Clinical features of patients with myasthenia gravis associated with autoimmune diseases.

We investigated the incidence and clinical features of patients with myasthenia gravis (MG) associated with autoimmune diseases. Associated autoimmune diseases were found in 28 of 142 consecutive Japanese MG patients (19.7%), amongst which Graves' disease (7.7%) and Hashimoto's thyroiditis (4.2%) were predominant. The clinical features of MG patients with Graves' disease were different from those of MG patients without autoimmune diseases in terms of age at onset of MG symptoms (35.5 +/- 4.0 years and 49.0 +/- 1.7 years; P < 0.05), positivity for the anti-acetylcholine receptor antibody (44.4% and 89.8%; P < 0.05), and association with thymic hyperplasia (72.7 and 17.9%; P < 0.05). The therapeutic outcome of MG patients with Graves' disease and that of those without autoimmune diseases were not significantly different. Further studies should be performed to investigate whether MG associated with Graves' disease is a distinct subtype of MG.

[Intestinal microbiocenosis in children with thymomegaly and acute lower respiratory tract infections and regimen of its correction].

57 children with thymomegaly from 3 months to 3 years of age with acute lower respiratory tract infections were studied. Disturbances of gut microflora - changes in both obligate and potentially harmful symbionts were detected in 70.2% of cases. In 47,5% of cases increased quantity of enterococci was observed. Decreased quantities of bifidobacteria and lactobacilli were observed in all and 27.5% of studied patients respectively. Most diverse gut microflora has been observed in children with pneumonia and thymomegaly of II level. During treatment of children with thymomegaly changes in gut microflora should be considered along with changes in the immune system.

Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis.

Abnormal overexpression of CXCL13 is observed in many inflamed tissues and in particular in autoimmune diseases. Myasthenia gravis (MG) is a neuromuscular disease mainly mediated by anti-acetylcholine receptor autoantibodies. Thymic hyperplasia characterized by ectopic germinal centers (GCs) is a common feature in MG and is correlated with high levels of anti-AChR antibodies. We previously showed that the B-cell chemoattractant, CXCL13 is overexpressed by thymic epithelial cells in MG patients. We hypothesized that abnormal CXCL13 expression by the thymic epithelium triggered B-cell recruitment in MG. We therefore created a novel transgenic (Tg) mouse with a keratin 5 driven CXCL13 expression. The thymus of Tg mice overexpressed CXCL13 but did not trigger B-cell recruitment. However, in inflammatory conditions, induced by Poly(I:C), B cells strongly migrated to the thymus. Tg mice were also more susceptible to experimental autoimmune MG (EAMG) with stronger clinical signs, higher titers of anti-AChR antibodies, increased thymic B cells, and the development of germinal center-like structures. Consequently, this mouse model finally mimics the thymic pathology observed in human MG. Our data also demonstrated that inflammation is mandatory to reveal CXCL13 ability to recruit B cells and to induce tertiary lymphoid organ development.

Tests for juvenile myasthenia gravis: comparative diagnostic yield and prediction of outcome.

The clinical picture, family history, laboratory data, treatment modalities, and outcome in 27 juvenile myasthenics seen over a 25-year period are presented. Onset was after 10 years of age in the majority of patients. Half presented with ocular signs, the other half with generalized-onset myasthenia. Half of those with ocular-onset myasthenia progressed to generalized myasthenia. The female-to-male ratio was 3.5:1. Myasthenia gravis was reported in the mother of one patient. Ptosis was the most common presenting sign. It was unilateral at onset in 33% of patients and remained unilateral in 11%. Pharmacologic tests (neostigmine methylsulfate and edrophonium chloride) were positive in 92% of patients. Serology was positive in 63%, whereas repetitive nerve stimulation was positive in 33% when distal nerves were stimulated and in 66% when proximal and distal nerves were stimulated. Seropositivity tended to increase with generalization of the myasthenic process. No statistically significant difference in seropositivity was noted between males and females. Anti-striated muscle antibodies were detected in two patients, neither of whom had thymoma. The yield of repetitive stimulation increased with generalization of the myasthenic process and when proximal nerves were stimulated. No statistically significant difference was noted in the decremental response between seropositive and seronegative patients. The majority of ocular myasthenics were treated with pyridostigmine bromide monotherapy. With generalization of the myasthenic process, other modes of medical and surgical therapies were needed. All patients given corticosteroids ultimately underwent thymectomy. The mean age at presentation and the duration of symptoms at presentation were longer in thymectomized patients than in those without thymectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperplasia of thymic gland.

