Randomized Double-Blind Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

Unilateral video-assisted thoracoscopic thymoma resection ­ Indications, early and mid-term results / Az unilateralis videoasszisztált torakoszkópos thymomaeltávolítás javallata, korai és középtávú eredményei

Introduction. Thymoma is the most common tumour of the anterior mediastinum. Video-Assisted Thoracic Surgery technique of thymoma resection is spreading world-wide, but the thoracoscopic method is still contentious in many ways. Authors evaluate the early and mid-term results of a 17 years period of VATS unilateral approach at 2 Hungarian thoracic surgical centers. Method. Depending on the anatomical situation of the thymoma, we performed thymectomy, or partial thymectomy (thymomectomy) for the Masaoka­Koga I­II­III stage thymoma from the right or left side through 2 or 3 intercostal ports. We managed the operations with ultrasonic dissector and electrocauter. By using international standards we evaluated perioperative morbidity, mid-term oncological results and clinical symptoms of myasthenia. Results. 23 of the 54 patients were man, 31 were woman, the average age was 58 (26­79) years, 23 of them had myasthenia. The conversion rate was 11,5% (7/61). The average operation time was 84 (39­150) minutes. The average hospitalisation time was 5.5 (3­19) days. The average size of the thymomas was 46 (18­90) mm. The histology resulted thymoma type A in 2 cases, AB in 19 cases, B1/2/3 in 11/11/1 cases, mixed B in 10 cases. The examination of the resection line was R0/1/2 in 42/11/1 cases. The Masaoka­Koga stages were: I (17), IIA (28), IIB (2), III (7). There was 25 thymomectomies, and 29 thymectomies. In seven cases there were extension of the operation to the pericardium (2), to the lung (2), to the phrenic nerve (6), and to innominate vein (1). The in-hospital mortality over 30 day was in 1 case (1.85%). The morbidity was 11/54 (20.4%). The average follow-up time was 62.56 (5­198) months. In the group with myasthenia the effectivity of the operation was 18/21 (85.7%), including complete remission of 5/21 (23.8%). Post-thymectomy myasthenia gravis developed in 2/31 cases (6.5%). The average 5 years survival was 100%, tumour-free 5 years survival was 96%. Conclusions. The higher proportion of the thymomectomy in the early results, higher conversion rate and lower R0 proportion might be in connection with the attitude of the surgeons, with the learning curve and with the limitations of the unilateral method. After a longer follow-up time late results may become more real and comparable. Instead of unilateral VATS technique we have changed to the subxyphoideal approach of VATS because of its better visualisation.

Application of video-assisted thoracoscopy in the surgical treatment of myasthenia gravis in adults without thymoma / Jobb oldali videoasszisztált thoracoscopos thymectomia a thymoma nélküli, felnottkori myasthenia gravis sebészi kezelésében

Introduction: Surgical technique of thymectomy performed for treatment of myasthenia gravis has considerably changed in the last almost 30 years. In addition to standard interventions ­ transsternal and transcervical thymectomy ­, video-assisted thoracoscopic interventions (VATS), later on robotic surgery came into general use. In our two institutions, we apply VATS thymectomy since 2011. Methods: There are several different surgical techniques for this purpose; we approached the mediastinum through the right thoracic cavity. We prepared initially 3, later on 2 perimammal ports for the access of the thymus; the patients were in supine position during surgery. We used an ultrasonic cutting device in all cases. In order to perform extended thymectomy, we removed the fatty tissue around the thymus and opened widely the left thoracic cavity, too. During patient enrollment, we preferred patients with normal or lower body weight. Results: During 8 years and 4 months, we operated on 92 patients using this method for myasthenia gravis without thymoma; there were 20 male and 72 female patients at the age of 33 years on average (19­75 years). Duration of surgery was 35­160 minutes, 82.3 minutes on average. The bulky fatty tissue around the thymus made the orientation and the complete removal more difficult in a few patients. We experienced vascular injury in 4 cases and injury of the contralateral lung in 3 cases. Conversion was necessary in 2 cases (1 sternotomy and 1 thoracotomy), there were no nerve injuries. Assisted ventilation was necessary in case of ten patients in the postoperative period for a few hours; all other patients were extubated on the operating table. There was no need for repeated intubation and tracheostomy; there was no respiratory insufficiency and perioperative mortality. Duration of ICU care was 1.1 days on the average (0­11 days), that of the total hospital care 4.8 days on average (3­15 days). Duration of thoracic drainage was 1.16 days on average (1­4 days). Two patients (2.41%) died within one and five years after surgery. During 12­108 months (48 months on average) follow-up of 81 patients, 21 patients (25.3%) suffering from myasthenia total recovery was observed, pharmacologic remission was achieved in 4 patients (5.3%), minimal manifestation remained in 23 patients (24.1%), while in 28 patients (33.73%) other improvement was observed. The status of 4 patients (4.82%) remained unchanged and that of 4 patients (5.3%) worsened. Conclusion: VATS thymectomy represents a completely new surgical method for surgeons having experience in transsternal surgical technique. Bulky mediastinal fatty tissue makes surgery very difficult. The perioperative period is advantageous for the patients and also the long term follow-up results are acceptable. It is questionable that the thymus can be completely removed with this method in all cases.

