Treatment Of Neuromuscular Disorders Research Articles

Liver and kidney damage induced by 4-aminopyridine in a repeated dose (28 days) oral toxicity study in rats: Gene expression profile of hybrid cell death

4-Aminopyridine (4-AP) is an orphan drug indicated for the treatment of neuromuscular disorders. There is a great controversy around the use of this drug because of its narrow safety index and because a large number of adverse effects have been reported. Moreover, it was shown to induce cell death in different cell lines, being reported mainly apoptosis and necrosis as the principal pathways of cell death mediated by blockage of K channels or the Na, K-ATPase, but until now it was not described in vivo cell death induced by 4-aminipyridine. To provide new subchronic toxicity data and specifically, evaluate if 4-AP is able to induce in vivo cell death process and the main pathways related to it, a repeated dose (28 days) oral toxicity study, at therapeutic range of doses, was conducted in rats. The anatomical pathology, the biochemical and hematological parameters were analyzed and a real-time PCR array analysis was developed with an Ingenuity Pathway Analysis (IPA). The leucocytes number, the lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzymatic activity were increased at all dose but the erythrocytes number, the hemoglobin concentration, the alkaline phosphatase (FAL) and alanine aminotransferase (ALT) enzymatic activity were increased only at highest dose studied. However, glucose levels decreased at all doses. The biochemical results are indicative of hepatic damage. The anatomy pathology studies showed cell death only on liver and kidney, and the real-time PCR array on liver tissue expressed a gene expression profile of necrotic and apoptotic induced cell death. The present work shows for the first time in vivo cell death on liver and kidney with features of apoptosis and necrosis induced by 4-AP and the gene expression profile shows that the cell death is mediated by necrotic and apoptotic pathways that support this finding.

Evidence-Based Guideline: IV Immunoglobulin in the Treatment of Neuromuscular Disorders: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Objective: To assess the evidence for the efficacy of IV immunoglobulin (IVIg) to treat neuromuscular disorders. Methods: The MEDLINE, Web of Science, and EMBASE databases were searched (1966–2009). Selected articles were rated according to the American Academy of Neurology9s therapeutic classification of evidence scheme; recommendations were based on the evidence level. Results and Recommendations: IVIg is as efficacious as plasmapheresis and should be offered for treating Guillain-Barre syndrome (GBS) in adults (Level A). IVIg is effective and should be offered in the long-term treatment of chronic inflammatory demyelinating polyneuropathy (Level A). IVIg is probably effective and should be considered for treating moderate to severe myasthenia gravis and multifocal motor neuropathy (Level B). IVIg is possibly effective and may be considered for treating nonresponsive dermatomyositis in adults and Lambert-Eaton myasthenic syndrome (Level C). Evidence is insufficient to support or refute use of IVIg in the treatment of immunoglobulin M paraprotein–associated neuropathy, inclusion body myositis, polymyositis, diabetic radiculoplexoneuropathy, or Miller Fisher syndrome, or in the routine treatment of postpolio syndrome or in children with GBS (Level U). IVIg combined with plasmapheresis should not be considered for treating GBS (Level B). More data are needed regarding IVIg efficacy as compared with other treatments/treatment combinations. Most studies concluded IVIg-related serious adverse effects were rare. Given the variable nature of these diseases, individualized treatments depending on patient need and physician judgment are important.

