L'inactivité physique est considérée comme le 4ème facteur de risque de décès dans le monde. Aujourd’hui un défi de santé publique est d’augmenter l’activité physique (AP) des citoyens. Cependant, l'augmentation du volume et de l'intensité de l'AP peut être impossible ou déconseillée dans certaines populations. La myasthénie auto-immune (MG) est une maladie rare dans laquelle un dysfonctionnement de la jonction neuromusculaire provoque une faiblesse et une fatigue. Les symptômes peuvent entraîner une déficience fonctionnelle et une activité réduite, menant à un déconditionnement secondaire. Le présent travail a étudié les symptômes cliniques, la qualité de vie et l'activité physique dans une cohorte de sujets atteints de MG. Les données présentées ici montrent que certaines personnes mènent un mode de vie sédentaire mais d'autres participent à des activités physiques régulières et de haute intensité. La qualité de vie ne semble pas être liée aux comportements d'activité physique et n'est pas améliorée par l'ajout d'un programme d'exercice structuré. Notamment, il a été démontré que l’exercice est sans danger dans les cas de MG stabilisée. De plus, l'exercice procure d'autres avantages tels qu’une meilleure capacité de marche et une éventuelle augmentation sensible de la force. Enfin, nous révélons que même si la fatigue est un symptôme caractéristique de la MG, nous n’avons pas trouvé de fatigue musculaire supérieure à celle de témoins sains, ce qui suggère que la fatigue perçue pourrait davantage être liée à la faiblesse musculaire. En conclusion, nous recommandons qu'un programme d’exercice physique adapté et sur-mesure soit proposé aux personnes atteintes de MG afin de prévenir le déconditionnement et les comorbidités secondaires. Des recherches supplémentaires sont nécessaires pour définir le type et le dosage optimal de l'exercice.Myasthénie auto-immune, qualité de vie, activité physique, exercice physique, fatigue / Physical Activity and Quality of Life in Auto-Immune Myasthenia GravisPhysical inactivity is considered the 4th leading risk factor for death worldwide, linked to increased chronic disease and social isolation. Public health campaigns to encourage increased activity are rife. However, increasing physical activity levels and intensities may not be possible or advised in certain patient populations. Myasthenia gravis (MG) is a rare, auto-immune disease in which dysfunction at the neuromuscular junction causes weakness and fatigue. Symptoms can cause functional impairment and reduced activity, creating the increased burden of deconditioning in addition to primary disease symptoms. The present work investigated clinical symptoms, MG-specific health-related quality of life and activity levels in individuals with MG. Data presented here show that whilst some individuals lead a sedentary lifestyle, others participate in regular, high-intensity exercise. QoL does not seem to be related to physical activity patterns and is not improved with the addition of a structured exercise program. Exercise provides other benefits such as increased walking capacity and a possible increase in strength. Importantly, exercise has been shown to be safe in stabilized myasthenia. Finally, we reveal that whilst fatigue is a hallmark symptom in MG, formal testing demonstrated that muscle fatigue was not greater than healthy controls suggesting that perceived fatigue may be related to weakness. In light of these results we would recommend that subjects with MG are encouraged to reduce their daily sedentary behaviour and to undertake a regular exercise program to prevent deconditioning and potentially improve functional capacities. The optimal type and dosage of exercise remains to be elucidated.

