Clinical Features, Treatment, and Prognostic Factors of Childhood-Onset Myasthenia Gravis in a Large Chinese Cohort.

BACKGROUND: To describe the clinical features of patients with childhood-onset myasthenia gravis (MG) (CMG) and explore predictors affecting the treatment outcomes. METHODS: A retrospective observational cohort analysis of 859 patients with CMG with disease onset before age 14 years was performed at Tongji Hospital. RESULTS: Patients in the pubertal-onset group (n = 148) had a worse disease course than those in the prepubertal group (n = 711), including a higher incidence of generalized MG (GMG) at presentation, generalization of ocular MG (OMG), and more severe Myasthenia Gravis Foundation of America (MGFA) classification. All patients were initially treated with pyridostigmine, 657 with prednisone, and 196 with immunosuppressants (ISs). However, 226 patients were resistant to prednisone treatment. Multivariate analysis revealed that thymic hyperplasia, higher MGFA class, disease duration before prednisone administration, and thymectomy before prednisone administration were independent predictors of prednisone resistance. At the last visit, 121 of the 840 patients with OMG had developed GMG after a median of 10.0 years from symptom onset and 186 patients (21.7%) achieved complete stable remission (CSR). In multivariable analysis, age at onset, thymic hyperplasia, prednisone, and IS treatment were associated with generalization, whereas age at onset, disease duration, anti-acetylcholine receptor antibodies (AChR-ab), MGFA class II, short-term prednisone treatment, and IS treatment were associated with CSR. CONCLUSIONS: The majority of patients with CMG have mild clinical symptoms and favorable outcomes, especially those with earlier onset age, shorter disease duration, and negative AChR-ab. In addition, early prednisone and ISs are shown to be effective and safe for most patients with CMG.

Graves' Disease with Thymic Hyperplasia: The Response of the Thyroid Function, Thyrotropin Receptor Autoantibody, and Thymic Size to Thiamazole Treatment.

We treated a 22-year-old woman suffering from Graves' disease and thymic hyperplasia. She was referred to our institution for a close investigation of thyrotoxicosis and thymic mass. Thyroid tests and magnetic resonance imaging resulted in a diagnosis of Graves' disease and thymic hyperplasia. The thyroid function and thyroid-stimulating hormone receptor antibody (TRAb) were normalized one and five months after thiamazole initiation, respectively. The thymic size began to decrease after 1 month and was further decreased after 5 months; it was normalized after 12 months. The correlation between TRAb titers and the thymic size (R2=0.99) suggested that the patient's autoimmunity might have contributed to the thymic hyperplasia.

Pathological Findings in Myasthenia Gravis Patients with Thymic Hyperplasia and Thymoma.

Thymectomy is routinely carried out in patients with myasthenia gravis (MG) and thymomas. However, there is still a dispute as to whether MG patients with thymic hyperplasia should undergo thymectomy. We aimed to investigate the pathological findings in the thymus in patients with co-existing MG and thymic hyperplasia or thymomas treated with thymectomy, as well as effects of immunosuppression. Thirty-three patients with MG were selected and grouped accordingly: patients with no thymic abnormalities, patients with thymic hyperplasia, and patients with thymomas. All patients were treated with methylprednisolone alongside immunosuppression. A separate cohort of 24 MG patients with thymic hyperplasia or thymomas and treated with thymectomy were selected. As controls, 5 patients with thymomas or thymic carcinoma without MG were selected. Expression of CD5, extracellular regulated protein kinases1/2 mitogen activated protein kinase (ERK1/2MAPKs) and CD95 ligand (FasL) in the thymus was examined. Methylprednisolone and immunosuppressive therapy are highly effective in MG patients with normal thymus tissue and MG patients with thymic hyperplasia compared to MG patients with thymomas alone. CD5 expression was highest in MG patients with thymic hyperplasia, correlating with expression of ERK1/2MAPKs. FasL expression was similar across all groups. Thymomas may be distinguished from thymic hyperplasia by expression of CD5 and ERK1/2MAPKs. Thymectomy is the preferred treatment for MG patients with thymomas but may not be necessary in MG patients with thymic hyperplasia who are treated with immunosuppressive therapy.

CD4+ FoxP3+ T regulatory cell subsets in myasthenia gravis patients.

