Tetsuro Konishi

National Hospital Organization Minami Kyoto Hospital, Kioto, Kyōto, Japan

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Publications (18)38.26 Total impact

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    ABSTRACT: We report a case of a 57-year-old woman with thymoma-associated generalized myasthenia gravis (MG) showing severe bulbar and respiratory symptoms, moderate weakness of the neck muscles, and mild weakness of extremity muscles. Corticosteroid treatment with various types of immunosuppressive agents, such as cyclosporine, tacrolimus, and azathioprine, did not improve her symptoms. Plasma exchange transiently improved her symptoms, and she was required to undergo plasmapheresis every 4 weeks. At first, cyclophosphamide pulse therapy was administered, which improved her symptoms transiently. Thereafter, rituximab (RTX) was administered. Six months after RTX administration, respiratory distress and dysphagia improved gradually, and reduction in the dosage of corticosteroids from 30 mg/day to 10 mg/day did not result in symptom deterioration. Therefore, the interval between successive plasmapheresis treatments was increased from 4 to 9 weeks 19 months after the first RTX administration. During a 26-month period from the first administration of RTX, the number of CD20+ B cells in peripheral blood decreased and remained at 0% to 26% of that before RTX treatment. The titer of anti-acetylcholine receptor antibodies did not change during the first course of treatment (0.6-0.9 nmol/l). The clinical symptom worsened with the increase of the number of CD20+ B cells in peripheral blood in the 27 month after 1st RTX administration. Therefore, RTX was administered a second time, after which the patient's clinical symptoms again improved gradually. The titer of anti-acetylcholine receptor antibodies came to be stable with 0.5-0.7 nmol and low level during the 2nd course. Corticosteroids could be discontinued in the 16th month. The findings suggest that RTX can be one of the choices for pharmacological therapy in patients with intractable MG accompanied by the presence of anti-acetylcholine receptor antibodies.
    04/2015; 55(4):227-32. DOI:10.5692/clinicalneurol.55.227
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    ABSTRACT: Purpose To examine the incidence and clinical features of epileptic seizures in Japanese patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). Methods We reviewed medical records of all patients who visited the Neurology Clinic in Utano National Hospital between January and December, 2009, and enrolled 63 MS patients who fulfilled the McDonald criteria (2005) (mean age, 41.1 years) and 31 NMO patients who fulfilled the Wingerchuk criteria (2006) (mean age, 44.6 years). Patients with a history of epileptic seizures were selected and their clinical features were obtained. Results Four MS patients (6.3%; 2 men and 2 women; mean age, 32.5 years) and 4 NMO patients (12.9%; 4 women; mean age, 36.0 years) had epileptic seizures. Disease onset age of MS patients with seizures was significantly younger than those without seizures by 13.1 years, and Expanded Disability Status Scale of NMO patient with seizures was significantly higher than those without seizures by 2.2. All 8 patients showed brain lesions on magnetic resonance imaging and 2 MS patients had tumefactive demyelinating lesions. Electroencephalography showed interictal epileptiform discharges in 5 patients. Seizure types of 6 patients were recognized as partial seizures based on clinical semiology. All patients responded to antiepileptic therapy well. In both MS and NMO, there were both seizures with and without concurrent relapse. Conclusions Similar to MS, NMO patients possibly have higher risk to develop epileptic seizures than general population.
    Epilepsy research 03/2013; 104(s 1–2):175–180. DOI:10.1016/j.eplepsyres.2012.09.005 · 2.02 Impact Factor
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    ABSTRACT: This study investigated the effect of 3,4-diaminopyridine (3,4-DAP), a potent potentiator of transmitter release, on neuromuscular transmission in vivo in a mouse model of myasthenia gravis (MG) caused by antibodies against muscle-specific kinase (MuSK; MuSK-MG) and ex vivo in diaphragm muscle from these mice. 3,4-DAP significantly improved neuromuscular transmission, predominantly by increasing acetylcholine (ACh) release, supporting presynaptic potentiation as an effective treatment strategy for MuSK-MG patients who have defective transmitter release. In MuSK-MG, we suggest that only low-dose acetylcholinesterase (AChE) inhibitors be used to avoid side effects, and we propose that 3,4-DAP may be effective as a symptomatic therapy.
