Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Η βαριά μυασθένεια (Myasthenia Gravis, MG) είναι μια αυτοάνοση νόσος η οποία χαρακτηρίζεται από διαταραχή στη νευροδιαβίβαση στο επίπεδο της νευρομυϊκής σύναψης. Η διάγνωση της MG βασίζεται στην κλινική συμπτωματολογία η οποία συνεπικουρείται από φαρμακολογικές, ηλεκτροφυσιολογικές και απεικονιστικές δοκιμασίες και επιβεβαιώνεται συνήθως από την ορολογική ανίχνευση αυτοαντισωμάτων έναντι συστατικών της νευρομυϊκής σύναψης. Οι σύγχρονες διαγνωστικές δοκιμασίες είναι συνήθως ικανές προς ανίχνευση της παρουσίας αντισωμάτων στο 85-90% περίπου των μυασθενών με γενικευμένη MG και στο 50% περίπου των ασθενών με οφθαλμική MG. Το κενό αυτό στη διάγνωση της MG δημιουργεί ένα σημαντικό πρόβλημα στις περισσότερες περιπτώσεις που ελέγχονται επειδή ένα αρνητικό αποτέλεσμα (το οποίο είναι το συχνότερο αποτέλεσμα στη συνήθη εργαστηριακή διάγνωση της MG) αφήνει μία ασάφεια σχετικά με την ύπαρξη MG. Πράγματι, ακόμη και ένας πολύ χαμηλός τίτλος θα μπορούσε να είναι επαρκής για να εξηγήσει την παρουσία της μυασθένειας, δεδομένου ότι δεν έχει διαπιστωθεί σημαντική συσχέτιση μεταξύ του τίτλου των αντισωμάτων και της σοβαρότητας της νόσου στον πληθυσμό των ασθενών. Ως εκ τούτου, υπάρχει αυξανόμενη ανάγκη για την ανάπτυξη ιδιαίτερα ευαίσθητων διαγνωστικών μεθόδων, για την αναμφισβήτητη απόδειξη της νόσου. Η πλέον ευαίσθητη διαγνωστική δοκιμασία είναι η ραδιολογική ανοσοκαθίζηση (Radioimmunoprecipitation assay, RIPA) και ο πλέον σημαντικός περιοριστικός παράγων για την ανίχνευση χαμηλού τίτλου αντισωμάτων, είναι η αδυναμία χρήσης μεγάλου όγκου ορού (μέγιστο είναι ~5-20 μl), η οποία θα καθιστούσε αναγκαία την επακόλουθη χρήση υψηλού όγκου αντί-ορού και η οποία θα οδηγούσε σε υπερβολικά μεγάλα άνοσο-ιζήματα, τα οποία με τη σειρά τους συνδέονται με απαράδεκτα επίπεδα μη ειδικού θορύβου υπόβαθρου. Με την ανάπτυξη στην παρούσα μελέτη της RIPA δύο-σταδίων ξεπεράσθηκαν σε μεγάλο βαθμό τα προβλήματα αυτά. Η δοκιμασία αυτή βασίζεται στην ακινητοποίηση του αντιγόνου-στόχου σε ένα αδιάλυτο υπόστρωμα, ακολουθούμενη από την επώαση με μεγάλους όγκους (π.χ. 0,1-1ml) του προς εξέταση ορού και την επακόλουθη απελευθέρωση των προσδεμένων αντισωμάτων με μικρό όγκο διαλύματος χαμηλού pH, τα οποία στη συνέχεια ανιχνεύονται και τιτλοδοτούνται με απλή RIPA με τη χρήση 125I-σημασμένων αντιγόνων. Δηλαδή χρησιμοποιήθηκε η αρχή του καθαρισμού με χρωματογραφία συγγένειας με όχι αυστηρό αλλά με απλό και εύκολο τρόπο, προκειμένου να εμπλουτισθεί ο ορός σε μεγάλο βαθμό στα ειδικά για το αντιγόνο αντισώματα πριν από τον προσδιορισμό και την τιτλοποίηση τους με τις συνήθεις ανοσολογικές δοκιμασίες. Έγινε προσπάθεια ανάπτυξης της προσέγγισης αυτής για την ανίχνευση αντισωμάτων έναντι του AChR και έναντι της MuSK. Έγιναν πολλές προσπάθειες για την εφαρμογή της για την ανίχνευση αντί-AChR αυτοαντισωμάτων. Σημειώθηκε μεγάλη πρόοδος, αλλά απαιτούνται επιπρόσθετες βελτιώσεις για την εφαρμογή της στην διάγνωση ρουτίνας. Για την ανίχνευση των αντί-MuSK αυτοαντισωμάτων με την προσέγγιση αυτή επετεύχθη σημαντικότερη βελτίωση. Η παρούσα συστηματική προσέγγιση απεδείχθη τουλάχιστον 20-50 φορές περισσότερο ευαίσθητη από την κλασική RIPA. Όλοι οι οροί οι οποίοι είχαν χαρακτηρισθεί προηγουμένως ως θετικοί ή αρνητικοί με την κλασική RIPA βρέθηκαν όπως αναμενόταν επίσης θετικοί ή αρνητικοί αντίστοιχα. Επιπλέον όμως μερικοί εκ των ορών οι οποίοι στο παρελθόν είχαν χαρακτηρισθεί ως αμφίβολοι βρέθηκαν σαφώς θετικοί, ή μερικοί άλλοι οι οποίοι είχαν χαρακτηρισθεί ως αρνητικοί αλλά παρουσίαζαν τίτλους ελαφρά υψηλότερους του μηδενός, αλλά όχι στατιστικά σημαντικούς ώστε να αξιολογηθούν ως υψηλότεροι του υπόβαθρου, βρέθηκαν θετικοί, ενώ άλλοι εξακολουθούν να παραμένουν αρνητικοί. Η δοκιμασία που αναπτύξαμε ήταν αρχικά περισσότερο επίπονη από ότι η κλασική RIPA, αλλά με την ανάπτυξη σημαντικών βελτιώσεων, η διαδικασία αυτή έχει απλουστευθεί ώστε να είναι δυνατός ο ταυτόχρονος έλεγχος μεγάλου όγκου (0,1-1 ml) πολλαπλών δειγμάτων ορών και έχει καταστεί δυνατή η χρήση της στην καθημερινή διάγνωση. Η βελτιωμένη