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ABSTRACT: Polymyositis (PM) is an inflammatory muscle disease characterized by chronic inflammation in skeletal muscle. Although most patients with PM respond to corticosteroids, some cases show an unsatisfactory response and other therapeutic options must be considered. Furthermore, glucocorticosteroid (GC) toxicity leads to a significant disability known as steroid myopathy, particularly in elderly patients. Here we report two patients with refractory PM. Combined treatment with high-dose GCs, tacrolimus, and intravenous immunoglobulin resulted in beneficial effects against myositis. However, muscle weakness and the disability progressed due to steroid myopathy, and subsequent oral intake became impossible because of swallowing disturbance in these two patients. Nutritional intervention, including branched-chain amino acids (BCAAs) and rehabilitation, was undertaken in addition to treatment against myositis. These treatments finally improved the muscle weakness and activities of daily living, and the two patients were discharged after recovery. The high-dose GC treatment caused elevation of serum levels of amino acids, including BCAAs, but these amino acids subsequently declined during BCAA replacement therapy. These findings suggest that the catabolic effects of the glucocorticoid treatment impair the balance of amino acids, including BCAAs, within the muscle, leading to steroid myopathy.
Modern Rheumatology 03/2013; · 1.58 Impact Factor
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ABSTRACT: We developed an assay that detects autoantibodies against the main immunogenic region (MIR) located at the extracellular end of the nicotinic acetylcholine receptor (AChR) α subunit, and investigated its clinical relevance in myasthenia gravis (MG).
In this retrospective cohort study, we measured MIR antibody (Ab) titres in sera obtained before treatment and analysed their associations with clinical parameters in 102 MG patients from two neurological centres. MIR Ab titres were determined using a modified competition immunoprecipitation assay in the presence or absence of monoclonal antibody 35.
11 of 23 (47.8%) ocular type and 66 of 72 (91.7%) generalised type MG patients were positive for the presence of MIR Abs, defined as a titre >16.8% (3 SDs above the mean for 70 healthy controls). A significantly higher MIR Ab titre (p<0.001) was shown in generalised type (47.9±19.2%) rather than in ocular type MG patients (16.4±8.4%). Bivariate regression analysis using both titre levels of MIR Ab and routine AChR binding Ab as variables revealed MIR Abs to be an exclusive indicator positively associated with disease severity (Myasthenia Gravis Foundation of America classification, p<0.0001; Quantitative MG score, p=0.008), the presence of bulbar symptoms (p<0.0001) and thymoma (p=0.016), and negatively associated with ocular MG (p<0.0001).
MIR Ab titre levels show much better correlations with factors related to disease severity compared with AChR binding Ab titres. The MIR Ab assay may be useful for predicting MG symptom severity, especially for discriminating between ocular and generalised types of MG.
Journal of neurology, neurosurgery, and psychiatry 07/2012; 83(9):935-40. · 4.87 Impact Factor
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ABSTRACT: Tacrolimus (FK506) is a macrolide T-cell immunomodulator used to treat myasthenia gravis (MG). Besides immunosuppression, tacrolimus has been reported to have the potential to increase muscle strength by enhancing ryanodine receptor (RyR) function. However, few attempts have been made to demonstrate the early effect of tacrolimus as an RyR enhancer in clinical investigation.
In 20 MG patients, masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The excitation-contraction (E-C) coupling time (ECCT) was calculated by the latency difference between CMAP and MRP. Bite force was measured using a pressure-sensitive sheet. Serial assessments of % decrement in masseteric repetitive nerve stimulation (RNS), ECCT and bite force were performed before and within 4 weeks of tacrolimus (3 mg day(-1)) treatment. The median (mean, range) interval of assessment was 2 (2.4, 1-4) weeks. We also measured serum antibodies against RyR, acetylcholine receptor and muscle-specific receptor tyrosine kinase.