Autoimmune myasthenia gravis (MG) is a muscular disease mediated by autoantibodies, mainly directed against the acetylcholine receptor (AChR). The pathogenic antibodies are especially produced in the thymus, which is often characterized by a hyperplasia with germinal centers. Recent studies demonstrated the overexpression of chemokines and the abnormal development of high endothelial venules (HEV) in the MG thymus. The aim of my thesis was to better understand the mechanisms that lead to thymic hyperplasia in MG by analyzing the role of chemokines in peripheral cell recruitment. We demonstrated that the number of HEVs correlated with the degree of hyperplasia suggesting a direct link between HEVs and peripheral cell recruitment. To define its mechanism of action, we examined which chemokines were expressed on thymic HEVs. We uniquely detected SDF-1 and observed that B cells, myeloid dendritic cells (mDCs), plasmacytoid DCs and monocytes/macrophages that expressed the SDF-1 receptor CXCR4 localized inside and around thymic HEV. In parallel we observed a decreased CXCR4 expression and a decreased number of mDCs and also monocytes in the periphery suggesting their recruitment to the MG thymus. As the MG thymus was recently characterized by the overexpression of CXCL13 in thymic epithelial cells (TECs), we investigated its contribution to thymic hyperplasia. We therefore generated a transgenic mouse model overexpressing in medullary TECs CXCL13 under the control of keratin 5. We demonstrated that transgenic K5-CXCL13 mice specifically overexpressed CXCL13 in the thymus, while no other tested chemokines were upregulated. Preliminary results showed that elevated levels of CXCL13 resulted in an increased number of B cells in the thymus of transgenic mice, which localized preferentially in loose aggregates in medullary areas. We are presently investigating if immunization with purified AChR induces experimental MG with thymic hyperplasia in these mice. Myasthenic mice with a hyperplastic thymus could present a new animal model for MG with a phenotype that is closer to the human disease than the current MG model. As the hyperplastic MG thymus displays the hallmarks of a viral signature, we investigated the effect of pathogen-associated molecules on thymic changes associated with MG. We demonstrated that dsRNA signaling induced by Poly(I:C) specifically triggers the overexpression of α-AChR in human TECs through the release of IFN-I. We also observed that IFN-I was able to upregulate CXCL13 and CCL21, similarly to what is observed in the MG thymus. In addition, Poly(I:C) injections in wildtype mice, but not in IFN-I receptor KO mice, specifically increase thymic expression of α-AChR and, in parallel, CXCL13 and CCL21 expression. In periphery, Poly(I:C) even induced an anti-AChR autoimmune response characterized by a significant production of serum anti-AChR antibodies and a specific proliferation of B cells. Overall the results obtained in the course of my PhD showed that the abnormal development of SDF-1-expressing HEVs and the CXCL13 overexpression play a central role in the recruitment of peripheral cells to the MG thymus. Once these cells have arrived in the inflammatory environment, which is characteristic for MG, they could develop an autoimmune reaction against AChR. New therapeutic molecules that control chemokine expression and angiogenic processes could diminish the development of thymic hyperplasia and avoid thymectomy or the use of corticoids.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-24T20:16:20Z No. of bitstreams: 1 Ezequiel Fernandes de Oliveira.pdf: 6004865 bytes, checksum: 1533cb1828601a79b30eb9ae6ce24420 (MD5) / Made available in DSpace on 2016-05-24T20:16:20Z (GMT). No. of bitstreams: 1 Ezequiel Fernandes de Oliveira.pdf: 6004865 bytes, checksum: 1533cb1828601a79b30eb9ae6ce24420 (MD5) Previous issue date: 2014-12-01 / Introduction: Autoimmune myasthenia gravis is an chronic disease inflammatory characterized by progressive weakness of the skeletal muscles due to a change in the synapses between the nerves and muscle fibers. The manifestations of the respiratory system are generally attributed to the weakness of the diaphragm and other accessory muscles of ventilation leading to breathlessness. Among these