Autoimmune neuropathies: Pathogenesis and future perspectives

Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 acute and chronic denervation in the left L5 myotome with the most severe denervation in the left TFL. Routine lower extremity sensory and motor nerve conduction studies were normal showing no evidence of a generalized polyneuropathy affecting large nerve fibers. This case demonstrates the rare phenomenon of “denervation hypertrophy” mimicking a soft tissue tumor in the muscle. The mechanism of denervation hypertrophy is unclear and better understanding of such enhanced selective muscle tissue regeneration that is the result of complex interactions of satellite cells, growth factors, immune system, and the hormones with the individual muscle fibers could have therapeutic implications. http://dx.doi.org/10.1016/j.nmd.2015.06.210

G.P.196 Quantifiable diagnosis of neuromuscular diseases through network analysis E. Rivas 1, A. Sáez 2, A. Montero-Sánchez 1, C. Paradas *,1, B. Acha 3, A. Pascual 1, C. Serrano 3, L. Escudero 3 1 Instituto de Biomedicina de Sevilla/Hospital U. Virgen del Rocío, Sevilla, Spain; 2 Escuela Técnica Superior Ingeniería, Universidad de Sevilla, Sevilla, Spain; 3 Universidad de Sevilla, Sevilla, Spain A very important clue for the diagnosis of neuromuscular diseases is the histological characterization of biopsy samples. However, the morphological analyses of muscle biopsies are mostly subjective and hard to quantify. We have developed an image analysis method named NDICIATM (Neuromuscular Diseases through Computerized Image Analysis) that captures the useful information contained in a muscle biopsy. The novelty of our approach is the use of network science to extract information from muscle biopsy sections. INDICIA characterizes muscular tissues by representing each image as a network with cells as nodes and cell contacts as links. The features of individual cells, together with attributes of the cellular network that connects them, produce a defining signature that allow classification of normal and pathological samples in different groups. The method includes a training process with diagnosed samples that select the characteristic that are more relevant for the comparison between two or more groups of images. After, the training process is possible to add new samples to the system. NDICIATM will quantify and classify these new images providing objective useful information for the diagnosis. http://dx.doi.org/10.1016/j.nmd.2015.06.211

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low functioning child autism with severe symptoms. Cognitive impairment and attention deficit disorders have been found in approximately a third of DMD boys, prevalence of autism in DMD patients is about 5%. Epilepsy has been reported in about 3–6% of DMD boys. Combination of DMD, autism and epilepsy has not been reported yet. http://dx.doi.org/10.1016/j.nmd.2015.06.212

G.P.198 Life as a teenage girl with NMD in Denmark is good – And difficult A. Hoejberg * The National Rehabilitation Center for Neuromuscular Disorders (RCFM), Aarhus C, Denmark Studies of people with impaired physical capacity seldom focus on gender but rather diagnosis, functional level or age. The goal of the study was to examine how Danish teenage girls with different neuromuscular diagnoses experience everyday life, resources, difficulties, quality of life, and coping strategies. Thirty-two girls aged 12–18 years participated in a semi-structured interview. They make up 60% of the population in this age group registered with RCFM. At project start, 21 were ambulant and 11 were primarily wheelchair users. The interview guide was developed on the basis of a focus group interview with seven young women with NMD aged 19–24 years, and research based and practical knowledge. The methodological approach was phenomenological from an interactionist perspective. The analysis was carried out by registering significant elements and subsequently condense these using an inductive as well as deductive approach. Being a teenage girl with a neuromuscular disorder is multi-facetted. Generally, the girls are doing well and are satisfied with conditions such as school, practical help, assistive devices, etc. At the concrete and body level, however, the neuromuscular disease involves a number of inconveniences that considerably reduce the girls’ chances of participating in activities with their friends in and outside school. More than half of the oldest girls sometimes stay away from social activities with their friends from fear of not being able to participate. A little more than half of the youngest girls and 75% of the oldest girls – all ambulant to some extent – say they would like to try new spare time activities. In spite of this, the girls seem to thrive and say that life with NMD becomes easier the older they get. More than 75% of the oldest girls are doing better in school now than 2 years ago and feel that others like to talk to them because they are good listeners. http://dx.doi.org/10.1016/j.nmd.2015.06.213

