EMG evidence of myopathy and the occurrence of titin autoantibodies in patients with myasthenia gravis.

We studied 65 patients with myasthenia gravis (MG). Clinical, neurophysiological, immunological, and histological findings suggested the coexistence of a presumed autoimmune myopathy. The clinical features were persistent pyridostigmine-resistant weakness and atrophy of striated muscles. The myopathy was found more often in patients with late-onset MG than in those with early-onset (37% vs 13%). Patients with myopathy were also prone to have other immune disorders (47% vs 13%). Elevated titres of antibodies against titin were detected more often in patients with electromyography (EMG) evidence of myopathy than in the sera of those without, and only in late-onset MG cases.

Myasthenia gravis.

The annual incidence rate of myasthenia gravis (MG) was estimated as 4.6 per million population, and the rate was found to be constant in calendar-time. Age- & sex-specific incidence rates disclosed a bimodal appearance for both sexes. According to the epidemiological data, the age limit between early onset and late onset of MG should be set at 50 years. The point prevalence rate has increased in time from 41 per million population in 1950 to 77 in 1988, and model calculation predicts an increased rate of 83 in year 2000. This reflects an improvement in the prognosis of MG. Standardized mortality rate for MG was estimated as 1.87. The total patient population was weighted 6 to 4 with predominance of females. A decrement of the muscle action potential (AP) and of the muscle twitch (TW) was found in 72% and 49% of the cases respectively, the diagnostic yield being proportional to the severity of MG. Post-tetanic facilitation of AP and TW was found in 25% and 20% of the cases respectively. The analogue estimates for post-tetanic exhaustion were 44% and 25% respectively. An abnormal staircase phenomenon was present in 37% of MG patients. Neurophysiological evidence of myopathy, which was not correlated to the degree of neuromuscular transmission failure, was found in 19% of the patients, more often in cases with late onset than in those with early onset (31% compared with 11%). The occurrence of myopathy was associated with pathological muscular biopsy (78%), and with anti-striated muscle antibodies (53%) suggesting that a myopathy of possibly autoimmune origin may coexist with MG. The overall diagnostic sensitivity of anti-AChR antibodies RIA was found to be 88%, the positivity being proportionate to the clinical severity of MG (ocular MG: early onset 71%, late onset 88%; severe generalized MG: early onset 89%, late onset 98%). The finding of anti-AChR antibodies is highly specific for MG (>99.9%). The distribution of antibodies titres was approximately lognormal. The concentration of the antibodies correlated with the clinical severity of the disease, female or male gender, and the pathology of the thymus gland. The improved outlook for MG during the last 4 decades may be ascribed to the combined results of all the new modalities of treatment. Experimental results towards selective plasma exchange are expounded. As opposed to MG patients with hyperplasia or involution of the thymus gland, thymoma cases exhibited exacerbation of the clinical course and also of the anti-AChR antibody titres after thymectomy. Possible steps to circumvent the therapeutical impasse in thymoma cases are discussed, such as combined immunosuppressive therapy along with surgery or conservative treatment for as long as possible.

Exacerbation of myasthenia gravis after removal of thymomas.

It appeared from this prospective and non-randomized study, that the removal of thymomas in myasthenia gravis (MG) patients resulted in rapid exacerbation of the clinical severity of the disease and of anti-acetylcholine receptor antibodies titres, which peaked after about 300 days and continued for up to 2 years. Long-term follow-up after thymomectomy (mean duration +/- SEM after surgery 5.5 +/- 0.8 years) showed that the immunological and clinical state observed prior to surgery was eventually restored, but long-term benefit attributable to surgery could not be demonstrated. Non-thymoma MG cases, however, exhibited post-operative amelioration in clinical course and decreasing antibodies titres, both of which were already significant one year after surgery, and additional improvement was observed at the time of long-term follow-up (mean 4.3 +/- 0.5 years). Furthermore, the prognosis for MG patients not operated on was also favourable. It is suggested that the occurrence of thymomas is linked to genetic factors and that neoplasia of the thymus may be part of immunoregulatory mechanisms with predominance of inhibition.

Anti-acetylcholine receptor (AChR) antibodies measurement in myasthenia gravis: the use of cell line TE671 as a source of AChR antigen.

