Successful treatment of myasthenia gravis with tacrolimus.

Tacrolimus (FK-506) is a calcium-calcineurin inhibitor, successfully used in transplant recipients. We report the successful use of tacrolimus as a single immunosuppressant in a patient who had developed myasthenia gravis (MG) during interferon alpha treatment. In this case, the coexistence of hepatitis C and type 2 diabetes mellitus contraindicated the use of both steroids and azathioprine, and cyclosporine A, although effective, had induced renal failure. Tacrolimus proved to be effective in the treatment of MG, was not significantly hepatotoxic, and was less nephrotoxic than cyclosporine.     

Update on immune-mediated therapies for myasthenia gravis

With the exception of thymectomy, immune modulatory treatment strategies and clinical trials in myasthenia gravis over the past 50 y were mainly borrowed from experience in other nonneurologic autoimmune disorders. The current experimental therapy paradigm has significantly changed such that treatments directed against the pathological mechanisms specific to myasthenia gravis are being tested, in some cases as the initial disease indication. Key advances have been made in three areas: (i) the expanded role and long-term benefits of thymectomy, (ii) complement inhibition to prevent antibody-mediated postsynaptic membrane damage, and (iii) neonatal Fc receptor (FcRn) inhibition as in vivo apheresis, removing pathogenic antibodies. Herein, we discuss these advances and the potential for these newer therapies to significantly influence the current treatment paradigms. While these therapies provide exciting new options with rapid efficacy, there are anticipated challenges to their use, especially in terms of a dramatic increase in cost of care for some patients with myasthenia gravis.     

Thymectomy in late-onset myasthenia gravis

Two cases of late-onset myasthenia gravis were successfully treated by thymectomy using a sternal splitting technique, in spite of the fact that no thymomas could be detected preoperatively. One patient was seriously ill, the other patient responded to medical treatment. Thymolipoma and malignant thymoma, respectively, were removed from the patients. It is stressed that not all thymomas produce antibodies to striated muscles and that CT-scan of the mediastinum is of limited value in the diagnosis of thymoma. It is suggested that patients with late-onset myasthenia gravis be offered thymectomy, even in the absence of detectable thymomas.     

Thymectomy in myasthenia gravis a review

The role of thymectomy in the management of myasthenia gravis is reviewed in the light of the published data and of a personal series. The patients in whom the operation is most successful are non thymomatous patients aged between 10 and 40 years with an MG history of less than 3 years. There is no sex prevalence. Lasting improvement may be expected. There are no proven correlations between biological indices like the germinal centers in the thymus and/or AChR antibody titers and the postoperative course of the disease. Complete removal of the thymus seems to be crucial and hence the transsternal approach is preferred. The operation, less effective in patients with thymona than in those with an active thymus, is nonetheless necessary to in these patients prevent putative damage to surrounding organs from thymona infiltration. Why thymectomy should be effective in patients with an active thymus and not in those with a thymona may be revealed by in vitro studies of the interactions between thymic cells and peripheral B cells, now in progress.

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Sommario Viene rivisto alla luce dei dati della letteratura e della casistica personale il ruolo della timectomia nella terapia della miastenia. Dei pazienti non portatori di timoma i migliori risultati si ottengono in quelli di età fra i 10 e i 40 anni con una durata della malattia minore di tre anni. Non vi è prevalenza di sesso. Ci si può attendere un miglioramento duraturo. Non vi sono prove di una correlazione tra gli indici biologici germinativi quali i centri germinali nel timo e o il titolo degli anticorpi contro i ricettori acetilcolinici e il decorso post-operatorio della malattia. É fondamentale la completa asportazione del timo e perciò è preferibile la scelta della tecnica di approccio transternale. Nei pazienti con timoma la timectomia è meno efficace ma l'intervento è necessario per evitare danni derivanti dall'infiltrazione del timoma sugli organi circostanti. Il perché della efficacia della timectomia nei pazienti con un timo attivo ma non in quelli con timoma potrà essere chiarito dagli studi in vitro sulle interazioni tra cellule timiche e quelle periferiche B, studi che sono ormai in stadio avanzato.