manifestations, we highlight the onset of sleep-disordered breathing (SDB) due to weakening of the muscles of the oropharynx. Objectives: To verify the lung function, respiratory muscle strength, and physiological variables during sleep in patients with myasthenia gravis clinically stable. Methods: This is a prospective cross-sectional descriptive study, following a study protocol previously published. Patients were recruited consecutively from the Setor de Investigação de Doenças Neuromusculares of the Universidade Federal de São Paulo in accordance with the eligibility criteria, and referred to the Sleep Laboratory of Universidade Nove de Julho, São Paulo (Brazil). Results: The study included 18 patients The mean age of 42,66±10,91 (15 women). Regarding lung function only two patients had a restrictive ventilatory pattern. The maximum ventilatory pressures observed were considerably reduced in most patients when compared to reference values. Regarding sleep, highlight observe a significant decrease in oxyhemoglobin saturation, reduced REM sleep time, increased stage NREM3, considerable increase of apnea and hypopnea per hour and a high risk for obstructive sleep apnea. Discussion: Data on sleep-related disorders in patients with Autoimmune myasthenia gravis in the literature are scarce and inconclusive, with few studies using basal nocturnal polysomnography. Conclusion: Clinically stable patients with autoimmune myasthenia gravis have a high prevalence of sleep respiratory disorders and a significant reduction in maximal inspiratory and expiratory pressures with reduced quality of life. / Introdução: A Miastenia gravis auto imune adquirida é uma doença crônica, inflamatória, caracterizada pela fraqueza progressiva dos músculos esqueléticos, devido a uma alteração na junção sináptica entre os nervos e as fibras musculares. As manifestações no sistema respiratório geralmente são atribuídas à fraqueza do músculo diafragma e demais músculos acessórios da ventilação levando à dispneia. Dentre estas manifestações, destacamos o surgimento dos transtornos respiratórios do sono (DRS) devido ao enfraquecimento da musculatura da região orofaríngea. Objetivos Verificar a função pulmonar, a força muscular ventilatória e as variáveis fisiológicas do sono em pacientes com Miastenia gravis. Métodos: Trata-se de um estudo transversal descritivo prospectivo. Os pacientes foram recrutados de forma consecutiva do Setor de Investigação de Doenças Neuromusculares da Universidade Federal de São Paulo de acordo com os critérios de elegibilidade, seguindo um protocolo padronizado e encaminhados ao Laboratório do Sono da Universidade Nove de Julho, São Paulo (Brasil). Resultados: Participaram deste estudo 18 pacientes com média de idade de 42,66±10,91 (15 mulheres). Em relação a função pulmonar apenas dois pacientes apresentaram um padrão ventilatório restritivo. As pressões ventilatórias máximas observadas foram consideravelmente reduzidas na maioria dos pacientes quando comparados a normalidade. Em relação ao sono, observamos uma queda significativa da saturação da oxihemoglobina, reduzido tempo de sono REM, aumento do estágio NREM3, considerável aumento do índice de apneia e hipopneia. Discussão Os dados sobre transtornos relacionados ao sono e qualidade do sono em Miastenia gravis na literatura são escassos e baseados nos resultados inconclusivos, com poucos estudos realizados por meio de polissonografia basal noturna. Conclusão: Pacientes com MG auto imune adquirida apresentam uma alta prevalência de distúrbios respiratórios sono e uma significativa redução das pressões máximas inspiratórias e expiratórias com consequente comprometimento da qualidade de vida.