Georg Matell

Determination of acetylcholine receptor antibody in myasthenia gravis: clinical usefulness and pathogenetic implications.

Antibodies to cholinergic receptor structures were found in 75% of 76 Finnish and 93% of 175 Swedish patients with myasthenia gravis. The amount of antibodies showed a positive correlation to the severity of the disease, and was reduced during immunosuppressive treatment, and by thymectomy. Thymoma patients had high values. The antibody was also found in the cerebrospinal fluid. Two healthy newborn babies of myasthenic mothers had antibodies during the first weeks of life, in spite of no clinical symptoms. The occurrence of IgM antibodies before IgM antibodies in two patients during the early stages of myasthenia gravis suggests that the antibody is not a primary cause of the disease.

Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis.

We have investigated theHLA-DRB and -DQB gene polymorphism in 131 myasthenia gravis (MG) patients. TheHLA genotypes in these patients were assigned by means of restriction fragment length polymorphism (RFLP)-definedDR-DQ haplotypes, correlating to serologic HLA class II typing. Using this technique we could, among randomly selected non-thymomatous (NT)-MG patients, confirm the strong association to DR3, and 70% of the patients were found to carry a specific DR3-positiveDR-DQ haplotype,T-3.1. Furthermore, an analysis of T-3.1− NT-MG patients revealed that 59 % were T-4.1÷ (DR4, DQw8). Thymic hyperplasia was found in approximately 85 % of the T-3.1+ , as well as of the T-4.1+ /3.1− patients. As previously observed, we found a clear dominance of females among the T-3.1+ NT-MG patients. However, among T-4.1+/3.1- patients, males were as common as females. Furthermore, the T-4.1+ patients were significantly older at the onset of disease than those who were T-3.1+. In female MG patients, the DRwl5-Dw2-positive haplotypeT-2.1 was strongly correlated with the presence of thymoma (T-MG). These data indicate that the HLA associations in early vs late onset of NT-MG are different, and that female patients with and without thymoma differ from each other with regard to HLA markers. Thus, at least three different HLA DR-DQ associations are found in subgroups of idiopathic MG.

Tumour necrosis factor-α polymorphism and secretion in myasthenia gravis

Abstract The mechanism behind the association between MHC genes and myasthenia gravis (MG) is not fully understood. In the present study we studied the associations with polymorphisms at HLA-DR3, HLA-B8 and TNF-α genes in Swedish patients and healthy individuals. The TNF-α-308 allele 2 was associated with female patients having disease onset before the age 40 and with thymic hyperplasia. Analysis of strongest associations between MG and alleles close to TNF-α indicated that the association of TNF-α was possibly stronger than for HLA-DR3 and nearly the same as for HLA-B8. Peripheral blood mononuclear cells from patients positive for TNF-α -308 allele 2 had higher secretion of TNF-α when stimulated by anti-CD3 antibodies. Our results indicate that a subgroup of MG patients who have been previously shown to be associated with MHC genes may have a higher inducible TNF-α level in vivo, thus resulting the pathological changes in the thymus and the early onset of MG.

EFFECTS OF SOME IMMUNOSUPPRESSIVE PROCEDURES ON MYASTHENIA GRAVIS

Clinical Observations. A total of 53 MG patients have been treated with different immunosuppressive methods (alone or combined) with the following effects: Thymectomy was performed in 38 patients. The improvement was excellent in 15, and moderate or uncertain in 20. In three patients severe long-lasting deterioration followed the operation. ACTH treatment (n=32): Initial deterioration during the 5-7 days of heavy ACTH treatment (1000 IU) was followed by an improvement lasting on an average 4 months. The improvement was good or moderate in 78% of the patients. Betamethazone treatment has been tried in six patients where ACTH and azathioprine was ineffective. In four of these patients the results were excellent. Azathioprine treatment has been given to 26 patients for periods up to 7 years. An improvement is measurable after 6-12 weeks and it seems maximal after about 1 year. Of the 26, 80% responded favorable with reduction in the need for cholinesterase inhibitors. Severe complications were seen in three patients with one death. Drainage of thoracic duct lymph was initiated in 14 patients up to 4 weeks with rapid improvement lasting as long as drainage was performed. Long-termed effects of the drainage may be present, however. Retransfusion of homologous cell-free lymph precipitated a return of the myasthenic symptoms. Biochemical Studies on Myasthenic Lymph. Using a membrane preparation from the electric organ from Torpedo marmorata and tritiated Naja naja siamensis neurotoxin we demonstrated a decreasing binding of toxin to the receptor in the presence of MG lymph gamma-globulin fraction. Gammaglobulins from controls showed almost no inhibition of the neurotoxin binding. Immunological Studies. An increased frequency of HL-A1 and 8 was found in female patients. LD typing was also performed. During a period of three weeks of thoracic duct drainage 130X10(9) or about 10% of total number of lymphocytes in the body were removed. In the lymph an initial decrease in the proportion of thymus-derived lymphocytes (T cells) occurred, which was accompanied by a sequent increase in the proportion of bone-marrow-derived lymphocytes (B cells). Towards the end of drainage this effect was reverted. Mitogenic stimulation using lymphocytes from thoracic duct drainage revealed no differences as compared to normal cells. The proportions of T and B cells was studied in the peripheral blood in nine patients treated with ACTH. During treatment there was an initial decrease in the proportion of T cells accompanied by a subsequent rise in the proportion of B cells, which was maximal after 3-10 days. These proportions were reverted to normal 1-5 days after the maximal change. The effect of azathioprine on T and B cells has also been studied.

