Changes in serum complements and their regulators in generalized myasthenia gravis.

OBJECTIVE: To investigate changes in serum complements and their regulators in the pathogenesis of myasthenia gravis (MG). METHODS: Forty-four patients with acetylcholine receptor antibody-positive MG, as well as 20 patients with non-inflammatory neurological disorders were enrolled. Serum complements (C3, C4 and soluble C5b-9) and complement regulators (vitronectin, clusterin and properdin) were extensively analysed by enzyme-linked immunosorbent assay and their associations with clinical profiles of MG were examined. RESULTS: Serum C3, C4 and clusterin levels were not significantly different between patients with MG and controls. The patients with MG had higher soluble C5b-9 (P = 0.09) and vitronectin (P = 0.001) levels than the controls; moreover, vitronectin levels decreased after treatment (P = 0.09). Serum properdin (P = 0.03) levels were lower in the patients with MG than in the controls, and negatively correlated with the MG Activities of Daily Living score (rs = -0.26, P = 0.09) and with the presence of bulbar palsy (P = 0.04). CONCLUSION: Our results show that activation of complements and an altered complement network could contribute to the inflammatory pathogenesis of MG.

Serum level of soluble urokinase plasminogen activator receptor (suPAR) as a disease severity marker of myasthenia gravis: a pilot study.

Myasthenia gravis (MG) is an autoantibody-mediated inflammatory disease of the neuromuscular junction. Biomarkers indicating disease activity in MG are warranted. Recently, the soluble urokinase plasminogen activator receptor (suPAR) has been reported to be associated with inflammation, tissue damage, disease activity and prognosis in various diseases, including autoimmune diseases. In this study, serum suPAR levels were measured in 40 patients with anti-acetylcholine receptor antibody-positive MG and 30 controls, and their correlations with clinical variables and severity scale scores were investigated. We identified that serum suPAR levels significantly correlated with MG activities of daily living scale (Spearman's ρ = 0·45; P = 0·004) and MG Foundation of America classification (Spearman's ρ = 0·37; P = 0·02) at serum sampling, but not with anti-acetylcholine receptor antibody titers. In conclusion, serum suPAR levels can be a candidate for a novel biomarker of disease activity in anti-acetylcholine receptor antibody-positive MG.

Frequency and features of myasthenia gravis developing after thymectomy.

BACKGROUND AND PURPOSE: Thymectomy is an effective treatment for myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) antibodies. We rarely encounter patients who develop MG after surgery for thymic tumors. This study aimed to investigate the characteristics and frequency of post-thymectomy onset (PostTx) MG. METHODS: We reviewed the clinical information of thymoma-associated MG in 158 patients. Of these, 18 (11%) patients with PostTx MG were identified. RESULTS: The presence of anti-AChR antibodies (82%) and electrophysiological abnormalities (50%) was confirmed before thymectomy in patients with PostTx MG. The clinical characteristics of PostTx MG were similar to those of pre-thymectomy onset (PreTx) MG. In PostTx MG, the duration between thymectomy and MG onset were distributed as < 6 months (early-onset PostTx MG) and ≥ 6 months (late-onset PostTx MG). Notably, some patients with late-onset PostTx MG were associated with thymoma relapse. CONCLUSION: Our results suggest that approximately 11% of patients with thymoma-associated MG were PostTx MG and pre-surgical assessment of anti-AChR antibody titer or electrophysiological testing may predict PostTx MG development. However, no difference in clinical manifestation and prognosis was observed between PreTx MG and PostTx MG.

Adequate tacrolimus concentration for myasthenia gravis treatment.

