E.U. paediatric MOG consortium consensus: Part 1 - Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM) in younger, and optic neuritis (ON) and/or transverse myelitis (TM) in older children. A proportion of patients experience a relapsing disease course, presenting as ADEM followed by one or multiple episode(s) of ON (ADEM-ON), multiphasic disseminated encephalomyelitis (MDEM), relapsing ON (RON) or relapsing neuromyelitis optica spectrum disorders (NMOSD)-like syndromes. More recently, the disease spectrum has been expanded with clinical and radiological phenotypes including encephalitis-like, leukodystrophy-like, and other non-classifiable presentations. This review concludes with recommendations following expert consensus on serologic testing for MOG-abs in paediatric patients, the presence of which has consequences for long-term monitoring, relapse risk, treatments, and for counselling of patient and families. Furthermore, we propose a clinical classification of paediatric MOGAD with clinical definitions and key features. These are operational and need to be tested, however essential for future paediatric MOGAD studies.

Different distribution of demyelination in chronic inflammatory demyelinating polyneuropathy subtypes.

In demyelinating polyneuropathies, distribution patterns of demyelination reflect underlying pathogenesis. Median and ulnar nerve conduction studies were reviewed in 85 typical chronic inflammatory demyelinating polyneuropathy (CIDP) patients and 29 multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Distal latencies were prolonged in typical CIDP and near normal in MADSAM. Abnormal amplitude reductions in the nerve trunks were more frequent in MADSAM than typical CIDP. Presumably because the blood-nerve barrier is anatomically deficient at the distal nerve terminals, antibody-mediated demyelination is a major pathophysiology in typical CIDP. In contrast, blood-nerve barrier breakdown is likely to be predominant in MADSAM.

Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.

Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Demographic and clinical data were collected. Eighty-six patients were identified over 4 years, resulting in an incidence of 0.66/1,00,000 per year. Most patients presented with polyfocal ADS without encephalopathy (30%), followed by polyfocal ADS with encephalopathy (24%), optic neuritis (ON, 22%), monofocal ADS (16%), transverse myelitis (3%), and neuromyelitis optica (3%). Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001). During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/1,00,000 children/year. A polyfocal disease onset of ADS was most common.

High prevalence of autoantibodies against phosphoglycerate mutase 1 in patients with autoimmune central nervous system diseases.

We identified the autoantibody against phosphoglycerate mutase 1 (PGAM1), which is a glycolytic enzyme, in sera from multiple sclerosis (MS) patients by proteomics-based analysis. We further searched this autoantibody in sera from patients with other neurological diseases. The prevalence of the anti-PGAM1 antibody is much higher in patients with MS and neuromyelitis optica (NMO) than in those with other neurological diseases and in healthy controls. It was reported that the anti-PGAM1 antibody is frequently detected in patients with autoimmune hepatitis (AIH). Results of our study suggest that the anti-PGAM1 antibody is not only a marker of AIH but also a nonspecific marker of central nervous system autoimmune diseases.

[Limbic encephalitis: the new cell membrane antigens and a proposal of clinical-immunological classification with therapeutic implications]. / Encefalitis límbica: los nuevos antígenos y propuesta de una clasificación clinicoinmunológica con implicaciones terapéuticas.

INTRODUCTION: Most studies of patients with limbic encephalitis, paraneoplastic or not, use rigid clinical-radiological entry criteria or select patients previously known to have cancer or to harbor well characterized paraneoplastic antibodies. In practice this selection excludes a significant number of patients with autoimmune encephalitides, some of which may represent new disorders. METHODS: Review of the literature and our clinical experience with patients with limbic encephalitis. Description of the studies that led to the identification of new antibodies and antigens related to several types of autoimmune encephalitis. RESULTS: 82 % of prospectively identified patients with non-viral limbic encephalitis at our institution had 526 antibodies against proteins of the CNS. These antibodies were directed against two category of antigens: a) intracellular or classical paraneoplastic antigens (Hu, Ma2, among other), and b) cell membrane antigens including the voltage-gated potassium channels and the newly identified antigens of the neuropil of hippocampus. Each category of antigens included several subgroups with distinctive clinical-immunological associations. While the encephalitides related to intracellular antigens are predominantly mediated by cytotoxic T-cell mechanisms and are poorly responsive to treatment, those related to cell membrane antigens appear to be mediated by antibodies and often respond to treatment. Among the newly identified antigens, the NR1/NR2B heteromers of the NMDA receptor are of great interest due to their critical role in synaptic plasticity and memory. Patients with antibodies against these receptors are young women with benign-appearing cystic tumors of the ovary (mature or immature teratomas), who develop a severe and characteristic encephalitis that we report in detail. Despite the severity of the disorder, patients often recover after treatment of the tumor and immunotherapy. CONCLUSIONS: Approximately 40 % of patients with classical or atypical limbic encephalitis develop relevant immune responses that are not identified by currently available commercial tests. Different from the previously known paraneoplastic antigens, which location is intracellular and associate with syndromes that are poorly responsive to treatment, the newly identified antigens of the neuropil of hippocampus are in the neuronal cell membrane and the related syndromes, although severe and potentially lethal, often respond to treatment.

Consensus definitions proposed for pediatric multiple sclerosis and related disorders.

BACKGROUND: The CNS inflammatory demyelinating disorders of childhood include both self-limited and lifelong conditions, which can be indistinguishable at the time of initial presentation. Clinical, biologic, and radiographic delineation of the various monophasic and chronic childhood demyelinating disorders requires an operational classification system to facilitate prospective research studies. METHODS: The National Multiple Sclerosis Society (NMSS) organized an International Pediatric MS Study Group (Study Group) composed of adult and pediatric neurologists and experts in genetics, epidemiology, neuropsychology, nursing, and immunology. The group met several times to develop consensus definitions regarding the major CNS inflammatory demyelinating disorders of children and adolescents. RESULTS: Clinical definitions are proposed for pediatric multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), recurrent ADEM, multiphasic ADEM, neuromyelitis optica, and clinically isolated syndrome. These definitions are considered operational and need to be tested in future research and modified accordingly. CONCLUSION: CNS inflammatory demyelinating disorders presenting in children and adolescents can be defined and distinguished. However, prospective research is necessary to determine the validity and utility of the proposed diagnostic categories.