     

Juvenile myasthenia gravis

Juvenile myasthenia gravis shares a similar pathophysiologic origin with adult myasthenia gravis, but there are important differences, mostly relating to epidemiology, presentation, and therapeutic decision making. Gender ratios and the proportion of seropositive patients differ in the pre‐ and postpubertal age groups. The diagnostic evaluation is similar to that in adults, although special techniques are sometimes necessary to perform single‐fiber electromyography in younger patients. Therapeutic decisions in affected children and adolescents are complicated by the greater long‐term consequences of using steroids, and thus other interventions, such as intravenous immunoglobulin (IVIg) and plasmapheresis, may play a greater therapeutic role in this population than in adults. Steroid‐sparing agents may contribute to the management of refractory cases, but they should be used with caution due to the risk of malignancy. Muscle Nerve, 2008     

Lifetime course of myasthenia gravis

Between 1940 and 2000 a total of 1976 patients with myasthenia gravis (MG) were studied. Diagnosis was made by improvement in weakness after anticholinesterase medication. The historical developments in diagnosis and treatment of MG are reviewed. We analyzed the clinical course of MG as influenced by age, gender, thymectomy, thymomectomy, and the presence of antibodies to acetylcholine receptors (AChR). The clinical course of MG was significantly influenced by age and gender, and these need special attention in managing patients. The most severe level of weakness and high mortality occurred during the first 1 to 2 years of the disease, after which many patients experienced improvement. For treating MG patients the usefulness of thymectomy remains to be proven, and novel drugs need to be developed to increase the number as well as normal functioning of the AChRs and other components of the neuromuscular system.     

Cytokines and the pathogenesis of myasthenia gravis

Myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG) are caused by autoantibodies against nicotinic acetylcholine receptor (AChR) in skeletal muscle. The production of anti-AChR antibodies is mediated by cytokines produced by CD4⁺ and CD8⁺ T helper (Th) cells. Emerging investigations of the roles of cytokines in MG and EAMG have revealed that the Th2 cell related cytokine interleukin 4 (IL-4), an efficient growth promoter for B-cell proliferation and differentiation, is important for anti-AChR antibody production. IL-6 and IL-10 have similar effects. The Th1 cytokine IFN-γ is important in inducing B-cell maturation and in helping anti-AChR antibody production and, thereby, for induction of clinical signs and symptoms. Results from studies of time kinetics of cytokines imply that IFN-γ is more agile at the onset of EAMG, probably being one of the initiating factors in the induction of the disease, and IL-4 may be mainly responsible for disease progression and persistance. Even though other Th1 cytokines like IL-2, tumor necrosis factor α (TNF-α), and TNF-β as well as the cytolytic compound perforin do not directly play a role in T-cell-mediated help for anti-AChR antibody production, they are actually involved in the development of both EAMG and MG, probably by acting in concert with other cytokines within the cytokine network. In contrast, transforming growth factor β (TGF-β) exerts immunosuppressive effects which include the down-regulation of both Th1 and Th2 cytokines in MG as well as EAMG. Suppressive effects are also exerted by interferon α (IFN-α). Based on elucidation of the role of cytokines in EAMG and MG, treatments that up-modulate TGF-β or IFN-α and/or suppress cytokines that help B-cell proliferation could be useful to improve the clinical outcome. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 543–551, 1997     

Cardiac involvement in myasthenia gravis

Non-specific ECG changes and histological changes in the myocardium in patients with myasthenia gravis (MG) have been described. In this study, the left ventricular function using systolic time intervals (STI) was assessed in patients with MG. 4 patients out of the 10 studied showed abnormalities of the STI which reverted towards normal after injection of neostigmine. This finding suggests that myocardial involvement in MG may be more common than clinically suspected.     

The cerebrospinal fluid in myasthenia gravis

We examined the number of leucocytes and the concentration of total protein, albumin and IgG in the cerebrospinal fluid (CSF) from 46 patients with myasthenia gravis (MG) and 50 controls. Mean leucocyte number in the MG patients was 1634 cells/ml (controls 1244), mean total protein 0.38 g/l (controls 0.32), mean IgG 0.034 g/l (controls 0.025) and mean albumin 0.199 g/l (controls 0.176). No evidence of intrathecal IgG synthesis was demonstrated. The CSF was normal in most cases. When pathological changes occurred they were slight and could be attributed to associated diseases or to iatrogenic blood contamination of the CSF. We demonstrated that an artificial blood contamination of the CSF, although macroscopically undetectable, increased the CSF albumin concentration and the CSF albumin/serum albumin ratio considerably.     

Seronegative myasthenia gravis: disease severity and prognosis

Around 10-20% of myasthenia gravis (MG) patients do not have acetylcholine receptor (AChR) antibodies (seronegative), of whom some have antibodies to a membrane-linked muscle specific kinase (MuSK). To examine MG severity and long-term prognosis in seronegative MG compared with seropositive MG, and to look specifically at anti-AChR antibody negative and anti-MuSK antibody negative patients. Seventeen consecutive seronegative non-thymomatous MG patients and 34 age and sex matched contemporary seropositive non-thymomatous MG controls were included in a retrospective follow-up study for a total period of 40 years. Clinical criteria were assessed each year, and muscle antibodies were assayed. There was no difference in MG severity between seronegative and seropositive MG. However, when thymectomized patients were excluded from the study at the year of thymectomy, seropositive MG patients had more severe course than seronegative (P < 0.001). One seropositive patient died from MG related respiratory insufficiency. The need for thymectomy in seronegative MG was lower than in seropositive MG. None of the seronegative patients had MuSK antibodies. This study shows that the presence of AChR antibodies in MG patients correlates with a more severe MG. With proper treatment, especially early thymectomy for seropositive MG, the outcome and long-term prognosis is good in patients with and without AChR antibodies.     