[Myasthenia gravis: perioperative complications of 1002 transsternal thymectomies - historical overwiev of 34 years long practice at one institution]. / Myasthenia gravis: 1002 transsternalis thymectomia perioperatív szövodményei ­ egy intézmény 34 éves gyakorlata történeti áttekintésben.

Introduction: Thymectomy became an important part of the treatment of myasthenia gravis, since Alfred Blalock reported about his first surgery 80 years ago. Despite of several different surgical techniques already accepted abroad, sternal approach was the almost exclusive exposure for thymectomy in Hungary till 2006. In this publication, we analyze the direct surgical consequences and complications of this method. Methods: At the Surgical Department of Budai MÁV Hospital, 1002 transsternal thymectomies were performed during 34 years on patients suffering from myasthenia gravis. Surgeries were performed for neurological indications, following careful medical investigations, involving specialists in neurology and internal medicine. In cases associated with thymoma, surgery was indicated for two reasons: removal of the thymus and the tumor at the same time. Neurological indications, patient preparation, perioperative treatment and surgical technique have considerably changed during these 34 years. We interpret the results according to the two eras based on the most frequently applied surgical techniques (simple and extended thymectomy); we publish the data separately of the patients with thymoma and those who underwent repeated surgery, focusing basically on breath-related complications. Results: The patients' age was 32 years on the average (8-73 years). Women/men ratio: 3.5:1. Myasthenia gravis was associated with thymoma in 12.7% of the patients. Repeated thymectomy was necessary in case of 11 patients; further two patients required repeated sternotomy after cardiac surgery. Respiratory failure occurred in 21,3% out of 525 myasthenic patients operated in the first 19-year-old era, emergency re-intubation and tracheostomy happened in 12,8% and in 11,2% as well. In the second 15-year-old period postoperative respiratory failure occurred in 12,7% with emergency re-intubation in 7,1% and tracheostomy only in 1,2% out of 338 myasthenic patients. Respiratory failure occurred in 19.1% out of 126 patients operated for thymoma; re-intubation was necessary in 12.8% of the cases and tracheostomy was performed in 20.6% of the patients. Respiratory failure occurred in 13 patients, who underwent repeated surgery (46.1%); the ratio of re-intubation was 15.4% and that of tracheostomies 46.1%. Serious surgical complications were infrequent also in the entire group of patients: 2 patients required repeated surgery due to sternal bleeding; one more patient underwent repeated surgery due to rupture of the drainage tube, 4 cases of mediastinitis in the first group, two cases of heart injury and one case of sternal disruption occurred in the second period. The overall mortality was 1.4%: 1.3% in the first period, 0.3% in the second period, 4% in the thymoma group and 7.7% after repeated surgeries. Conclusions: In a historical overview, the ratio of serious respiratory and airway complications and the mortality after transsternal thymectomies has considerably decreased, but the postoperative respiratory failure and the surgical risk of transsecting the sternum still pose a real risk.

Association of myasthenia gravis with polymorphisms in the gene of histamine N-methyltransferase.