S.I.1 Standards of care in neuromuscular disorders

Abstract Care guidelines for neuromuscular disorders (NMDs) are of importance firstly because it is difficult for health professionals to acquire the necessary knowledge about all aspects of the diseases, and secondly because families should be offered the most informed treatment and counseling regardless of where they live. Thirdly, and often forgotten, trials of new treatments for NMDs will not yield interpretable results if levels of diagnosis and care are not standardized. For this reason, it should be a major task for major stakeholders in the neuromuscular community to contribute to the development of best practice guidelines for standards of diagnosis and care. Much has been accomplished in this field during the past five years, e.g. production of care guidelines for spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), congenital muscular dystrophies (CMD), and congenital myopathies. We can from the work performed learn about essential factors to consider in developing guidelines, and work ahead of us to make optimal use of them. Common successful features for the four above mentioned care guidelines are that they were all (1) produced on initiative from patient organizations, (2) combining existing evidence with consensus among a large number of experts in different care areas utilizing Delphi-like procedures, (3) made available as publications for healthcare professionals as well as in user friendly versions aimed at families (family version still to be accomplished for congenital myopathies), (4) disseminated freely on the web (e.g. www.treat-nmd.eu/care ). Despite the success in developing standards of care for at least some of the major neuromuscular disorders, much work is still needed to improve them, and to develop guidelines for other neuromuscular disorders. Lessons learned that will be discussed in the lecture include suggested revisions of method for developing the care guidelines (e.g. addition of families’ opinion on care issues, clear plan for updating of guidelines, recommendations of outcome measures, and systematic definition of level of evidence for given recommendations), as well as improving methods of making best use of the care guidelines. Apart from measures to improve dissemination and implementation of the care guidelines, improvements to be discussed include how to assess implementation, and finally how to assess if the care recommendations actually do have a positive impact on health. The latter, to make use of relevant outcome measures to measure the effect of the recommendations, is particularly important when we develop guidelines that largely depend on expert opinion in lack of higher level of evidence. Such guidelines should, it may be argued, be regarded as a non-randomized long term clinical study, with an obligation to document their possible benefits.

Neuromuscular disease and the pulmonologist

The heterogeneous nature of neuromuscular disorders (NMDs) continues to promote slow but steady advances in diagnosis, classification, and treatment. This review focuses on the updates in the general management and treatment of NMDs, with emphasis on key updates in muscular dystrophy, myotonic dystrophy, mitochondrial myopathy, spinal muscular atrophy, and hereditary neuropathies. Current research shows that improvements in morbidity and mortality in various NMDs may be possible. Key components include advances in identification and classification of individual NMDs; attention to anesthetic and surgical risks; aggressive pulmonary care; and implementations of a proactive, multidisciplinary, standard-of-care approach. Innovative molecular and pharmaceutical therapeutic options are being investigated in many of these disorders, but unfortunately no new intervention has borne out. Important advances were made in the last year in the field of neuromuscular disease. However, because of their heterogeneous nature and rarity, diagnosis and treatment of these disorders either as a single disorder or as a group continue to be both a clinical and a research challenge. It is of utmost importance that clinicians and researchers be aware of these disorders to aid in identification and treatment.

Evidence-based guideline: Intravenous immunoglobulin in the treatment of neuromuscular disorders [RETIRED

To assess the evidence for the efficacy of IV immunoglobulin (IVIg) to treat neuromuscular disorders. The MEDLINE, Web of Science, and EMBASE databases were searched (1966-2009). Selected articles were rated according to the American Academy of Neurology's therapeutic classification of evidence scheme; recommendations were based on the evidence level. IVIg is as efficacious as plasmapheresis and should be offered for treating Guillain-Barré syndrome (GBS) in adults (Level A). IVIg is effective and should be offered in the long-term treatment of chronic inflammatory demyelinating polyneuropathy (Level A). IVIg is probably effective and should be considered for treating moderate to severe myasthenia gravis and multifocal motor neuropathy (Level B). IVIg is possibly effective and may be considered for treating nonresponsive dermatomyositis in adults and Lambert-Eaton myasthenic syndrome (Level C). Evidence is insufficient to support or refute use of IVIg in the treatment of immunoglobulin M paraprotein-associated neuropathy, inclusion body myositis, polymyositis, diabetic radiculoplexoneuropathy, or Miller Fisher syndrome, or in the routine treatment of postpolio syndrome or in children with GBS (Level U). IVIg combined with plasmapheresis should not be considered for treating GBS (Level B). More data are needed regarding IVIg efficacy as compared with other treatments/treatment combinations. Most studies concluded IVIg-related serious adverse effects were rare. Given the variable nature of these diseases, individualized treatments depending on patient need and physician judgment are important.