    Journal of neuroimmunology 03/2012; 245(1-2):75-8. DOI:10.1016/j.jneuroim.2012.02.010 · 2.47 Impact Factor
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    ABSTRACT: Antibodies against acetylcholine receptors (AChRs) cause pathogenicity in myasthenia gravis (MG) patients through complement pathway-mediated destruction of postsynaptic membranes at neuromuscular junctions (NMJs). However, antibodies against muscle-specific kinase (MuSK), which constitute a major subclass of antibodies found in MG patients, do not activate the complement pathway. To investigate the pathophysiology of MuSK-MG and establish an experimental autoimmune MG (EAMG) model, we injected MuSK protein into mice deficient in complement component five (C5). MuSK-injected mice simultaneously developed severe muscle weakness, accompanied by an electromyographic pattern such as is typically observed in MG patients. In addition, we observed morphological and functional defects in the NMJs of EAMG mice, demonstrating that complement activation is not necessary for the onset of MuSK-MG. Furthermore, MuSK-injected mice exhibited acetylcholinesterase (AChE) inhibitor-evoked cholinergic hypersensitivity, as is observed in MuSK-MG patients, and a decrease in both AChE and the AChE-anchoring protein collagen Q at postsynaptic membranes. These findings suggest that MuSK is indispensable for the maintenance of NMJ structure and function, and that disruption of MuSK activity by autoantibodies causes MG. This mouse model of EAMG could be used to develop appropriate medications for the treatment of MuSK-MG in humans.
    American Journal Of Pathology 12/2011; 180(2):798-810. DOI:10.1016/j.ajpath.2011.10.031 · 4.59 Impact Factor
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    ABSTRACT: In order to clarify the immunological characteristics of multiple sclerosis (MS) and neuromyelitis optica (NMO), we analyzed CD3, CD4, CD8, CD20, CD4(+)CD25(+), CD4(+)CD29(+), and CD8(+)CD11a(high) cells in peripheral blood from patients with MS (16 stable, 6 active) and NMO (15 stable, 7 active), as well as 9 with NMO spectrum, 6 with clinically isolated syndrome (CIS), and 13 with other neurological diseases using flow cytometry. Significant decreases in the numbers of CD8(+) CD11a(high) cells were observed in stable and active MS and CIS. Our findings indicate that CD8(+)CD11a(high) cells play different roles in MS and NMO, and their presence may be related to the pathogenesis of MS from the early stage.
    European Neurology 03/2010; 63(3):159-163. DOI:10.1159/000283929 · 1.36 Impact Factor
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    ABSTRACT: In order to clarify the clinical characteristics and effects of acetylcholinesterase inhibitors of patients with generalized myasthenia gravis with antibodies to muscle specific kinase (MuSK), we investigated seven patients with MuSK antibodies and eleven patients without both antibodies of acetylcholine receptor and MuSK. All patients with MuSK antibodies showed bulbar symptoms, which frequency was significantly higher compared to those in patients without double antibodies. The frequency of positive result of Tensilon test was significantly lower in patients with MuSK antibodies than in those without double antibodies. In response to intravenous edrophonium chloride, MuSK positive patients showed adverse reactions in a small dosage of edrophonium chloride, less than 5 mg, such as fasciculation on facial muscles and stuffy sensation of throat. The adverse responses to a small dosage of intravenous edrophonium chloride injection is useful information to distinguish patients with seronegative generalized MG, whether they have MuSK antibodies or not. When acetylcholinesterase inhibitors medication is tried to patients with MuSK antibodies, if necessary, a small dosage of inhibitors should be used to avoid cholinergic hypersensitivity.