Bite force increased after tacrolimus treatment accompanying clinical improvement assessed by Myasthenia Gravis Foundation of America classification, but the bite force difference did not reach statistical significance. Wilcoxon matched-pairs signed-ranks test detected a significant ECCT shortening in 12 patients assessed after 1-2 weeks of tacrolimus treatment as well as in eight patients assessed after 3-4 weeks. In contrast, masseteric CMAP and % decrement showed no significant changes after short-term tacrolimus treatment.
Tacrolimus induces ECCT shortening accompanying clinical improvement despite no improvement in % decrement within 2 weeks.
This early effect of tacrolimus may imply a pharmacological enhancement of RyR function to improve E-C coupling in MG.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 02/2012; 123(9):1886-90. · 3.12 Impact Factor
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ABSTRACT: Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by pathogenic autoantibodies (Abs) against acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). The seropositivity rates for routine AChR binding Ab and MuSK Ab in MG are 80-85% and 5-10% for MG patients in Japan, respectively. The autoimmune target in the remaining patients is unknown. In 2011, autoantibodies against low-density lipoprotein receptor-related protein 4 (Lrp4) were identified in Japanese MG patients and thereafter have been reported in Germany and the USA. We developed a simple technique termed Gaussia luciferase immunoprecipitation for detecting antibodies to Lrp4. As a result, nine generalized MG patients from 300 lacking AChR Ab are positive for Lrp4 antibodies. Thymoma was not observed in any of these patients. These antibodies inhibit binding of Lrp4 to its ligand and are predominantly of the IgG1 subclass. In other reports of Lrp4 ab, Lrp4 ab positive sera inhibited agrin-induced aggregation of AChRs in cultured myotubes, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that Lrp4 is a third autoantigen in patients with MG, and anti-Lrp4 autoantibodies may be pathogenic. Further studies including neuromuscular junction biopsy are needed to clarify the pathomechanism of Lrp4 ab positive MG.
Rinshō shinkeigaku = Clinical neurology. 01/2012; 52(11):1303-5.
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ABSTRACT: Japanese spotted fever (JSF), first reported in 1984, is a rickettsial disease characterized by high fever, rash, and eschar formation. A 61-year-old man was admitted to a local hospital in Nagasaki City, Japan, after several days of high fever and generalized skin erythema. His condition deteriorated and laboratory findings indicated disseminated intravascular coagulation (DIC). The patient was transferred to our hospital with mental disturbance and status epilepticus. Treatment included minocycline, and new quinolone. Definitive diagnosis was made with a serological test showing increased antibody levels against Rickettsia japonica. Rickettsial infections are rare, but should be seriously considered for the differential diagnosis of aseptic meningitis and encephalitis, as they show no response to conventional antibiotic treatment.
Internal Medicine 01/2012; 51(7):783-6. · 0.94 Impact Factor
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ABSTRACT: A 25-year-old man was referred to our hospital with a 2-month history of progressive proximal extremity weakness. His serum creatine kinase (CK) level was extremely elevated, and chest X-ray revealed bilateral hilar lymphadenopathy and small nodules in bilateral lung fields. Biopsy specimens obtained from muscle and lung revealed non-caseating epithelioid cell granulomas. On the basis of these findings, the patient was diagnosed with sarcoidosis and acute sarcoid myositis. Although steroid pulse therapy was administered repeatedly, the muscle symptoms did not improve, and the serum CK level remained high. We added 7.5 mg oral methotrexate once per week to oral prednisolone, and this improved both the muscle weakness and the CK level. Concurrent administration of methotrexate could be a therapeutic option for cases with acute sarcoid myositis refractory to steroid therapy.
Muscle & Nerve 12/2011; 44(6):994-9. · 2.37 Impact Factor
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ABSTRACT: The aim of this study was to elucidate the relationship between the impairment of excitation-contraction (E-C) coupling and anti-ryanodine receptor (RyR) antibody in patients with myasthenia gravis (MG).