αυτή μέθοδος εφαρμόζεται σήμερα για την ανίχνευση αντί-MuSK αντισωμάτων και αποσκοπεί στην ανίχνευση πολύ μικρών ποσοτήτων αυτοαντισωμάτων στον ορό των μυασθενικών οι οποίοι έχουν χαρακτηρισθεί ως οροαρνητικοί ή αμφίβολοι. / Myasthenia Gravis (MG), is an autoimmune disease, characterized by impairment in neurotransmission at the neuromuscular junction level. The diagnosis of MG is based on clinical symptomatology, assisted by pharmacological, electrophysiological and imaging tests and is usually confirmed by serological detection of autoantibodies to components of the neuromuscular junction. The available diagnostic tests are usually able to detect the presence of antibodies in 85-90% of myasthenic patients with generalized MG and 50% of patients with ocular MG. This gap in the diagnosis of MG creates a major problem in most cases during diagnosis because a negative result (which is the most common result in ordinary laboratory diagnosis of MG) leaves an ambiguity regarding the existence of MG. Even a very low titer of specific antibodies, would be sufficient to explain the presence of myasthenia, since there has been no significant correlation between the titer of antibodies and the severity of disease among patients. Therefore, there is increasing need for the development of highly sensitive diagnostic methods for the unambiguous confirmation of the disease. The most sensitive diagnostic test so far, is the radiological immunoprecipitation assay (Radioimmunoprecipitation, RIPA) and the most important limiting factor for detecting low antibody titer, is the inability to use large volumes of serum (maximum is ~ 5- 20 ml), which would require the subsequent use of high-volume of anti-serum, which will result in excessively large immuno-sediments, which in turn are associated with unacceptable levels of nonspecific background values. With the development of two-step RIPA assay in this study we have largely overcome these problems. This test is based on the immobilization of target antigen to an insoluble substrate, followed by incubation with large volume (eg 0,1-1ml) of the test serum and release of bound antibodies with small volume of low pH solution, which are then detected and titrated with simple RIPA using 125I-labeled antigens. We used the principle of enrichment of serum to a large extent in antigen-specific antibodies by affinity purification with no strict but simple and easy way, before the final identification and titration of specific antibodies with standard immunoassays. We attempted the development of this approach in order to detect antibodies against AChR and MuSK. Numerous efforts have been made to implement this method in order to detect AChR autoantibodies, but although there was substantial progress, additional improvements are required for its application in routine diagnosis. With this approach we achieved significant improvement for detection of anti- MuSK autoantibodies. This systematic approach was proved to be at least 20-50 times more sensitive than classical RIPA. All sera which were previously classified as positive or negative with standard RIPA were also positive and negative respectively, as expected. In addition some of the sera which were previously classified as ambiguous were clearly positive and some others who were classified as negative but were slightly higher than zero, but not statistically significant so as to assess them as higher than the background, were positive, while others still remain negative. This newly developed test was originally more laborious than the classical RIPA, but with the development of significant improvements, the process has been simplified and allows the simultaneous testing of large volumes (0,1-1 ml) of multiple serum samples and its use has been made possible in everyday diagnosis. This improved method is currently applied to detect anti-MuSK antibodies and is designed to detect very small amounts of autoantibodies in the serum of myasthenic patients who are classified as seronegative or ambiguous.