Acetylcholine receptor (AChR) from the human rhabdomyosarcoma cell line TE671 was compared with that of human ischaemic muscle AChR as a source of the antigen for the diagnosis of myasthenia gravis (MG). The sera, which were anti-TE671 cell AChR antibody-negative, all came from patients with low anti-human muscle AChR antibody titers. None of the sera that were seronegative as a result of the human muscle AChR RIA became positive with TE671 cell AChR. The overall sensitivity was 7% less using TE671 cell AChR. The lower sensitivity was observed irrespective of the clinical form of MG. It also appeared from this study that epitopes specific to the junctional isoform of human AChR are essential for the detection of low antibody titers, which accounts for this feature, since TE671 cells only express the extrajunctional isoform of AChR in the surface membrane. Accordingly, AChR from cell line TE671 cannot replace human muscle AChR in the conventional diagnostic immunoprecipitation RIA. There are, however, many other useful implications of AChR from cell line TE671.

Brain extraction and distribution of 99mTc-bicisate in humans and in rats.

Blood-brain barrier (BBB) passage of the flow tracer ethylenediylbis-L-cystein diethylester (bicisate, ECD) was measured repeatedly in five patients by means of the intravenous (i.v.) double-indicator technique using 24Na+ as an intravascular cotracer. After i.v. injection, the arterial concentration curve of 99mTc-bicisate was delayed and dispersed compared with that of the intravascular cotracer, presumably due to lung retention of the flow tracer. The corrected cerebral venous output curves were fitted using a three-compartment model with four parameters. At resting cerebral blood flow (CBF) values, the unidirectional brain extraction was 0.57 +/- 0.05, the permeability-surface area product for passage from blood to brain (PS1) was 0.48 +/- 0.07 ml/g/min, and the distribution volume for bicisate was 0.74 +/- 0.20 (mean +/- SD). In a single patient, BBB transport after i.v. injection of bicisate was compared with that of a similar flow tracer, d,l-hexamethylpropyleneamine oxime (HM-PAO), and similar values were found for the two tracers. In 19 rats, the brain extraction of bicisate was measured by means of the intracarotid double-indicator technique. The brain extraction was measured at resting, decreased, and increased CBF values. Low CBF values were obtained by hyperventilation and high values by hypercapnia. The degree of backflux of tracer from brain to blood was evaluated by means of the three-compartment model and was found to be negligible in these experiments. The brain extraction was 0.70 +/- 0.1 and PS1 was 0.94 +/- 0.27 ml/g/min. During hypercapnia, CBF increased from 0.77 to 1.09 ml/g/min, leading to a significant decrease in brain extraction, from 0.70 to 0.56.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical implementation of anti-acetylcholine receptor antibodies.

A multivariate analysis of anti-acetylcholine receptor (AChR) antibodies and clinical parameters other than treatment (modified Osserman groups, age, type of onset, sex, and thymus pathology) was performed for all incident (n = 366) myasthenia gravis (MG) cases in its white population in Denmark during the past 15 years. Sera from 244 healthy individuals and from 295 patients with diseases other than MG were analysed as controls. Formal statistics for the anti-AChR antibodies assay (immunoprecipitation RIA using crude human AChR extract) were calculated. The distribution of antibodies titres greater than 0.1 nMole/l was found to be approximately lognormal. For MG patients the 95% reference interval was 0.2-1549 nMoles/l, and in control sera the range was 0.0-0.4 nMole/l. Using 0.5 nMole/l as the cut-off level and regarding all results less than this value as normal titres, it appeared that the assay was highly specific (> 99.99%) for MG. In a population of MG patients significance should be attributed to values in the range 0.3-0.4 nMole/l. The overall diagnostic sensitivity was found to be 88%. The sensitivity appeared to be proportionate to clinical severity of MG. The percentage with a normal titre was higher (16%) for early onset of MG, compared with 7% for late onset. No significant difference in relation to the frequency of "negative titre" was found in relation to sex. Anti-AChR antibodies titre was found to correlate with clinical severity, female or male gender, and pathology of thymus. The groups of MG patients were not matched for the various clinical parameters but multiple regression analysis controlling for these variables revealed independent effects of clinical severity and sex though not of age. Normal thymus (including involuted gland) and thymoma were correlated with low to intermediate tires, and hyperplastic thymus with high level of antibodies. The clinical implementation of anti-AchR antibodies is reviewed from 1976 and up to the present. The problems with false positive results are thoroughly expounded.

Neurophysiological evaluation in myasthenia gravis. A comprehensive study of a complete patient population.

