Details of a Researcher - Seki, Morinobu

Papers - Seki, Morinobu

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Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors

Matsubara S., Seki M., Suzuki S., Komori T., Takamori M.

Journal for ImmunoTherapy of Cancer (Journal for ImmunoTherapy of Cancer) 7 ( 1 ) 256 2019.09

© 2019 The Author(s). Background: Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies. Methods: Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined. Results: Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively. Conclusions: In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.

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Diagnostic Potential of Multimodal MRI Markers in Atypical Parkinsonian Disorders.

Seki M, Seppi K, Mueller C, Potrusil T, Goebel G, Reiter E, Nocker M, Kremser C, Wildauer M, Schocke M, Gizewski ER, Wenning GK, Poewe W, Scherfler C

Journal of Parkinson's disease (Journal of Parkinson's disease) 9 ( 4 ) 681 - 691 2019.08

ISSN 1877-7171

BACKGROUND: The diagnostic potential of multimodal MRI approaches to discriminate among progressive supranuclear palsy (PSP), Parkinson variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD) has not been well investigated. OBJECTIVE: To identify disease-specific neurodegenerative patterns and evaluate the diagnostic accuracy of dedicated MRI, iron concentration (R2*), microstructural integrity (mean diffusivity; MD and fractional anisotropy; FA) as well as volumes were analyzed in patients with PSP, MSA-P and PD. METHODS: 3T MRI of 18 PSP and 16 MSA-P patients were compared with 16 PD patients matched for age and disease duration as well as 21 healthy controls. Statistical parametric mapping (SPM) was applied to objectively identify focal MRI changes throughout the whole-brain. Following dimensionality reduction of significant and multiple comparison-corrected SPM clusters through principal component analysis (PCA), stepwise receiver-operating characteristic curve analysis (ROC) was applied to determine the diagnostic potential of multimodal MRI parameters. RESULTS: PCA revealed two components involving multiple regions identified from SPM analysis. The first component was primarily composed of the mean MD value of the thalamus and the mean MD and FA values of the dentatorubrothalamic tract and the corpus callosum. The second component mainly consisted of mean MD and FA values of the middle cerebellar peduncle. ROC analysis showed 92% of PSP patients were differentiated correctly from MSA-P and PD and 80% of MSA-P patients could be distinguished from PD. CONCLUSION: Multimodal MRI improved the detection of disease-specific neurodegenerative patterns in PSP and MSA-P and highlights its potential to improve the diagnostic accuracy of atypical parkinsonian disorders.

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Inflammatory myopathy associated with PD-1 inhibitors

Seki M., Uruha A., Ohnuki Y., Kamada S., Noda T., Onda A., Ohira M., Isami A., Hiramatsu S., Hibino M., Nakane S., Noda S., Yutani S., Hanazono A., Yaguchi H., Takao M., Shiina T., Katsuno M., Nakahara J., Matsubara S., Nishino I., Suzuki S.

Journal of Autoimmunity (Journal of Autoimmunity) 100 105 - 113 2019.06

ISSN 08968411

© 2019 Elsevier Ltd Objective: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). Methods: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. Results: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%)patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. Conclusions: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

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Myelopathy due to human T-cell leukemia virus type-1 from the donor after ABO-incompatible liver transplantation

Wakabayashi T., Obara H., Seki M., Shinoda M., Kitago M., Yagi H., Abe Y., Matsubara K., Yamada Y., Oshima G., Oki K., Nagoshi N., Watanabe K., Hibi T., Itano O., Hoshino K., Suzuki N., Kuroda T., Kitagawa Y.