Η Μυασθένεια είναι μια αυτοάνοση νόσος της νευρομυϊκής σύναψης που χαρακτηρίζεται από την παραγωγή αυτοαντισωμάτων έναντι, συνήθως, του AChR, καθώς και άλλων πρωτεϊνών της σύναψης. Στην παρούσα εργασία, πραγματοποιήθηκε μελέτη γενετικής συσχέτισης για την ταυτοποίηση πολυμορφισμών που πιθανώς εμπλέκονται στην εκδήλωση της Μυασθένειας. Για το σκοπό αυτό, επιλέχθηκαν πολυμορφισμοί οι οποίοι εδράζονται σε γονίδια που αποτελούν σημαντικούς ρυθμιστές της ανοσολογικής απόκρισης και έχουν προηγουμένως συσχετισθεί με άλλες αυτοάνοσες νόσους. Τα υποψήφια γονίδια είναι τα: interferon regulatory factor 5 (IRF-5), TNFα-induced protein 3 (TNFAIP3) και interleukin-10 (IL-10). Στη μελέτη συμμετείχαν 101 μυασθενείς και ισάριθμα υγιή άτομα ως ομάδα αναφοράς, όλοι ελληνικής καταγωγής. Οι μέθοδοι γονοτύπησης που εφαρμόσθηκαν περιλαμβάνουν τον προσδιορισμό αλληλουχίας κατά Sanger, την HRM ανάλυση, την PCR-RFLP και την PCR σε συνδυασμό με ηλεκτροφόρηση σε αγαρόζη, στην περίπτωση ενός in/del 30 bp. Μια στατιστική τάση συσχέτισης (p=0.068) ανιχνεύθηκε για τους πολυμορφισμούς στον υποκινητή της IL-10 μεταξύ των μυασθενών με πρώιμη ηλικία έναρξης της νόσου (early-onset) και αυτών που εμφάνισαν τη νόσο ηλικιακά αργότερα (late-onset). Για τους υπόλοιπους πολυμορφισμούς που μελετήθηκαν, δεν παρατηρήθηκαν στατιστικά σημαντικές διαφορές. Η μελέτη αυτή αποτελεί την πρώτη προσπάθεια συσχέτισης πολυμορφισμών των γονιδίων IRF-5 και TNFAIP3 με τη Μυασθένεια, σε οποιονδήποτε πληθυσμό. Όσον αφορά τους πολυμορφισμούς του υποκινητή της IL-10, περαιτέρω μελέτες σε πολυπληθέστερες ομάδες πιθανώς να αποκαλύψουν μια στατιστικώς ισχυρότερη συσχέτιση. / Myasthenia gravis (MG) is a heterogeneous autoimmune disease characterized by the production of autoantibodies against proteins of the postsynaptic membrane, in the neuromuscular junction. The contribution of genetic factors to MG susceptibility has been evaluated through family and twin studies, however, the precise genetic background of the disease remains elusive. We conducted a case-control association study in 101 unrelated MG patients, of Hellenic origin and 101 healthy volunteers in order to assess the involvement of common genetic variants in susceptibility to MG. We focused on three candidate genes which have been clearly associated with several autoimmune diseases, aiming to investigate their potential implication in MG pathogenesis. These are interferon regulatory factor 5 (IRF-5), TNFα-induced protein 3 (TNFAIP3), also known as A20, and interleukin-10 (IL-10), key molecules in the regulation of immune function. Genotyping was performed by PCR-RFLP, direct automated sequencing, High Resolution Melt curve Analysis (HRM) and PCR-agarose gel electrophoresis analysis in the case of a 30 bp in/del polymorphism. A statistical trend of association (p=0.068) between IL-10 promoter single nucleotide polymorphisms (SNPs) and the subgroups of early and late-onset MG patients was revealed. No statistically significant differences were observed in the rest of the variants examined. As far as we are aware, this is the first worldwide attempt to address the possible association between IRF-5 and TNFAIP3 common genetic variants and the genetic basis of MG.

