Raised prolactin levels in myasthenia gravis: two case reports and a study of two patient populations.

OBJECTIVES: To describe two patients with myasthenia gravis (MG) and prolactinoma and analyze the associations between MG and prolactin (PRL) levels. DESIGN: Two case reports and a case-control study of PRL levels in 192 patients with MG. PARTICIPANTS: The Immunological Research Laboratory, Center for Molecular Medicine, Department of Medicine and the Department of Neurology, Karolinska Institutet, Stockholm, Sweden; St Petersburg Medical Academy for Postgraduate Studies, and St Petersburg State Medical Pediatric Academy, Russia. RESULTS: Two women with MG and thymic hyperplasia accompanied by prolactinomas are described. The levels of plasma PRL were raised in 101 women with MG, but not in 91 men. There was an association between high PRL levels and high levels of autoantibodies against the acetylcholine receptor. CONCLUSIONS: There is an association of MG with raised levels of PRL in women. PRL has stimulating effects on immune activation and the increased levels might thus be implied in the pathophysiology of MG.

Epidemiology of myasthenia gravis: a population-based study in Stockholm, Sweden.

A regional database of myasthenia gravis (MG) patients was used to estimate the prevalence and selected characteristics of the disease in the county of Stockholm, Sweden. The prevalence of MG was 14.1/100,000 (17.1 for women and 10.8 for men). The mean age at onset for women and men was 34.9 and 48.5 years, respectively. About 60% of patients were diagnosed within the first year after initial symptoms. Generalized MG was found in 79% of patients, and 10% had severe symptoms. Almost two thirds of the patients had undergone thymectomy, and 30% needed immunosuppressive treatment. The increase in the prevalence of MG since the 1960s probably reflects an improvement in prognosis and higher detection rates of patients with milder symptoms. A delay in diagnosis indicates that early signs and symptoms of MG are still not well known by all doctors.

Polymorphisms at - 174 and in the 3' flanking region of interleukin-6 (IL-6) gene in patients with myasthenia gravis.

We examined the bi-allelic polymorphism at - 174 in the promoter region and the polymorphism in the 3' flanking AT rich region of the interleukin-6 (IL-6) gene in Swedish patients with myasthenia gravis (MG) and ethnically matched healthy individuals. There was no association between the polymorphisms and the disease. There was no relation of the polymorphisms to the clinical variables, the thymic histopathologies, the level of serum acetylcholine receptor antibodies or the concentrations of IgG and its subclasses. Our data yield no evidence for the IL-6 gene contributing to the disease susceptibility.

Tumour necrosis factor-alpha polymorphism and secretion in myasthenia gravis.

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-alpha genes in Swedish patients and healthy individuals. The TNF-alpha-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-alpha indicated that the association of TNF-alpha was possibly stronger than for HLA-DR3 and nearly the same as for HLA-B8. Peripheral blood mononuclear cells from patients positive for TNF-alpha -308 allele 2 had higher secretion of TNF-alpha 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-alpha level in vivo, thus resulting the pathological changes in the thymus and the early onset of MG.

Decreased beta2-adrenergic receptor density on peripheral blood mononuclear cells in myasthenia gravis.

Beta2-adrenergic receptors (beta2AR) are present on both lymphocytes and skeletal muscle cells. Antibodies and T cells that react with these receptors are present in patients with myasthenia gravis (MG). Immune reactivity against the beta2AR may thus modify both the immune and the muscle functions in MG. In this study, we analysed the density and affinity of beta2AR on peripheral blood mononuclear cells using a radioligand binding assay. The density (Bmax) of the receptor on cells from patients with MG was significantly lower than that on cells from patients with other neurological disorders and healthy individuals. The affinity (Kd) of the receptor and the concentration of the second messenger, cAMP, in the cells did not differ between the groups. Serum antibodies against beta2AR were demonstrated in 22% of 27 MG patients vs. 0% of 26 healthy controls. Incubation of cells with serum or purified IgG containing antibodies against the beta2AR resulted in a decline in ligand binding of the receptor in samples from three out of five patients. Thus, this study suggests that a downregulation of the beta2AR may occur in MG. This downregulation might be of importance in the patho-genesis of the disease and its symptoms.