G.P.197 Triple trouble – DMD, autism, epilepsy L. Mrazova *,1, Z. Jurikova 1, P. Danhofer 1, J. Pejcochova 1, P. Vondracek 1, J. Zamecnik 2, T. Honzik 3, H. Oslejskova 1 1 Department of Children Neurology, University Hospital in Brno, Masaryk University in Brno, Brno, Czech Republic; 2 Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic; 3 Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic Duchenne muscular dystrophy is an X linked progressive neuromuscular disorder caused by the absence of protein called dystrophin due to a mutation in the dystrophin gene. DMD has a prevalence of 1:3500 live male births. We are presenting case report of a boy with combination of DMD, epilepsy and autism. He was admitted to neurologists at 8 months for epileptic seizures – infantile spasm. In laboratory results elevation of ALT, AST and CK was seen and the patient was transferred to metabolic center where he underwent muscle biopsy with result of absence of dystrophin. MLPA of dystrophin gene showed deletion of exons 10 and 11. During hospitalizations we observed that patient’s mental and speech development were delayed and we also realized atypical social contact. He was examined by pediatric psychologist with conclusion of

IMMUNE-MEDIATED PERIPHERAL NERVE, NEUROMUSCULAR JUNCTION AND MUSCLE DISORDERS I.I.5 Autoimmune neuropathies: Pathogenesis and future perspectives H. Willison * Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK In human autoimmune neuropathies, a heterogeneous group of inflammatory disorders affecting the peripheral nervous system, different clinical forms can be distinguished by anti-glycolipid antibody profiling. Glycolipids act as plasma membrane receptors for a wide range of antibodies, lectins and microbes affecting human disease and physiology. To date, around 20 single glycolipids are recognised as antigens in patients with both acute and chronic syndromes. Acute phase anti-GM1 IgG antibodies to GM1 and GD1a gangliosides occur in the acute motor axonal form of Guillain–Barré syndrome (GBS). Long lived IgM antibodies associate with chronic forms of the disease.

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A range of animal models have been developed that demonstrate anti-glycolipid antibodies are pathogenically causal for the nerve diseases with which they are associated. In many of these models complement activation is a crucial step in mediating nerve membrane injury, and therapeutically tractable in man. The key glycobiological feature of GBS is its relationship to a preceding Campylobacter jejuni infection, whose surface lipo-oligosaccharide (LOS) bears ganglioside mimics. The recent discovery of new categories of anti-glycolipid antibodies whose binding is dependent upon heteromeric glycolipid complexes has created a shift of emphasis in this research area. Heteromeric complexes are formed by structurally distinct glycolipids that cis-interact in the plane of the plasma membrane, and in doing so form new molecular shapes capable of either enhancing or attenuating recognition by neuropathy-associated autoantibodies. This presentation will summarise existing knowledge in the area and consider future research directions. http://dx.doi.org/10.1016/j.nmd.2015.06.214

I.I.6 Myasthenia: Novel antigens and therapies J. Verschuuren * Department of Neurology, Leiden University Medical Centre, The Netherlands Myasthenia gravis with acetylcholine receptor (AChR) antibodies is the most well-known acquired autoimmune disorder of the neuromuscular junction. MuSK, LRP4, Agrin, ColQ and the VGCC are other antigens at this synapse that are accessible to antibodies. Each is associated with a distinct clinical phenotype. In myasthenic disorders of the postsynaptic muscle membrane ocular or bulbar weakness predominates, while the presynaptic disorder, Lambert–Eaton myasthenic syndrome, presents with proximal leg weakness. The genetic background indicates differences, even between groups of different ages within one autoimmune disorder. HLA-B8DR3 is associated with early-onset AChR MG, but not with late-onset AChR. The immunopathogenesis is also significantly different. AChR MG is caused by complement activating IgG1 antibodies, while MuSK antibodies are IgG4, which cannot activate complement, but mechanically block the MuSK-LRP4 complex. These insights have direct consequences for the choice of therapy. Although several symptomatic or immunosuppressive treatments are available, about 15% of MG patients have been found refractory to immunotherapy or suffers from severe side effects. Symptomatic therapy includes acetylcholinesterase inhibitors. The role of thymectomy in earlyonset AChR MG is studied in an ongoing international trial. Plasma exchange or intravenous immunoglobulin treatment are used for treatment of myasthenic crisis, and corticosteroids and several immunosuppressive drugs for chronic immunosuppressive treatment. An increasing number of new drugs are being tested in MG. These drugs often have their origin in transplantation medicine, the treatment of cancer or other autoimmune disorders. To adequately test these new therapies a well defined study population, as well as outcome measures are necessary. http://dx.doi.org/10.1016/j.nmd.2015.06.215

