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The main therapeutic strategy against human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) characterized by lower extremity motor dysfunction is immunomodulatory treatment, with drugs such as corticosteroid hormone and interferon-α, at present. However, there are many issues in long-term treatment with these drugs, such as insufficient effects and various side effects. We now urgently need to develop other therapeutic strategies. The heparinoid, pentosan polysulfate sodium (PPS), has been safely used in Europe for the past 50 years as a thrombosis prophylaxis and for the treatment of phlebitis. We conducted a clinical trial to test the effect of subcutaneous administration of PPS in 12 patients with HAM/TSP in an open-labeled design. There was a marked improvement in lower extremity motor function, based on reduced spasticity, such as a reduced time required for walking 10 m and descending a flight of stairs. There were no significant changes in HTLV-I proviral copy numbers in peripheral blood contrary to the inhibitory effect of PPS in vitro for intercellular spread of HTLV-I. However, serum soluble vascular cell adhesion molecule (sVCAM)-1 was significantly increased without significant changes of serum level of chemokines (CXCL10 and CCL2). There was a positive correlation between increased sVCAM-1and reduced time required for walking 10 m. PPS might induce neurological improvement by inhibition of chronic inflammation in the spinal cord, through blocking the adhesion cascade by increasing serum sVCAM-1, in addition to rheological improvement of the microcirculation. PPS has the potential to be a new therapeutic tool for HAM/TSP.

A 54-year-old female was admitted to our hospital because of the Raynaud phenomenon and muscle weakness of the upper limbs. The neurological findings showed somatic and proximal limb weakness. Laboratory studies showed a high serum creatine kinase level. Computerized tomography (CT) revealed enlargement of the thymus. A muscle biopsy showed a small number of degenerating and regenerating fibers but no inflammatory infiltrations. At first, she was initially treated with a three-day course of intravenous methylprednisolone (1 g/day). However, the weakness progressed and the serum creatine kinase level remained high. She was subsequently treated with a combination of tacrolimus (3 mg/day) and prednisolone, but showed no any improvement of the muscle weakness. Following additional treatment with intravenous immunoglobulin, she showed improvement in her muscle weakness. Further, anti-signal recognition particle antibodies were identified after treatment. There have been no previous reports of myopathy with antibodies against the signal recognition particle and enlargement of the thymus, so we herein report the details of this unique case.

A 60-year-old woman suffered from high fever (38°C) and abnormal behavior, was admitted to our hospital on the seventh day of the fever. At admission, she was stuporous, and a cerebrospinal fluid (CSF) analysis revealed pleocytosis (55/μl, monocytes). Fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images showed high-intensity signals in the medial temporal lobe, inferior surface of the frontal cortex, right cerebellar vermis, and left thalamus. We diagnosed herpes simplex encephalitis, based on the finding of an elevated titer of herpes simplex virus antibody in the CSF (2.90). She was started on treatment with acyclovir and steroid pulse therapy, which was followed by rapid clinical improvement. After recovering from the stupor, the patient exhibited the symptoms of hypersomnia with low orexin level in the CSF. Thus, we should bear in mind that other than consciousness disturbance, patients with herpes simplex encephalitis can also present with rare complications due to the extent of the lesions.

A 29-year-old man diagnosed as having pulmonary sarcoidosis in 2008, and hypothyroidism secondary to thyroidectomy for Basedow's disease was admitted to our hospital with pustular psoriasis in November 2010. He experienced high fever (38°C) and headache in late October 2010. Gadolinium-enhanced T1-weighted image showed multiple micronodular lesions with leptomeningeal enhancement, mainly in the brainstem. Cerebrospinal fluid (CSF) analysis revealed pleocytosis, raised protein level and hypoglycorrhachia (7 mg/dl). The patient was also found to have osteonecrosis of the left femoral head. Antituberculous treatment and steroid pulse therapy were started, but produced no improvement of either the symptoms or the laboratory data. Finally, the patient was diagnosed as having meningeal disseminated sarcoidosis by meningeal biopsy in late March 2011. He was started on treatment with 60 mg prednisolone per day, which resulted in marked clinical improvement. It should be borne in mind that marked hypoglycorrhachia in the CSF can also be seen in meningeal disseminated sarcoidosis.

