Suppressive potencies of calcineurin inhibitors against the mitogen-induced blastogenesis of peripheral-blood mononuclear cells of myasthenia gravis patients.

The calcineurin inhibitors, tacrolimus and ciclosporin, are two useful immunosuppressive drugs for the treatment of myasthenia gravis (MG), for patients who have low responses to glucocorticoids. We have studied the suppressive potencies of tacrolimus and ciclosporin on concanavalin A-induced blastogenesis of peripheral-blood mononuclear cells (PBMCs) obtained from 38 MG patients and 26 healthy volunteers. Differences in the IC50 values of the two calcineurin inhibitors between the patients and the healthy subjects were evaluated. The median (range) IC50 values for tacrolimus and ciclosporin on the blastogenesis of PBMCs of MG patients were 0.06 (0.001-100) and 0.41 (0.09-83.0) ng mL(-1), respectively. In contrast, the median (range) IC50 values of tacrolimus and ciclosporin on healthy PBMCs were 0.16 (0.001-0.33) and 5.59 (1.4-31.3), respectively, and thus ciclosporin potencies against PBMCs of MG patients were significantly higher than those against PBMCs of healthy subjects (P < 0.0001). The differences in tacrolimus IC50 values between the patients and healthy subjects were not significant. There was a correlation between ciclosporin IC50 values against the blastogenesis of PBMCs of MG patients and the duration of the disease (r = 0.35, P = 0.049). A significant correlation between the IC50 values of ciclosporin and those of prednisolone against the blastogenesis of PBMCs of MG patients was also observed (r = 0.56, P = 0.003). Furthermore, the ciclosporin IC50 values significantly correlated with the periods of glucocorticoid administration for MG treatment (r = 0.42, P = 0.038). Such correlations were not observed with the tacrolimus IC50 values. These results suggested that glucocorticoid administration had an influence on PBMC response to the suppressive efficacy of ciclosporin in MG.

Extrathymic tumors in patients with myasthenia gravis: a 35-year retrospective study.

OBJECTIVE: Autoimmune diseases are frequently associated with malignant tumor. In addition, prolonged immunosuppression may favor the development of malignancy. While the coincidence of myasthenia gravis and extrathymic tumor has been reported, the risk and features of these tumors are not well understood. REVIEW SUMMARY: We treated 305 patients with myasthenia gravis from 1968-2003, including 48 thymoma cases. Two hundred twenty-nine patients had undergone thymectomy and 76 had not. We examined cancer risk, tumor characteristics, and associations to medications. We encountered 9 cases of extrathymic tumor. Cancer risk in the thymoma cases was 6.3% and 2.3% in the nonthymoma cases, a statistically insignificant difference. Azathioprine was administered to only 14 in this series of patients; however, 2 patients developed cancer. CONCLUSIONS: Cancer risk in patients with myasthenia gravis is 2.6%, similar to that of the general population in Japan. We neurologists need to be aware that prolonged immunosuppression may favor the development of malignancy.

[A case of primary HIV infection presenting as mononeuritis multiplex].

A 34-year-old man presented with gait disturbance. He had a low grade fever and diarrhea for a few days prior to admission. Two weeks after he started to have diarrhea, he developed gait disturbance with a left foot drop. The cerebrospinal fluid obtained on admission showed pleocytosis (30/microl) and increased protein. The motor nerve conduction velocities (MCV) of the left peroneal nerve and the tibial nerve were slow, but the right peroneal and tibial MCVs were within normal limits. A test for human immunodeficiency virus (HIV) antibody was positive. The Western blot was positive with bands of gp160 and p24, confirming HIV infection. Seroconversion-related neuropathy of HIV was diagnosed. Acute HIV infection should be included in the differential diagnosis of mononeuritis multiplex. Before full-fledged AIDS development, it is important to find early stage of HIV infection in patients, so that we can treat them more effectively by means of anti-HIV drugs.

[A case of Brown-Vialetto-van Laere (BVVL) syndrome in Japan].