Annals of Hepatology (Annals of Hepatology) 18 ( 2 ) 397 - 401 2019.03

ISSN 16652681

© 2019 Fundación Clínica Médica Sur, A.C. We report the case of a 53-year-old-man who developed human T-cell leukemia virus type-1-associated myelopathy (HAM) after ABO-incompatible liver transplantation for alcoholic liver cirrhosis. The living donor was seropositive for human T-cell leukemia virus type-1 (HTLV-1) and the recipient was seronegative for HTLV-1 before transplantation. After transplantation, the recipient developed steroid-resistant acute cellular rejection, which was successfully treated using anti-thymocyte globulin, and he was eventually discharged. He underwent spinal surgery twice after the transplantation for the treatment of cervical spondylosis that had been present for a period of 9 months before the transplantation. The surgery improved his gait impairment temporarily. However, his gait impairment progressed, and magnetic resonance imaging revealed multiple sites of myelopathy. He was diagnosed with HAM 16 months after the transplantation. Pulse steroid therapy (1000 mg) was administered over a period of 3 days, and his limb paresis improved. Presently, steroid therapy is being continued, with a plan to eventually taper the dose, and he is being carefully followed up at our institution. Our case suggests that liver transplantation involving an HTLV-1-positive living donor carries the risk of virus transmission and short-term development of HAM after transplantation.

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The reorganization of functional architecture in the early-stages of Parkinson's disease

Tuovinen N., Seppi K., de Pasquale F., Müller C., Nocker M., Schocke M., Gizewski E., Kremser C., Wenning G., Poewe W., Djamshidian A., Scherfler C., Seki M.

Parkinsonism and Related Disorders (Parkinsonism and Related Disorders) 50 61 - 68 2018.05

ISSN 13538020

© 2018 Elsevier Ltd Introduction: The study aim was to identify longitudinal abnormalities of functional connectivity and its relation with motor disability in early to moderately advanced stages of Parkinson's disease patients. Methods: 3.0T structural and resting-state functional MRI was performed in healthy subjects (n = 16) and Parkinson's disease patients (n = 16) with mean disease duration of 2.2 ± 1.2 years at baseline with a clinical follow-up of 1.5 ± 0.3 years. Resting-state fMRI analysis included region-to-region connectivity in correlation with UPDRS-III scores and computation of Global Efficiency and Degree Centrality. Results: At baseline, patients' connectivity increased between the cerebellum and somatomotor network, and decreased between motor regions (Rolandic operculum, precentral gyrus, supplementary motor area, postcentral gyrus) and cingulate connectivity. At 1.5 years follow-up, connectivity remained altered in the same regions identified at baseline. The cerebellum showed additional hyperconnectivity within itself and to the caudate nucleus, thalamus and amygdala compared to controls. These differences correlated with UPDRS-III scores. Seed-based connectivity revealed increased involvement of the default mode network with precentral gyrus in patients at follow-up investigation. Conclusion: Resting-state fMRI identified marked disturbances of the overall architecture of connectivity in Parkinson's disease. The noted alterations in cortical motor areas were associated with cerebellar hyperconnectivity in early to moderately advanced stages of Parkinson's disease suggesting ongoing attempts of recovery and compensatory mechanism for affected functions. The potential to identify connectivity alterations in regions related to both motor and attentional functions requires further evaluation as an objective marker to monitor disease progression, and medical, as well as surgical interventions.

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Diagnostic potential of dentatorubrothalamic tract analysis in progressive supranuclear palsy

Seki M., Seppi K., Mueller C., Potrusil T., Goebel G., Reiter E., Nocker M., Steiger R., Wildauer M., Gizewski E., Wenning G., Poewe W., Scherfler C.

Parkinsonism and Related Disorders (Parkinsonism and Related Disorders) 49 81 - 87 2018.04