Translational research in the diagnosis and therapy of hereditary muscular diseases and national registry of neuromuscular diseases

Translational research enables transfer (translation) of basic laboratory, preclinical research to clinical practice, whereas results of clinical practice induce and direct further basic research. In the treatment of hereditary muscle diseases, pharmacological agents are used, while gene and stem cell therapies are still in the phase of clinical or preclinical trials. Standardization of models for testing therapeutic approaches, definition of certain diseases and definition of criteria for assessing therapeutic protocols and treatment efficiency represent a rational basis for clinical application of different therapeutic strategies. Completion of the European projects Translational Research in Europe – Assessment and Treatment of Neuromuscular Disorders (NMD-TREAT) and CARENMD has a very important role in the creation of uniform access to diagnostic and therapeutic procedures for patients with neuromuscular diseases. National registries have an important role in assessing the frequency, screening of patients, and planning of clinical trials of different therapeutic approaches including gene therapy, thereby contributing to improved quality of life and care of patients with neuromuscular diseases.

Developing standard procedures for pre-clinical efficacy studies in mouse models of spinal muscular atrophy: Report of the expert workshop “Pre-clinical testing for SMA”, Zürich, March 29–30th 2010

A workshop was held in Zurich (Switzerland) to develop standard procedures and protocols for pre-clinical efficacy studies in mouse models of spinal muscular atrophy (SMA). The workshop was organized by the Network of Excellence TREAT-NMD (Translational Research in Europe – Assessment and Treatment of Neuromuscular Disorders), launched 2007, that addresses the fragmentation currently existing in the evaluation, diagnosis and care of neuromuscular diseases on one side, and in the procedures of drug development from research to the design of clinical trials on the other side. Within this frame, one aspect that needs particular care is the design and performance of pre-clinical animal studies that should predict the efficacy of a new treatment in patients. In the absence of commonly accepted guidelines and standardized protocols, data from different laboratories are often not comparable and the result is a duplication of efforts. The workshop was attended by 30 key researchers from Europe and North America, as well as industry representatives (Santhera Pharmaceuticals, Psychogenics, Genyzme, Trophos) and patient organisations (SMA Foundation, AFM-Association Franc aise contre les Myopathies). The goals of the workshop were (1) to select endpoints that best assess drug efficacy in mouse

Changes in contractile properties of muscles receiving repeat injections of botulinum toxin (Botox)

Botulinum toxin type A (BTX-A) is a frequently used therapeutic tool to denervate muscles in the treatment of neuromuscular disorders. Although considered safe by the US Food and Drug Administration, BTX-A can produce adverse effects in target and non-target muscles. With an increased use of BTX-A for neuromuscular disorders, the effects of repeat injections of BTX-A on strength, muscle mass and structure need to be known. Therefore, the purpose of this study was to investigate the changes in strength, muscle mass and contractile material in New Zealand White (NZW) rabbits. Twenty NZW rabbits were divided into 4 groups: control and 1, 3 and 6 months of unilateral, repeat injections of BTX-A into the quadriceps femoris. Outcome measures included knee extensor torque, muscle mass and the percentage of contractile material in the quadriceps muscles of the target and non-injected contralateral hindlimbs. Strength in the injected muscles was reduced by 88%, 89% and 95% in the 1, 3 and 6 months BTX-A injected hindlimbs compared to controls. Muscle mass was reduced by 50%, 42% and 31% for the vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM), respectively, at 1 month, by 68%, 51% and 50% at 3 months and by 76%, 44% and 13% at 6 months. The percentage of contractile material was reduced for the 3 and 6 months animals to 80–64%, respectively, and was replaced primarily by fat. Similar, but less pronounced results were also observed for the quadriceps muscles of the contralateral hindlimbs, suggesting that repeat BTX-A injections cause muscle atrophy and loss of contractile tissue in target muscles and also in non-target muscles that are far removed from the injection site.