    Rinsho shinkeigaku = Clinical neurology 10/2009; 49(10):660-3. DOI:10.5692/clinicalneurol.49.660
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    ABSTRACT: Patients with relapsing neuromyelitis optica (NMO) showing contiguous long spinal cord lesions extending over three vertebral segments on the MRI and with positive anti-aquaporin 4 antibodies in sera are usually treated with glucocorticoids or azathioprine. However, some NMO patients even after adequate treatments show relapses. Rituximab (anti-CD 20) therapy has recently been reported to inhibit relapses. We used rituximab to treat three NMO patients defined by the revised NMO criteria of Wingerchuk et al, with rituximab for 2 years and 3 months (mean) at an intervals of about nine months. The annualized relapse rate for the 3 patients during the year before rituximab therapy was 4, 5, and 6, respectively, and this decreased to 3, 1, and 0 in the year after therapy. Case 1 showed three relapses after therapy: however, the symptoms and signs of each of the relapses were milder and the patient showed good responses to steroid pulse therapy. One year after therapy, relapses had disappeared in all cases (observation periods; 18, 18, and 9 months, respectively). After rituximab therapy, these NMO patients showed a decreased mean annualized relapse rate (from 5.0 to 0.6) and EDSS score (from 8.7 to 8.0) after rituximab therapy. No adverse effects were seen. We recommend rituximab therapy for NMO patients resistant to other immunosuppressive therapies such as oral glucocorticoid administration introduced after a severe relapse. However, during long term rituximab treatment, attention needs to be given to infections such as progressive multifocal leucoencephalopathy.
    Rinsho shinkeigaku = Clinical neurology 08/2009; 49(8):457-62. DOI:10.5692/clinicalneurol.49.457
  • Kazuhiro Shigemoto · Tetsuro Konishi · Mitsuhiro Ohta
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    ABSTRACT: Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by autoantibodies. That is, the binding of autoantibodies to postsynaptic membranes in neuromuscular junctions (NMJ) results in weakening of the ocular, bulbar and limb muscles and produces the characteristic syndrome of MG. About 80 to 85% of patients witth MG have autoantibodies against acetylcholine receptors (AChR). Antibodies against muscle-specific kinase (MuSK) have been found in 30% of MG patients without AChR antibodies. Here we describe recent progress toward understanding the pathogenic role of MuSK antibodies in the decline of muscle strength that typifies MG.
    Nippon rinsho. Japanese journal of clinical medicine 07/2008; 66(6):1149-54.
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    ABSTRACT: We investigated the psychiatric disorders in subacute myelo-optico-neuropathy (SMON) patients by structured interview. The prevalence of major depressive disorder in SMON patients was estimated by structured interview and using Beck's depression inventory (BDI) questionnaires. Psychiatric conditions were evaluated in 26 SMON patients (9 males, 17 females, mean age 70.7 years) living in Kyoto prefecture through a structured interview given by psychiatrists. BDI questionnaires and clinical symptoms of SMON were investigated in 106 patients, ranging from 51 to 91 years in age (mean, 73.5) with SMON patients living in Kinki area. BDI questionnaires were obtained from 92 age-matched aged healthy people, ranging from 57 to 91 years in age (mean, 75.8), living in Kyoto city. Among the psychiatric disorders in SMON patients, the prevalence of major depressive disorder and suicidal ideation significantly increased during the period of clioquinol intake and four patients (15.4%) out of 26 SMON patients still suffer from major depressive disorder. The prevalence of major depressive disorder in SMON patients was estimated at 15.1% (16/106) and this percentage was about seven times as frequent as in the age-matched aged healthy people (2.2%; 2/92). In female SMON patients, the degree of the depressive states was significantly correlated with the severe degree of dysesthesia of the lower extremities, and it was inversely correlated with the duration of SMON disease and the total scores of the Barthel index. This is the first report that shows the prevalence of major depressive disorder in SMON patients at present, which was seven times more frequent than age-matched aged healthy persons.