A 68-year-old woman was admitted to our hospital because of sudden onset of involuntary movements, similar to those associated with chorea, of the right side of the body and for further evaluation of thrombocythemia. She had no family history of chorea. Neurological findings did not show any abnormality except for chorea of the right side. Laboratory studies showed increased number of white blood cells (14,000/microl) and platelets (188.3 x 10(4)/ microl). Lupus anticoagulant, anti-cardiolipin antibody, and ceruloplasmin levels were within the normal range. Her NAP score was 240, and result for bcr-abl gene expression was negative. Bone marrow puncture showed hypercellularity and increased number of megakaryocytes (550/microl), but there was no atypism. On the basis of these laboratory findings, she was diagnosed with essential thrombocythemia T1-weighted magnetic resonance imaging (MRI) showed a hyperintense lesion extending from the region around the left globus pallidum to putamen. The MRI findings of our study were similar to those related to diabetic hemichorea; however, the results of some tests did not indicate diabetes mellitus. An MRI scan showing high T1 signal intensity in the basal ganglia might not be specific for diabetic hemichorea. In this case, MRI revealed the cause of hemichorea to be micocirculatory failure or small cerebral hemorrhages.

We investigated whether matrix metalloproteinase-2 (MMP-2) is induced in peripheral blood T cells after their contact with tumor necrosis factor-alpha (TNF-alpha)-stimulated glioblastoma cell line (T98G), expressing vascular cell adhesion molecule-1 (VCAM-1), in patients with HTLV-I-associated myelopathy (HAM) compared to control patients with other neurological disorders (OND). Gelatin zymography revealed that the incremental ratio of gelatinolytic activity of MMP-2 in culture supernatants derived from T cells cocultured with TNF-alpha-stimulated T98G to that of supernatants derived from cultures of T cells alone was significantly higher in HAM patients than in control patients with OND. Immunoblot analysis of immunoprecipitates of culture supernatant showed that increased gelatinolytic activity of MMP-2 was due to increased production of MMP-2 protein in T cells. Increased gelatinolytic activity of MMP-2 in T cells of HAM patients was blocked by pretreatment of TNF-alpha-stimulated T98G with anti-VCAM-1 antibody before coculture with T cells, indicating that MMP-2 induction was VCAM-1-mediated. Although no significant differences were noted in the percentage of VLA-4-positive cells in cultured T cells between HAM patients and control patients with OND, our results indicate that VCAM-1-mediated MMP-2 induction is up-regulated in T cells of HAM patients.

A 40-year-old woman noticed blurred vision of the right eye. The optic disc edema of bilateral eyegrounds was noted, and brain MRI showed abnormal signals of the brainstem at a neurosurgical clinic. On her first visit, blood pressure was as remarkably high as 250/130 mmHg. Neurologically, only optic disc edema of bilateral eye-grounds was found. Both T2-weighted MRI and FLAIR showed hyperintense signal areas mainly from the ventral pons to medulla oblongata. These areas were not enhanced with gadolinium. About three weeks after the administration of an antihypertensive agent, brain MRI revealed no abnormal signal. About three months later, the blurred vision disappeared and ophthalmological abnormalities subsided. We diagnosed her with a brainstem variant of RPLS, presenting with visual disturbance caused by hypertensive retinopathy.

A 67-year-old woman was admitted to our hospital with progressive aphasia. There was no family history of similar diseases or any history of dura transplantation. Cranial magnetic resonance imaging (MRI) showed high signal areas in the temporal and parietal cortex predominantly on the left side on both T2-weighted images and on diffusion-weighted images. There were no periodic synchronous discharges observed on the electroencephalogram. As prion protein gene codon 180 point mutation (Val/Ile) was detected, we diagnosed her as having Creutzfeldt-Jakob disease (CJD). The characteristics of CJD of this type differ from those of sporadic CJD. To date, few papers on CJD with point mutation of codon 180 have been reported from Japan.