Bayesian characterization of external anal sphincter muscles using quantitative electromyography

Objectives Based on the analysis of electromyographic (EMG) data muscles are often characterized as normal or affected by a neuromuscular disease process. The objective of this work was to compare the accuracy of Bayesian muscle characterization to conventional means and outlier analysis of motor unit potential (MUP) feature values. Methods Quantitative MUP data from the external anal sphincter muscles of control subjects and patients were used to compare the sensitivity, specificity, and accuracy of the methods under examination. Results The results demonstrated that Bayesian muscle characterization achieved similar accuracy to combined means and outlier analysis. Thickness and number of turns were the most discriminative MUP features for characterizing the external anal sphincter (EAS) muscles studied in this work. Conclusions Although, Bayesian muscle characterization achieved similar accuracy to combined means and outlier analysis, Bayesian muscle characterization can facilitate the determination of “possible”, “probable”, or “definite” levels of pathology, whereas the conventional means and outlier methods can only provide a dichotomous “normal” or “abnormal” decision. Therefore, Bayesian muscle characterization can be directly used to support clinical decisions related to initial diagnosis as well as treatment and management over time. Decisions are based on facts and not impressions giving electromyography a more reliable role in the diagnosis, management, and treatment of neuromuscular disorders. Significance Bayesian muscle characterization can help make electrophysiological examinations more accurate and objective.

Muscle-derived stem cells isolated as non-adherent population give rise to cardiac, skeletal muscle and neural lineages

Stem cells with the ability to differentiate in specialized cell types can be extracted from a wide array of adult tissues including skeletal muscle. Here we have analyzed a population of cells isolated from skeletal muscle on the basis of their poor adherence on uncoated or collagen-coated dishes that show multi-lineage differentiation in vitro. When analysed under proliferative conditions, these cells express stem cell surface markers Sca-1 (65%) and Bcrp-1 (80%) but also MyoD (15%), Neuronal β III-tubulin (25%), GFAP (30%) or Nkx2.5 (1%). Although capable of growing as non-attached spheres for months, when given an appropriate matrix, these cells adhere giving rise to skeletal muscle, neuronal and cardiac muscle cell lineages. A similar cell population could not be isolated from either bone marrow or cardiac tissue suggesting their specificity to skeletal muscle. When injected into damaged muscle, these non-adherent muscle-derived cells are retrieved expressing Pax7, in a sublaminar position characterizing satellite cells and participate in forming new myofibers. These data show that a non-adherent stem cell population can be specifically isolated and expanded from skeletal muscle and upon attachment to a matrix spontaneously differentiate into muscle, cardiac and neuronal lineages in vitro. Although competing with resident satellite cells, these cells are shown to significantly contribute to repair of injured muscle in vivo supporting that a similar muscle-derived non-adherent cell population from human muscle may be useful in treatment of neuromuscular disorders.

Investigating Novel Therapeutic Targets and Molecular Mechanisms to Treat Botulinum Neurotoxin A Intoxication

Botulinum neurotoxin (BoNT) has recently catapulted into the public consciousness in two seemingly disparate roles: potential use as a biological weapon and treatment of neuromuscular disorders. This bacterially produced protein is the most potent toxin known to humans, with a lethal dose estimated at approximately 1 ng/kg of body weight. BoNT intoxication occurs via a multistep process that includes recognition of peripheral neuronal cell membrane receptors, endocytosis and translocation of the light chain metalloprotease into the cytosol, and catalytic cleavage of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins critical for vesicle fusion and neurotransmitter release. Each of these distinct steps has been studied at the molecular level and is a valid target for the development of pharmacological interventions to prevent the considerable mortality associated with botulism. Alternatively, clinical uses of BoNT continue to expand at an ever-increasing rate; however, further optimization of BoNT therapy is critical to maximize efficacy.

BIOMECHANICAL STABILITY ANALYSIS OF THE λ-MODEL CONTROLLING ONE JOINT

Computer modeling and control of the human motor system might be helpful for understanding the mechanism of human motor system and for the diagnosis and treatment of neuromuscular disorders. In this paper, a brief view of the equilibrium point hypothesis for human motor system modeling is given, and the lambda-model derived from this hypothesis is studied. The stability of the lambda-model based on equilibrium and Jacobian matrix is investigated. The results obtained in this paper suggest that the lambda-model is stable and has a unique equilibrium point under certain conditions.