Although myasthenia gravis (MG) is a classic autoantibody-mediated disease, T cells are centrally involved in its pathogenesis. In recent years a number of studies have analyzed the role of CD4+ FoxP3+ regulatory T cells (Treg) in the disease with contradictory results. Here, the generation of Treg was significantly reduced in thymoma as compared to thymic hyperplasia and normal thymus tissue (p=0.0002). In the peripheral blood, Treg subsets classified according to CD49d, HELIOS and CD45RA expression changed after thymectomy and in the long-term course of immunosuppression. Compared to healthy volunteers the frequency of CD45RA+FoxP3low Treg was reduced in MG patients in general (p=0.037) and in particular in patients without immunosuppression (p=0.036). In our study, thymectomy and immunosuppressive treatment were associated with changes in Treg subpopulations. The reduced frequency of CD45RA+FoxP3low Treg we observed in MG patients might play a role in MG pathogenesis.

Seronegative myasthenia gravis and Graves' disease. Is there a link?

Graves' disease (GD) and myasthenia gravis (MG) are common autoimmune diseases but their coexistence is very rare. They may possibly share the same pathogenetic mechanisms. Recent research has shown the involvement of autoantibodies, lymphocytes, cytokines and chemokines in the pathogenesis of MG and GD. It appears that Th17 cell lineage is involved in autoimmune thyroid disease (AITD) and seems to be key factor in the development of both MG and GD.A 34-year-old male with seronegative myasthenia gravis due to thymic hyperplasia was diagnosed with also GD and opthalmopathy. Several diagnostic and therapeutic issues regarding the relevant literature are discussed.

Impaired pulmonary perfusion associated with thymus hyperplasia in an infant candidate for Fontan operation.

An enlarged thymus adversely affected pulmonary artery development and perfusion in a 4-month-old boy with asplenia syndrome and a single ventricular circulation with aorto-pulmonary shunt. Steroid administration for 4 weeks successfully reduced thymus volume, concomitant with improvement of pulmonary vasculature and perfusion. Given the importance of pulmonary physiology in the Fontan circulation, the effects of thymic hyperplasia on pulmonary circulation should be taken into consideration in the overall management of candidates for Fontan surgery.

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.

[Clinical analysis of reactive thymic hyperplasia following chemotherapy for childhood malignant lymphoma].

BACKGROUND & OBJECTIVE: Reactive thymic hyperplasia following chemotherapy for malignant tumors is likely to be misdiagnosed as tumor residue or relapse, therefore, leads to unnecessary treatment. This study was to analyze the clinical features of reactive thymic hyperplasia following chemotherapy for childhood malignant lymphoma. METHODS: Clinical data of 13 children with reactive thymic hyperplasia following chemotherapy for malignant lymphoma, treated from Mar. 1999 to Mar. 2004, were retrospectively analyzed. Of the 13 cases, 5 were Hodgkin's disease (HD), and 8 were non-Hodgkin's lymphoma (NHL). All patients received computed tomography (CT) to evaluate the therapeutic effect. When a new thymic mass emerged, positive electron tomography/computed tomography (PET/CT) was performed to identify its quality. RESULTS: At diagnosis, 10 patients had mediastinal involvement. Reactive thymic hyperplasia occurred following the completion of chemotherapy in 9 cases, or during the maintenance of chemotherapy in 4 cases. CT showed that the longest diameters of the new mediastinal masses were 2.2-6.0 cm (mean 3.7 cm). The interval from last chemotherapy cycle to the occurrence of thymic hyperplasia was 2-12 months (mean 4 months). PET/CT was performed to 5 cases, and showed no vital tumors in the mediastinum. Three cases were misdiagnosed as tumor residue or relapse, and received second-line therapy. All patients were followed-up for 1-6 years (median 4 years), and none suffered tumor relapse. CONCLUSIONS: Reactive thymic hyperplasia may occur following intensive chemotherapy for childhood malignant lymphoma. It should not be misdiagnosed as malignant tumors and overtreated.

Thymic hyperplasia presenting as anterior mediastinal mass in 2 patients with Graves disease.

Graves disease is an autoimmune thyroid condition characterized by the production of autoantibodies against the thyrotropin receptor. The autoantibodies mimic the effect of the hormone on thyroid cells, which stimulates autonomous production of thyroxine and triiodothyronine. It has been hypothesized that cross-reactivity of autoantibodies may result in Graves ophthalmopathy and dermopathy. A seldom-recognized feature of Graves disease is thymic hyperplasia. We report 2 patients with Graves disease and incidentally discovered anterior mediastinal masses presumed to be thymic hyperplasia. In both cases, these masses regressed spontaneously after treatment of hyperthyroidism.