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-25T18:25:43Z No. of bitstreams: 1 Sergio Roberto Nacif.pdf: 1795162 bytes, checksum: 7b6d72682614593467c7e6265c34a637 (MD5) / Made available in DSpace on 2016-05-25T18:25:43Z (GMT). No. of bitstreams: 1 Sergio Roberto Nacif.pdf: 1795162 bytes, checksum: 7b6d72682614593467c7e6265c34a637 (MD5) Previous issue date: 2014-12-16 / Introduction: Obstructive sleep apnea (OSA) is a breathing disorder characterized by the collapse of the upper airway and has significant prevalence in the general population and specifically in neuromuscular diseases. Objective: To determine the effectiveness of the negative expiratory pressure (NEP) test as a screening to the OSA in myasthenia gravis patients. Method: The study included 15 patients (12 women) from the Setor de Investigação de Doenças Neuromusculares and Associação Brasileira de Miastenia Grave (ABRAMI), which underwent overnight standard polysomnography (PSG), spirometry, manovacuometer and NEP test. Results: The mean age was 41.46 ± 11.32 years, mean weight of 78.4 ± 15.28 kg and the mean body mass index was 29.34 ± 5,3kg / m2. The physiological variables of sleep observed in PSG draw attention to the oxygen saturation nadir, for the sleep latency and total sleep rapid eyes movement (REM) time, apnea-hypopnea index (AHI) and snoring time. The mean AHI was 17.5 ± 21.7, being most obstructive origin events. Regarding the Berlin Questionnaire, only one of the fifteen patients evaluated presented low risk for OSA. Regarding the Epworth Sleepiness Scale, we observed that six patients (40%) did not presented excessive daytime sleepiness, three (20%) had mild drowsiness, five individuos presented moderate (33.4%) and only one patient (6.6%) was classified with severe excessive daytime sleepiness with a score of 22 to a maximum of 24 points. The statistics analyses verify the existence of correlation between anthropometric variables, physiological PSG variables, Epworth Sleepiness Scale and Berlin questionnaire show higher values for body mass index (BMI), waist circumference and AHI. Conclusion: We can conclude that patients with MG have lower values of ventilatory maximum pressures associated with normal lung function. They also feature a considerable number of sleep disordered breathing associated with fall oxyhemoglobin saturation and reduced REM sleep, with consequent presence of excessive daytime sleepiness and high risk for OSA. Although we did not observe a correlation between the PNE test with AHI, our data show that patients with moderate-severe OSA have greatly reduced V0,2% (<20%). / Introdução: A apneia obstrutiva do sono (AOS) é um distúrbio respiratório caracterizado pelo colapso da via aérea superior com importante prevalência na população em geral e especificamente nas doenças neuromusculares. Objetivo: Verificar a eficácia do teste da pressão negativa expiratória (PNE) como proposta de screening para AOS em pacientes com Miastenia gravis. Método: Participaram deste estudo 15 pacientes (12 mulheres) provenientes do Setor de Investigação de Doenças Neuromusculares e Associação Brasileira de Miastenia Grave, os quais foram submetidos à polissonografia basal noturna (PSG), espirometria, manovacuometria e teste da PNE. Resultados: A média de idade foi de 41,46 ± 11,32 anos, peso médio de 78,4 ± 15,28 kg e o índice de massa corpórea médio foi de 29,34 ± 5,3kg/m2. As variáveis fisiológicas do sono observadas na PSG chamam a atenção para a saturação periférica mínima de oxigênio, para a latência e tempo total de sono REM, IAH e tempo de ronco. O IAH médio foi de 17,5 ± 21,7 sendo a maioria eventos obstrutivos. A análise estatística para verificação da existência de correlação entre as variáveis PNE e IAH mostrou um R de -0,5 com um valor de p= 0,06 e, para PNE/IDO/h um R -0,45 com um valor de p= 0,08. Quando correlacionamos os valores obtidos no teste de PNE com pressões de -6 e -10cm/H2O observamos uma excelente correlação de R = 0,825 com um p = 0,0000. Em relação ao questionário clínico de Berlim, dos quinze pacientes avaliados apenas um apresentou baixo risco para AOS. As análises estatísticas para verificação da existência de correlação entre as variáveis antropométricas, fisiológicas da PSG, escala de Epworth e questionário de Berlim mostram valores significativos apenas para o IMC, circunferência abdominal e IAH. Conclusão: Pacientes com MG apresentam redução das pressões máximas ventilatórias associado a função pulmonar normal. Também apresentam um considerável IAH associado a queda da saturação da oxihemoglobina e redução do sono REM, com consequente presença de sonolência excessiva diurna e alto risco para AOS. Embora não tenha sido observado uma correlação entre o teste do PNE com o IAH, nossos dados mostram que pacientes com Myasthenia gravis com AOS moderada-grave apresentam grande redução do V0,2%.

No description available.