Plasma Exchange in Neuroimmunological Disorders

Plasma exchange is a well-established therapeutic procedure commonly used in many neurological disorders of autoimmune etiology. In this second part of our review, we assess the role of plasma exchange in the treatment of neuromuscular disorders. In Guillain-Barré syndrome and other immune-mediated neuropathic disorders, randomized controlled trials have demonstrated the therapeutic efficacy of plasma exchange. Myasthenia gravis and Lambert-Eaton syndrome represent neuromuscular disorders where plasmapheresis might be of potential efficacy.

Preliminary studies with a neurotoxin obtained from Bungarus caeruleus venom

The neurotoxin purified from the venom of Bungarus caeruleus causes a neuromuscular blockade on acetylcholine-induced muscle twitch response in isolated frog rectus abdominis muscle preparation. Neuromuscular blockade produced by d-tubocurarine on acetylcholine-induced muscle twitch response in an isolated frog rectus abdominis muscle preparation was reversed to normal muscle twitch response in presence of neostigmine. Whereas the purified neurotoxin produced an irreversible neuromuscular blockade in presence of the same strength of neostigmine. As it is already known, botulinum toxin, which also brings about neuromuscular blockade, is effectively used as a drug in the treatment of painful movement disorders. Since the purified toxin also causes paralysis of the muscle, we propose its possible efficacy in the treatment of neuromuscular disorders.

Interleukin-15 Administration Improves Diaphragm Muscle Pathology and Function in Dystrophic mdx Mice

Interleukin (IL)-15, a cytokine expressed in skeletal muscle, has been shown to have muscle anabolic effects in vitro and to slow muscle wasting in rats with cancer cachexia. Whether IL-15 has therapeutic potential for diseases such as Duchenne muscular dystrophy (DMD) is unknown. We examined whether IL-15 administration could ameliorate the dystrophic pathology in the diaphragm muscle of the mdx mouse, an animal model for DMD. Four weeks of IL-15 treatment improved diaphragm strength, a highly significant finding because respiratory function is a mortality predictor in DMD. Enhanced diaphragm function was associated with increased muscle fiber cross-sectional area and decreased collagen infiltration. IL-15 administration was not associated with changes in T-cell populations or alterations in specific components of the ubiquitin proteasome pathway. To determine the effects of IL-15 on myofiber regeneration, muscles of IL-15-treated and untreated wild-type mice were injured myotoxically, and their functional recovery was assessed. IL-15 had a mild anabolic effect, increasing fiber cross-sectional area after 2 and 6 days but not after 10 days. Our findings demonstrate that IL-15 administration improves the pathophysiology of dystrophic muscle and highlight a possible therapeutic role for IL-15 in the treatment of neuromuscular disorders especially in which muscle wasting is indicated.

Neuromuscular rehabilitation and electrodiagnosis. 4. Pediatric issues

Kim C-T, Strommen JA, Johns JS, Weiss JM, Weiss LD, Williams FH, Rashbaum IG. Neuromuscular rehabilitation and electrodiagnosis. 4. Pediatric issues. This self-directed learning module highlights the physician’s role in the diagnosis and treatment of neuromuscular disorders in pediatric populations. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article discusses both clinical and electrodiagnostic features of common neuromuscular disorders in pediatric populations. The diagnostic value of somatosensory evoked potential is reviewed in a case of traumatic spinal cord injury without radiographic abnormality. Therapeutic interventions of progressive muscular dystrophy are discussed, as well as the differential diagnosis of floppy infant syndrome, the most common pediatric electrodiagnostic referral. Overall article objectives (a) To become familiar with electrodiagnosis and rehabilitation for common neuromuscular disorders in the pediatric population, (b) to undrstand electrodiagnostic findings of Guillain-Barré syndrome corresponding to pathophysiology, (c) to become familiar with somatosensory evoked potentials, and (d) to be able to make differential diagnosis of floppy infant syndrome based on clinical findings as well as electrodiagnosis.

A molecular basis underlying differences in the toxicity of botulinum serotypes A and E.