Masseteric compound muscle action potential (CMAP) and mandibular movement-related potentials (MRPs) were recorded simultaneously after stimulating the trigeminal motor nerve with a needle electrode. The E-C coupling time (ECCT) was calculated as the latency difference between CMAP and MRP. For each patient, we selected a representative data set when there was no abnormal decrement in response to repetitive nerve stimulation. The 26 data sets were divided into an anti-RyR-positive group (n=12) and an anti-RyR-negative group (n=14).
Masseteric ECCT was significantly longer (p=0.017) in anti-RyR-positive group (median, mean, range; 3.6, 3.8, 3.0-5.9 ms) than in anti-RyR-negative group (3.1, 3.1, 2.7-4.0) although there were no significant differences in masseteric CMAP amplitude and % decrement between the two groups. The bite force was significantly lower in anti-RyR-positive group than in normal controls.
Presence of anti-RyR antibodies is associated with significantly prolonged masseteric ECCT compared to absence of the antibodies in MG.
Anti-RyR antibody contributes to E-C coupling impairment in the masseter muscle in patients with MG.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 11/2011; 123(6):1242-7. · 3.12 Impact Factor
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Masakatsu Motomura
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ABSTRACT: Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by autoantibodies against acetylcholine receptors (AChR) and muscle-specific receptor tyrosine kinase (MuSK). These seropositivity rates in AChR positive and MuSK positive MG in Japan are 80-85% and 5-10%, respectively. The incidence of late-onset MG has been increasing all over the world. A nationwide epidemiological survey in Japan also revealed that the rates of late-onset MG (onset after 50 years) had increased from 20% in 1987 to 42% in 2006. In 2010, a guideline for standard treatments in late-onset MG was published from Japanese Scoiety of Neurological Therapeutics. Based on individual experiences and the limited evidence, epidemiological characteristics of MG onset age, clinical features, and the standard treatment for late-onset patients are included in it. In this guideline summary, the ocular form was more frequent in late-onset compared to early-onset group, the indication of thymectomy in late-onset MG is less than that of early-onset MG and the combination of corticosteroids and immunosuppressive agents are recommended in order to reduce doses of corticosteroids in late-onset MG.
Rinsho shinkeigaku = Clinical neurology 08/2011; 51(8):576-82.
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Journal of neurology, neurosurgery, and psychiatry 08/2011; 82(8):942-3. · 4.87 Impact Factor
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ABSTRACT: We herein review the histochemical findings and fine structural changes of motor endplates associated with diseases causing neuromuscular transmission abnormalities. In anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG), type 2 fiber atrophy is observed, and the motor endplates show a reduction in the nerve terminal area, simplification of the postsynaptic membrane, decreased number of acetylcholine receptors, and deposition of immune complexes. In anti-MuSK antibody-positive MG, the fine structure shows a decrease in the postsynaptic membrane length, but the secondary synaptic cleft is preserved. There is no decrease in the number of AChRs, and there are no deposits of immune complexes at the motor endplates. Patients with Lambert-Eaton myasthenic syndrome show type 2 fiber atrophy, their motor endplates show a decrease in both the mean postsynaptic area and postsynaptic membrane length in the brachial biceps muscle. Congenital myasthenic syndrome with episodic apnea is characterized only by small-sized synaptic vesicles; the postsynaptic area is preserved. In subjects with congenital myasthenic syndrome with acetylcholinesterase deficiency, quantitative electron microscopy reveals a significant decrease in the nerve terminal size and presynaptic membrane length; further, the Schwann cell processes extend into the primary synaptic cleft, and partially or completely occlude the presynaptic membrane. The postsynaptic folds are degenerated, and associated with pinocytotic vesicles and labyrinthine membranous networks. Patients with slow-channel congenital myasthenia syndrome show type 1 fiber predominance, and their junctional folds are typically degenerated with widened synaptic space and loss of AChRs. Patients with AChR deficiency syndrome caused by recessive mutations in AChR subunits also show type 1 fiber predominance, and while most junctional folds are normal, some are simplified and have smaller than normal endplates. Rapsin and MuSK mutations cause type 1 fiber predominance, and the small postsynaptic area is associated with AChR decrease.
