Etsuji Saji

Cognitive impairment and cortical degeneration in neuromyelitis optica

Neuromyelitis optica spectrum disorder (NMOsd) is an inflammatory and demyelinating syndrome characterized by optic neuritis and myelitis. Several magnetization transfer magnetic resonance imaging (MRI) studies have revealed abnormalities in normal‐appearing gray matter in NMOsd. The aim of this study is to elucidate the characteristics and pathogenesis of cognitive impairment and neurodegeneration in NMOsd brains.

Clinicopathological features in anterior visual pathway in neuromyelitis optica.

Neuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin‐4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia–neuron interaction in NMOsd.

Relapse of multiple sclerosis in a patient retaining CCR7-expressing T cells in CSF under fingolimod therapy

Fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor, and it traps lymphocytes in secondary lymphoid organs and precludes their migration into the central nervous system. We report the case of a patient who suffered a relatively severe relapse of multiple sclerosis (MS) during the initial 3 months of fingolimod therapy, with retention of CCR7 expression on CD4+ T cells in the cerebrospinal fluid (CSF) despite decreased numbers of lymphocytes and decreased expression of CCR7 on CD4+ T cells in the blood. These data suggest that fingolimod may cause differential effects on the CSF and blood lymphocytes of patients with MS during the initial months of therapy.

Treatment responsive opsoclonus–ataxia associated with ovarian teratoma

Opsoclonus–ataxia syndrome (OAS) is characterised by the subacute onset of ataxia and involuntary chaotic saccades occurring in all directions of gaze. OAS is often accompanied by myoclonus and may result from paraneoplastic, parainfectious and idiopathic aetiologies. Paraneoplastic OAS may be caused by neuroblastoma in children, and small cell lung carcinoma or breast cancer with anti-Ri antibodies in adults.1 We report here a patient with ovarian teratoma and a treatment responsive paraneoplastic OAS with subclinical supratentorial hypoperfusion on single photon emission computed tomography (SPECT). A 24-year-old woman developed abdominal pain and vertigo with unstable gait in the absence of any preceding infection. Findings on CT of the abdomen indicated a left ovarian tumour, 13 cm in diameter. Routine laboratory studies showed no elevations in levels of carcinoembryonic antigen, α-fetoprotein or carbohydrate antigen 125. The patient underwent unilateral salpingo-oophorectomy and removal of a teratoma that contained tissues derived from the three embryological layers without immature features, including a dense meshwork of astrocytes, small mature neurons, numerous axons positive for phosphorylated neurofilament and catecholaminergic neurons (figure 1A, B). Following tumour resection she continued to have severe …

The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells

The nature of the inflammatory response in the MS brain is poorly defined. Machado-Santos et al. report that chronic inflammation is dominated by tissue resident CD8+ T-cells and CD20+ B-cells, which are activated in lesions with demyelinating or neurodegenerative activity.

Differences in T cell cytotoxicity and cell death mechanisms between progressive multifocal leukoencephalopathy, herpes simplex virus encephalitis and cytomegalovirus encephalitis

During the appearance of human immunodeficiency virus infection in the 1980 and the 1990s, progressive multifocal leukoencephalopathy (PML), a viral encephalitis induced by the JC virus, was the leading opportunistic brain infection. As a result of the use of modern immunomodulatory compounds such as Natalizumab and Rituximab, the number of patients with PML is once again increasing. Despite the presence of PML over decades, little is known regarding the mechanisms leading to death of infected cells and the role the immune system plays in this process. Here we compared the presence of inflammatory T cells and the targeting of infected cells by cytotoxic T cells in PML, herpes simplex virus encephalitis (HSVE) and cytomegalovirus encephalitis (CMVE). In addition, we analyzed cell death mechanisms in infected cells in these encephalitides. Our results show that large numbers of inflammatory cytotoxic T cells are present in PML lesions. Whereas in HSVE and CMVE, single or multiple appositions of CD8+ or granzyme-B+ T cells to infected cells are found, in PML such appositions are significantly less apparent. Analysis of apoptotic pathways by markers such as activated caspase-3, caspase-6, poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF) showed upregulation of caspase-3 and loss of caspase-6 from mitochondria in CMVE and HSVE infected cells. Infected oligodendrocytes in PML did not upregulate activated caspase-3 but instead showed translocation of PARP-1 from nucleus to cytoplasm and AIF from mitochondria to nucleus. These findings suggest that in HSVE and CMVE, cells die by caspase-mediated apoptosis induced by cytotoxic T cells. In PML, on the other hand, infected cells are not eliminated by the immune system but seem to die by virus-induced PARP and AIF translocation in a type of cell death defined as parthanatos.