Hyperplasia of the thymus is the most common anterior mediastinal mass in infants. It is however exceedingly difficult to evaluate by the weight of the gland as it continues to grow after birth until puberty and thereafter undergoes progressive atrophy. It normally maintains most of the radiographic characteristics of the normal thymus. Massive thymic hyperplasia, a rare variant of true thymic hyperplasia is extremely rare during the first two decades of life and clinically can cause mediastinal compression or acute and recurrent pulmonary infection. Two such cases are reported and the clinico-pathology is briefly described and discussed.

[Role of the thymus in the physiopathology of myasthenia]. / Rôle du thymus dans la physiopathologie de la myasthénie.

In myasthenia gravis (MG), the frequency of histologic abnormalities (hyperplasia in young patients, thymoma in older cases) and clinical improvement after thymectomy indicate involvement of the thymus in the pathophysiology of the disease. MG patient thymuses are characterized by the following features: increased amount of B cells (in hyperplasia) and functional abnormalities, mainly activation of B, T and epithelial cells. Moreover, thymic lymphocytes are sensitized to acetylcholine receptor (AChR): first, AChR specific T and B lines can be grown from MG thymus cultures, second, cultured thymic lymphocytes proliferate in the presence of AChR and produce anti-AChR antibodies. AChR molecules are expressed in thymic myoid cells and AChR-like molecules could be displayed at the surface of other cell types. Thus, autosensitization conditions are combined in MG thymus, and potential mechanisms are discussed. It could be a primary event, autosensitization of lymphocytes to AChR taking place initially in the thymus. Or it could be a secondary process, lymphocytes sensitized to AChR in the periphery could be trapped by myoid cells and restimulated in the thymus. In thymoma, autoimmunization occurs differently: the autoimmune process could be initiated by the tumor epithelial cells which express an AChR-like protein. The possible role of severe architectural disturbance in MG thymus (particularly in thymoma), altering thymic lymphocyte selection and maturation is also discussed.

[Advances in the research on immunopathogenesis of myasthenia gravis]. / Postepy w poznaniu immunopatogenezy miastenii.

Microscopic structure and immunologic function of the thymus gland are outlined, with an emphasis on its role in the process of T and B lymphocytes maturation. Other types of thymic cells are also described, including epithelial and myoid cells that presumably have a central role in initiation of an autoimmunologic process leading to myasthenic symptoms development. A detailed account is presented of issues concerning pathophysiology of myasthenia, the structure of nicotinic acetylcholine receptor (AchR) at neuromuscular junctions, and mechanisms underlying its destruction by autoantibodies. The role of T and B lymphocytes, of various cytokine types, of autoantibodies to various striated muscle antigens, as well as a possible role of genetic and bacterial factors in the development of myasthenia gravis are discussed. In conclusion it is stressed that since recent research findings go beyond the classic theory of myasthenia, a new consistent theory of the disease immunopathogenesis must be created in the future to place all the newly discovered phenomena in a logical conceptual structure.

[The thymo-lymphatic system in congenital thymomegaly (clinico-morphological study)]. / Sostoianie timiko-limfaticheskoi sistemy pri vrozhdennoi timomegalii (kliniko-morfologicheskoe issledovanie).

To elucidate the functional capacity of the thymus and to evaluate immunity in congenital thymomegaly the authors studied 200 autopsy thymicolymphatic specimens obtained from children under 5 who had died from congenital malformations or acute respiratory diseases. The sections were studied histologically, histochemically and using immunofluorescence to detect thymalin and measure blood thymic hormones. The hormones secretion in congenitally thymomegaly was found reduced, the deficiency growing with the disease progression. Congenital thymomegaly is defined as a primary immunodeficiency of the T-cell immunity system predominantly, which demonstrates hypo- or dysfunction of the enlarged thymus combined with elevated proliferative activity and T-lymphocyte semimaturation.