Botulinum neurotoxins (BoNTs) block neurotransmitter release through their specific proteolysis of the proteins responsible for vesicle exocytosis. Paradoxically, two serotypes of BoNTs, A and E, cleave the same molecule, synaptosome-associated protein with relative molecular mass 25K (SNAP-25), and yet they cause synaptic blockade with very different properties. Here we compared the action of BoNTs A and E on the plasma membrane fusion machinery composed of syntaxin and SNAP-25. We now show that the BoNT/A-cleaved SNAP-25 maintains its association with two syntaxin isoforms in vitro, which is mirrored by retention of SNAP-25 on the plasma membrane in vivo. In contrast, BoNT/E severely compromises the ability of SNAP-25 to bind the plasma membrane syntaxin isoforms, leading to dissociation of SNAP-25. The distinct properties of botulinum intoxication, therefore, can result from the ability of shortened SNAP-25 to maintain its association with syntaxins-in the case of BoNT/A poisoning resulting in unproductive syntaxin/SNAP-25 complexes that impede vesicle exocytosis.

Corticosteroid use in the treatment of neuromuscular disorders: empirical and evidence-based data.

Corticosteroids have been used to treat neuromuscular disorders for many years. With few randomized, controlled trials, efficacy has been established primarily from empirical data. This has led to a range of treatment regimens varying in terms of initial dosing, dosing schedules, and taper rates. The goals of this review were to examine the literature for data concerning corticosteroid pharmacokinetics and for evidence-based treatment regimens in several prototypic neuromuscular disorders. The results provide a number of sound principles for corticosteroid use, but also indicate that corticosteroid regimens and patient management are largely based on empirical clinical experiences.

Skeletal muscle regeneration after insulin-like growth factor I gene transfer by recombinant Sendai virus vector.

We scrutinized the applicability and efficacy of Sendai virus (SeV) vectors expressing either LacZ or human insulin-like growth factor-I (hIGF-I) in gene transfer into skeletal muscle. Seven days after the intramuscular injection of LacZ/SeV X-gal labeled myofibers were demonstrated in rat anterior tibialis muscle with/without bupivacaine treatment and the transgene expression persisted up to 1 month after injection. Recombinant hIGF-I was detected as a major protein species in culture supernatants of a neonatal rat myoblast cell line L6 and thus induced the cells to undergo myogenetic differentiation. The introduction of hIGF-I/SeV into the muscle showed a significant increase in regenerating and split myofibers which were indicative of hypertrophy, and also an increase in the total number of myofibers, in comparison to that seen in the LacZ/SeV-treated control muscle. These results demonstrate that SeV achieves high-level transgene expression in skeletal muscle, and that hIGF-I gene transfer using SeV vector may therefore have great potential in the treatment of neuromuscular disorders.

Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines.

This review summarizes the current status of intravenous immunoglobulin (IVIg) in the treatment of autoimmune neuromuscular disorders and the possible mechanisms of action of the drug based on work in vivo, in vitro, and in animal models. Supply of idiotypic antibodies, suppression of antibody production, or acceleration of catabolism of immunoglobulin G (IgG) are relevant in explaining the efficacy of IVIg in myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and antibody-mediated neuropathies. Suppression of pathogenic cytokines has putative relevance in inflammatory myopathies and demyelinating neuropathies. Inhibition of complement binding and prevention of membranolytic attack complex (MAC) formation are relevant in dermatomyositis (DM), Guillain-Barré syndrome (GBS), and MG. Modulation of Fc receptors or T-cell function is relevant in chronic inflammatory demyelinating polyneuropathy (CIDP), GBS, and inflammatory myopathies. The clinical efficacy of IVIg, based on controlled clinical trials conducted in patients with GBS, CIDP, multifocal motor neuropathy (MMN), DM, MG, LEMS, paraproteinemic IgM anti-myelin-associated glycoprotein (anti-MAG) demyelinating polyneuropathies, and inclusion body myositis is summarized and practical issues related to each disorder are addressed. The present role of IVIg therapy in other disorders based on small controlled or uncontrolled trials is also summarized. Finally, safety issues, risk factors, adverse reactions, spurious results or serological tests, and practical guidelines associated with the administration of IVIg in the treatment of neuromuscular disorders are presented.