INTRODUCTION: Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine. Histamine modulates immune responses and plays a role in the pathogenesis of autoimmune disorders. METHODS: The non-synonymous HNMT C314T polymorphism and the A939G single-nucleotide polymorphism (SNP) influencing HNMT mRNA stability were genotyped in 213 patients with myasthenia gravis (MG) and 342 healthy controls. RESULTS: The carrier frequency of the A allele of the A939G SNP was over-represented among patients with anti-AchR and anti-Titin antibodies (P = 0.05 and P = 0.004, respectively); the presence of the minor G allele was protective against anti-AchR and anti-Titin positive MG (OR = 0.67 and OR = 0.54, respectively). The combination of the G allele carrier status with wild-type C314C homozygosity was also protective against MG (OR = 0.55, P = 0.008) and against the development of anti-AchR antibodies (OR = 0.37, P = 0.01). DISCUSSION: The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found.

Interleukin-4 receptor alpha polymorphisms in autoimmune myasthenia gravis in a Caucasian population.

Autoimmune myasthenia gravis is a T-cell-dependent, antibody-mediated, rare neuromuscular disorder. Interleukin-4, acting via interleukin-4 receptor alpha, plays a pivotal role in B-cell differentiation and antibody production and has been implicated to influence disease progression in experimental autoimmune myasthenia gravis. Polymorphisms of the interleukin-4 receptor alpha gene have been shown to be associated with various autoimmune diseases. We compared the distribution of three polymorphisms of the interleukin-4 receptor alpha gene (S503P, rs1805015, Q576R, rs1801275, I75V, rs1805010), all affecting interleukin-4 signaling, in two cohorts of myasthenia gravis patients with ethnically matched controls. Although the distribution of the S503P and Q576R polymorphisms did not differ significantly between the groups, the frequency of the GG rare homozygote genotype of the I75V polymorphism was significantly higher in patients with myasthenia gravis. Our data suggest that the reduced responsiveness to interleukin-4 because the I75V polymorphism may contribute to the pathogenesis of myasthenia gravis.

Clinical and biological heterogeneity of autoimmune myasthenia gravis.

Although myasthenia gravis (MG) has long been considered a well-established autoimmune disease associated with autoantibodies, which are convincingly pathogenic, accumulating data indicate both clinical and biological heterogeneity similar to many other putative autoimmune disorders. In a subset of patients, thymus plays a definite role: thymic autoimmunity results in generation of autoantibodies within the thymus, which cross-react with antigens at the neuromuscular junction, or thymoma leads to deficient central tolerance and impaired T cell selection. Heterogeneity on the autoantibody level may be associated with genetic heterogeneity and clinical phenotypes with different treatment responses.

The autoimmunity-related polymorphism PTPN22 1858C/T is associated with anti-titin antibody-positive myasthenia gravis.

Genetic variation in the intracellular tyrosine phosphatase PTPN22 has been recently associated with susceptibility to various autoimmune diseases. Myasthenia gravis (MG) is a complex genetic disease with a distinct clinical and pathological heterogeneity. We conducted a case-control association study for the PTPN22 1858C/T polymorphism in Hungarian and German MG patients (n = 282) and regional controls (n = 379). We detected an association of the PTPN22 1858T allele with MG in the subgroup of nonthymoma patients with anti-titin antibodies present (n = 50; T allele frequency 21% vs 11% in controls; p = 0.005, odds ratio 2.1, 95% confidence interval 1.23-3.58). This overrepresentation was reported independently in both Hungarian and German MG patients compared with regional controls. We conclude that the common autoimmune polymorphism PTPN22 1858C/T may account for disease susceptibility in a subset of nonthymoma MG patients with anti-titin antibodies present.

Tumour necrosis factor alpha gene (TNF-alpha) -376 polymorphism in Hungarian patients with primary progressive multiple sclerosis.