[Hypophyseal-adreno-gonadal system function in myasthenia patients with tumorous and nontumorous pathology of the thymus]. / Sostoianie gipofizarno-adrenogonadnoi sistemy u bol'nykh miasteniei pri opukholevoi i neopukholevoi patologii vilochkovoi zhelezy.

Overall twenty-five patients (all women) who ranged from 16 to 56 years old were examined. They were divided into two groups: group I was formed of subjects with hyperplasia of the thymus gland, group II--thymoma. Blood serum levels of prolactin, progesterone, estriol, estradiol, testosterone hydrocortisone. All patients showed a significant increase in average blood plasma levels of estrogens, testosterone and prolactin. Average levels of progesterone and hydrocortisone in patients with thymus hypertrophy were lower than in controls, while in thymoma patients these were much higher. The data submitted are indicative of substantial differences in the endocrine status of myasthenia patients depending on tumor or nontumor lesion of the thymus gland, which fact may suggest different pathogenetic mechanisms of development of the condition.

[Combined effect of immobilization stress and gamma-irradiation on the blood-forming system in mice]. / Sochetannoe vliianie immobilizatsionnogo stressa i gamma-izlucheniia na krovetvornuiu sistemu myshei.

Experiments with mice BALB/C were aimed at studying effects of immobilization stress and consecutive total gamma-irradiation at the dose of 2.0 Gy. Disorders in the blood system were shown to be a function of phase of the general adaptation syndrome (GAS). Acute gamma-irradiation on the stage of GAS resistance inhibited adaptive and compensatory potentials of the blood-forming system, whereas chronic stress by itself increased the spontaneous rate of chromosomal aberrations in nucleus-containing bone marrow cells in experimental animals.

Thyrotoxic myopathy mimicking myasthenic syndrome associated with thymic hyperplasia.

A 41-year-old man with progressive limb weakness manifested fluctuating muscle weakness as seen in myasthenia gravis (MG). Laboratory investigations revealed hyperthyroidism without the complication of MG. Electrophysiological studies demonstrated abnormal features of neuromuscular transmissions resembling those of the Lambert-Eaton myasthenic syndrome rather than those of MG. A CT scan showed a mediastinal mass that suggested thymic hyperplasia which often complicates MG or hyperthyroidism. Medical treatment of hyperthyroidism resulted in resolution of MG-like symptoms and regression of thymic hyperplasia on CT concomitant with normalization of thyroid function. This case highlights the fact that careful investigations are needed to differentiate MG-like symptoms from genuine MG in cases of hyperthyroidism with thymic lesions.

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.

Epithelial cell proliferation in thymic hyperplasia induced by triiodothyronine.

A significant hyperplasia of the thymus was induced in mice, treated with triiodothyronine during the first month of life. Stereological data showed that, in both treated and control mice, mononucleate epithelial cells were four times more numerous in the medulla that in the cortex. After triiodothyronine treatment, their absolute number in both cortex and medulla increased two-fold. The number of thymic epithelial cells could thus be regulated by thyroid hormones. The cortical volume in treated mice was also twice that of controls but medullar volume showed and increase of only fifty percent. Cortical epithelial cells increased at the same rate of the cortex volume by medullary epithelial cells grew more rapidly. In fact the medullary volume enlargement could be be explained mainly by the growth of the epithelium. Medullary lymphocytes did thus not preliferate in the same way as cortical lymphocytes after thyroid hormone administration. The recently described multinucleate epithelial cells were not modified in number and were thus insensitive to thyroid hormones.

[Characteristics of the endocrine and immune systems and lipid metabolism in children with lymphatico-hyperplastic diathesis]. / Osobennosti éndokrinnoi, immunnoi sistem i zhirovogo obmena u detei s limfatiko-giperplasticheskim diatezom.