Electrical and mechanical responses to single shocks, slow and fast nerve stimulation (RNS), quantitated EMG, anti-acetylcholine receptor (AChR) and anti-striated muscle (SM) antibodies (ab) were determined in 145 patients with myasthenia gravis (MG). Anti-AChR ab were found in 93% of the myasthenic sera. Decrement of muscle and mechanical responses occurred in 72% and 49%, respectively, the diagnostic yield being positively related to severity of MG. Anti-AChR ab were found in 81% of patients without RNS abnormalities. Decrement at RNS occurred in 33% of the cases without anti-AChR ab compared with 78% of those with elevated titres. Regional curare test (RCT) was diagnostic in 75% of cases with normal RNS. As the combined diagnostic yield of RNS and anti-AChR ab was 96%, RCT and single fibre EMG are rarely indicated. Post-tetanic facilitation and exhaustion, and an abnormal staircase phenomenon occurred in 25%, 44% and 37%, respectively. None of these parameters correlated with severity, type or onset of MG. EMG evidence of myopathy, positively correlated with the presence of anti-SM ab, occurred in 19% of patients examined, 3 times more frequent in those with late onset of MG than in those with early onset; thus myopathy of possible autoimmune origin may coexist with MG. An adequate electrophysiological diagnostic strategy for MG patients is proposed.

Epidemiology of myasthenia gravis in Denmark. A longitudinal and comprehensive population survey.

The incidence of myasthenia gravis (MG) was found to be constant in calendar time. The mean annual incidence rate was 4.4 per million population. Age- and sex-specific incidence rates disclosed a bimodal appearance for both sexes, with a peak age at onset located in the early-onset group and another peak for late onset of MG. Early onset of MG appeared 10 years later for male individuals than for female individuals, whereas the peak for late onset of MG was located at the same age for both sexes. It is suggested that the separation between early onset and late onset of MG should be at the age of 50 years for both sexes, rather than at 35 to 40 years as accepted in most studies. The prevalence of MG has increased in time. On January 1, 1988, the point prevalence rate was 77 per million population (female subjects, 96, and male subjects, 57). This reflects an improvement in prognosis despite the fact that life expectancy was found to be significantly lower for MG patients than that of the sex- and age-matched population. The factors causing increased mortality were found to be operative throughout the duration of the disease. Maximum severity of disease was reached within 2 years from onset in 78% of the cases, and more than 50% of all MG-related deaths occurred during the same period. In the course of MG, 70% of all patients experience generalized muscular weakness, and 30% to 40% also suffer from respiratory problems.

Aniracetam tested in chronic psychosyndrome after long-term exposure to organic solvents. A randomized, double-blind, placebo-controlled cross-over study with neuropsychological tests.

In order to examine if the nootropic drug, aniracetam, was capable of improving cognitive performance, 44 subjects suffering from chronic psychosyndrome after long-term exposure to organic solvents were included in a randomized, double-blind, placebo-controlled, cross-over study. The treatment periods were 3 months with aniracetam 1 g daily and 3 months with placebo. Neuropsychological tests as well as a physical and neurological examination were performed at entry into the study and after each treatment period, together with an evaluation of the subjects' overall condition. Neither the doctors' nor the subjects' own assessment of the overall condition indicated that the trial medication had had any effect. No significant changes in neuropsychological symptoms were observed. A statistically significant difference in favour of antiracetam was found in only 1 of the 19 neuropsychological test measures, namely a test for constructional ability. However, in another test on visuo-spatial function, a statistically significant result was found in favour of placebo. Thus, aniracetam was found to be ineffective in the treatment of subjects suffering from chronic psychosyndrome after long-term exposure to organic solvents.

Plasma exchange with selective immunoadsorption of anti-acetylcholine receptor antibodies.

Protein A-Sepharose and tryptophan polyvinyl alcohol affinity gels have been evaluated as possible agents for the selective, extracorporeal removal of anti-acetylcholine receptor (AChR) antibodies from the sera of patients with myasthenia gravis. Protein A-Sepharose was shown to be very effective. Specific anti-AChR IgG antibodies of subclasses 1 and 2 were reduced to the same extent (i.e. from 50 to 60% decrease) as the total IgG, although the latter was present at concentrations more than a 1000-fold greater. Anti-AChR antibody of subclass IgG3 was less effectively adsorbed. A full-scale in vitro experiment using one plasma volume and an automatic continuous monitor demonstrated the removal of 43% of the circulating anti-AChR antibodies and the IgG within 70 min, which is comparable to the amount removed by the present, unselective, membrane plasma exchange technique. In contrast, tryptophan polyvinyl alcohol was not effective in immunoadsorption under these circumstances.

Psychotherapy for victims of torture.

Three groups of torture victims were studied with the aim of establishing a concept of psychotherapy for such victims. Analysis of the first group, consisting of 200 case-reports made by Amnesty International medical groups, resulted in a general outline of the psychological methods of torture and their main impact on the victims. A second group of 24 torture victims was examined by the authors, and a quantitative assessment of long-term neuropsychological complaints and a qualitative insight into these symptoms achieved. In-depth interviews with victims in the third group which, consisted of the victims from the second group and six others, together with the results from the other two groups, formed the basis of a concept of psychotherapy for torture victims.