Published papers

© 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.

© 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.

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.

© 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.

© 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.

© 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.

We report an 18-year-old woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, who developed psychiatric symptoms, progressive unresponsiveness, dyskinesias, hypoventilation, hypersalivation and seizures. Early removal of an ovarian teratoma followed by plasma exchange and corticosteroids resulted in a prompt neurological response and eventual full recovery. Serial analysis of antibodies to NR1/NR2B heteromers of the NMDAR showed an early decrease of serum titres, although the cerebrospinal fluid titres correlated better with clinical outcome. The patients' antibodies reacted with areas of the tumour that contained NMDAR-expressing tissue. Search for and removal of a teratoma should be promptly considered after the diagnosis of anti-NMDAR encephalitis.

© 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.

Anti-NMDAR encephalopathy is included in paraneoplastic limbic encephalopathy and show the good response to treatment compared to other paraneoplastic syndromes. Treatment of anti-NMDAR encephalopathy includes immunotherapy and/or tumor removal. About 65% of patients with anti-NMDAR encephalopathy had fully or near-full recovery. Immunotherapy is principally necessary and effective in patients with and without tumor. Corticosteroids and intravenous immunoglobulin are most frequently used. It is likely that patients who do not respond to one form of immunotherapy might respond to others regimens including plasmapheresis, cyclophosphamide, and rituximab. A tumor was found in 58% of patients with anti-NMDAR encephalopathy. Early removal of tumor should be considered based on following reasons. First, patients with ovarian teratoma showed higher mortality and higher titer of anti-NMDAR antibody compared with those without. Second, relapsing neurological symptoms occurred in 13% of patients, usually related to a delay in tumor diagnosis. Third, when a tumor was found and removed, recovery was faster and predictable. However, early removal of tumor cannot be conducted because of unstable conditions such as hypoventilation and dyskinesias. In supportive cares, severe central hypoventilation requires mechanical ventilation. The involuntary movements and facial dyskinesias are refractory to anti-epileptic drugs. In conclusion, search for and removal of an ovarian teratoma should be promptly considered after the diagnosis of anti-NMDAR encephalopathy.

Limbic encephalitis (LE) refers to an inflammatory disorder involving the hippocampus, amygdala and insular cortex. LE is now regarded as a more frequent disorder than it was previously thought, and the concept of LE has been expanded because of the development of neuroimaging and the increasing recognition of the associated antibodies. We categorized LE into 5 groups. LE caused by virus infection, autoantibody-mediated LE, LE with autoimmune disease, LE associated with drugs and LE during pregnancy. LE having the antibodies against intracellular antigens frequently related to cancer and are resistant to treatment. While, LE with antibodies against cell-membrane antigens, including NMDAR, AMPAR, GABA(B)R, VGKC, tend to respond better to antitumor therapy and immunotherapy.

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.

A new subtype of autoimmune encephalitis associated with antibodies against GABAB receptor was recently identified. Although immune-mediated functional abnormalities are suggested for the pathogenesis, functional brain imaging such as perfusion SPECT has not been documented. A 62-year-old woman with anti-GABAB receptor associated encephalitis underwent 123I-IMP SPECT in the beginning and after methylprednisolone pulse therapy. Three-dimensional stereotactic surface projection analysis was used to evaluate the cortical distribution of perfusion abnormality. The patient presented with clinical features of subacute limbic encephalitis. Antibodies to GABAB receptor were identified in her serum and cerebrospinal fluid (CSF), but no tumor was detected. Despite normal magnetic resonance imaging (MRI) findings, the first SPECT revealed hypoperfusion of the frontal, parietal and medial temporal lobes, as well as thalamus, and cerebellum. These areas are known to contain high levels of GABAB receptors. In contrast, the SPECT revealed hyperperfusion in the motor strip and left temporal lobe, which are areas related to some of the patient's symptoms, including seizures, orolingual dyskinesia, and Wernicke aphasia. After treatment with pulses of methylprednisolone, the neuropsychiatric symptoms resolved and the SPECT findings showed substantial improvement in most of these regions. In conclusion, the findings suggest that immunotherapy improved the cortical dysfunction mediated by GABAB receptor antibodies. © 2011 The Authors.

© 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.