The effect of thymectomy on autoreactive T- and B-lymphocytes in myasthenia gravis.

Eleven patients with myasthenia gravis were followed for three years after thymectomy. Acetylcholine receptor-specific T-cell stimulation was found in 8/11 patients before operation as compared to 2/11 three years after thymectomy. Changes of T-cell antireceptor-reactivity were commonly paralleled by changes in disease severity. The numbers of cells secreting IL-2 upon stimulation with human acetylcholine receptor correlated with those secreting IFN-gamma. T-cell reactivity against a monoclonal acetylcholine receptor antibody did not decrease after thymectomy. Such reactivity could reflect a beneficial immune response counteracting anti-receptor reactivity. The frequency of autoantibody-secreting cells remained unchanged, while the serum concentration of acetylcholine receptor antibodies started to decrease one year after thymectomy. All examined thymus-cell suspensions contained autoreactive T- and B-lymphocytes. There was a preferential enrichment of autoreactive lymphocytes in the thymus in a few patients with recent onset of disease.

Acute effects of intravenous injection of beta-adrenoreceptor- and calcium channel at antagonists and agonists in myasthenia gravis.

The effect of intravenous injection of propranolol, verapamil, terbutaline, calcium, and edrophonium on neuromuscular transmission has been studied with repetitive nerve stimulation and clinical tests in 10 patients with myasthenia gravis (MG). The drugs were given intravenously in doses commonly used in clinical practice. Only minor clinical effects were noted except for edrophonium. The mean decrement of the deltoid muscle was not significantly changed after injection of propranolol (before 31%, 15 min after injection 27%) and verapamil (before 29%, 15 min after injection 26%). Terbutaline applied after propranolol and calcium applied after verapamil improved the decrement substantially. Edrophonium applied after propranolol or verapamil also greatly improved the decrement. We conclude that there is no rapid deterioration of neuromuscular transmission in patients with moderately severe MG after injections with therapeutic doses of propranolol and verapamil. However, we do not know if the most severely disabled MG patient could have reacted otherwise. We consider that, in cardiovascular emergencies, propranolol and verapamil may be used even in severe MG but with resuscitation equipment as well as specific antidotes available.

T and B lymphocytes reacting with the extracellular loop of the beta 2-adrenergic receptor (beta 2AR) are present in the peripheral blood of patients with myasthenia gravis.

Eighteen percent of patients with myasthenia gravis (MG) have serum antibodies against a synthetic peptide corresponding to the second extracellular loop of the human beta 2AR (residues 172-197). In this study we examined T and B cell responses to the peptide, using assays to detect individual cells secreting interferon-gamma (IFN-gamma) and IL-4 or antibodies against the peptide, and by measuring thymidine incorporation in response to the peptide. The peptide from the beta 2AR induced cytokine secretion from blood mononuclear cells in 67% of MG patients, compared with 14-28% of the control groups. Cells secreting antibodies binding to the peptide were present in 54% of MG patients and in 19-28% of controls. The numbers of beta 2AR-reactive cells were higher in MG patients than in controls. Peptide-induced increase in thymidine incorporation in cells was also more frequently demonstrated in patients (26%) compared with controls (about 10%). Activation of cells was dependent on monocytes and on MHC class II DR antigen. Based on the pattern of the cytokine secretion induced, beta 2AR-reactive T cells comprise both T helper type-1 and type-2 subsets. In addition, control peptide-reactive T and B cells were much less frequently demonstrated in the patients, and the number of such cells did not differ between the groups. Our results show that beta 2AR-reactive cells are present in most patients with MG. Such autoreactive antibodies and cells might play a role in the pathogenesis of the disease by influencing the function of skeletal muscle and immune systems.

Evaluation of a knowledge-based decision-support system for ventilator therapy management.

Evaluation of knowledge-based systems differs from that of conventional systems in terms of verification and validation techniques. Furthermore, evaluating medical decision-support systems is difficult because the field is thus far comparatively unexplored. This paper presents an evaluation of a medical knowledge-based system called VentEx that supports decision-making in the management of ventilator therapy. Real patient data from 1300 hours of patient care involving 12 patients with 6 diagnoses are used to validate the knowledge base. The results range from 4.5% to 15.6% disagreement between the setting recommendations produced by VentEx and a gold standard, and 22.2% disagreement for recommendations for weaning. A comparison between the standard and two physicians showed that VentEx produced advice of the same quality as the physicians.