The data on the genealogic anamnesis and of the incidence of lymphohyperplastic diathesis (LHD) are presented. The measurements of the size of the thymus depending on the age were made with account of the thymicothoracic index. Substantial alterations were discovered in the function of the endocrine system (high content of somatotropic hormone, reduced content of ACTH, hydrocortisone, and TTH), a decline of the relative amount of T and B lymphocytes, and persistent hypoimmunoglobulinemia (G, M, A). The high content of total lipids, cholesterol, triglycerides, low density and very low density lipoproteins and the reduced content of high density lipoproteins were detectable since the first months of life, persisting, up to 3 years of life. Children with LHD should be registered in the dispensary second health group since the first months of life.

[Pathogenesis of thymomegaly in children]. / K patogenezu timomegalii u detei.

A scheme of pathogenesis of thymomegaly based on the laboratory findings of 575 children with thymus enlargement, was drawn up to prove that thymus enlargement was not constitutional abnormality in children but thymus pathology. Routine clinical methods, investigation of the body proportions, indices of immunity and adrenocortical and thyroid function were used. Disorder of thymus function and associated changes in the state of some endocrine glands were proved. The clinical picture of thymus enlargement in children was like this: lymphoproliferative and endocrine-metabolic symptoms, compression of the vital organs by the thymus, immunity disorders.

[Characteristics of adenohypophseal secretory activity in children with thymomegaly]. / Osobennosti sekretornoi aktivnosti adenogipofiza u detei s timomegaliei.

The radioimmunological method was applied in the study of ACTH, STH, and prolactin content in thymomegaly combined with pneumonia, and in practically healthy children. A comparative analysis of hormonal parameters depending on the functional condition of the thymus demonstrated a directly proportional correlation between the STH, prolactin level, and the thymus hyperplasia; there proved to be a reverse relationship between the ACTH level and thymomegaly. Hypoadrenocorticotropinemia, hypersomatotropinemia, and hyperprolactinemia could be used as diagnostic criteria in thymomegaly.

[Potential reserve capabilities of the adenohypophyseal-adrenal cortex system in children with thymus hyperplasia and prospects for treatment]. / Potentsial'nye rezervnye vozmozhnosti sistemy adenogipofiz-kora nadpochechnikov u detei s timomegaliei i perspektivy lecheniia.

The potentialities of the adrenocortical system and thymic condition after corticotropin use were studied in young children with thymic hyperplasia combined with pneumonia. The results of the hormonal status studies after zinc-corticotropin suspension load indicate the secondary adrenocortical hypofunction. Corticotropin use within 5 to 10 days in a dose of 1 E/kg body weight intramuscularly is adequate to obtain the thymic involution in thymomegaly.

[Model of thymus gland dysfunction]. / Modelirovanie narusheniia funktsii timusa.

The thymus dysfunction induced by different doses of lymphocyte-stimulating substance, thymozine, antilymphocyte immunoglobulin and prednisolone effect upon the hormonal-immunologic balance of the hypophyseal-thymus-adrenocortical system, was studied in guinea pigs. It was stated that thymomegalia is accompanied by intensified lymphopoiesis (mainly, owing to T-lymphocytes), somatostimulating hormone and prolactin hypersecretion by adenohypophysis and the adrenocortical glucocorticoid function inhibition. Inverse proportional changes are seen in the thymus hypoplasia. The data obtained may serve as a reliable criterion for physiology and pathology of the thymus and conjugated organs and systems.

[Characteristics of hormonal homeostasis in children with thymus enlargement syndrome]. / Osobennosti gormonal'nogo gomeostaza u detei s sindromom uvelicheniia vilochkovoi zhelezy.

Hormonal homeostasis was examined in 104 children aged 1 to 14 years with thymus enlargement. There was a significant growth of somatotropic hormone in children of the first 3 years of life, characterized by thyroid dysfunction and hypofunction increase with age, by a tendency towards ACTH and hydrocortisone lowering under 6 years of age, and a significant decrease of those parameters in children over 6 years. The children with thymus enlargement also showed other disorders of hormonal homeostasis.