Tumour necrosis factor alpha (TNF-alpha) is associated with clinical activity in relapsing-remitting multiple sclerosis (RRMS) and the development of progressive disease. Our aim was to investigate the TNF-alpha -376 polymorphism in primary progressive MS (PPMS) patients. Polymerase chain reaction and restriction fragment length polymorphism were carried out on 45 PPMS patients, 45 age and sex-matched RRMS patients and 45 healthy controls (HC). The GG genotype and the guanine allele (G) were detected significantly more often in the PPMS group as compared with the HC group (p=0.027; p=0.032). The G allele may be one of the factors responsible for progression in PPMS.

Paraneoplastic chronic demyelinating neuropathy and Lambert-Eaton myasthenic syndrome associated with multiple anti-neural antibodies and small-cell lung cancer.

Lambert-Eaton myasthenic syndrome (LEMS) developed in a patient with presumed chronic inflammatory demyelinating polyneuropathy (CIDP) and negative chest CT. Since antibodies against both Hu and voltage-gated calcium channel (VGCC) were detected, repeated chest CT was performed, which eventually showed a pulmonary mass lesion. Biopsy revealed small cell lung cancer (SCLC) indicating the importance of repeated chest CT in LEMS even when an existing autoimmune-like disease and negative CT may suggest an autoimmune origin. This is the first report of paraneoplastic CIDP and LEMS associated with anti-Hu, anti-VGCC and SCLC.

Aberrant transcriptional regulatory network in T cells of multiple sclerosis.

To identify the molecular network of the genes deregulated in multiple sclerosis (MS), we studied gene expression profile of purified CD3(+) T cells isolated from Hungarian monozygotic MS twins by DNA microarray analysis. By comparing three concordant and one discordant pairs, we identified 20 differentially expressed genes (DEG) between the MS patient and the genetically identical healthy subject. Molecular network of 20 DEG analyzed by KeyMolnet, a comprehensive information platform, indicated the close relationship with transcriptional regulation by the Ets transcription factor family and the nuclear factor NF-kappaB. This novel bioinformatic approach proposes the logical hypothesis that aberrant regulation of the complex transcriptional regulatory network contributes to development of pathogenic T cells in MS.

[Association of coeliac disease and myasthenia gravis]. / Coeliakia es myasthenia gravis együttes elofordulása.

Coeliac disease is a malabsorption syndrome induced by the gluten-containing cereals leading to the damage of small intestinal mucosa. A case of a young woman is presented whose coeliac disease became overt in the puerperium. Despite strict adherence to gluten-free diet, her muscle weakness affecting several muscle regions persisted. Following a diagnostic work-up covering numerous co-disciplines, the diagnosis of myasthenia gravis was set up underlying her muscle symptoms. After the thorough review of the corresponding literature, the authors could not find any case report on the association of coeliac disease with myasthenia gravis.

Myasthenia in a patient with sarcoidosis and schizophrenia.

A 44-year-old male patient was hospitalised with paranoid schizophrenia in 1985. Depot neuroleptic treatment was started which successfully prevented further psychotic relapses for the next ten years. His myasthenia gravis started with bulbar signs in 1997 and the symptoms soon became generalized. The diagnosis of myasthenia gravis was confirmed by electromyography, by positive anticholinesterase test and by the detection of anti-acetylcholine receptor antibodies in the serum. Mediastinal CT examination showed enlarged hilar lymph nodes on the left but no thymic pathology was observed. Mediastinoscopy was performed and biopsies were obtained from the affected nodes. Histology revealed sarcoidosis. The patient suffered respiratory crisis following the thoracic intervention (in September 1998). Combined oral corticosteroid (64 mg methylprednisolone/e.o.d.) and azathioprine (150 mg/day) treatment regimen was initiated and complete remission took place in both the myasthenic symptoms and the sarcoidosis. The follow-up CT scans showed no mediastinal pathology (January 2000). During steroid treatment a transient psychotic relapse occurred which was successfully managed by supplemental haloperidol medication added to his regular depot neuroleptics. The patient currently takes 150 mg/day azathioprine and receives 40 mg/month flupentixol depot i.m. His physical and mental status are stable and he has been completely symptom free in the last 24 months. The association of myasthenia gravis and sarcoidosis is very rare. To our best knowledge no case has been reported of a patient suffering from myasthenia gravis, sarcoidosis, and schizophrenia at the same time.