaluate various metabolic factors for the diagnosis and metabolic monitoring of mitochondrial encephalomyopathies. All patients (n = 9) showed pathological venous lactate/pyruvate (L/P) ratios, which normalized in three patients after 6 months of coenzyme Q10 (CoQ) therapy. Thus, the L/P ratio proved to be the clinically most useful parameter in the evaluation and monitoring of mitochondrial diseases, showing higher sensitivity than lactate measurements only. CoQ may exert a favourable effect in some patients with mitochondrial diseases.     

Classification and treatment of the juvenile idiopathic inflammatory myopathies

This article reviews the current status of the classification and treatment of the juvenile idiopathic inflammatory myopathies. The intent of classification is to define homogeneous groups that share similar clinical features, disease courses, and responses to therapy. The classification scheme proposed includes clinicopathologic subsets, serologic subjects based on the presence of myositis-specific and myositis-associated autoantibodies, and environmental triggers of myositis. Juvenile dermatomyositis is the most common and widely recognized of these disorders. The second part reviews the history of treatment of juvenile dermatomyositis and discusses agents to consider for patients with refractory disease, unacceptable steroid toxicity, or poor prognostic factors.     

Fibrillations in regenerating muscle in dystrophic myopathies

In the presented study we attempted to demonstrate a correlation between muscle regeneration and fibrillations in electromyography in dystrophic myopathies. Especially in Emery-Dreifuss muscular dystrophy there is much abnormal spontaneous activity, and NCAM (neural cell adhesion molecule)and cytoskeletal protein vimentin expressing myocytes are predominantly seen. Therefore, definitely regenerating fibers are identified apart from only a few remnants of previous necrosis. Moreover, in the other biopsies of dystrophic myopathies there are also scattered and clustered NCAM and vimentin expressing regenerating myofibers. Here, regressive fiber changes, like necrosis, are more prominent. Furthermore, most regenerating fibers show pseudo-cholinesterase activity indicating innervation. Interestingly, motor end-plate changes in regeneration and in disuse atrophy are very similar. They predominantly consist of terminal sprouting and pseudo-cholinesterase spread. However, in disuse atrophy there is no abnormal spontaneous spread in electromyography. Therefore, in regenerating muscle not innervation, but regeneration itself is likely to be the cause of fibrillations. In conclusion, a correlation is evident between regenerating muscle and fibrillations in electromyography.     

The role of immunocytochemistry in congenital myopathies

The use of stents does not appreciably improve restenosis (usually resulting from intimal hyperplasia) as compared to percutaneous transluminal angioplasty (PTA) alone. The development of small-caliber probes for afterloading therapy in the biliary tract allowed us to use these for therapy in the vascular system. Using a special 9 F catheter, exact measurement of the length of the stented vascular segment and of the insertion length of the afterloading probe could be reproducibly performed. We used a Nucletron (Micro) Selectron HDR planning system version 10.10 for exact calculation, monitoring, and control of the afterloading procedure. Our source was iridium 192 (10 Ci) with a diameter of 1.1 mm. The program controls and monitors the insertion and removal of the iridium probe from the source into the special catheter through to the tip, and monitors the irradiation duration. The exposure time was around 200 seconds for a surface dose of 12 Gy. To date, a total of 40 patients have been treated with endovascular afterloading. All patients suffered from clinically relevant reocclusions or restenoses in stented vascular segments of the superficial femoral artery following successful PTA or laser treatment, within 6 to 8 months after the last therapy. In all patients it was possible to perform re-PTA treatment without remaining residual stenoses in the stented region. The additional time required as compared to PTA alone was approximately 45 minutes with most of this time spending for transportation between the cath lab and afterloading room. The follow-up period of the 40 patients ranged from 4 months to 71/2 years. In 33 patients, there was no deterioration of the clinical stage and no restenosis. One patient suffered from an acute thrombosis approximately 3 months after stent implantation, another patient had a stenosis 3 cm above the stented vascular segment 12 months after irradiation treatment. Follow-up examinations have revealed no evidence of nerve lesions following irradiation therapy. The tissue surrounding the artery showed no change following irradiation therapy, either in the CT, color-coded Doppler, endovascular ultrasonic scan or MRI. No complaints of discomfort were reported during or after irradiation. With the exceptions mentioned above, there was no evidence of any complications.