Here we report a sixty-year-old woman of Brown-Vialetto-van Laere (BVVL) syndrome in Japan. She had sensorineural deafness, weakness and atrophy of her extremities from 15 years of age. Her neurological symptoms slowly progressed. She first visited our hospital in 1993 when she was 49 years old. At that time, she had distal muscle weakness and atrophy of the four extremities and bulbar palsy. Deep tendon reflexes were absent and the plantar toe reflex was flexor. EMG revealed neurogenic changes and the nerve conduction studied were normal. The vital capacity was marked decreased. On August 10, 2003, she was admitted to our hospital because of CO2 narcosis. She had III, VII, X, XI, XII cranial nerve palsy, distal muscle weakness and atrophy of the four extremities. From her neurological symptoms and signs, we made a diagnosis of BVVL syndrome. MRI revealed no high signal in pyramidal tract by FLAIR image. ABR showed no response, and VEP demonstrated delay of the P100. She was intubated, and was attached to a respirator to improve her CO2 narcosis. After treatment she improved and did not need to be assisted by a respirator during daytime. During night time, she had apnea, and her blood gas showed the retention of CO2, and she still required the respiratory assistance during her sleep. This is the first report of BVVL syndrome in Japanese literature.

Autosomal dominant childhood onset slowly progressive leukodystrophy--a Japanese family with spastic paraparesis, ataxia, mental deterioration, and skeletal abnormality.

Autosomal dominant leukodystrophy is an extremely rare disease. Here we report on a dominantly inherited disease in a Japanese family with slowly progressive clinical course. Their symptoms and signs started in early childhood and very slowly progressed. In most patients spastic gait was the initial symptom. Neurological manifestations were characterized by pyramidal signs, ataxia, and mental deterioration. In addition to these neurological signs, the skeletal anomalies such as scoliosis and congenital hip dislocation were also present. MR images showed no abnormality in the early stage, but T2-weighted images revealed high intensity areas in the cerebral and cerebellar white matter, and the dentate nucleus in the advanced stage. Proton MR spectroscopy showed decrease of N-acetylaspartate/creatine ratio and increase of choline/creatine ratio in the advanced stage. Proton MR spectroscopy revealed normal N-acetylaspartate/creatine ratio and increase of choline/creatine ratio in the early stage. We suggested that these patients had abnormality in the white matter when MRI was still normal. We considered that intracranial demyelination was gradually progressed as the symptoms got aggravated.

Ulcerative colitis presenting as sensorineural deafness, brainstem encephalopathy, and white matter lesions.

BACKGROUND: Several rare neurologic complications of ulcerative colitis have been reported. REVIEW SUMMARY: We report a 69-year-old Japanese woman who developed bilateral sensorineural deafness, 2 attacks of bilateral ophthalmoplegia, and bilateral facial nerve palsy in association with ulcerative colitis. Laboratory data showed elevated cerebrospinal fluid (CSF) protein without pleocytosis, abnormal auditory brainstem evoked potentials, and multiple high signal lesions on magnetic resonance imaging of the brainstem and cerebral deep white matter. Her symptoms improved with corticosteroid therapy except for sensorineural deafness and an exacerbation of cerebral deep white matter lesions without any new clinical signs. CONCLUSION: Immunologic mechanisms may have led to her central and peripheral nervous system findings in addition to her colon disorder.

Relapse of ocular symptoms after remission of myasthenia gravis--a comparison of relapsed and complete remission cases.

Extended thymectomy and high-dose alternate-day prednisolone administration may increase the chance of remission in myasthenia gravis (MG) patients. In cases of remission, ocular symptoms sometimes reappear after a gradual decrease or discontinuation of prednisolone administration. We compared relapsed patients with those who experienced complete remission. We found that the period from onset of MG to thymectomy and initiation of prednisolone administration was longer in the relapsed cases, which suggests that early thymectomy and administration of prednisolone can lead to a superior outcome in MG patients.

Tacrolimus hydrate (FK506): therapeutic effects and selection of responders in the treatment of myasthenia gravis.

Tacrolimus hydrate (FK506) reduces myasthenic symptoms due to its immunosuppressive properties. We studied the therapeutic effects of FK506 and noted improvement in 7 of 13 myasthenic patients on the clinical muscle test (myasthenia gravis, MG score). Two other patients with relapsing ocular symptoms improved. We also examined patient sensitivity to FK506, but could not predict such sensitivity before FK506 treatment in the present study.

Bone density in myasthenia gravis patients receiving long-term prednisolone therapy.

Osteoporosis is an adverse effect of prednisolone therapy, although no study has been conducted on myasthenia gravis patients receiving high-dose prednisolone. We measured bone density in 36 patients (26 females and 10 males) who had undergone long-term prednisolone administration, and found a decrease in bone density in 31% of female patients and osteoporosis in only 11.5% (three cases). This frequency is lower than the presumptive rate of the general population in Japan (22.6%). No osteoporosis was detected in male patients. In conclusion, prednisolone-treated patients with myasthenia gravis have an acceptable risk of bone loss if prophylactic medication is administered.