BACKGROUND AND PURPOSE: A single, oral dose of 3 mg/day tacrolimus, approved for myasthenia gravis (MG) treatment in Japan, was shown to reduce steroid dose and anti-acetylcholine receptor (AChR) antibody titers as well as to improve MG symptoms. However, no studies have investigated the association between tacrolimus concentration and its clinical efficacy in MG. In this study, we aimed to determine the optimal tacrolimus concentration for MG treatment. METHODS: The trough tacrolimus concentration in 51 patients with MG (positive for anti-AChR antibody, n = 48; negative for anti-AChR and anti-muscle-specific tyrosine kinase antibodies, n = 3) who received 3 mg/day tacrolimus for more than 1 year was measured using a chemiluminescent enzyme immunoassay. The clinical characteristics of patients with MG as well as the dose of prednisolone used before and after tacrolimus treatment were evaluated retrospectively. RESULTS: The median trough tacrolimus concentration was 5.4 (range, 2.9-7.6) ng/mL, which was correlated with 'minimal manifestation or better status' (P = 0.0190, r = 0.3273) and the reduction in anti-AChR antibody 1 year after tacrolimus initiation (P = 0.0170, r = 0.3465). When the cut-off value for tacrolimus was defined as 4.8 ng/mL using a receiver operating characteristic curve, patients with adequate tacrolimus concentration (≥4.8 ng/mL) showed more reduction in anti-AChR antibody titers and more improvement in MG-related activities in daily life scores. More patients with adequate tacrolimus concentration achieved 'minimal manifestation or better status' compared with those with low tacrolimus concentration. CONCLUSIONS: An adequate tacrolimus concentration is required for better MG prognosis.

Serum cytokine and chemokine profiles in patients with myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune-mediated inflammatory disease of the neuromuscular junction. Previous studies of animal MG models have suggested important roles of cytokines in MG pathogenesis, but adequate studies on cytokines in human MG are lacking. Using a multiplex suspension array system, we measured the serum levels of 27 cytokines/chemokines in 47 anti-acetylcholine receptor antibody-positive patients with MG and 20 normal controls (NC) to investigate the contribution of cytokines/chemokines toward MG pathogenesis. Correlations between clinical parameters and cytokine/chemokine levels in patients with MG were also examined. The serum levels of interleukin (IL)-15 (mean ± standard deviation: 6·85 ± 6·97 pg/ml) and vascular endothelial growth factor (VEGF) (96·21 ± 71·60 pg/ml) significantly increased, whereas IL-4 levels (3·57 ± 0·86 pg/ml) decreased in patients with MG compared with NC (IL-15: 4·42 ± 1·55 pg/ml; VEGF: 63·51 ± 32·95 pg/ml; IL-4: 4·15 ± 0·81 pg/ml, P < 0·05). In addition, eight cytokines (IL-4, IL-8, IL-15, eotaxin, macrophage inflammatory protein-1α, macrophage inflammatory protein-1ß, VEGF and IL-1b) were significantly changed among MG patients with thymoma, MG patients without thymoma and NC (P < 0·05). Some cytokines, such as IL-4, IL-15, and VEGF, may play roles in the pathogenesis of MG.

Distal sensory axonopathy after sarin intoxication.

A 51-year-old man inhaled sarin during a terrorist attack on the Tokyo subway system and died 15 months later. Neuropathologic examination revealed marked nerve fiber decrease in the sural nerve, moderate nerve fiber loss in the sciatic nerve, and unremarkable dorsal root ganglia, dorsal roots, and posterior column of the spinal cord. This pathology is consistent with dying-back degeneration of the peripheral nervous system and could represent a late sequela of sarin intoxication.

[A case of mononeuritis multiplex associated with type I (monoclonal) IgG kappa cryogloblinemia].

We here reported a fifty-three year-old woman with mononeuritis multiplex, associated with type I cryoglobulinema induced IgG kappa MGUS (monoclonal gammopathy of undetermined significance). She first experienced numbness in the extremities, that showed stepwise deterioration for several weeks. The nerve conduction study revealed axonal neuropathy, and laboratory examination detected type I cryoglobulinema. The sural nerve biopsy demonstrated with severe axonal degeneration with focal accentuation, lacking any inflammatory response. Single cryofiltration definitely stopped the progression of the symptoms. The prompt clinical response to the removal of cryoglobulin, without the administration of anti-inflammatory drugs, confirmed the direct etiological correlation between type-1 cryoglobulin and the neuropathy, and may favor ischemic, rather than inflammatory nature of this rare type of neuropathy.