I.I.7 Contribution of myopathological analysis to myositis classification in a multidisciplinary approach W. Stenzel * Charité – Universitätsmedizin, Neuropathology, Berlin, Germany Diagnosis of inflammatory myopathies is based on evaluation of a certain clinical syndrome, laboratory results, electromyography and the myopathological assessment of a muscle biopsy. Recently, several additional parameters have been taken into consideration; among these, serological autoantibody testing is the most relevant. The current classification of inflammatory myopathies (IIMs) comprises polymyositis (PM),

dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), sporadic inclusion body myositis (sIBM), and non-specific myositis (NSM). This classification has been a subject of intense critique at various levels. First, the entity of polymyositis has been questioned, since many of these patients developed either sIBM later on, or should better be grouped among the IMNM group or the NSM/overlap myositis group. Second, dermatomyositis encompasses a multitude of subgroups with different clinical, therapeutical and prognostic implications. It has been shown recently that certain subgroups can be defined by different myositis specific autoantibodies, such as TIF1γ, Mi-2, NXP2 or MDA-5. Anti-TIF1γ+ and NXP2+ adult patients show an increased risk of systemic malignancy, while antiMi-2+ patients harbour a classical dermatomyositis with good response to treatment, and NXP2+ juvenile DM patients have a strongly increased risk of developing calcinosis. The morphology and in situ immune mechanisms of the skeletal muscle of these subentities are presented. Third, necrotizing myopathy was recently added to the IIMs; however, IMNM still comprises a heterogeneous group of diseases. Recently interesting advances have been achieved, illuminating the immunopathogenesis from anti-SRP+, antiHMGCR+ patients and anti-synthetase syndrome-associated myositis. These entities will be discussed in the light of clinical, serological, morphological and immunological characteristics. http://dx.doi.org/10.1016/j.nmd.2015.06.216

I.I.8 Genomic insights into inflammatory myopathies S. Greenberg * Brigham and Women’s Hospital and Children’s Hospital Boston Harvard Medical School, Boston, MA, USA The inflammatory myopathies are typically divided into 4 main categories: inclusion body myositis, dermatomyositis, polymyositis, and immune mediated necrotizing myopathy. The mechanisms driving muscle injury in these diseases are poorly understood. Most of what has been learned about these mechanisms has come from the examination of muscle tissue by light microscopy. Over the past decade, further insight has been gained regarding the pathogenesis of dermatomyositis and inclusion body myositis from genomic studies. These approaches yield large-scale data sets which have been fruitfully mined with computational approaches to identify pathways, immune cells, and mechanisms that had not been previously thought to play a role in these diseases. These insights have furthered the development of diagnostics and of therapeutic candidates. http://dx.doi.org/10.1016/j.nmd.2015.06.217

IMMUNE-MEDIATED PERIPHERAL NERVE, NEUROMUSCULAR JUNCTION AND MUSCLE DISORDERS G.O.7 Choosing the “best” animal model for pre-clinical trials of autoimmune myasthenia gravis G. Shelton * University of California San Diego, Department of Pathology, La Jolla, CA, USA Since the early 1970s when the autoimmune nature of myasthenia gravis (MG) was first established by Patrick and Lindstrom, and the dramatic increase in muscle strength in response to cholinesterase inhibitors was recognized by Lennon and Seybold in weak rabbits immunized with acetylcholine receptors (AChRs), the experimental autoimmune myasthenia gravis (EAMG) model in rodents has been the animal model most commonly used in studies of MG. The EAMG model has been of immense value in our understanding of the effects of