Made available in DSpace on 2015-12-10T14:24:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-23. Added 1 bitstream(s) on 2015-12-10T14:30:08Z : No. of bitstreams: 1 000848649.pdf: 1399689 bytes, checksum: ae8884abe366a7d62cbc2bc66d58a529 (MD5) / Introdução: A miastenia gravis é uma doença que afeta a junção neuromuscular e leva a fraqueza da musculatura esquelética. O tratamento atual pode ser clínico ou cirúrgico através da ressecção completa do timo. Objetivo: Comparar, através de uma revisão sistemática da literatura, os resultados do tratamento cirúrgico e clínico da miastenia gravis. Métodos: Foi realizada uma busca nos principais bancos de dados a fim de encontrar ensaios clínicos randomizados que comparassem as duas modalidades terapêuticas. Como não existem estudos dessa categoria, foram selecionados aqueles com menor nível de evidência e que continham as duas intervenções, com pelo menos 10 pacientes em cada braço do estudo. A análise estatística foi feita com software StatsDirect, versão 3.0.121. Resultados: A busca encontrou 592 artigos na base Medline, 1925 artigos na base Embase e 204 artigos na base Lilacs. Após a exclusão dos estudos duplicados, 51 artigos foram analisados integralmente e nove foram selecionados para esta revisão. O número total de pacientes avaliados foi de 3.211. A mortalidade nos grupos cirúrgico e clínico foram respectivamente de 7 e 19%, com diferença estatística significante. A taxa de remissão nos grupos foi de 17% para o grupo cirúrgico e de 13% para o clínico, sem significância estatística. Para o desfecho melhora, o grupo cirúrgico apresentou uma taxa de 23% e o clínico de 29%, também sem diferença estatística. Conclusões: Apesar da baixa evidência disponível, a timectomia pode ser considerada uma opção terapêutica na miastenia gravis, com menores índices de mortalidade e taxas de remissão e controle semelhantes ao tratamento clínico / Introduction: Myasthenia gravis is a disease that affects the neuromuscular junction and leads to weakness of the skeletal muscles. Current treatment is guided by the clinical and surgical conduction through the complete resection of the thymus. Objective: Compare, through a systematic review, the results of surgical and medical treatment of myasthenia gravis. Methods: A search was conducted in major databases to find randomized controlled trials that compared the two treatment modalities. As there are no studies that category, were selected studies with a lower level of evidence and that contained both interventions and at least 10 patients in each arm of the study. Statistical analysis was performed with StatsDirect version 3.0.121 software. Results: The search found 592 articles in Medline, 1925 articles in the Embase and 204 articles in the Lilacs. After exclusion of duplicate studies, 51 articles were fully analyzed and nine were selected for this review. The total number of patients was 3,211. The mortality in the surgical and medical groups were respectively 7 and 19%, with significant differences. The remission rate in both groups was 17% for the surgical group and 13% for clinical, without statistical significance. To improve the outcome, the surgical group had a rate of 23% and 29% of the clinical, also no statistical difference. Conclusion: Despite the low available evidence, thymectomy may be considered a therapeutic option in myasthenia gravis, with lower rates of mortality and rates of remission and control similar to clinical treatment Keywords: myasthenia gravis, thymectomy, clinical treatment