Spinal myoclonus in the periscapular muscles after mastectomy assessed by FDG-PET.

We describe a 64-year-old woman who developed spinal myoclonus around the left scapula after long thoracic nerve injury by mastectomy. Involuntary muscle twitching was semi-rhythmic, and ultrasonography identified contraction of the serratus anterior, teres major, and rhomboid muscles. FDG-PET imaging revealed markedly increased glucose uptake only in the serratus anterior. Lidocaine injection into this muscle resulted in complete cessation of the involuntary movement, and then she was successfully treated with botulinum toxin type A. These findings raise the possibility that the myoclonus was primarily caused by ectopic firing of the injured long thoracic nerve, then spreading to adjacent muscles possibly via a central mechanism mediated by group Ia afferents. The new imaging tools, such as FDG-PET and ultrasonography, were useful to determine the therapeutic target muscle.

O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) uptake in mouse thymoma cells, and its biodistribution in mice and human volunteers.

PURPOSE: To evaluate O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) uptake in mouse malignant thymoma (EL4), and its biodistribution in mice and humans. MATERIAL AND METHODS: First, 18F-FET uptake in EL4 cells was examined in an in vitro study. Second, the kinetics of 18F-FET uptake and its biodistribution were examined in mice after subcutaneous injection of EL4 cells and complete Freund's adjuvant. Finally, the kinetics of 18F-FET uptake and its biodistribution in healthy human volunteers were examined. RESULTS: In an in vitro study, 18F-FET was extensively incorporated in EL4 cells. In an animal study, 18F-FET accumulation in normal organs peaked within 30 min postinjection. The mean ratios of 18F-FET uptake in tumors and in inflammatory lesions to that in muscle tissue at 60 min postadministration were 2.18 (range 2.00-2.29) and 1.04 (range 0.95-1.14), respectively. In a human study, static images were taken 60 min after 18F-FET administration. Mean standardized uptake values (SUVs) of the liver (1.52, range 1.38-1.71) and kidneys (1.90, range 1.74-2.24) were nearly equal or slightly higher than that of muscle tissue (1.19, range 0.99-1.33). CONCLUSION: This study demonstrates that 18F-FET accumulation in thymoma is significantly higher than in normal organs. 18F-FET could be a useful tracer for tumor imaging.

[Anterior pituitary function in patients with cerebrovascular disease: with special reference to growth hormone secretion in response to TRH administration (author's transl)].

HGH secretion in response to TRH was studied in patients with cerebrovascular disease in order to elucidate an influence of cerebrovascular lesions on the hypothalamus-anterior pituitary function. Blood specimens were obtained before and at the time of 10, 20, 30, 40, 60, 90 and 120 minutes after the intraveneous administration of 200 microgram of TRH in 17 patients with cerebral hemorrhage and in 8 patients with cerebral infarction. With regards to the natural fluctuations of serum HGH caused by cerebrovascular disease, the blood specimens were obrained at the time of 0, 30, 60, 90 and 120 minutes without the administration of TRH in 4 patients with cerebral hemorrhage and in 4 patients with cerebral infarction. Serum HGH was measured using the RIA method and the following results were obtained: 1) An increase in serum HGH was observed in 1 patient with cerebral hemorrhage out of 8 patients with cerebrovascular disease without TRH administration. 2) In 5 out of 17 patients with cerebral hemorrhage, an increase in serum HGH was observed following TRH administration. Three out of these 5 patients were included in the group of non-coma, and 4 out of the 5 patients were female. 3) In 2 out of 8 patients with cerebral infarction, an increase in serum HGH was observed following TRH administration.

[Anterior pituitary function in patients with cerebrovascular diseases with special reference to TSH secretion in response to TRH administration (author's transl)].