Immunosuppressive Drugs: Azathioprine in the Treatment of Myasthenia Gravis

Azathioprine may be tried for treatment of severe myasthenia gravis, in a dose of 2 mg/kg BW. With careful monitoring the side reactions may be controlled. The therapeutic response will occur after a time delay of 4-8 months. About one-third of patients with type II MG (severe, late onset, HLA B8-) will proceed to a complete but azathioprine-dependent remission, and the remaining two-thirds to a marked improvement. In type I MG (early onset, HLA B8+) azathioprine is less effective but will help keep down the need for corticosteroids or plasmapheresis.

TREATMENT OF SEVERE MYASTHENIA GRAVIS WITH LARGE DOSES OF ACTH

Although corticotropin has been availahle for nearly 20 years, its place in the treatment of m’yasthenia gravis has not yet been definately settled, although many positive reports have been published.’ ’’ fi I ’ IY ” ‘4 Probably, one important reason for the present rather restrictive attitude to ACTH treatment in myasthenia gravis has been the severe deterioration, resembling myasthenic crisis often observed during ACTH administration, which even has caused deathL6 ”” and which seems to be quite characteristic for myasthenia gravis. However, the advent of special, intensive medical care units, including facilities for respirator treatment, cardiocirculatory resuscitation and constant qualified supervision, has made it possible to keep alive paretic patients for considerable periods of time. In 1963, Osserman and GenkinsL3 reported that such intensive care in the treatment of myasthenic crisis had considerably reduced the mortality rate. In spite of this, the outlook for patients suffering from myasthenic crisis still remains dark. As pointed out by Osserman and Genkins, it is rare for a patient who has had a myasthenic crisis to attain complete remission. Since 1959, however, we have successfully treated a number of patients in myasthenic crisis with intensive medical care and large doses of ACTH in order to induce remissions. As judged by these cases, the combination of intensive medical care with heavy dosage of corticotropin seems to improve radically the prognosis in severe myasthena gravis.

Myasthenia gravis: a long term follow-up study of Swedish patients with specific reference to thymic histology

Background: Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission. The majority of patients show abnormal thymic histology. Setting: The study was performed at the Myasthenia Gravis Centre, Karolinska University Hospital, and at the Immunological Research Laboratory, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. Patients and methods: Information was collected retrospectively from 1956 and prospectively from 1975 on clinical data, concomitant diseases, concentration of serum acetylcholine receptor antibodies (AChR-abs), immunosuppressive treatment (IS) and response to it, in 537 patients of whom 326 were thymectomised. Follow-up time was 1.5–50 years. Results: Age at onset of MG increased from a median age of 24 years before 1975 to a median age of 61 years after 2000. Thymoma was found in 65, hyperplasia (HPL) in 185 and a normal thymus in 76 patients. The trans-sternal surgical approach for thymectomy was used in 255 patients (78%). In five patients with thymoma, MG appeared after thymectomy. Of 537 patients, 466 (87%) had circulating AChR-abs. IS was given to 300 (56%) patients, mostly those with thymoma (85%). In total, 441 patients (82%) showed an improvement. One-third of patients with HPL, a quarter of those with thymoma, one-fifth of those with a normal thymus and one-seventh of those not operated on went into remission. Conclusion: The prognosis for the majority of patients with MG is favourable, irrespective of thymic histology. The cause may be the use of immunomodulating therapy.

Failing Transcervical Thymectomy in Myasthenia Gravis: An Evaluation of Transsternal Re-exploration

Twenty cases of failing transcervical thymectomy are reported. They were selected for transsternal re-exploration from a series of 95 patients who had previously undergone transcervical thymectomy because of myasthenia gravis (MG). A specific method for pre-operative detection of remnants of the non-tumorous thymic gland is lacking, but the applied clinical selection criteria were so far reliable: generalized, disabling, fluctuating MG despite cholinesterase inhibitor and/or immunosuppressive treatment, and no or inconsistent improvement after transcervical thymectomy. At transsternal re-exploration the commonest findings were intact lower thymic lobes with persistent venous drainage into the brachiocephalic vein. Presence of thymic tissue was histologically confirmed in all the excised specimens (weight range 10-60, mean 23 g), and the examination showed thymic hyperplasia in 18 cases, fatty involution of the gland in two, and a lympho-epithelial thymoma in one case. The re-operation was followed by objectively registrable improvement in all but one of the 20 patients during observation periods of 8-75 (mean 21) months. There was statistically significant reduction in disability scores (means 8.2-4.9) and in need for anticholinesterase medication (to 67% of pretreatment dose). Immunosuppression became unnecessary in 6 of 11 patients and could be reduced in 4 patients. The incidence of failure in transcervical thymectomy was alarmingly high (27%), and more re-operations are anticipated. Since the transcervical approach involves a high risk of incomplete thymectomy, its use should be abandoned. However, in most of the patients with re-operation, subsequent progress has been sufficiently promising for advocacy of sternotomy whenever the clinical criteria of failure are fulfilled.

The Effect of Thoracic Duct Lymph Drainage in Myasthenia gravis

The following effects were noticed when lymph was drained from the thoracic duct of four patients with severe myasthenia gravis. (1) A pronounced improvement in the myasthenic symptoms was seen after

FOLLOW UP COMPARISON OF SUPRASTERNAL VS. TRANSSTERNAL METHOD FOR THYMECTOMY IN MY ASTHENIA GRAVIS

Since 1965 the suprasternal ( S ) approach has routinely been used for thymectomy in Uppsala and Stockholm. During the same period the transsternal (T) method (median sternotomy) has been used in Gothenburg. A three-year follow-up study for comparing these two methods was made. This retrospective study has been made possible since a ) the authors have cooperated in the development of a clinical score system for the evaluation of MG patients, b) all patient data were fed into a common data base making possible patient selection through strictly defined criteria, c) patient material, clinical practise and physicians’ experience were comparable in the three centers, and d) indications for thymectomy were similar in the three centers.