ISSN 13538020

© 2018 Elsevier Ltd Background: The differentiation of progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) remains a major clinical challenge. Objectives: To evaluate the diagnostic potential of observer-independent assessments of microstructural integrity within infratentorial brain regions to differentiate PSP-Richardson's syndrome (PSP-RS), PSP-P and PD. Methods: 3T MRI parameters of mean diffusivity, fractional anisotropy, grey and white matter volumes from patients with PSP-RS (n = 12), PSP-P (n = 12) and mean disease duration of 2.4 ± 1.7 years were compared with PD patients (n = 20) and healthy controls (n = 23) by using statistical parametric mapping and the spatially unbiased infratentorial template. Subsequently MRI measurements of the dentatorubrothalamic tract were determined observer-independently by a validated probabilistic infratentorial atlas. The impairment of gait and postural stability was evaluated by a sum-score derived from the Unified Parkinson Disease Rating Scale. Results: Significant mean diffusivity increases, fractional anisotropy decreases and corresponding volume loss were localized in mesencephalic tegmentum, superior cerebellar peduncle, decussation of superior cerebellar peduncle and dentate nucleus in PSP-RS and PSP-P compared to PD and healthy controls. Altered microstructural integrity of the dentatorubrothalamic tract in PSP-RS was significantly more pronounced compared to PSP-P and correlated significantly with the gait and postural stability sum-score. Linear discriminant analysis identified diffusion tensor imaging measures of the dentatorubrothalamic tract and the gait and postural stability sum-score to classify correctly 95.5% of PRP-RS, PSP-P and PD patients. Conclusions: Observer-independent analysis of microstructural integrity within the dentatorubrothalamic tract in combination with assessments of gait and postural stability differentiate PSP-P from PSP-RS and PD in early to moderately advanced stages.

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Possible Involvement of Hypotension in Postprandial Headache: A Case Series

Takizawa T., Shibata M., Hiraide T., Seki M., Takahashi S., Suzuki N.

Headache (Headache) 57 ( 9 ) 1443 - 1448 2017.10

ISSN 00178748

© 2017 American Headache Society Background: It is commonly known that headaches are induced by intake of specific food, drink, and/or additive. In addition, some patients experience postprandial headache independent of ingestion of specific items. Currently, information on the pathophysiology underlying this particular type of headache is scarce. Case reports: We report two cases in which headaches were observed after each meal. Postprandial hypotension was demonstrated in both cases. Tonometry-based continuous blood pressure measurement during head-up tilt revealed sympathetic dysfunction. In one patient, meta-iodobenzylguanidine (MIBG) myocardial scintigraphy detected cardiac sympathetic denervation, and diagnosis of pure autonomic failure was made. In both cases, treatment of postprandial hypotension was effective in relieving postprandial headache. Discussion: The possibility of postprandial hypotension should be explored in patients with headache that occurs after meal. To this end, tonometry-based blood pressure measurement and MIBG myocardial scintigraphy may be useful diagnostic investigations. Treating postprandial hypotension may be effective in alleviating the symptoms.

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慢性期脳梗塞患者における血管内皮機能低下とロスバスタチンによる改善作用

伊藤義彰, 関守信, 小泉健三, 滝沢翼, 山田哲, 此枝史恵, 鈴木則宏

Therapeutic Research (ライフサイエンス出版(株)) 36 ( 12 ) 1177 - 1182 2015.12

ISSN 0289-8020

目的:虚血性脳血管障害の慢性期再発予防には、スタチンによる脂質プロファイルの改善が有用であることが知られている。スタチンの脳梗塞再発予防効果として血管内皮機能の改善を評価した。対象と方法:脳卒中専門外来を受診した虚血性脳血管障害慢性期症例およびハイリスク症例を対象に血流介在血管拡張反応(FMD)を施行した。このうち、高コレステロール血症を有し新たにロスバスタチン5mgを投与した症例については、投与後にFMDを行い前値と比較した。結果:病型別には、心原性塞栓症に比較して、ラクナ梗塞(p=0.02)およびアテローム血栓性脳梗塞(p=0.009)で有意に%FMDが低値であった。リスク別には、脂質異常症あり群はなし群と比較して有意に%FMDが低値であった(p=0.05)が、高血圧、糖尿病と%FMDに相関は認めなかった。ロスバスタチン5mgを投与した15例のうち内服前に%FMDがすでに良好であった症例を除いた11例では、ロスバスタチン投与後に%FMDは有意に改善した(p=0.04)。考察:FMDは脳梗塞の病型別、リスク別の血管内皮障害の程度を鋭敏に評価できる検査であることが改めて示された。ロスバスタチンはこの血管内皮機能を改善することが明らかとなり、脳梗塞予防効果の一機序である可能性が示唆された。(著者抄録)

Adult phenylketonuria presenting with subacute severe neurologic symptoms

Seki M., Takizawa T., Suzuki S., Shimizu T., Shibata H., Ishii T., Hasegawa T., Suzuki N.