Epidemiology of myasthenia gravis in Norway

The number of patients with myasthenia gravis diagnosed and registered in Norway from 1912-1981 has been collected, representing essentially all diagnosed cases during these 70 years. Until 1948, Oslo University Hospital, the National Hospital, had the only neurological department. in Norway. Since then, neurological departments have been established throughout our country. All these departments and all practising neurologists in Norway responded to the appeal for the necessary information on their diagnosed patients up to the end of 1981. The majority of the results are based on the period 1951-1981. The National Bureau of Statistics has registered the deaths of myasthenia gravis cases since 1951, and since 1956 where it has constituted an underlying or contributory cause. The incidence rate by diagnosis per million population 1951-1981 is 2.6 for males, 5.3 for females and 4 for both sexes. The prevalence per million population is 52 for males, 127 for females and 90 for both sexes. The mortality in males is 144% and in females 155% of the mortality in the population. The excess mortality is much greater in patients below 60 years of age, especially in females where a value of 483% if found.     

Acetylcholine receptor antibody in myasthenia gravis

Radioimmunoassay techniques were used to detect antibodies to the acetylcholine receptor (AAChR) in 164 patients with adult-onset myasthenia gravis. AAChR levels above 0.6 nM/l were considered pathological and were found in 67% of the patients with an average value of 58.99 +/- 125.02 nM/l (0.6-900.0). Correlation, with clinical functional status, the histopathological thymus alterations and the different therapeutics used did not disclose any statistically significant differences.     

Myasthenia gravis: Antibodies to acetylcholine receptor in ocular myasthenia gravis

Summary To improve the sensitivity of the radioimmunoassay method for anti-AChR-antibody, large amounts of sera from patients with myasthenia gravis, and higher concentrations of antigens and rabbit anti-human-IgG-antiserum, were used. These procedures enabled measurement of the titre value of over 0.04 pmol/ml serum and this value revealed a sensitivity about 10 times higher than that predicted using the previous model.Antibodies against AChR were found in 13 out of 17 ocular myasthenia patients (70%) and 35 of 37 with generalized myasthenia (90%). However, the average titre value of sera in those with ocular myasthenia was significantly lower than the value obtained in the generalized cases. Even in the patients with ptosis or ophthalmoparesis, in the early stage (less than one year) of ocular myasthenia, anti-AChR-antibodies were not detectable using this more sensitive assay method.

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Zusammenfassung Um die Empfindlichkeit der Radioimmunoassay-Methode für Anti-AChR-Antikörper zu verbessern, wurden eine große Menge des myasthenischen Serums, höhere Konzentration des Antigens und Kaninchen-Anti-Menschen-IgG-Antiserum gebraucht.Mit dieser Methode konnten wir den Wert über 0.04 pmol/ml Serum vermessen. Diese neue Methode zeigt etwa zehnfach höhere Empfindlichkeit als die vergangenen Methoden.Antikörper gegen AChR waren in 13 von 17 okulären Myastheniepatienten (70%) und in 35 von 37 generalisierten Myastheniepatienten (90%) gefunden worden. Aber der durchschnittliche Messungswert des Serums im Patienten der okulären Form war signifikant niedriger als der der generlisierten Form. Wenn der Patient auch Augenptose oder Augenparese hatte, waren die Anti-AChR-Antikörper mit unserer empfindlichen Methode im Frühstadium (innerhalb eines Jahres) nicht nachgewiesen worden.

     

Psychiatric disturbances associated with myasthenia gravis

Seventy-four myasthenic patients (54 F, 20 M; mean age 49.6 years) were evaluated using the diagnostic criteria of the DSM-III in order to investigate the prevalence of psychiatric disturbances in this order. Fifty-one had had thymectomies, of whom 28 females had hyperplasia, two females and five males had involution of the thymus, and 10 females and six males had thymomata. Psychiatric disturbances were observed in 38 subjects (51%), in particular, adjustment disorders with depressed mood and mixed emotional features (19%) (22% including adjustment disorder with anxious mood), affective disorders (13.5%) and personality disorders (18%).