Factitious disorder presenting with acute cardiovascular symptoms.

A 23-year-old female student exhibited all the characteristics of chronic factitious disorder with physical symptoms (Munchhausen's syndrome): deliberate simulation of illness, peregrination, fantastic pseudology and dramatic circumstances on admittance. The patient induced impressive blood pressure peaks by the Valsalva manoeuvre. She also simulated arrhythmias, seizures and unconsciousness. Her symptoms had previously led to comprehensive cardiological, neurological and endocrinological evaluations and treatment in at least three different countries in two continents. A literature survey suggests that facitious cardiovascular symptoms have become more frequent during recent decades.

Treatment of myasthenia gravis with anti-CD4 antibody: improvement correlates to decreased T-cell autoreactivity.

We treated a patient with severe myasthenia gravis with a chimeric (murine/human) anti-CD4 monoclonal antibody (cM-T412) for 7 days and followed the therapeutic effect by standardized muscle function tests, single-fiber electromyography, and immunologic examinations of disease-specific B- and T-cell functions. Clinical and electrophysiologic improvement began within 4 days, lasted for 3 months, and was maximal between days 16 and 58. The CD4+ lymphocytes decreased to a minimum of 80 cells per microliters of peripheral blood, recovered slowly during the first year of follow-up, and did not correlate with changes in disease severity. T-cell stimulation by human acetylcholine receptor was abolished by the treatment but became detectable at the time of worsening of symptoms. The concentration of acetylcholine receptor antibodies in serum was not decreased by the treatment. The results suggest that anti-CD4 antibody administration could be effective in the treatment of severe myasthenia gravis and indicate that acetylcholine receptor-specific T lymphocytes might contribute to the disturbed neuromuscular transmission in the disease.

VentEx: an on-line knowledge-based system to support ventilator management.

This paper will demonstrate the clinical application of a knowledge-based decision-support system called VentEx for ventilator management. VentEx has been implemented using a knowledge-based development tool on a PC under the Microsoft Windows multitasking environment. It is integrated into a computer aided ventilator system including the Siemens Elema Servo Ventilator 900 C equipped with a Servo Computer Module 990 and the CO2 analyser 930. The system provides advanced ventilator monitoring with expert advice concerning ventilator strategy and settings based on data from on-line monitoring. The knowledge base has been primarily validated and the system has been clinically tested by the intensive care unit staff. Different approaches such as knowledge acquisition, representation and system integration have been outlined and discussed.

Beta 2-adrenergic receptor antibodies in myasthenia gravis.

Although autoantibodies against the nicotinic acetylcholine receptor are the characteristic feature of the autoimmune disease myasthenia gravis (MG), no strong correlation is found between the autoantibody titer and the degree of clinical severity. Numerous studies have attempted to detect the presence of other autoantibody populations that might have a role in the pathology of the disease. We report, for the first time, that 18% of the MG patients we screened have antibodies in their serum to a peptide corresponding to the second extracellular loop of the human beta 2-adrenergic receptor (residues 172-197). Affinity purified antibodies to the beta 2-adrenergic receptor peptide 172-197 reacted with the human beta 2-adrenergic receptor protein obtained from transfected E. coli cell membrane extracts, but did not cross-react with the human AChR. Sufficient material was obtained from nine MG patients and it was found that the gamma globulin fraction from these patients immunoprecipitated the receptor, and that affinity purified IgG to peptide 172-197 competed for receptor binding with the beta-antagonist iodo-cyanopindolol. Using truncated peptides or amino acid modification procedures, no immunodominant B-cell epitope could be detected within region 172-197. Thus, a subpopulation of MG patients possesses anti-beta 2-adrenergic receptor antibodies which are a distinct set of autoantibodies with possible pharmacological activity.

Mechanical ventilation in medical and neurological diseases: 11 years of experience.