Journal of Clinical Neuroscience (Journal of Clinical Neuroscience) 22 ( 8 ) 1361 - 1363 2015.08

ISSN 09675868

© 2015 Elsevier Ltd. All rights reserved. We report a 48-year-old Japanese woman with phenylketonuria (PKU) who presented with severe neurological symptoms more than 30 years after discontinuation of dietary treatment. She was diagnosed with PKU at 6-years-old and was treated with a phenylalanine restricted diet until she was 15 years old. When she was 48-years-old she started having difficulty walking. After several months, she presented with severe disturbance of consciousness and was admitted. She was diagnosed as having neurological complications associated with PKU. We observed temporal changes in her laboratory data, brain MRI and single-photon emission computed tomography (SPECT) scan findings. Brain MRI on T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted images revealed high intensity lesions in her bilateral frontal lobes and 123I-IMP SPECT showed marked and diffuse hypoperfusion in the bilateral cerebrum and cerebellum. After the resumption of dietary treatment, serum phenylalanine concentrations immediately decreased to the normal range. However, her neurological symptoms took longer to improve. We also found no clear temporal association between MRI findings and clinical severity. SPECT abnormalities showed marked improvement after treatment. It is well known that PKU patients who discontinue the dietary restriction from their childhood develop minor neurological impairments. However, PKU patients with late-onset severe neurological symptoms are very rare. To our knowledge, this is the first report regarding SPECT findings of PKU patients with late-onset severe neurological deterioration.

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Immune-mediated neuropathy with anti-disialosyl IgM antibodies in diffuse large B-cell lymphoma: A case report and literature review

Shihashi G., Yagi T., Suzuki S., Seki M., Kohashi S., Ueda T., Kameyama K., Kusunoki S., Nakajima H., Okamoto S., Suzuki N.

Internal Medicine (Internal Medicine) 54 ( 13 ) 1647 - 1651 2015.07

ISSN 09182918

© 2015 The Japanese Society of Internal Medicine. A 36-year-old man with diffuse large B-cell lymphoma presented with polyneuropathy, and the diagnostic work-up revealed the presence of IgM antibodies against gangliosides with disialosyl residues (GD1b, GD3). He was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone and received high-dose intravenous immunoglobulin for the treatment of neuropathy. After initiating the treatments, the patient's neurological impairment improved dramatically. He currently remains in complete remission without a flare-up of the polyneuropathy. Based upon our experience and other case reports of lymphoma with immune-mediated neuropathy caused by anti-disialosyl ganglioside IgM antibodies, we conclude that determining the anti-ganglioside antibody profile and beginning early treatment should be considered promptly for patients with malignant lymphoma who develop polyneuropathy.

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Intracerebral hemorrhage due to venous thrombosis of developmental venous anomaly during pregnancy

Seki M., Shibata M., Itoh Y., Suzuki N.

Journal of Stroke and Cerebrovascular Diseases (Journal of Stroke and Cerebrovascular Diseases) 24 ( 7 ) e185 - e187 2015.07