Congenital myasthenic syndrome (CMS) and myasthenia gravis (MG) are, respectively, inherited or autoimmunological disorders caused by aberrant neuromuscular transmission, which manifests as fatiguable muscle weakness. A novel subtype of CMS, resulting from mutations in GFPT1 and characterised by a limb girdle pattern of muscle weakness, has been described. The gene encodes L glutamine:D fructose-6-phosphate amidotransferase 1 (GFAT1) – a key rate limiting enzyme in the hexosamine biosynthetic pathway, providing building blocks for glycosylation of proteins and lipids. The research focused on the molecular bases of the CMS resulting from mutations in the ubiquitously expressed gene, but with symptoms largely restricted to the neuromuscular junction (NMJ). The work has established a link between the NMJ and GFPT1 CMS by demonstrating that the AChR cell surface is decreased in GFPT1 patient muscle cells and in GFPT1-silenced cell lines. The decrease is likely to be caused by reduced steady-state levels of individual AChR α, δ and ε, but not β, subunits. To optimise treatment for myasthenic disorders, a comparative in vivo trial of therapy with pyridostigmine bromide and salbutamol sulphate, and pyridostigmine bromide alone, was conducted. Supplementation of the AChE inhibitor-based therapy with the β2-adrenergic receptor agonist had a beneficial effect. This offers promise for more effective treatments for CMS and MG affected individuals. Molecular causes of MG were also investigated. The search for novel antibody targets was conducted with the use of a designed cell-based assay for the detection of anti COLQ autoimmunoglobulins in MG patient sera. The antibodies were detected in 24 out of 418 analysed samples, but their pathogenicity has not been determined.

Congenital myasthenic syndromes (CMS) are a group of heterogeneous disorders caused by mutations in genes encoding for proteins that are essential for neuromuscular transmission. All CMS share the clinical feature of fatigable muscle weakness. The differential diagnosis of CMS is wide, with a range of diseases going from autoimmune myasthenia gravis to muscle disorders. In this thesis, it was shown that measuring antibodies to clustered acetylcholine receptors (AChRs) by cell-based assay is helpful in the differential diagnosis of CMS. The findings of the current investigations showed that mutations in COL13A1, encoding the Collagen Type XIII α1 chain, were responsible for the symptoms of several patients with previously undefined myasthenias. In addition, this work described the clinical and complementary features of a novel CMS subtype due to mutations in the glycosylation pathway gene GMPPB. Investigations on a novel MUSK missense mutation (p.Ala617Val) uncovered previously unrecognised mechanisms of how levels of MuSK phosphorylation are critical to maintain synaptic structure, and guided suitable treatment for the patient. The study on the clinical and molecular basis of stridor, a novel clinical feature recently identified in patients with DOK7-CMS, prompted the identification of a novel DOK7 isoform, which warrants further investigation to elucidate its role in AChR clustering. Finally, the therapy of patients with severe AChR-deficiency was optimised thanks to a case series study that showed a robust improvement following the addition of β2-adrenergic agonists to their long-term treatment regime that included pyridostigmine.