Pseudo-myasthenia gravis and thymic hyperplasia in Graves' disease.

BACKGROUND: Diagnostic confusion between thyroid disease and myasthenia gravis (MG) can arise because the two may have similar clinical features, and also because of the more frequent coexistence of these autoimmune disorders in the same individual. In MG, autoantibodies directed against the acetylcholine receptor result in muscle weakness. Thymic pathology is well recognized in MG, with thymic hyperplasia frequent in early onset MG and thymoma more common in later onset MG. In Graves' disease, autoantibodies against thyroid antigens result in hyperthyroidism. A seldom-recognized feature of Grave's disease is the occurrence of an enlarged thymus (thymic hyperplasia) on chest CT, or of thymic lymphoid hyperplasia pathologically. CASE STUDY: This report describes a case in which the discovery of a mediastinal mass during imaging of the thyroid, and the presence of myasthenic-like symptoms, in a patient with Graves' disease prompted investigations into whether the patient also had MG. RESULTS: Despite symptoms which strongly suggested MG, subsequent investigations did not confirm the diagnosis, and treatment of Grave's lead to a resolution of the symptoms and regression of the thymic enlargement seen on CT. CONCLUSIONS: The case study highlighted clinical similarities between Grave's disease and myasthenia gravis which might cause diagnostic confusion, and also the investigations which are useful in order to differentiate the two diseases. In addition to common clinical features, the autoimmune diseases Grave's disease and myasthenia gravis may both produce radiological thymic enlargement.

[Thymus hyperplasia following chemotherapy]. / Hyperplasie thymique post-chimiothérapie.

Hyperplasia of the thymus, an uncommon development following chemotherapy, raises doubt concerning possible tumor recurrence. We report a case of thymic hyperplasia in a 12-year-old girl who was given chemotherapy for a cervicomediastinal lymphoma. Three months after treatment end, dry cough and an enlargered mediastinum suggested recurrence, but histological examination of tissue biopsy demonstrated benign reactive hyperplasia. Outcome was favorable without recurrence after corticosteroid therapy. According to the literature, thymic hyperplasia is neither tumor nor treatment specific. It generally occurs in children but may be observed in young adults. Hyperplasia of the thymus following chemotherapy would appear to be a good prognosis factor.

[Thymic hyperplasia. Description of a clinical case]. / Ipertrofia timica. Descrizione di un caso clinico.

Thymomegaly, which was in the past considered as predisposition to sudden death infants, is judged today as paraphysiological. The study achieved on a 10 months' patient shows the complexity in determining the diagnosis of simple thymic hyperplasia, when together with a massive thymus enlargement are conditions which divert to other pathologies, as in this tested clinical case.

[Myasthenia gravis and steroid therapy].

In the past 20 years, we experienced 242 myasthenic patients in our hospital. Fifty five cases were administered high doses of adrenocorticosteroid hormone for a long time. Among them, we analysed 39 cases with complete clinical records from admission to the present. We analysed 5 additional cases in whom responses to the therapy somewhat unique in that four cases have not shown any improvement until the drug was reduced to certain dosages, and in the 5th case change of method from alternate-day to every day brought good recovery of the symptoms. As a result, adrenocorticosteroid hormone was effective for 100% of the patients in this series. However, complete remission appeared in the above mentioned 10 patients (26%), after 2-3 years' continuous administration. Prognosis was far better in those who showed shorter durations between the onset of the disease and thymectomy or thymectomy than in those of longer one. In these cases, the maximum daily doses were 60-100 mg in alternate-day administration, and the total amount of prednisolone was 9-15 g in individual cases. Through data of these cases, it is recommended that the maximum dosage is to be continued for as long as 2 to 19 weeks with average 7 weeks.

[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.

The influence of preoperative drug treatment on the extent of hyperplasia of the thymus in primary thyrotoxicosis.

Thymic biopsies taken from women at the beginning of the operation of subtotal thyroidectomy were studied by the point-counting histometric technique. In all patients with primary thyrotoxicosis, the thymus is hyperplastic. After pretreatment with antithyroid drugs, the pattern of thymic involution with age is similar to, but at higher levels, than that in control groups of patients with non-toxic goitre in whom there is no evidence of immunological abnormality. By contrast, after propranolol pretreatment very little age involution is seen. The differences in the appearance of the thymus in female primary thyrotoxixosis patients prepared for operation with different drug treatment regimes are probably related to the pharmacological actions of the drugs and may indicate an interaction between primary immunological and secondary endocrinological factors in the disease process.