Made available in DSpace on 2015-08-20T17:09:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-27. Added 1 bitstream(s) on 2015-08-20T17:26:14Z : No. of bitstreams: 1 000839732.pdf: 2196761 bytes, checksum: 01e9f7144c74e299f1fc89396be7049a (MD5) / No estado de São Paulo é comum aplicação de pesticidas na agricultura sem equipamentos de proteção, com grande exposição dos trabalhadores aos agentes tóxicos. O uso doméstico de inseticidas também é muito difundido. Foram demonstrados defeitos da transmissão neuromuscular, com miastenia, relacionados a pesticidas organofosforados. Inseticidas do grupo químico das piretrinas e piretróides, de uso doméstico, atuam sobre o sistema nervoso dos insetos e dos seres humanos. O objetivo deste trabalho foi procurar correlações entre Miastenia Grave e exposição crônica a pesticidas em nosso meio. Foi aplicado questionário sobre exposição a pesticidas em 217 pacientes com diagnóstico clínico e ENMG de Miastenia Grave, sendo 163 mulheres e 54 homens, com idades de 14 a 84 anos, provenientes dos serviços médicos da UNESP e UNIFESP, e em 227 controles, sendo 179 mulheres e 48 homens, com idades de 17 a 78 anos. Os dados foram analisados estatisticamente pelo Teste de Associação do Qui-quadrado. A análise estatística do total de pacientes expostos e não expostos sugeriu possível associação de exposição a pesticidas com miastenia grave (p < 0.0001) / In the São Paulo state is very common application of pesticides in agriculture without protective equipment, with great exposure of workers to the toxic agents, and domestic use of insecticides is also widespread. Neuromuscular transmission defects with myasthenia related to the organophosphate pesticides were demonstrated in human and animals. The chemical group of pyrethrins and pyrethroids has action on the peripheral nervous system of insects and humans. The aim of this study was to search correlations between Myasthenia Gravis and chronic exposure to pesticides in our geographic region. Questionnaires were applied on exposure to pesticides in 217 patients with clinical and EMG diagnosis of Myasthenia Gravis, 163 women and 54 men, aged from 14-84 years, seen in two medical services of UNESP and UNIFESP, and in 227 controls, 179 women and 48 men, aged from 17-78 years. Data were statistically analyzed by the Association Chi-square test. The statistical analysis of all patients exposed or not exposed suggested possible association of myasthenia gravis with chronic exposure to pesticides (p <0.0001)

Autoimmunity is a failure to tolerate circulating or cell surface expressed self antigens,leading to activation of the immune system and attack of self tissues. Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a disease caused by antibodies to MuSK and hallmarked by fatigable muscle weakness. MuSK is a tyrosine kinase that interacts with low-density lipoprotein receptor-related protein 4 (LRP4), resulting in maintenance of the high density of acetylcholine receptors (AChRs) at the neuromuscular junction; this high density is essential for efficient transmission of signals from nerve to muscle, and MuSK antibodies impair this transmission. MuSK antibodies are predominantly IgG4, a subclass that does not induce immunological damage. Thus how these antibodies cause neuromuscular junction dysfunction is not clear. Potential mechanisms of the MuSK antibodies were explored in in vitro experiments. Plasmas from fourteen MuSK-MG patients were studied. IgG antibodies and IgG subclass profiles were measured with flow cytometry. Total IgG, Fabs, IgG4 and IgG1-3 subclass antibodies were prepared and purified; these were used to investigate the effects on MuSK surface expression, binding of LRP4 to MuSK, and agrin-LRP4-MuSK-induced AChR clustering in C2C12 mouse myotubes. No evidence for MuSK endocytosis by MuSK IgG, IgG1-3 or IgG4 antibodies was found. The predominant IgG4 subclass, and the monovalent IgG Fabs, blocked binding between LRP4 and MuSK but both IgG4 and IgG1-3 subclass antibodies were equally able to disperse pre-formed and newly-induced AChR clusters in C2C12 myotubes. The block of LRP4-MuSK interaction by IgG4 antibodies is likely to be a major pathogenic mechanism in MuSK-MG, which may lead to disrupted signal transduction, reduced AChR aggregation and neuromuscular transmission failure at the neuromuscular junction. In addition, MuSK IgG1-3, until now described as nonpathogenic, may also contribute to the reduced AChR density and neuromuscular dysfunction in MuSK-MG. These results provide new evidence concerning the pathogenic antibodies and their mechanisms in MuSK-MG.