Σκοπός: Η θυμεκτομή αποτελεί κοινώς αποδεκτή θεραπεία της μυασθένειας με τις διάφορες προσπελάσεις να αναφέρονται ως ανάλογης αξίας για την επίτευξη ύφεσης της νόσου. Έχοντας πλέον την μόνιμη σταθερή ύφεση ως καθαρή και μετρήσιμη νευρολογική έκβαση των μυασθενικών ασθενών μετά θυμεκτομή και γνωρίζοντας ότι η ύφεση της νόσου αποτελεί χρόνο-εξαρτώμενο γεγονός, πραγματοποιήσαμε μια αναδρομική μελέτη των ασθενών με μυασθένεια που αντιμετωπίστηκαν χειρουργικά με σκοπό τον πιο αξιόπιστο καθορισμό του ρόλου των μεγίστων θυμικών εκτομών και την ταυτοποίηση προγνωστικών παραγόντων για ύφεση της νόσου μετά θυμεκτομή. Υλικό και μέθοδος. Η μελέτη περιλαμβάνει 78 ασθενείς που υποβλήθηκαν σε τροποποιημένη μέγιστη θυμεκτομή από το 1990 έως το 2007. Οι ενδείξεις θυμεκτομής περιελάμβαναν: οφθαλμική μυασθένεια ανθιστάμενη στη φαρμακευτική αγωγή, γενικευμένη μυασθένεια και μυασθένεια με θύμωμα. Τα στοιχεία που συλλέχθηκαν αφορούσαν τη βαρύτητα της νόσου (τροποποιημένη Osserman ταξινόμηση), την προεγχειρητική φαρμακευτική αγωγή, την ηλικία έναρξης της νόσου (≤ 40/ > 40 έτη), το χρονικό διάστημα που μεσολάβησε από τη διάγνωση στη θυμεκτομή (≤ 12/ > 12 μήνες), το φύλο, την ιστολογία του θύμου αδένα, τη θνητότητα και τις επιπλοκές. Στους ασθενείς με θύμωμα περαιτέρω στοιχεία που ελήφθησαν υπόψη αφορούσαν τον ιστολογικό τύπο του θυμώματος κατά την Παγκόσμια Οργάνωση Υγείας και το στάδιο του όγκου κατά Masaoka. Η εκτίμηση της νευρολογικής έκβασης στο τέλος του μετεγχειρητικού follow up έγινε βάση της νέας ταξινόμησης του Αμερικανικού Ιδρύματος για τη Βαρεία Μυασθένεια με την πλήρη σταθερή ύφεση να λαμβάνεται υπόψη για τον καθορισμό της επάρκειας της διενεργηθείσας εκτομής και για τη σύγκριση των αποτελεσμάτων μας με αυτά προηγουμένων μελετών. Η στατιστική ανάλυση των αποτελεσμάτων έγινε με το SPSS 17 και αφορούσε δύο ομάδες ασθενών ανάλογα με την παρουσία ή μη θυμώματος. Η μέθοδος Kaplan-Meier χρησιμοποιήθηκε για την εκτίμηση της επίπτωσης των υπό εκτίμηση προγνωστικών παραγόντων στην επίτευξη της πλήρους ύφεσης ενώ η Cox Regression ανάλυση αποτέλεσε το μοντέλο για την ανάλυση της ταυτόχρονης επίδρασης των υπό μελέτη παραμέτρων στην επίτευξη πλήρους σταθερής ύφεσης. Τιμές του p < 0.05 θεωρήθηκαν στατιστικά σημαντικές. Αποτελέσματα: 51 ασθενείς είχαν μυασθένεια χωρίς θύμωμα και 27 ασθενείς παρανεοπλασματική μυασθένεια. Δεν υπήρχαν στατιστικά σημαντικές διαφορές στα προεγχειρητικά κλινικά χαρακτηριστικά των ασθενών πλην της αναμενομένης εμφάνισης της νόσου σε απώτερη ηλικία στους ασθενείς με θύμωμα. Η θνητότητα ήταν μηδενική ενώ η χειρουργική νοσηρότητα, ανάλογη προηγουμένων μελετών θυμεκτομής με διαφορετικού τύπου προσπέλασεις, ανήλθε στο 7,7% και ήταν ως επί το πλείστον ήσσονος σημασίας. Το ποσοστό μετεγχειρητικής μυασθενικής κρίσης ήταν μόλις 3,8%. Οι ασθενείς με μυασθένεια και θύμωμα βίωσαν όψιμη νευρολογική έκβαση ανάλογη αυτής των ασθενών χωρίς θύμωμα (πιθανότητα ύφεσης 74,5% vs 85,7%, p= 0.632). Η μη χρήση στεροειδών στην προεγχειρητική φαρμακευτική αγωγή, ως έμμεσος δείκτης της βαρύτητας της νόσου, σχετίστηκε με στατιστικά καλύτερη πιθανότητα για πλήρη ύφεση των συμπτωμάτων τόσο στους ασθενείς με θύμωμα (95% CI 2.687-339.182, p= 0.006) όσο και σε αυτούς χωρίς θύμωμα (CI 95% 1.607-19.183, P= 0.007) στην πολυπαραγοντική ανάλυση. Αξιόλογη διαφορά, αν και στατιστικά μη σημαντική, για τη έκβαση της νόσου είχε η πρώιμη σε σχέση με την απώτερη χειρουργική αντιμετώπιση των ασθενών. Στη σύγκριση των 27 ασθενών με μυασθένεια και θύμωμα με 12 επιπλέον ασθενείς που υποβλήθηκαν στην ίδια επέμβαση για θύμωμα άνευ μυασθένειας η παρουσία των συμπτωμάτων μυϊκής αδυναμίας συνδυάστηκε με στατιστικά σημαντική βελτίωση της επιβίωσης των ασθενών (100% vs 38,8% στη 10ετία, p< 0.001). Στους ασθενείς με μυασθένεια χωρίς θύμωμα και απώτερης ηλικιακά έναρξης της νόσου το ποσοστό σημαντικής βελτίωσης των μυασθενικών συμπτωμάτων, εξαιρουμένης της πλήρους ύφεσης, ήταν 70%. Στους ασθενείς με μυασθένεια και θύμωμα η ιστολογική ταυτοποίηση των θυμωμάτων κατά την Παγκόσμια Οργάνωση Υγείας προέκυψε στατιστικά σημαντική τόσο στην μονοπαραγοντική όσο και στην πολυπαραγοντική ανάλυση με τα θυμώματα τύπου Β2, Α και Β3 να επιτυγχάνουν από πολύ καλή έως άριστη πιθανότητα πλήρους ύφεσης και τα θυμώματα τύπου ΑΒ, Β1 και C να έχουν