    Internal Medicine 02/2008; 47(24):2127-31. DOI:10.2169/internalmedicine.47.0971 · 0.90 Impact Factor
  • Tetsuro Konishi · Kiyoe Ohta · Kazuhiro Shigemoto · Mitsuhiro Ohta
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    ABSTRACT: Anti-alkaline phosphatase antibody (AP Ab) was specific in 9% of 249 anti-acetylcholine receptor (AChR) Ab-positive myasthenia gravis (MG) (SPMG) patients but not in patients with AChR Ab-negative MG (SNMG), other neurological and immunological diseases, or healthy volunteers. No cross-reactivity and no significant titer correlation were found between AP Ab and AChR Ab. We confirmed immunologically by radioimmunoassay and western blot analysis the presence of antibodies directed against AP. AP Ab-positive SPMG patients were characterized clinically as having female predominance and a more severe form of generalized MG than AP Ab-negative SPMG patients, and about half required artificial ventilation at maximum severity. AP Ab's pathogenic role in MG is yet unclarified, but our findings show AP to be a novel antigen among the various autoantigens present in MG patients and in whom AP Ab may modify clinical symptoms.
    Journal of the Neurological Sciences 01/2008; 263(1-2):89-93. DOI:10.1016/j.jns.2007.06.006 · 2.47 Impact Factor
  • K Ohta · K Shigemoto · A Fujinami · N Maruyama · T Konishi · M Ohta
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    ABSTRACT: We investigated the presence of antibodies (Abs) against muscle-specific tyrosine kinase (MuSK) in Japanese myasthenia gravis (MG) patients. MuSK Abs were found in 23 (27%) of 85 generalized seronegative MG (SNMG) patients but not in any of the ocular MG patients. MuSK Ab-positive patients were characterized as having female dominance (M:F, 5:18), age range at onset 18 to 72 (median 45) years old, and prominent oculobulbar symptoms (100%) with neck (57%) or respiratory (35%) muscle weakness. Limb muscle weakness was comparatively less severe (52%), thymoma absent. Most patients had good responses to simple plasma exchange and steroid therapy. MuSK IgG from all 18 patients was exclusively the IgG 4 subclass and bound mainly with the MuSK Ig 1-2 domain. Serial studies of 12 individuals showed a close correlation between the variation in MuSK Ab titers and MG clinical severity (P = 0.01 by Kruskal-Wallis). MuSK Ab titers were sharply decreased in patients who had a good response to early steroid therapy or simple plasma exchange, but there was no change, or a rapid increase on exacerbation after thymectomy. Measurement of MuSK Ab titers aids in the diagnosis of MG and the monitoring of clinical courses after treatment.
    European Journal of Neurology 10/2007; 14(9):1029-34. DOI:10.1111/j.1468-1331.2007.01870.x · 4.06 Impact Factor
  • European Neuropsychopharmacology 10/2007; 17. DOI:10.1016/S0924-977X(07)70602-8 · 4.37 Impact Factor
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    T Konishi · Y Yoshiyama · M Takamori · T Saida
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    ABSTRACT: Efficacy and safety of long term use of FK506 (2-4.5 mg/day) for a maximum of two years were evaluated in 12 patients with generalised myasthenia gravis (MG). At the end of the study, eight patients (67%) showed improvement in either MG score or Activities in Daily Living score, and prednisolone dosage could be reduced in seven patients (58%), with a mean reduction ratio of 37%. Long term use of FK506 for MG can be more effective than short term administration, with no serious side effects.
    Journal of Neurology Neurosurgery & Psychiatry 04/2005; 76(3):448-50. DOI:10.1136/jnnp.2004.042176 · 6.81 Impact Factor
  • S Yoshida · T Konishi · T Nishizawa · Y Yoshida
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    ABSTRACT: A 78-year-old woman has suffered from pure red-cell aplasia (PRCA) associated with generalized myasthenia gravis and thymoma. Cyclosporin A (CyA) with corticosteroid increased numbers of erythroid cells in her bone marrow cells but she required monthly blood transfusions. Administration of tacrolimus as a substitution for CyA inhibited progression of anemia without the need for further blood transfusion. No serious side effects were observed. This case demonstrates that tacrolimus is another option of treatment for PRCA in patients who fail to respond to CyA.
