Dear participants,

It is a pleasure for us to be involved in this course as part of the Masters in Neuroimmunology Program. Inflammatory neuropathies comprise a large and heterogeneous group of potentially severe and disabling diseases, which are, however, amenable to treatment. Here, we offer an overview of the specific disease entities within the group of inflammatory neuropathies, including their immunopathogenesis, diagnosis, and treatment options. Interestingly, the results obtained in animal models suggest that some of the mechanisms, described here, for autoimmune inflammatory neuropathies are also active in primary genetic myelin disorders. We look forward to a fruitful and interactive course.

Ralf Gold

Welcome Letter
Dear Students,
Erdem Tuzun and I are delighted to take you through the autoimmune disorders of the neuromuscular junction (NMJ), and as you will see, we will even venture into the central nervous system.
Since the NMJ is the archetypal synapse, and the diseases that affect it are prototypical antibody-mediated conditions, we discuss them at some length. However, this first requires that you know something about neuromuscular transmission and its key components, as these are the targets for of autoimmune attack. This, in turn, requires a brief review of immunology. With this foundation, we can begin a discussion of the diseases of the NMJ, most importantly, myasthenia gravis, but also seronegative myasthenia, Lambert Eaton myasthenic syndrome, and acquired neuromyotonia. You will then see how, using our knowledge of a very rare disease that affects the periphery and the central nervous system (Morvan’s syndrome), we and others have been able to more broadly explore antibody-mediated diseases of the CNS. The text covers these diseases systematically and the references encompass the most general aspects, but there is ample opportunity for further explorfation of the literature.
What we hope you will appreciate, more than anything, from this module is the history of the research on NMJ disease and how experimental and basic science have combined to provide an understanding of these conditions; the extent to which the identification of specific target antigens has revolutionized our understanding of them and thus of their diagnosis and treatment; and how research into NMJ disease has helped us in identifying other, unrecognized or neglected, immunotherapy-responsive conditions of the CNS.
My contribution to this module consists of the clinical immunology aspects while Dr Tüzün covers most of the clinical questions and the more detailed immunology, particularly of the experimental model of myasthenia. We hope you enjoy this module and interacting with us.

Angela Vincent
Professor of Neuroimmunology,
Honorary Consultant in Immunology,
University of Oxford

Erdem Tüzün
Consultant Neuroimmunologist,
University of Istanbul, Turkey.

Abstract: Neuromuscular transmission was the original model for studying synaptic transmission in the nervous system largely because of the easy accessibility of the neuromuscular junction. There are genetic, neurotoxic, and autoimmune diseases of the neuromuscular junction. Genetic diseases are rare and caused by mutations in many of the key molecules involved in transmission. Neurotoxicity occurs due to poisoning by venomous species and also by botulinism, which is still clinically important in some parts of the world. Autoimmunity, the main topic of this Unit, occurs when autoantibodies bind to specific targets at the neuromuscular junction, which leads to defective transmission. Here, we first briefly describe the structure and function of the neuromuscular junction, and then discuss the clinical, pathological, and immunological features of four autoimmune disorders of neuromuscular transmission: myasthenia gravis, myasthenia gravis with MuSK antibodies, the Lambert Eaton myasthenic syndrome, and acquired neuromyotonia. Each of these conditions is caused by autoantibodies to a receptor or ion channel.
These diseases will be discussed in detail and provide the paradigms for understanding the newly described CNS disorders that are briefly reviewed at the end of the Unit. Collectively, many of these conditions can now be called 'autoimmune channelopathies.'

Development of the Unit
This Unit consists of four parts. The first consists of the anatomy, physiology, and biochemistry of neuromuscular transmission, about a brief presentation of the molecules that are targets for the autoimmune diseases under discussion, and a simple overview of how antibodies are produced. The second, largest section discusses in some detail myasthenia gravis, which is the main autoimmune disorder of neuromuscular transmission, as well as its pathology and etiology; it also offers a few comments on the different treatments. In the third section, we briefly describe the other two autoimmune disorders, Lambert Eaton myasthenic syndrome and acquired neuromyotonia. In the fourth, we take note of the newly described diseases of the central nervous system, which, due to the characteristic presence of antibodies directed against ion channels and receptors, are proving to be immunotherapy responsive.

Las miopatías inflamatorias se consideran enfermedades autoinmunes raras. Su prevalencia es de 1-5 por 100.000 habitantes/año. Sus formas principales son la dermatomiositis, la polimiositis, la miopatía necrosante inmunomediada y la forma esporádica de la miositis con cuerpos de inclusión. Además, algunos autores consideran la afectación muscular del síndrome antisintetasa como un subtipo de miositis diferenciado de las formas clásicas comentadas previamente, incluido en los síndromes de solapamiento con otras enfermedades autoinmunes. En términos generales, la dermatomiositis es la forma más frecuente, mientras que la miositis con cuerpos de inclusión lo es en mayores de 65 años, en particular en Estados Unidos. Aunque existen datos clínicos distintivos entre las distintas formas, el diagnóstico preciso sólo se establece con el estudio histológico muscular en manos expertas y con el perfil de los autoanticuerpos. En el caso de la dermatomiositis, las lesiones dermatológicas típicas también tienen gran valor diagnóstico. El diagnóstico de polimiositis como entidad aislada, por el contrario, siempre es un diagnóstico de exclusión. La miositis con cuerpos de inclusión tiene formas de presentación excepcionales, como la debilidad selectiva de musculatura axial, la debilidad de cuádriceps y de flexores de los dedos de las manos o la presencia de disfagia aparentemente aislada.

Las cuatro formas clásicas de miopatía inflamatoria se pueden asociar a otras enfermedades autoinmunes, mientras que sólo la miopatía necrosante inmunomediada y la dermatomiositis se asocian claramente a neoplasia (el 20% de los casos del adulto). Hoy en día, se han descrito subtipos clínicos y/o histológicos diferenciados, que junto con el descubrimiento de cada vez más anticuerpos específicos, hace que los criterios clasificatorios clásicos de Bohan y Peter estén más que obsoletos, y a lo largo de los años se han ido publicando nuevos criterios para su diagnóstico y clasificación.

Las miopatías inflamatorias son patologías sistémicas, en las que puede existir, aparte del músculo y la piel, afectación de otros órganos, como el pulmón, la articulación, el corazón y el tubo digestivo. Esta afectación es variable en función del tipo histológico y, sobre todo, del perfil de autoanticuerpos, y puede condicionar el pronóstico del paciente, especialmente en presencia de enfermedad pulmonar intersticial.

El tratamiento se basa en la utilización de corticoides y agentes citotóxicos, y las gamma­globulinas y los tratamientos biológicos como rituximab se reservan para los casos graves o refractarios a las primeras opciones. El tratamiento siempre es prolongado, y la morbididad, ya sea por la enfermedad o por efectos indeseables de los tratamientos, es elevada.