ISSN 10523057

© 2015 by National Stroke Association. Background Nowadays, developmental venous anomaly (DVA) is recognized as the most common cerebral vascular malformation. Most DVAs are diagnosed incidentally on routine brain imaging, but they are occasionally symptomatic. We report the case of a 26-year-old Japanese woman with intracerebral hemorrhage due to venous thrombosis of DVA. Methods We examined her neurologic examinations carefully. We also observed her laboratory data, brain computed tomography (CT), and magnetic resonance imaging (MRI) findings. Results She was 8 weeks pregnant and suffered from nausea, vomiturition, and appetite loss because of hyperemesis gravidarum. She presented with a sudden generalized seizure and was referred to our hospital. Brain CT showed a small hemorrhage and a tubular high-density structure compatible with an acutely thrombosed collecting vein in the right frontal lobe. T2∗-weighted MRI also revealed a thrombosed collecting vein along with multiple medullary veins, which looked like caput medusa. She was diagnosed with an intracerebral hemorrhage and symptomatic epilepsy secondary to thrombosis of the DVA. After the acute phase of the disease, systemic anticoagulation therapy was administered to the patient to prevent the recurrence of venous thrombosis. We suspected that hyperemesis gravidarum with intravascular dehydration might have increased the risk of thrombosis in this patient. Conclusions Thrombosis of the collecting vein of DVA is extremely rare. This is the first report regarding DVA thrombosis during pregnancy, to our knowledge.

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Fatal intracranial hemorrhage after intravenous thrombolytic therapy for acute ischemic stroke associated with cancer-related nonbacterial thrombotic endocarditis

Yagi T., Takahashi K., Tanikawa M., Seki M., Abe T., Suzuki N.

Journal of Stroke and Cerebrovascular Diseases (Journal of Stroke and Cerebrovascular Diseases) 23 ( 8 ) e413 - e416 2014.09

ISSN 10523057

© 2014 National Stroke Association. Nonbacterial thrombotic endocarditis (NBTE) is associated with hypercoagulability in patients with inflammatory states such as cancer and autoimmune diseases. Cardiac vegetations caused by NBTE often lead to life-threatening systemic thromboembolism that most frequently affects the brain, spleen, and kidneys. A 54-year-old woman diagnosed with ovarian cancer suddenly developed back pain and left hemiparesis. Although intravenous alteplase (rt-PA) therapy was administered to treat hyperacute ischemic infarction detected by magnetic resonance imaging, intracranial hemorrhage occurred in the left hemisphere several hours later as the patient started to lose consciousness. Transthoracic echocardiography then detected aseptic vegetations on the mitral and aortic valves, indicating NBTE associated with ovarian cancer. Because therapies for NBTE are limited to heparinization and control of underlying diseases, thrombolytic therapy for acute embolic stroke in NBTE has not yet been validated. We postulated that thrombolytic therapy for cancer-related NBTE might easily cause hemorrhagic complications because cancer-related NBTE is often similar to the state of disseminated intravascular coagulation.

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Screening for impaired cognitive domains in a large Parkinson's disease population and its application to the diagnostic procedure for Parkinson's disease dementia.

Ohta K, Takahashi K, Gotoh J, Yamaguchi K, Seki M, Nihei Y, Iwasawa S, Suzuki N, Keio Parkinson's Disease Database.

Dementia and geriatric cognitive disorders extra 4 ( 2 ) 147 - 59 2014.05

ISSN 1664-5464

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[Roles of metabolic compartmentalization by astrocytes and neurons in the pathophysiology and treatment of Parkinson's disease].

Takahashi S, Seki M, Suzuki N

Brain and nerve = Shinkei kenkyu no shinpo 65 ( 12 ) 1497 - 508 2013.12

ISSN 1881-6096

Roles of metabolic compartmentalization by astrocytes and neurons in the pathophysiology and treatment of parkinson's disease

Takahashi S., Seki M., Suzuki N.

