Neuromuscular Therapy from Bench to Bedside
01. November 2012 (online)
Neurology is a therapeutic specialty. Fortunately, the days of “diagnose and adios” are long gone, and we work in an era of unparalleled treatment opportunity for our patients. In no neurologic subspecialty is the focus on treatment more apparent than in neuromuscular medicine. Neuromuscular experts have had effective therapies for autoimmune disorders of nerve, neuromuscular junction, and muscle for many years. Although the array of potential immune-modulating therapies continues to expand, diseases for which there has been no treatment, or reasonable hope for disease altering therapy, are entering clinical trials. In this issue of Seminars in Neurology, an outstanding faculty reviews the core clinical features of a wide spectrum of neuromuscular diseases, summarizes the current understanding of disease mechanism, and details standard of care therapies as well as approaches under active investigation in human and preclinical studies. The goal is to provide the clinical neurologist a summary of currently available treatments for their patients, as well as a view of what the future might hold.
The issue is organized anatomically beginning with the motor neuron and ending with muscle. Not long ago, the idea of including an article on amyotrophic lateral sclerosis (ALS) in a journal dedicated to therapy would seem far-fetched. Although effective disease altering therapy for ALS remains elusive, Drs. Gibson and Bromberg give us valid reason for hope in their review of ongoing and planned clinical trials. Inflammatory demyelinating polyradiculoneuropathies have been a therapeutic bright spot in neurology since the first description of steroid responsiveness in what would eventually be called CIDP in 1958 by Austin. Traditional therapies employed in standard regimens are imperfect; however, Drs. Arcila-Londono, Lewis, Peltier, and Donofrio provide excellent updates on efforts to improve how we use currently available treatments such as IVIg as well as evolving therapies, including the rapidly expanding list of biologic agents. The optimism surrounding therapy for inflammatory neuropathy has been balanced by a sense of therapeutic nihilism for one of the most common neurologic disorders in the world, diabetic neuropathy. As with ALS, no significant disease-altering therapies are available, yet our understanding of disease pathogenesis, including the importance of obesity, dyslipidemia, and prediabetes suggest many potential therapeutic targets. My colleague, Dr. Singleton and I review chronic and acute forms of diabetic neuropathy, and the spectrum of pharmacologic and nonpharmacologic treatments available, as well as exciting new potential methods of targeted drug delivery. Although classification and molecular diagnosis of Charcot-Marie-Tooth disease (CMT) may have been reasonably viewed as an academic exercise not long ago, improved understanding of the molecular mechanisms of these disorders is leading us to potential therapies. Clinical trials for CMT are now a reality, and Dr. Jun Li reviews the most common hereditary neuropathies, outlines an easily applied diagnostic approach, and suggests potential therapeutic approaches. Effective therapies for myasthenia gravis have been available for some time. However, there is a need for better approaches and important questions regarding currently available approaches remain unanswered (e.g., the role of thymectomy). Drs. Nick Silvestre and Gil Wolfe provide an up-to-date review of therapy for myasthenia gravis.
As with myasthenia gravis, neurologists have been using immunomodulatory therapy for inflammatory myopathies for many years. However, although many patients with dermatomyositis and polymyositis respond well to traditional approaches, many others are refractory to this therapy. Fortunately, our understanding of the immunobiology of myositis has improved significantly in the past decade and a host of new treatment options are available or under investigation. One of the most interesting developments in the past few years is recognition of necrotizing autoimmune myopathies as a significant disorder. The most common myopathy of adulthood is inclusion body myositis. Multiple attempts to treat inclusion body myositis using immune-suppressing medications have failed. However, several exciting new therapies are under investigation. Drs. Dimachkie and Barohn provide a comprehensive review of idiopathic inflammatory myopathies, and in a second article, inclusion body myositis.
There is no other field in neurology, or medicine, where there is more enthusiasm and therapeutic optimism than in the muscular dystrophies. For decades, the only treatment for these often devastating diseases has been symptomatic, or corticosteroid therapy for dystrophinopathies. However, recent advances in molecular genetics have led to a variety of novel therapeutic approaches, including exon-skipping therapies, small interfering RNAs, and antisense oligonucleotides. Three leaders in the field review the clinical features and evolving therapies. Drs. Johnson and Heatwole summarize developments in myotonic dystrophy, and Dr. Flanigan provides an update on the muscular dystrophies.
Finally, many patients with neurologic disorders are disabled by neuropathic pain. Few proven therapies are available. There are several new approaches available or in development. Dr. Backonja summarizes mechanisms in neuropathic pain and reviews general therapeutic strategies and novel therapies that have made the transition from the bench to the patient's bedside.
Because of space limitations, it is impossible to review all of the exciting therapeutic developments in neuromuscular medicine. Many other disorders long thought refractory to treatment are entering clinical trials, including spinal muscular atrophy  and chemotherapy-induced neuropathy. Some rare metabolic and genetic disorders now have FDA-approved therapy including Pompe disease, and others are the subject of ongoing clinical trials, such as familial amyloid polyneuropathy. Although it is all too easy to become frustrated at the failure of animal models to predict human response to therapy, or to decry our lack of disease-altering therapy for devastating disorders such as ALS, we should take a step back and recognize how far our field has come, and how bright the future may be.
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