Brain and nerve = Shinkei kenkyū no shinpo 07/2011; 63(7):719-27.
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ABSTRACT: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction, and approximately 60% of patients with LEMS have a tumor, mostly small cell lung cancer (SCLC), as a paraneoplastic neurological syndrome. The clinical data of Japanese patients in the present study are as follows: the ratio of men to women is 3: 1 (mean age, 62 years; age range, 17-80 years). Of the patients with LEMS, 61% have SCLC, whereas the others do not have cancer. Clinical symptoms are usually characterized by proximal muscle weakness and dysautonomia. In less than 10% of the patients, there are signs of cerebellar dysfunctions (paraneoplastic cerebellar degeneration with LEMS; PCD-LEMS), and these are usually associated with SCLC. The diagnosis can be confirmed by detecting a specific antibody in a radioimmunoprecipitation assay and finding reduced amplitude of compound muscle action potential that increases by over 100% after maximum voluntary activation or 50Hz of nerve stimulation. The pathomechanism of LEMS is characterized by impaired transmission across the neuromuscular junction because of autoantibodies directed against the presynaptic P/Q-type voltage-gated calcium channels (P/Q-VGCCs). Histopathologic evaluation of the cerebellum in patients with PCD-LEMS showed a reduced number of P/Q-type VGCCs in the molecular layer. Therefore, it was hypothesized that P/Q-VGCC antibodies may induce cerebellar dysfunction after entering the CNS in patients with PCD-LEMS. Specific tumor therapy in patients with LEMS as well as cancer often improves the neurologic deficit. Tumor removal is the primary treatment for LEMS. If the result of the primary screening is negative, screening should be repeated after 3-6 months and thereafter every 6 months for up to 2 years. Most patients benefit from 3, 4-diaminopyridine administered with pyridostigmine. In those with severe weakness, intravenous gamma globulin (IVIg) or plasmapheresis confers short-term benefits. Prednisone when administered alone or in combination with immunosuppressive drugs can achieve long-term control of the disorder.
Brain and nerve = Shinkei kenkyū no shinpo 07/2011; 63(7):745-54.
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Hiroyuki Murai,
Natsumi Yamashita,
Makoto Watanabe,
Yoshiko Nomura, Masakatsu Motomura,
Hiroaki Yoshikawa,
Yosikazu Nakamura,
Naoki Kawaguchi,
Hiroshi Onodera,
Shigeru Araga,
Noriko Isobe,
Masaki Nagai,
Jun-ichi Kira
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ABSTRACT: To clarify the prevalence and clinical characteristics of myasthenia gravis (MG) in Japan.
We performed a nationwide epidemiological survey of MG in Japan. The clinical features were compared among five groups of patients, divided according to onset age. A generalized additive model (GAM) was used to assess the linearity of these relationships.
A total of 8542 patients were reported, and detailed data were analyzed for 3141 patients. The estimated number of MG patients in Japan was 15,100, giving a prevalence of 11.8 per 100,000. Elderly-onset MG (≥ 65 years) accounted for 7.3% in 1987 (adjusted for population in 2005), but this had increased to 16.8% in 2006. Infantile-onset MG (0-4 years) accounted for 10.1% in 1987, and was still as high as 7.0% in 2006. The rate of ocular MG was highest (80.6%) in infantile-onset and lowest (26.4%) in early-onset disease, but the rate rose again in the late-onset group. GAM analysis of the ocular form showed a U-shaped curve, with a dip in the 20s. Anti-acetylcholine receptor antibodies were positive in only 50% of infantile-onset, but nearly 90% of elderly-onset patients. GAM analyses assessing the concurrence of thymoma and hyperplasia both showed reversed U-shapes, with peaks in the 50s and 20s-40s, respectively.
Persistent high incidence of infantile-onset disease and clinical heterogeneity according to onset age are characteristic features of MG in Japan.