Unusual fatty infiltration of the soleus muscle in a patient with congenital nemaline myopathy: fat-suppression muscle MRI.

A 27-year-old man developed gait disturbance over a three-year period. Histochemical analysis suggested nemaline bodies, type I fiber atrophy and type II fiber hypertrophy. Conventional magnetic resonance imaging (MRI) showed a severe degree of homogenous hyperintensity in the soleus muscle. Fat-suppression MRI exhibited marked diffuse hypointensity in the soleus muscle. MRIs demonstrated unusual fatty proliferation of the soleus muscle. Fat-suppression MRI of skeletal muscles is beneficial in evaluating the accurate topography and degree of fatty infiltration. Radiological patterns of muscle damage are variable in patients with congenital nemaline myopathy, similar to the heterogeneous clinical aspects.

[Dimethyl sulphoxide suppresses hydroxyl radical formation of muscle fiber necrosis induced by bupivacaine hydrochloride].

We induced acute skeletal muscle necrosis by using bupivacaine hydrochloride in Wistar rats and found that both 2,5- and 2, 3-dihydroxybenzoic acid significantly increased in the skeletal muscle. Dimethyl sulphoxide, a free radical scavenger, was administrated for 5 days, and resulted in significant lowering of the concentrations of 2, 5- and 2, 3-dihydroxybenzoic acid for four days. Histologically, the diameter of the regenerated muscle fiber seemed to grow by using dimethyl sulphoxide. Dimethyl sulphoxide may decrease the muscle degeneration. These results suggest that dimethyl sulphoxide is an effective hydroxyl radical scavenger, and may be a candidate for the treatment of myopathy.

[A case of Fahr's disease presenting "diffuse neurofibrillary tangles with calcification"].

77-year-old woman presented memory disturbance, hallucination, and personality change since the summer of 1988. Laboratory findings revealed normal serum Ca, P, HS-PTH levels and Ellsworth-Howard test was intact. Neuroradiological studies disclosed calcification in the dentate nucleus, putamen, globus pallidus and thalamus. We made a diagnosis of Fahr's disease. During the follow-up period of 13 years, brain MRI showed gradual atrophy in temporal lobes. This case was characterized by the clinical and neuroradiological findings of "diffuse neurofibrillary tangles with calcification: DNTC". We discussed the relations of Fahr's disease and DNTC in the literatures. From our long time observation of this case, we suggest that Fahr's disease includes DNTC.

Triphasic waves in a patient with tuberculous meningitis.

We report on the case of a 32-year-old woman with tuberculous meningitis (TBM) with electroencephalogram (EEG) output displaying triphasic waves (TWs). The EEG on day 8 revealed generalized slowing, frontal bilateral TWs, a background of 2Hz delta waves, and no epileptiform activity. The patient's condition improved slowly with antituberculosis chemotherapy treatment. A follow-up EEG on day 34 showed marked improvement, with no TWs, background activity improved to a 12Hz symmetric alpha wave pattern, and no epileptiform activity, as before. To our knowledge, this is the first report of TWs observed in a TBM case.

Autoimmune polyglandular syndrome type 2 with myasthenia gravis crisis.

We describe a rare case of autoimmune polyglandular syndrome type 2 initially presenting as Addison disease and autoimmune thyroid disease, with subsequent development of autoimmune hepatitis and myasthenia gravis (MG) crisis in a Japanese woman. MG improved with oral prednisolone followed by plasmapheresis for immunoadsorption; thymectomy was not performed. Conventional treatment for MG was effective and safe in this case, in which there was positivity for human leukocyte antigen A23, B52, B62, DR11, and DR15.

Familial Creutzfeldt-Jakob Disease with a codon 200 mutation presenting as thalamic syndrome: diagnosis by single photon emission computed tomography using (99m)Tc-ethyl cysteinate dimer.