Gray matter lesions and cognitive impairment in multiple sclerosis

Multiple sclerosis (MS) has long been considered to be the autoimmune disease that primarily affects oligodendrocyte and myelin in the white matter (WM) of the CNS. However, renewed interest in the gray matter (GM) pathology including cortical and deep GM of MS is emerging. Radiological and pathological assessments demonstrate that substantial cortical demyelination is prominent in all stages or courses of MS, and cortical neurodegeneration is also present in even normal-appearing GM in MS. Patients with MS have cognitive impairment as represented by the latent start of impairment from the very early stage of the disease course, and not only WM lesions but also GM lesions might be good predictors for cognitive impairment in MS. Although the cause of the GM lesions in MS has not been fully determined, an increase in knowledge of the structure of GM lesions in MS brains will result in more targeted therapeutic approaches to the disease.

The 3rd MS Summer College in Kobe (6–7 August 2016)Practical issues and new horizons in MS, NMOSD and related disorders

Day 1: 6 August 2016 Opening Remarks 13.00–13.05 Kazuo Fujihara (Fukushima Medical University, Fukushima, Japan) (1) Lecture 1 13.05–14.05 Chair: Takashi Yamamura (National Center of Neurology and Psychiatry, Kodaira, Japan) (L-1) Pathomechanisms of neuromyelitis optica spectrum disorder Monika Bradl (Medical University Vienna, Vienna, Austria) (2) Lecture 2 14.05–14.35 Chair: Yuji Nakatsuji (Osaka University, Osaka, Japan) (L-2) Involvement of anterior visual pathway in multiple sclerosis and neuromyelitis optica Izumi Kawachi (Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan) (3) Poster presentation 14.35–15.30 Chair: Kazuhide Ochi (Hiroshima University, Hiroshima, Japan) (P-1) Fingolimod suppresses bone resorption in female patients with multiple sclerosis Masakazu Nakamura, Yusei Miyazaki, Masaaki Niino, Ippei Kanazawa, Masako Suzuki, Masanori Mizuno, Shin Hisahara, Toshiyuki Fukazawa, Eri Takahashi and Seiji Kikuchi (Hokkaido Medical Center, Sapporo, Shimane University, Izumo, Iwate Medical University, Morioka, Sapporo Medical University, Sapporo Neurology Hospital, Sapporo, Japan) (P-2) Clinical importance of the early diagnosis of progressive multifocal leukoencephalopathy Motohiro Yukitake (Saga Central Hospital, Saga, Japan) (P-3) Clinical features of the patients with multiple sclerosis treated without diseasemodifying drugs Mizuki Kitamura, Takahiro Nakayama, Ichiro Imafuku (Department of Neurology, Yokohama Rosai Hospital, Yokohama, Japan) (P-4) T and B lymphocyte subsets of anti myelin oligodendrocyte glycoprotein-related disorder and anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder in remission Satoru Tanaka, Akihiro Kubota, Miki Kojima, Shoko Izaki, Satoru Ohji, Kimihiko Kaneko, Douglas Sato, Ichiro Nakashima, Hikoaki Fukaura and Kyoichi Nomura (Saitama Medical University, Saitama Medical Center, Saitama, Tohoku University, Sendai, Japan) (P-5) Clinical phenotype switching in a myelin oligodendrocyte glycoprotein antibodypositive patient Ryusei Nishigori, Yoko Warabi, Shinsuke Tobisawa, Toshihiro Yamazaki, Masaki Yonehara, Kota Bokuda, Ichiro Nakashima and Eiji Isozaki (Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan, Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan) (P-6) Cerebrospinal fluid collapsin response mediator protein 5 as a diagnostic biomarker of neuromyelitis optica spectrum disorder with anti-aquaporin-4 immunoglobulin G Shuhei Nishiyama, Tatsuro Misu, Yoshiki Takai, Toshiyuki Takahashi, Ichiro Nakashima, Kazuo Fujihara and Masashi Aoki (Tohoku University, Sendai, Yonezawa National Hospital, Yonezawa, Fukushima Medical University, Fukushima, Japan) (4) Oral presentation 15.30–16.35 Chair: Takuya Matsusita (Kyushu University, Japan), Hiroshi Kuroda (Tohoku University, Japan) (O-1) Lateral olfactory tract usher substance protein, an endogenous Nogo receptor antagonist, is associated with the induction of experimental autoimmune encephalomyelitis Keita Takahashi, Yuji Kurihara, Hideyuki Takeuchi, Kohtaro Takei and Fumiaki Tanaka (Yokohama City University Graduate School of Medicine, Yokohama, Yokohama City University Graduate School of Medical Life Science, Yokohama, Japan) (O-2) Th1 cells reduce expression of connexin43 in astrocytes via activation of microglia Mitsuru Watanabe, Katsuhisa Masaki, Ryo Yamasaki, Jun Kawanokuchi, Hideyuki