We used two-color flow cytometric analysis to investigate CD26+ (Ta1+) cells in peripheral blood T lymphocytes from patients with human T-lymphotropic virus type-I (HTLV-I) - associated myelopathy (HAM). The percentage of CD26+ cells among CD3+ cells was markedly increased in patients with HAM, compared with anti-HTLV-I seropositive carriers (p

Background: Human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic myelopathy characterized by motor dysfunction of the lower extremities and urinary disturbance. Immunomodulatory treatments are the main strategy for HAM/TSP, but several issues are associated with long-term treatment. We conducted a clinical trial with prosultiamine (which has apoptotic activity against HTLV-I-infected cells) as a novel therapy in HAM/TSP patients. Methods: We enrolled 24 HAM/TSP patients in this open-label clinical trial. Prosultiamine (300 mg, orally) was administered once daily for 12 weeks. We monitored changes in the motor function of the lower extremities and urinary function as well as copy numbers of the HTLV-I provirus in peripheral blood mononuclear cells (PBMCs). Results: Improvement in the motor function of the lower extremities based on a reduction in spasticity (for example, decrease in time required for walking and descending a flight of stairs) was observed. In an urodynamic study (UDS), bladder capacity and detrusor pressure and then maximum flow rate increased significantly. Detrusor overactivity and detrusor-sphincter dyssynergia improved in 68.8% and 45.5% of patients observed at pretreatment, respectively. Improvement in UDS corresponded with improvements in the score of nocturia-quality of life questionnaire. HTLV-I proviral copy numbers in PBMCs decreased significantly (approximately 15.4%) compared with pretreatment levels.Conclusions: These data suggest that prosultiamine can safely improve motor dysfunction of the lower extremities and urinary disturbance as well as reduce HTLV-I provirus levels in peripheral blood. It therefore has potential as a new therapeutic tool for HAM/TSP patients.Trial registration: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number, UMIN000005969. Please see related commentary: http://www.biomedcentral.com/1741-7015/11/183., BMC Medicine, 11(1), 182; 2013

In 11 of 18 patients with human T-lymphotropic virus type-I (HTLV-I) associated myelopathy (HAM) gait, sensory, and/or sphincter disturbance improved with plasmapheresis (4 to 6 sessions in 2 weeks), and the effects were maintained for 2 to 4 weeks. Plasmapheresis lowered the titre of HTLV-I antibody in serum but not in cerebrospinal fluid, and change of HTLV-I antibody titres did not correlate with the effects of plasmapheresis. These results suggest that plasmapheresis is useful treatment, at least in producing a temporary improvement, in patients with HAM, and that some humoral factor(s), but not HTLV-I antibody, may be important in the pathogenesis of HAM.

We detected deposits of IgG, C3, and C9 (immune complexes) at the limb muscle motor end-plates (biceps brachii muscle) in 16 of 19 patients who exhibited only ocular signs and symptoms of myasthenia gravis that were improved by intravenous injections of edrophonium chloride. Circulating anti-acetylcholine receptor (anti-AChR) antibodies were negative in 6 of the 16 patients, but the motor end-plate fine structure in the postsynaptic regions was abnormal in all 16. Single-fiber EMG revealed no abnormalities in 8 of 13 patients studied. Our results indicate that the detection of immune complexes at the limb muscle end-plate provides a highly sensitive and confirmative method for diagnosing patients with minimal or atypical myasthenia gravis who have no detectable anti-AChR antibodies in their serum.

The motor end-plate fine structure was studied in 3 patients with type A botulism and compared with that in 4 patients with Lambert-Eaton myasthenic syndrome (LES). In the botulism cases a biopsy of the biceps brachii muscle was performed at the chronic stage. The skeletal muscle showed a neurogenic change. The nerve terminal area had decreased and the postsynaptic regions had been denuded of their nerve terminals in 16% of the regions (9.8% in control). No highly simplified postsynaptic regions were observed. The findings are consistent with those observed at the motor end-plates in motoneuron diseases. By contrast, in LES no changes were observed in the presynaptic region. In the postsynaptic region, the postsynaptic membrane length and membrane density decreased and hypertrophy of the junctional folds was not observed.