    Clinical & Laboratory Haematology 03/2005; 27(1):67-9. DOI:10.1111/j.1365-2257.2004.00654.x · 1.30 Impact Factor
  • Tetsuro Konishi · Mitsuru Sanada · Kazuya Takehana
    Journal of Neurology 10/2004; 251(9):1154-5. DOI:10.1007/s00415-004-0504-2 · 3.38 Impact Factor
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    ABSTRACT: To investigate the usefulness of low-dose FK506 for the treatment of myasthenia gravis (MG), we treated 19 patients with generalized MG in a 16-week open clinical trial of FK506 (3-5 mg/day). At the end of the trial, total MG scores (range: 0-27 points) improved by 3 points or more in 7 of 19 patients (37%), and activities of daily living (ADL) scores (range: 0-6 points) also improved by 1 point or more in 8 of 19 patients (42%). Nine of 19 patients (47%) showed improvement in either MG or ADL scores. Significant reduction of anti-acetylcholine receptor antibody titers and interleukin 2 production were observed at the end of this study. Minor but commonly observed side effects were an increase in neutrophil count and a decrease in lymphocyte count. No serious adverse events such as renal toxicity or diabetes mellitus were observed during the 16-week treatment period. FK506 could safely serve as an adjunct to steroid therapy for MG at low dosage.
    Muscle & Nerve 11/2003; 28(5):570-4. DOI:10.1002/mus.10472 · 2.28 Impact Factor
  • Kyoko Saida · Zhao Zhigang · Kyoko Ozawa · Tetsuro Konishi · Takahiko Saida
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    ABSTRACT: Mizoribine (MZR), imidazole nucleotide, inhibits purine synthesis and helper T cell functions. It is used as an immunosuppressant in chronic rheumatic arthritis in Japan. Twenty-four patients with relapsing-remitting and chronic progressive multiple sclerosis (MS) were studied for the long-term effects of MZR over 8 years. Average daily MZR doses of 200 mg along with prednisolone (PSL) were administered in the patients studied. Ten of 24 patients were treated for more than 5 years. The mean relapse rate per year at entry (1.50 +/- 0.24, mean +/- SE, n = 22) decreased [0.46 +/- 0.24 (n = 19)] after two years. In 70% of the patients, the disability did not worsen. Eleven of 18 patients showed a mild decrease of the total lesion size in magnetic resonance imaging (MRI). MZR was well tolerated and could be used for long-term in MS as an adjunctive immunosuppressant to PSL, and the PSL doses could be decreased. A further randomized controlled trial with PSL is necessary.
    Internal Medicine 09/1999; 38(8):636-42. DOI:10.2169/internalmedicine.38.636 · 0.90 Impact Factor
  • M. Matsui · M. Tahara · M. Tanaka · K. Tanaka · T. Konishi
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    ABSTRACT: In order to clarify the immunological characteristics of multiple sclerosis (MS) and neuromyelitis optica (NMO), we analyzed CD3, CD4, CD8, CD20, CD4+CD25+, CD4+CD29+, and CD8+CD11ahigh cells in peripheral blood from patients with MS (16 stable, 6 active) and NMO (15 stable, 7 active), as well as 9 with NMO spectrum, 6 with clinically isolated syndrome (CIS), and 13 with other neurological diseases using flow cytometry. Significant decreases in the numbers of CD8+ CD11ahigh cells were observed in stable and active MS and CIS. Our findings indicate that CD8+CD11ahigh cells play different roles in MS and NMO, and their presence may be related to the pathogenesis of MS from the early stage.
    European Neurology 63(3):159-163. · 1.36 Impact Factor