Bibliographic record ONDRÁČKOVÁ, Radka. Application of physiotherapy in treating myasthenia gravis. Prague: Charles University, 2nd Faculty of Medicine, Department of Rehabilitation and Sports Medicine, 2015, p. 90, Supervisor of the work: Doc. PaedDr. Libuše Smolíková, Ph.D. Abstract Myasthenia gravis is an autoimmune disease affecting the neuromuscular transmission. It manifests in muscular weakness and tiredness, which characteristically fluctuate and change throughout the time. The most typically affected muscles are extraocular, mimic, oropharyngeal and the muscles of lower and upper extremities. The danger of respiratory difficulties is aggravated by worsening physical condition, which comes as a consequence of muscular weakness and with the onset of the myasthenic crisis. The work is focused on the use of respiratory physiotherapy and aerobic physical activity in patients with myasthenia gravis. The aim is to verify the effect of respiratory physiotherapy and aerobic physical activity to improve lung function and condition, and the disease stabilization. Keywords Myasthenia gravis, neuromuscular disease, physiotherapy, respiratory physiotherapy, aerobic training

Introdução: A miastenia gravis (MG) é uma doença autoimune caracterizada por diminuição da força nos músculos voluntários, que se agrava com o esforço, podendo evoluir com alterações de voz e deglutição. Objetivo: Caracterizar as manifestações laríngeas da MG. Métodos: Foi realizado um estudo transversal por meio da avaliação de 37 pacientes portadores de MG, no período de maio de 2015 a novembro de 2016. Os pacientes foram recrutados no Ambulatório de Neurologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP. Além dos dados clínicos e demográficos, todos os pacientes foram analizados pelo Índice de Desvantagem Vocal-10 (IDV-10), análise perceptivo-auditiva da voz, videolaringoestroboscopia e videoendoscopia da deglutição. Resultados: Na avaliação de voz, foi identificada disfonia em 89,2% dos sujeitos, sendo 59,5% de grau discreto e 29,7% moderado a grave. A autopercepção da desvantagem vocal foi significativamente maior nos pacientes diagnosticados com algum grau de disfonia. Foram identificadas alterações anatômicas em 8 pacientes à videolaringoestroboscospia. Ao comparar o grau da doença com as variáveis contração faríngea e sensibilidade laríngea na VED, observou-se maior ocorrência nos sujeitos com doença mais avançada e comprometimento bulbar. A associação entre as alterações de sensibilidade laríngea e estase indicou que os pacientes com ausência de sensibilidade tiveram estase para saliva, líquido e principalmente para purê e sólido. Conclusões: Portadores de MG apresentam alterações de voz e deglutição relacionadas à doença. A disfonia causa um impacto na vida do paciente com diagnóstico de MG. As alterções da deglutição estiveram presentes em pacientes com acometimento generalizado e maior evolução da doença / Introduction: Myasthenia gravis (MG) is an autoimmune disease characterized by a reduction in the strength of the voluntary muscles, aggravated by effort, with the possibility of developing with voice and deglutition disorders. Objective: Characterize the laryngeal manifestations of MG. Methods: A tranversal study was carried out by evaluating 37 patients with MG in the period between May 2015 and November 2016. Patients were recruited in the Neurology outpatient center at the Hospital das Clínicas, \"Faculdade de Medicina, Universidade de São Paulo\". Besides clinical and demographic data, all patients were analyzed according to the Vocal Disadvantage Index-10 (VDI-10), auditory-perceptual voice analysis, videolaryngostroboscopy and videoendoscopy of swallowing. Results: In the voice evaluation, dysphonia was identified in 89.2% of patients, 59.5% with a discreet degree and 29.7% from moderate to severe. Self-perception of the vocal disadvantage was significantly greater in patients diagnosed with some degree of dysphonia. Anatomical changes were identified in 8 patients through viodeolaryngostroboscospy. When comparing the degree of the disease with the variables pharyngeal contraction and laryngeal sensitivity in the VED, a greater incidence in patients with a more advanced disease and bulbar involvement was noticed. The association between the changes in laryngeal sensitivity and stasis showed that patients with a lack of sensitivity had stasis for saliva, liquid and mainly for purée and solids. Conclusions: MG patients present changes in voice and deglutition related to the disease. Dysphonia causes a great impact in the life of the patient diagnosed with MG. Changes in deglutition were present in patients with generalized involvement and greater progression of the disease