TSH secretion in response to TRH was studied in patients with cerebrovascular diseases in order to elucidate the influence of cerebrovascular lesions on the hypothalamus-anterior pituitary function. Blood specimens were obtained before and at intervals of 10, 20, 30, 40, 60, 90 and 120 minutes after the intravenous administration of 500 microgram of TRH. Serum TSH was measured using the RIA method. In 20 normal subjects, the serum TSH level before TRH administration was 1.0 +/- 1.4 microunits/ml (MEAN +/- SD). Following the intravenous administration of TRH, serum TSH increased and reached the maximum level of 9.0 +/- 2.3 microunits/mil at 30 minutes and returned near to the original level at 120 minutes. The response was the same for both male & female patients. In 17 patients with cerebral hemorrhage, the response of serum TSH to TRH was variable, including the types of excess, delayed or low response besides the normal response. In severe cases, cases of acute phase and male patients, a marked variability in the response was observed. In 8 patients with cerebral infarction, a low response of serum TSH to TRH was observed in all cases. There was no difference of the response with regard to severity of the diseases, duration after onset or sex difference of the patients.

[The incidence of antithyroid antibodies in relatives of patients with thyroid disorders (author's transl)].

In order to elucidate a predisposition for so-called autoimmune thyroid disorders such as Graves' disease, chronic thyroiditis and myxedema, the incidence of thyroid antibodies was studied in relatives of patients with thyroid disorders. The relatives studied were all limited within a two degree relationship of the patients. Serum antibodies to thyroglobulin and thyroid microsome were determined by susing the method of a hemagglutination test. The following results were obtained; 1) Thirty six of 103 relatives (35%) were found to have such antibodies, and sixteen (7.0%) of 230 hospital controls were positive. This difference was significant (P less than 0.001). 2) There was no difference in the incidence among relatives of patients with Graves' disease and those chronic thyroiditis. 3) With regard to age, the incidence in the more than 20 years old group was significantly greater than that in the under 19 years old group. 4) There was no difference in the incidence between male and female. These results suggested that the relatives of patients with so-called autoimmune thyroid disorders may have a predisposition for thyroid disorders.

[Anterior pituitary function before and after treatment in twenty-three patients with isolated adrenocorticotropic hormone (ACTH) deficiency reported in Japan (author's transl)].

Anterior pituitary function in 23 patients (16 men and 7 women, aged 27 to 68) with isolated ACTH deficiency was analyzed. Four were our own cases while the other 19 cases were ascertained by questionnaire. Both the baseline TSH levels and the peak TSH responses to TRH were high before treatment in more than half the cases but were normalized after treatment. This abnormality was found in patients younger than 50. The peak prolactin responses to TRH were excessive before and after treatment in three-fourths of the cases but decreased after treatment. The peak HGH responses to ITT were excessive in 3 patients before treatment an increased after treatment in 5 out of 6 cases. The peak LH and FSH responses to LH-RH were low or high in 20-30% of cases, but these abnormal responses were reduced to half after treatment. These results demonstrate that many disorders of the anterior pituitary function were found in patients with isolated ACTH deficiency but that these disorders became normal after treatment.

Hypertrophic pachymeningitis with anti-neutrophil cytoplasmic antibody (p-ANCA), and diabetes insipidus.

We treated a patient with idiopathic cranial hypertrophic pachymeningitis and elevated serum titer of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) reactive against myeloperoxidase. This 67-year-old man showed multiple cranial nerve-palsies, central diabetes insipidus (DI), and an intrasellar mass. DI and intrasellar mass had been present for 3 years, and DI had been well controlled by intranasal desmopressin. His nerve-palsies were most likely caused by thickened dura matter detected by the brain MRI. Granuloma may develop in the sella, and MRI findings in our patient are compatible to it. Corticosteroid and oral cyclophosphamide therapy improved his neurological symptoms and serum p-ANCA level with showing good correlation. DI improved temporally for 2 months. Few other cases of hypertrophic pachymeningitis with elevated p-ANCA have been reported, however the etiology is unknown. As p-ANCA antibodies have been detected in many of vasculitides, microvasculitis may be involved in some cases of idiopathic hypertrophic pachymeningitis.