Journal of the neurological sciences 03/2011; 305(1-2):97-102. · 2.32 Impact Factor
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Muscle & Nerve 02/2011; 43(2):294-5. · 2.37 Impact Factor
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ABSTRACT: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, where acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein (LDL) receptor-related protein 4 (Lrp4) are essential. About 80% and 0% to 10% of patients with generalized MG have autoantibodies to AChR and MuSK, respectively, but pathogenic factors are elusive in others. Here we show that a proportion of AChR antibody-negative patients have autoantibodies to Lrp4. These antibodies inhibit binding of Lrp4 to its ligand and predominantly belong to the immunoglobulin G1 (IgG1) subclass, a complement activator. These findings together indicate the involvement of Lrp4 antibodies in the pathogenesis of AChR antibody-negative MG.
Annals of Neurology 02/2011; 69(2):418-22. · 11.09 Impact Factor
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Yasumori Izumi,
Hiroshi Kojima,
Yasushi Koga,
Kazuaki Yokota,
Hideki Mori,
Tadayoshi Ohno,
Taiichiro Miyashita,
Masahiro Ito, Masakatsu Motomura,
Masanobu Mine,
Hironori Ezaki,
Yuka Jiuchi,
Daisuke Niino,
Kouichi Ohshima,
Kiyoshi Migita
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ABSTRACT: A 56-year-old HTLV-I-positive woman, initially diagnosed as having Sjögren's syndrome, presented with muscle weakness, myalgia, face erythema and leg edema. Based on the presence of various autoantibodies, the diagnosis of overlap syndrome (dermatomyositis/Sjögren's syndrome) was made. Treatment with high-dose corticosteroid plus cyclosporine improved her symptoms. However, three months after the start of these treatments, exacerbation of myositis occurred. A muscle biopsy revealed prominent perivascular accumulation of mononuclear cells with perifascicular atrophy, which were consistent with dermatomyositis. Tacrolimus, which was substituted for cyclosporine led to marked improvement of the myositis symptoms.
Internal Medicine 01/2011; 50(17):1849-53. · 0.94 Impact Factor
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ABSTRACT: We report a 36-year-old woman presenting with hypertensive encephalopathy followed by bulbar palsy and quadriplegia. After an extensive screening for secondary causes of hypertension, the patient was suspected of having pheochromocytoma due to increased levels of catecholamines in the plasma and the urine, and positive (131)I-metaiodobenzylguanidine (MIBG) accumulation in the gallbladder. However, MIBG accumulation was not reproducible without any tumors accompanying this accumulation in the gallbladder. A diagnosis of acute intermittent porphyria was finally confirmed based on the characteristic pictures, increased urinary excretion of porphobilinogen, and identification of a heterozygous missense mutation of R173W in the hydroxymethylbilane synthase gene. This case highlights a pitfall in utilizing MIBG to detect a source of excessive catecholamine and also suggests the importance of having a complete clinical history and extensive work-up of any possible differential diagnosis. We also review the potential mechanism by which false-positive MIBG accumulation occurs.
Internal Medicine 01/2011; 50(9):1029-32. · 0.94 Impact Factor
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Shintaro Hara,
Tomoko Henmi,
Atsushi Kawakami,
Keita Fujikawa,
Hiroshi Mukae,
Yuji Ishimatsu,
Noriho Sakamoto,
Tomoyuki Kakugawa,
Kenzou Kaji,
Manabu Fujimoto, [......],
Toshiaki Tsukada,
Katsuya Satoh, Masakatsu Motomura,
Mami Tamai,
Hideki Nakamura,
Hiroaki Ida,
Tomayoshi Hayashi,
Tomoki Origuchi,
Katsumi Eguchi,
Shigeru Kohno
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ABSTRACT: We report the first 3 cases of inflammatory myopathy with abundant macrophages (IMAM) to be found in an Asian country. Diagnosis of IMAM was based on the infiltration of CD68+ macrophages into biopsied specimens, particularly the fascia. Proximal skeletal muscle symptoms and signs, elevation of creatine kinase, and myogenic changes in electromyography were found in all of the cases, and magnetic resonance imaging clearly revealed thickening of the fascia. Since dermatomyositis (DM)-specific skin alterations were not found, none of the patients in this study fulfilled Bohan and Peter's criteria for DM; however, anti-PL-7 antibody was detected in case number 1. In addition, CD20+ B-cell infiltration into the fascia was also detected in all of the cases, indicating further transition to DM. Severe illness, namely macrophage activation syndrome and acute respiratory distress syndrome, occurred in case 1 but was resolved with intensive combination therapy. The other 2 cases also required glucocorticoids to achieve remission.