απογοητευτική έκβαση όσον αφορά την ίαση. Συμπεράσματα: Η παρούσα μελέτη δείχνει ότι η τροποποιημένη μεγίστη θυμεκτομή είναι ασφαλής και σχετίζεται με υψηλή πιθανότητα για ίαση των μυασθενικών ασθενών με και χωρίς θύμωμα. Οι ασθενείς πρέπει να αντιμετωπίζονται χειρουργικά πρώιμα μετά τη διάγνωση με κυριότερο προγνωστικό παράγοντα για το απώτερο νευρολογικό αποτέλεσμα την προεγχειρητική βαρύτητα της νόσου. Η ασφαλής και πιο αξιόπιστη εκτίμηση της τελευταίας απαιτεί πιο αντικειμενικά κριτήρια όπως αυτά που θεσπίστηκαν από το Αμερικανικό Ίδρυμα για τη Βαρεία Μυασθένεια. Η ενσωμάτωση σε αυτά τα κριτήρια μοριακών παραμέτρων που φαίνεται να επηρεάζουν την πρόγνωση της νόσου, ενδεχόμενα να βελτιώσουν την αξιοπιστία της κλινικής σταδιοποίησης του MGFA και να αναδείξουν υποομάδες ασθενών με διαφορετική νευρολογική πρόγνωση μετά από θυμεκτομή. Επίσης η πρώιμη διάγνωση των θυμωμάτων εξαιτίας των συνυπαρχόντων μυασθενικών συμπτωμάτων μπορεί να οδηγήσει σε καλύτερη επιβίωση τους συγκεκριμένους ασθενείς. Τέλος η νευρολογική έκβαση των ασθενών με θυμωματώδη μυασθένεια σχετίζεται με τον ιστολογικό τύπο των θυμωμάτων, αλλά όχι αναγκαία και με την κακοήθη συμπεριφορά τους. / Objective: Thymectomy represents a widely accepted treatment for myasthenia gravis with different surgical approaches reported as comparably efficient in achieving disease’s remission. With the complete stable remission being currently accepted as a clear measurable outcome of patients with myasthenia undergoing surgical treatment and the knowledge that disease’s remission should be evaluated as a time dependent event we proceeded to a retrospective analysis of our experience on the surgical management of myasthenic patients. The objective was to access the effect of maximal resection on the neurological outcome and identify predictors of disease remission. Materials and methods: The study group consisted of 78 patients who underwent modified maximal thymectomy for myasthenia from 1990 to 2007. Indications for thymectomy included: ocular myasthenia refractory to medical treatment, generalized myasthenia and thymomatous myasthenia. The data collected included preoperative disease’s severity (modified Osserman classification), preoperative medical treatment, age at onset of the disease (≤ 40/ > 40 years), time elapsed between diagnosis and thymectomy (≤ 12/ > 12 months), gender, thymus gland histology, mortality and morbidity. In thymoma patients further analysis was carried out according the World Health Organization histological classification and the Masaoka stage of the tumors. The evaluation of the neurological outcome at the end of follow up was performed according the Myasthenia Gravis Foundation of America classification. Both the effectiveness of the resection performed and the comparison of our results with those of previous studies were done using the complete stable remission as the end point of the study. The statistical analysis of the results was carried out using the SPSS 17. Kaplan-Meier life table analysis was performed and the log rank test was used to evaluate the effect of the variables examined on the distribution of disease’s remission over time. The Cox proportional hazard model was also applied to verify the concurrent effect of the evaluated factors on the achievement of complete stable remission. P values < 0.05 were considered statistically significant. Results: 51 patients suffered of non thymomatous myasthenia while 27 patients had myasthenia with thymoma. The two groups were comparable in refer to the clinical features of the patients apart the more advanced age at the time of the diagnosis for thymoma patients. There was no perioperative mortality, while the surgical morbidity was comparable to the one reported in other series of patients with different surgical approaches and was 7.7%. The rate of