Mechanical ventilation (MV) is imperative in many forms of acute respiratory failure (ARF). The aim of this work was to review all episodes of MV in a Medical Intensive Care Unit (MICU) during the 11-year period 1976-1986. Four per cent (n = 1008) of 24,899 admissions to the MICU were treated with MV. The mean age of ventilator-treated patients was 53 +/- 18 years, and obviously it increased during the period of study. The average duration of MV was 4.7 d. MICU mortality, hospital mortality and 2-year mortality rates for patients subjected to MV were 33%, 38% and 46%, respectively. The mortality rate did not change during the study period. Cerebrovascular and malignant diseases carried the highest mortality rates, 75 and 79%, respectively, whereas mortality in patients ventilated because of drug overdose (n = 313) was only 2%. The results of this study confirm previously published findings concerning the outcome of MV, and we conclude that the effects of MV remain discouraging in medical and neurological patients. Improved quality of ventilator therapy and monitoring, as well as continued research directed at the causes of ARF, are equally important in reducing the mortality in ARF.

Statistical models for prediction of arterial oxygen and carbon dioxide tensions during mechanical ventilation.

The possibility of constructing statistical models for prediction of alveolar oxygen and carbon dioxide tensions has been investigated in 20 mechanically ventilated patients in acute respiratory failure (ARF). Linear multiple regression analysis using PaCO2 and PaO2 as dependent variables was used to construct (a) models for individual patients, (b) models for specific diagnostic groups and (c) general models (all patients). The coefficient of determination (R2) was highest for the individual patient models (0.38-0.99) and lowest for the general models (0.28-0.49). In order to achieve a high predictive accuracy, models matching individual patients should be constructed on the basis of initial invasive blood gas measurement. Statistically derived models may bring better understanding of the behaviour of factors influencing arterial gas tensions in ARF and may be of value in the management of patients on mechanical ventilation.

Kave: a tool for knowledge acquisition to support artificial ventilation.

A decision support system for artificial ventilation is being developed. One of the fundamental goals for this system is the application of the system when a domain expert is not present. Such a system requires a rich knowledge base. The knowledge acquisition process is often considered to be the bottleneck in acquiring such a complete knowledge base. Since no single available method, for example interviewing domain experts, is sufficient for removing this bottleneck, we have chosen a combination of different methods. The different backgrounds of knowledge engineers and domain experts could cause communication restrictions and difficulties between them, e.g. they might not understand each others knowledge domain and this will affect formulation of the knowledge. To solve this problem we needed a tool which supports both the knowledge engineer and the domain expert already from the initial phase of developing the knowledge base. We have developed a knowledge acquisition system called KAVE to elicit knowledge from domain experts and storing it in the knowledge base. KAVE is based on a domain specific conceptual model which is a result of cooperation between knowledge engineers and domain experts during identification, design and structuring of knowledge for this domain. KAVE includes a patient simulator to help validate knowledge in the knowledge base and a knowledge editor to facilitate refinement and maintenance of the knowledge base.

Multivariable optimization of mechanical ventilation. A linear programming approach.

The proposed method aims at improved ventilatory care with reduced morbidity. It combines two important aspects of mechanical ventilation: gas exchange and lung mechanics. A single criterion was selected as optimization index of lung trauma: peak respiratory power (PRP) defined as the maximum product of pressure times flow during inspiration. Arterial blood gases reflect gas exchange and constitute the constraints of the problem. The constraints as well as the optimization index are expressed as linear functions of the input variables (frequency of breathing, tidal volume, and positive end expiratory pressure). A linear programming approach can therefore be used to determine the values of input variables that minimize PRP and at the same time keep arterial blood gases within the prescribed limits. The coefficients of the constraints and the optimization index equation are found by manipulating input variables in order to obtain four different values of PaO2, PaCO2 and PRP (there are four coefficients in each equation). The coefficients can then be calculated and the optimization procedure run. In a pilot study 5 patients suffering from diseases of varying pulmonary pathology were investigated with this method. In 4 out of 5 the ventilator treatment improved in terms of blood gas values (mean increase in PaO2 was 4.7%) and reduction of mechanical load on the lungs (mean PRP reduction was 20%). Lower PRP is accompanied by lower mean power and pressure values, which results in increased cardiac output. Presently, the main problem is the time it takes to determine the patient coefficients (approx one hour), a procedure that needs to be simplified.