INTRODUÇÃO: A técnica de eletromiografia de fibra única (EMGFU), mediante análise do jitter, é o método neurofisiológico mais sensível para a confirmação do distúrbio da junção neuromuscular na miastenia gravis (MG). Os registros são tradicionalmente obtidos com agulha de fibra única, de alto custo e reutilizável. Por causa da necessidade atual do uso de material descartável, a agulha concêntrica vem sendo utilizada em substituição à agulha de fibra única. A técnica utilizada é semelhante, porém os potencias de ação para a análise do jitter são obtidos com eletrodo de agulha concêntrica (Eletromiografia de fibra única - jitter com agulha concêntrica, EMGFU-JAC). Contudo, os estudos são escassos e as metodologias utilizadas são heterogêneas com a utilização dessa agulha. OBJETIVOS: Este estudo tem por objetivo mensurar os valores de jitter obtidos com agulha concêntrica, no músculo Orbicularis Oculi, em sujeitos saudáveis e em pacientes com MG autoimune adquirida e avaliar a validade do método nas formas generalizada e ocular da doença. MÉTODOS: Foram estudados 20 sujeitos saudáveis, 20 pacientes com miastenia gravis forma generalizada (grupo MGG) e 13 com a forma ocular da doença (grupo MGO). A EMGFU-JAC foi realizada em todos os participantes, idealmente com 20 medidas de jitter em cada estudo. O jitter foi expresso como a média das diferenças consecutivas (MCD). Em todos os pacientes do estudo foram realizados o teste de estimulação repetitiva e dosagem sérica de anticorpo antirreceptor de acetilcolina (ac-AChR) no momento da análise do jitter. Nos pacientes soronegativos para ac-AChR, foi pesquisado o anticorpo antimúsculo específico tirosina-quinase (ac-MuSK). Foram definidos o limite superior da normalidade (LSN) para a média do MCD de cada estudo e para valores individuais de MCD. Os critérios de anormalidade foram: (1) média do MCD acima do LSN; ou (2) mais de 10% dos valores individuais de MCD acima do LSN. A definição do LSN para valores individuais de MCD baseou-se no conceito de que dois entre 20 valores de MCD acima do LSN são aceitáveis em um músculo saudável, para a técnica de contração voluntária. Portanto, estimou-se o LSN para o 18o valor mais alto de MCD (18o par). Para análise da acurácia do método, foram construídas duas curvas ROC (Receiver Operating Characteristic) para as variáveis média do MCD e 18o par, no grupo de pacientes (MGG e MGO) versus controle. RESULTADOS: No grupo controle a média das médias do MCD foi (19,0 ± 2,4)us e a média do 18o valor mais alto de cada estudo foi (24,5 ± 3,6)us. Esses valores obtidos apresentaram distribuição Gaussiana e o LSN foi definido como a média desses valores + 2 DP. O LSN para a média do MCD foi 24us, e 32?s para valores individuais de MCD. No grupo MGG, a análise do jitter foi anormal em todos os 20 pacientes por ambos os critérios de anormalidade, exceto em um paciente que apresentou anormalidade por apenas um dos critérios. No grupo MGO, apenas um dos 13 pacientes não preencheu os critérios de anormalidade. No grupo de pacientes, a positividade da EMGFU-JAC foi maior do que o teste de estimulação repetitiva e dosagens de anticorpos. Nas curvas ROC para as variáveis médias do MCD e 18o par, o valor de melhor sensibilidade (93,9%), sem resultados falsos positivos, foi 24,7us e 33,1us, respectivamente. CONCLUSÕES: A EMGFU-JAC apresenta alta sensibilidade e especificidade na identificação de distúrbio da transmissão neuromuscular em pacientes com MG. A utilização da agulha concêntrica é válida para a análise do jitter, como alternativa à agulha de fibra única / INTRODUCTION: Single fiber electromyography (SFEMG) technique, through jitter analysis, is the most sensitive neurophysiological method for confirmation of neuromuscular junction disorder in myasthenia gravis (MG). Records are traditionally obtained with single fiber needle, which is reusable and has a high-cost. Due to the current need of using disposable material, concentric needle has been used to replace single fiber needle. The technique is similar, but the action potential for jitter analysis is obtained with concentric needle electrode (SFEMG - concentric needle jitter, SFEMG-CNJ). However, studies are scarce and methodologies used are heterogeneous with the use of this needle. OBJECTIVES: This study aims to measure jitter values obtained with concentric needle in the Orbicularis Occuli muscle in healthy subjects and in patients