Role of meningeal lymphoid follicle-like structures in the CNS inflammatory disorders

cells with a naive phenotype decreased from baseline to Month 1 (36.7% to 2.3%), whereas the percentage of CD4 memory cells increased (62.5% to 97.4%). The percentages of both cell types then gradually returned toward baseline levels, but did not reach baseline levels by Month 12. The proportion of CD4 T cells with a regulatory phenotype increased from baseline to Month 1 (3.8% to 12.5%), and remained elevated at Month 12. A similar pattern was observed for CD8 T-cell subsets. The proportion of B cells with a mature naive phenotype decreased from 56.4% to 5.4% from baseline to Month 1, whereas the immature cell fraction increased from 4.7% to 36.8%; relative proportions then approached baseline levels by Month 6. Conclusions:Alemtuzumab-induced lymphocytedepletionwasselective andresulted inanincreasedproportionofmemoryandregulatoryTcells. A distinctive pattern of lymphocyte repopulation was observed within weeks. These effects may explain alemtuzumabs sustained benefit despite infrequent (yearly) administration. Study Supported by: Genzyme, a Sanofi Company, and Bayer Healthcare Pharmaceuticals.

Cortical degeneration in neuromyelitis optica: Potential pathogenesis of cognitive impairment

Neuromyelitis optica (NMO) is an inflammatory and demyelinating syndrome of the central nervous system (CNS) that is characterized by optic neuritis and myelitis. Detection of NMO immunoglobulin G autoantibody (NMO-IgG), which targets the water channel aquaporin-4 (AQP4; the main channel regulating water homeostasis in the CNS), in the serum of NMO patients distinguishes NMO from other demyelinating disorders with stringent diagnostic accuracy. Hallmarks of pathological features of NMO lesions in the spinal cord and optic nerves are “pattern specific loss of AQP4 immunoreactivity with deposits of activated complements in a vasculocentric pattern around thickened hyalinized blood vessels”. Although the brain is widely recognized to be relatively spared in NMO, most magnetization transfer and diffusion tensor magnetic resonance imaging studies of patients with NMO have found abnormalities in normal-appearing gray matter as well as normal findings or minimal changes in normal-appearing white matter, irrespective of abnormalities seen with conventional magnetic resonance imaging. These findings suggest selective or more severe lesioning of gray matter, which is a site of high AQP4 expression. In multiple sclerosis (MS) patients, there has been renewed interest in cognitive dysfunction, which affects 45–65% of patients sometime during the course of the disease. These processes in MS might primarily arise within gray matter regions and result in cortical subpial demyelination concomitant with meningeal infiltration, or they could be secondary pathological changes in the gray matter regions resulting from continuing damage in the cerebral white matter. However, little is known about the characteristic features of cognitive decline in patients with NMO and its detailed pathogenesis. In a recent study, we showed that 57% of NMO spectrum disorder (NMOsd) patients and 47% of MS patients had impaired performance by assessments with the Rao’s Brief Repeatable Battery of Neuropsychological Tests. Cognitive impairment in NMOsd was common even in the limited form of the disease, showing that NMOsd can progress insidiously from the early stages of disease. Furthermore, neuropathological assessments showed neuronal loss in cortical layers II, III and IV, with non-lytic reaction of AQP4-negative astrocytes in layer I, massive activated microglia in layer II and meningeal inflammation in NMOsd brains. All NMO cases showed no evidence of cortical demyelination, in contrast with MS cases. These data show that NMOsd and MS patients have similar cognitive profiles, as represented by the latent start of impairment from the very early stage of the disease course. Conversely, compared with MS, NMOsd patients conclusively have distinct characteristic features of neuropsychological, radiological and pathological modalities in the brain. These significant hallmarks of NMOsd might influence neuronal dysfunction in the brain and cognitive impairment, given the detrimental effects including cytokine diffusion, disruption of water homeostasis associated with AQP4 dynamics, or other unidentified mechanisms. Further research must now investigate the essential mechanisms of cognitive impairment and neurodegeneration.