The clinical features of familial Creutzfeldt-Jakob disease with a codon 200 point mutation [fCJD (E200K)] are similar to those of sporadic CJD (sCJD). MRI diffusion-weighted imaging (MRI-DWI) has been reported to be useful for the early diagnosis of CJD. We describe a Japanese fCJD (E200K) case in which thalamic symptoms were the initial manifestations. On admission, electroencephalography (ECG) showed no periodic synchronous discharge (PSD), and MRI showed no abnormalities. However, single photon emission computed tomography (SPECT) using (99m)Tc-ethyl cysteinate dimer ((99m)Tc-ECD) revealed hypoperfusion in the right thalamus. We conclude that the thalamic form of CJD tends to show no high-intensity area (HIA) by MRI-DWI, and that SPECT may be more useful for visualizing the affected area responsible for the thalamic symptoms at an early stage.

P-glycoprotein function in peripheral blood mononuclear cells of myasthenia gravis patients treated with tacrolimus.

Tacrolimus hydrate (FK506) reduces the symptoms of myasthenia gravis (MG) due to its immunosuppressive properties. A drug efflux pump P-glycoprotein (P-gp) actively transports FK506 out of target cells, thereby reducing their efficacy. We investigated the influence of FK506 therapy on the P-gp function of peripheral-blood mononuclear cells (PBMCs) in MG patients. Six MG patients treated with FK506 (MG(FK+)), four MG patients treated without FK506 administration (MG(FK-)), and 18 healthy subjects were included in this study. P-gp function was estimated by transporter activity that was inferred from a decrease in fluorescent P-gp substrate Rhodamine 123 (Rh123) and its inhibition by cyclosporine A (CsA). The P-gp efflux function in MG (FK+) patients assessed by the Kolmogorov-Smirnov (KS) statistic D was lower than in the healthy subjects (p=0.0084). However, PBMC sensitivity to FK506 in MG (FK+) patients was significantly higher compared to that of the healthy subjects (p=0.02). There was a significant correlation between the Rh123 efflux activity and PBMC sensitivity to FK506 in vitro (p=0.011). The data raise the possibility that FK506 treatment attenuated P-gp function in the PBMCs of the MG patients.

Myasthenia gravis and diabetes mellitus: a 35-year retrospective study.

BACKGROUND: The most common treatment of myasthenia gravis is high-dose prednisolone administration and thymectomy. A well-known adverse effect of prednisolone is hyperglycemia, however, to date there is no such detailed report. PATIENTS AND METHODS: We treated 325 myasthenia gravis patients in a recent 35 years period, and found 11 patients with diabetes mellitus. We compared these 11 diabetic patients with previously-reported cases. RESULTS: These 11 patients did not have any antibody against beta-cells in the pancreas such as anti-glutamic acid decarboxylase antibody. In 10 of 11 patients diabetes mellitus was controlled with oral medications. CONCLUSION: Myasthenic patients with diabetes mellitus could be classified into 2 groups, one group with positive organ-specific autoantibodies to many organs (with type 1 diabetes mellitus), and the other group with diabetes mellitus onset during prednisolone administration (with type 2 diabetes mellitus).

Myasthenia gravis with concomitant severe paraspinal muscle degeneration and mitochondrial DNA4977 deletion.

Recent reports have discussed the many causes of dropped head syndrome and bent spine syndrome. We described a case of myasthenia gravis with concomitant severe degeneration of spinal muscle, mitochondrial DNA4977 deletion and sensorineural deafness. These associations were thought to be independent, however this is an important case to consider the etiology of bent spine syndrome.

Autoimmune thrombocytopenic purpura, autoimmune hemolytic anemia and gastric cancer appeared in a patient with myasthenia gravis.

We report a case of myasthenia gravis (MG) associated with autoimmune thrombocytopenic purpura (AITP) and autoimmune hemolytic anemia (AIHA), and after that gastric cancer appeared. A 51-year-old man began to suffer from fluctuated muscle weakness in 1985. Muscle weaknesses became exacerbated, and he was admitted to our hospital in 1989. He was diagnosed as MG associated with AITP. After a thymectomy (hyperplasia), prednisolone therapy was started, subsequently his condition was satisfactory. In March 1995, he developed severe anemia and icterus. He was diagnosed as Evans' syndrome (AIHA and AITP) with MG. High-doses of immunoglobulin administration improved the anemia, but thrombocytopenia continued. In November 2002, he suffered marked petechia; the platelet count decreased to 1000/microl. Methylprednisolone pulse therapy and platelet transfusion were started. Gastrofiberscopy was performed and biopsy specimens revealed signet cell-type adenocarcinoma. On December 19, 2002, subtotal gastrectomy and splenectomy were performed. After that, his condition has remained satisfactory, without MG symptoms or thrombocytopenia. This is the first such case report in the literature.