with autoimmune acquired MG and to assess the validity of the method in generalized and ocular forms of the disease. METHODS: 20 healthy subjects, 20 patients with generalized myasthenia gravis (GMG group) and 13 with the ocular form of the disease (OMG group) were studied. SFEMG-CNJ was performed on all participants, ideally with 20 jitter values in each study. Jitter was expressed as the mean consecutive difference (MCD). Repetitive nerve stimulation and serum acetylcholine receptor antibody (AChR-ab) were performed in all patients in the study, by the time of jitter analysis. Tyrosine kinase specific antibody muscle antibodies (MuSK-ab) were performed in AChR-ab negative patients. The upper limit of normality (ULN) for the mean MCD and for individual jitter values were defined. The abnormality criteria were: (1) mean MCD above ULN; or (2) more than 10% of individual jitter values above ULN. The definition of ULN for individual jitter values was based on the concept that two out of 20 jitter values above ULN are acceptable in a healthy muscle for voluntary contraction technique. Therefore, the ULN for the 18th highest jitter value (18 pair) was estimated. To analyze the method\'s accuracy, two ROC curves (Receiver Operating Characteristic) for the mean MCD and 18th pair in the group of patients (MGG and MGO) versus control were constructed. RESULTS: In the control group the mean of MCD means was (19.0 ± 2.4)us and the mean of the 18 highest value of each study was (24.5 ± 3.6)us. These values showed Gaussian distribution and the ULN was set as the mean of these values + 2 SD. The ULN for the mean MCD was 24us, and 32us for individual values of MCD. In GMG group, jitter analyses were abnormal in all 20 patients based on both abnormality criteria, except in one patient, who had abnormalities in only one of the criteria. In OMG group, only one patient from 13 met neither of the abnormality criteria. In patients, the positivity of SFEMG-CNJ was higher than repetitive nerve stimulation test and antibody detection. The ROC curve threshold showing the best sensitivity (93.9%) with no false positive results was 24.7Us for the mean MCD and 33.1us for individual pairs, respectively. CONCLUSIONS: SFEMG-CNJ has high sensitivity and specificity in identifying neuromuscular transmission disorder in patients with MG. The use of concentric needle is valid for jitter analysis as an alternative to single fiber needle

<p>Myasthenia gravis (MG) is an autoimmune neuromuscular disorder that causes fluctuating muscle weakness. MG may be divided into an ocular form and a generalized form based on the involved muscles. Treatment differs between these different MG forms. The majority (80%) of patients with generalized MG are seropositive for antibodies against the acetylcholine receptor (AChR-Ab). Recently a new antibody was detected against muscle specific tyrosine kinase (MuSK) in about 40% of patients who are AChR-Ab seronegative. A few patients with MuSK-Abs have muscular atrophies, as well as electrophysiological myopathy.</p><p>In this thesis we have characterized MuSK-Ab seropositive [MuSK(+)] patients using clinical parameters, including health-related quality of life (hrQoL), neurophysiology and muscle morphology, and compared them to patients with and without AChR-Abs. The question concerned which factors contribute to their muscle weakness. Additionally, we wanted to determine if single-fiber electromyography (SFEMG) in a limb muscle has any predictive value for generalization of ocular MG. </p><p>Our results suggest that MuSK(+) patients more often have a myopathic electromyography pattern, although this pattern is found also in other immunological subtypes of MG. The myopathic pattern may be associated with the frequently found mitochondrial abnormalities. However, disturbed neuromuscular transmission is the primary cause of muscle weakness in the majority of MuSK(+) patients, as well as in AChR-Ab seropositive patients. The disease-specific hrQoL MG questionnaire was successfully validated into Swedish and these scores correlated with disturbed neuromuscular transmission in a proximal arm muscle. Abnormal SFEMG findings occur also in muscles outside of the facial area in ocular MG, although this is not predictive of subsequent generalization. </p><p>MuSK (+) patients have little or no beneficial effect of acetylcholine esterase inhibitors (AChEI). On the contrary AChEI may produce profound adverse effects. We present the hypothesis that this effect of AChEI is due to abnormal receptor morphology in MuSK(+) patients.</p>