Rheumatology International 12/2010; · 1.88 Impact Factor
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ABSTRACT: We describe a rare case of thymoma with Lambert-Eaton myasthenic syndrome. A 62-year-old woman reporting weakness in her legs and arms was found to have an anterior mediastinal mass on computed tomography. Electromyography showed incremental response to repeated stimulations, and thymoma with Lambert-Eaton myasthenic syndrome was diagnosed. The patient was successfully treated with video-assisted thoracoscopic extended thymectomy.
The Annals of thoracic surgery 06/2010; 89(6):2001-3. · 3.74 Impact Factor
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ABSTRACT: We experienced a case of a 63-year-old woman with primary Sjögren's syndrome (pSS) complicated with inflammatory myopathy and interstitial lung disease (ILD). She had suffered from morning stiffness and dry mouth for 1 year without being medically examined. A chest CT scan demonstrated ground glass opacity and a reticular shadow in the lower lung field. A diagnosis of SS was made based on positive findings from Schirmer's test, sialography of the parotid gland, a labial salivary gland biopsy and the presence of anti-SS-A antibody. Musculoskeletal symptoms were absent; however, the elevation of creatine kinase (CK) as well as magnetic resonance imaging (MRI)-proven inflammatory change of bilateral muscles of the thigh was evident. Histological examination of the thigh revealed diameter variation, degeneration of muscle fibers and inflammatory cell infiltration in the perivascular area, corresponding to the inflammatory myopathy of pSS. Oral prednisolone 30 mg/day was introduced, and serum CK rapidly decreased within 2 weeks. ILD also responded well to prednisolone without relapse. These clinical outcomes are consistent with extraglandular organ involvement of pSS.
Rheumatology International 05/2010; · 1.88 Impact Factor
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Masakatsu Motomura
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ABSTRACT: Myasthenia gravis (MG) is the most common autoimmune disorder of the neuromuscular junction and is clinically characterized by weakness and muscle fatigue. We have classified MG into 3 types on the basis of the antibody pattern. The first type associated with acetylcholine receptor (AChR) autoantibodies, which predominantly belong to IgG1 subclass and are measured by a conventional radioimmunoprecipitation assay with 125I-alpha-bungarotoxin. This subtype occurs in approximately 80% of patients with MG and leads to the loss of AChR number and function, mainly by complement-mediated destruction of the neuromuscular junction. Approximately 40% of patients with MG who have AChR antibodes have a thymoma as a paraneoplastic neurological syndrome. However, the role of antigen expression by thymomas is unclear. The second type of MG occurs in a proportion of "seronegative" patients who did not have AChR autoantibodies. These patients process IgG autoantibodies to muscle-specific tyrosine kinase (MuSK); these antibodies are predominantly of the IgG4 subclass but are not associated with complement-mediated damage to the neuromuscular junction or with the presence of thymomas. In most patients with MuSK antibodies, the symptoms of MG improve after plasma exchange; these patients show a good response to steroid and immunosuppressive drugs but a poor response to thymectomy. MG not associated with the presence of the 2 abovementioned pathogenic autoantibodies is classified as heterogeneous "double seronegative" MG. Our classification is superior to the present classifications with regard to the mechanism, treatment, and prognosis of the disease.
Brain and nerve = Shinkei kenkyū no shinpo 04/2010; 62(4):411-8.