Brain and Nerve (Brain and Nerve) 65 ( 12 ) 1497 - 1508 2013.12

ISSN 18816096

Mitochondrial dysfunction has been implicated in the pathogenesis of both idiopathic and familial Parkinson's disease (PD). Dopamine neurons in the substantia nigra exhibit autonomous pacemaking activity to maintain an optimal dopamine concentration in the striatum, resulting in the activation of energy metabolism. ATP production in neuronal cells is dependent on mitochondrial glucose oxidation, and reactive oxygen species (ROS) production associated with neuronal activation might be a major cause of mitochondrial damage in dopamine neurons. Alpha-synuclein, a major component of Lewy bodies, induces mitochondrial damage, and several genes responsible for familial PD encode molecules necessary for normal mitochondrial function. In addition, the auto-oxidation of dopamine produces dopamine quoinone and ROS. Astroglia provide neurons with lactate produced from glucose via glycolysis in response to neuronal activation. The co-activation of the pentose-phosphate pathway (PPP), a shunt pathway of glycolysis, in astroglia plays a pivotal role in protecting neurons against ROS with glutathione peroxidase and the reduced form of glutathione (GSH). In addition to the allosteric regulation of the PPP, which is associated with the activation of glycolysis, the PPP in astroglia can also be activated by ROS through the Kelch-like enoyl-CoA hydratase-associated protein 1 (KeapD/nuclear factor-erythroid 2 p45 subunit-related factor 2 (Nrf2) system. A rate-limiting enzyme of the PPP, glucose-6-phosphate dehydrogenase (G6PDH), is transcriptionally regulated by the Keapl/Nrf2 system, which is a master regulator of phase 2 detoxifying enzymes. ROS is thought to modify the thiol residue of Keapl and to facilitate Nrf2 dissociation from Keapl. Thereafter, Nrf2 translocates into the nucleus where it induces the transcription of G6PDH. The pharmacological activation of the Keapl/Nrf2 PPP in astroglia may provide a novel strategy for preventing the onset and progression of PD.

Clinical features and varieties of non-motor fluctuations in Parkinson's disease: A Japanese multicenter study

Seki M., Takahashi K., Uematsu D., Mihara B., Morita Y., Isozumi K., Ohta K., Muramatsu K., Shirai T., Nogawa S., Gotoh J., Yamaguchi K., Tomita Y., Yasutomi D., Nihei Y., Iwasawa S., Suzuki N.

Parkinsonism and Related Disorders (Parkinsonism and Related Disorders) 19 ( 1 ) 104 - 108 2013.01

ISSN 13538020

Objective: This multicenter cross-sectional study aimed to investigate the clinical features and varieties of non-motor fluctuation in Parkinson's disease (PD). Methods: To identify motor and non-motor fluctuation, we employed the wearing-off questionnaire of 19 symptoms (WOQ-19) in 464 PD patients. We compared the frequency of levodopa-related fluctuation as identified by the WOQ-19 with recognition by neurologists. We compared patients with both motor and non-motor fluctuations with those who only had motor fluctuations. Non-motor fluctuations were separated into psychiatric, autonomic, and sensory categories for further analysis. Results: The patients' average age was 70.8 ± 8.4 years (mean ± SD) and disease duration was 6.6 ± 5.0 years. The frequency of motor fluctuations was 69% and for non-motor fluctuation 40%. Fifty-three percent of patients with motor fluctuations also had non-motor fluctuations, whereas 93% of patients with non-motor fluctuations also had motor fluctuations. The WOQ-19 showed a sensitivity of 82% but a specificity of only 40%. The patients with both non-motor and motor fluctuations exhibited more severe motor symptoms, more non-motor symptoms and higher levodopa daily doses (p < 0.05). Patients had significantly higher fluctuation rates if they had psychiatric (49%) and sensory (45%) symptoms than patients with autonomic symptoms (32%, p < 0.01). Forty-eight percent of patients with non-motor fluctuations exhibited more than one type of non-motor fluctuation. Conclusion: Forty percent of PD patients presented with non-motor fluctuations, and almost half of these exhibited more than one type. Appropriate recognition of levodopa-related fluctuations, both motor and non-motor, can lead to treatment modifications in PD patients. © 2012 Elsevier Ltd.

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Recent concept of limbic encephalitis: Progress in anti-NMDA receptor encephalitis

Suzuki S., Seki M., Suzuki N.