症例. 27才,女性. 11才初潮, 16才より11年間無月経. 25才眼瞼下垂,複視出現.テンシロンテスト陽性,尺骨神経反復刺激でwaning現象,血中抗アセチルコリン受容体抗体価の上昇,筋生検所見より重症筋無力症と診断.一方, luteinizing hormone, follicular stimulating hormoneの著明な上昇, estradiolの低値, 1週間連続のhuman menopausal gonadotropin負荷に対する無反応よりhypergonadotropic hypogonadismと診断された.血清中の抗卵巣抗体,抗透明帯抗体は陰性.卵巣生検では,卵胞は全くなかった.両者の合併例の報告は過去11例とまれであり,両者が共通の機序により引き起こされているという確固たる証拠は現在のところ得られていない.

Two patients with "pure akinesia" who showed the characteristic changes of progressive supranuclear palsy (PSP) at necropsy are described. They had akinesia but no rigidity or tremor, and ophthalmoplegia was not observed during the course of illness. The symptoms of "pure akinesia" was not improved by levodopa therapy but was considerably improved by L-threo-3,4-dihydroxy-phenylserine. At necropsy, pathological findings were not different from those reported for PSP. It is suggested that "pure akinesia" is an atypical manifestation of PSP, and that norepinephrinergic neurons may be involved in some types of PSP.

— Transcranial electrical stimulation of the motor cortex was performed in 7 patients with human T-lymphotropic virus type-I associated myelopathy (HAM) and 15 normal subjects. The mean value of central motor conduction time (CCT) for the thenar and hypothenar muscles in patients with HAM was not different from that in normal subjects. In contrast, mean CCT value for the tibialis anterior and gastrocnemius muscles in patients with HAM was 8.54-10.34 ms longer than the value in normal subjects. These findings indicate that the lesion of pyramidal tract involvement in patients with HAM is mainly localized in the descending corticomotoneuron pathways at the thoracic spinal cord level. This technique could be used in a clinical study without untoward side effects, and may be valuable in detecting clinically silent lesions involving the pyramidal tract.

小出血を繰り返し,手掌口症候群,視性幻覚, MLF症候群,外転神経麻痺,小脳失調症など多彩な神経症状を呈した特発性橋出血の33才,男性例を報告した.最初左手掌口症候群,右MLF症候群,右外転神経麻痺が出現, CT上橋被蓋部に出血を認めた.血腫の縮小と平行して症状は改善したが,再度橋出血が増大するとともに,左MLF症候群,左外転神経麻痺,左顔面神経麻痺,視性幻覚が出現し,血腫の再縮小とともに,これらの症状は消退した.血管造影上は, AVM, aneurysmなどは証明されなかった.限局した突発性橋出血を繰り返したために,意識障害なしに,種々の神経症状の出現をみたものと考えた.

To the Editor. —Human T-cell lymphotropic virus type I (HTLV-I)—associated myelopathy (HAM) is a chronic progressive myelopathy characterized by high antibody titers to HTLV-I in the serum and cerebrospinal fluid (CSF), and the presence of adult T-cell leukemia/lymphoma (ATLL) cells in both the peripheral blood and CSF.1Nagasaki prefecture, located on the Kyushu island of Japan, is one of the endemic areas of ATLL.2Although familial clusters had been reported in ATLL,3there have been no reports of familial clusters of HAM. We herewith describe eight patients from four families with HAM without histories of blood transfusion. All eight of the patients who had a gait disturbance of slowly progressive course are illustrated in the Figure. They are from four families. Most of the patients (except for patient 6) also suffered from urinary problems such as frequency, hesitancy, and retention. Neurologic evaluation revealed spastic paraplegia.

症例は40才,女性.昭和56年より眼瞼下垂,複視,四肢筋の易疲労性出現し,当科へ第1回目の入院.諸検査にて重症筋無力症(MG)の診断を受け胸腺摘出術を行なった.昭和59年10月よりレイノー現象,抗核抗体陽性,免疫複合体高値,全補体価の低値などが出現し,昭和61年5月胸膜炎を伴い第2回目の入院となり全身性エリテマトーデス(SLE)の診断を受けた. MGの胸腺摘出後にSLEが発症した報告はまれで本例は貴重な症例と考えた.