postoperative myasthenic crisis was only 3.8%. Thymoma and non thymoma patients experienced comparable complete stable remission prediction (74.5% vs 85.7% at 15 years, p= 0.632). The absence of steroids in the preoperative medical regimen was statistically associated with the achievement of complete stable remission in both thymoma (95% CI 2.687-339.182, p= 0.006) and non thymoma patients (CI 95% 1.607-19.183, P= 0.007) in multivariate analysis. There was an important difference, although not statistically significant, for the neurological outcome between early and late surgical treatment. When the 27 patients with myasthenia and thymoma were compared with other 12 patients similarly operated for thymoma without symptoms and signs of muscular weakness we found that the presence of myasthenia was statistically associated with improved survival (100% vs 38.8% at 10 years, p< 0.001). Non thymoma patients presenting with late onset myasthenia, experienced high improvement (complete stable remission excluded) rate reaching up to 70% at the end of follow up. Among patients with thymomatous myasthenia gravis the World Health Organization histological classification was statistically associated with the late neurological outcome. Thymoma types A, B3 and B2 reached a high to excellent prediction of disease’s remission while types AB, B2 and C had a disappointing neurological outcome. Conclusons: The present study demonstrated that the modified maximal thymectomy is a safe procedure, associated with an excellent neurological outcome in both thymomatous and non thymomatous myasthenia. The patients should be operated early after the diagnosis is made with the disease’s severity being the prime determinant of the possibility to achieve complete remission of myasthenic symptoms. The evaluation of disease’s severity requires objective criteria like the ones proposed by the Myasthenia Gravis Foundation of America. The inclusion in these criteria of molecular markers related to myasthenia’s prognosis and its neurological outcome after thymectomy may further enhance its validity and may allow the identification of subgroups of patients with different disease prognosis after thymectomy. The presence of muscular weakness may lead to early diagnosis and surgical treatment of thymomas with improved survival. Finally the neurologic outcome in thymoma patients after thymectomy may be statistically associated with the World Health Organization classification subtypes but not necessarily with the aggressiveness of these tumors.

Myasthenia Gravis (MG) is an autoimmune disease affecting neuromuscular transmission, in which the thymus is considered pathogenic organ. Earlier ideas suggesting that MG is only the receptors disease have been proven wrong. There are immunopathological changes in both target structures [specific receptors for acetylcholine (AChR] muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein 4 (Lrp4)], the thymus, as well as in peripheral lymphoid organs. Initial findings of the humoral immunity defect with the decisive role of the pathologic autoantibodies, were corrected with findings of the immune dysregulation at the level of T lymphocytes. According to today's knowledge, the development and maintenance of MG involves almost all cell types of immune function in the autoimmune inflammation: helper CD4+ T lymphocytes, cytotoxic CD8+ T lymphocytes, regulatory CD4+CD25+ T lymphocytes, Th17 lymphocytes, B lymphocytes and plasma cells. Thymus plays a dominant immunopathogenetic role in younger patients with MG, while extrathymic mechanisms are applied in older patients. As a result of that, the thymectomy (TE) is generally accepted as part of treatment for MG. However, there is still no data verified by a prospective controlled study, which would demonstrate a useful result of this treatment...