Japanese Journal of Clinical Immunology (Japanese Journal of Clinical Immunology) 36 ( 2 ) 86 - 94 2013

ISSN 09114300

Patients with limbic encephalitis usually present with rapidly progressive short-term memory deficits, psychiatric symptoms, and seizures. The recent concept of limbic encephalitis has been expanded. Especially, various types of autoimmune limbic encephalitis are associated with autoantibodies of intracellular or cell membrane antigens. Sine autoimmune limbic encephalitis is also associated with some types of tumors, it has also an aspect of paraneoplastic syndrome. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a new category of treatment-responsive limbic encephalitis associated with anti-NMDAR antibodies, which is the most frequent autoantibody to cell membrane antigen. The autoantibodies are detected in the CSF and serum of young women with ovarian teratoma, who typically develop schizophrenia-like psychiatric symptoms. There is a highly characteristics syndrome evolving in 5 stages; the prodromal, psychotic, unresponsive, hyperkinetic, and gradual recovery phases. The hyperkinetic phase is the most prolonged and crucial. This disorder is usually severe and can be fatal, but it is potentially reversible. Although the pathogenesis remains unclear, this disorder is considered to be the autoantibody-mediated encephalitis. This review focuses in the recent concept of limbic encephalitis and clinical characteristics of anti-NMDA receptor encephalitis. © 2013 The Japan Society for Clinical Immunology.

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[Recent concept of limbic encephalitis: progress in anti-NMDA receptor encephalitis].

Suzuki S, Seki M, Suzuki N

Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 36 ( 2 ) 86 - 94 2013

ISSN 0911-4300

REM sleep behavior disorder in Japanese patients with Parkinson's disease: A multicenter study using the REM sleep behavior disorder screening questionnaire

Nihei Y., Takahashi K., Koto A., Mihara B., Morita Y., Isozumi K., Ohta K., Muramatsu K., Gotoh J., Yamaguchi K., Tomita Y., Sato H., Seki M., Iwasawa S., Suzuki N.

Journal of Neurology (Journal of Neurology) 259 ( 8 ) 1606 - 1612 2012.08

ISSN 03405354

REM sleep behavior disorder (RBD) is known to be observed more frequently in patients with an a-synucleinopathy such as Parkinson's disease (PD) than in the general population. The precise prevalence of RBD in Japanese PD patients is not known. Therefore, we investigated the prevalence and the clinical characteristics of patients with RBD in a large population of Japanese patients with PD. We investigated various clinical features and employed the Japanese version of the RBD screening questionnaire on 469 non-demented Japanese PD patients in this multicenter study. Probable or possible RBD was detected in 146 patients (31.1%) and was significantly associated with longer PD duration, higher Hoehn and Yahr stage, higher Unified Parkinson's Disease Rating Scale part III subscale (7 items), more motor fluctuations, and a higher levodopa-equivalent daily dose (p<0.01). As to the major autonomic dysfunctions, severe constipation was significantly more frequent in PD patients with RBD than in those without it (p<0.01). The RBD symptoms of 53 patients (39.0%) preceded the onset of PD motor symptoms. The median interval from the onset of RBD symptoms to PD motor symptoms was 17.5 years, and 3 patients had intervals of over 50 years. This large-scale multicenter study revealed that RBD is a frequent nonmotor symptom in Japanese patients with PD, which may precede the onset of motor symptoms. Moreover, RBD that increases with the duration and severity of PD may be associated with autonomic dysfunction. © Springer-Verlag 2012.

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Differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis

Seki M., Suzuki S., Ishii K., Izawa Y., Takahashi S., Toyama Y., Nakamura M., Suzuki N.

Internal Medicine (Internal Medicine) 51 ( 3 ) 321 - 324 2012.02

ISSN 09182918

We describe the clinical features of limbic encephalitis that developed after palliative spinal cordotomy in 2 patients with malignant thoracic astrocytoma. Both patients showed short-term memory loss, hallucinations of smells and psychiatric symptoms. Brain MRI on T2-weighted and fluid-attenuated inversion recovery sequences revealed high intensity lesions in bilateral temporal lobe areas. We considered that both patients had paraneoplastic limbic encephalitis associated with astrocytoma because of various clinical and radiological features. But the possibility of intracranial dissemination of astrocytoma could not be fully excluded. The differential diagnosis between intracranial dissemination of spinal cord astrocytoma and paraneoplastic limbic encephalitis may be sometimes difficult. © 2012 The Japanese Society of Internal Medicine.

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