Hiroki Masuda

Serum antinuclear antibody may be associated with less severe disease activity in neuromyelitis optica.

Antinuclear antibody‐positive multiple sclerosis (MS) patients have shorter disease duration and lower Expanded Disability Status Scale (EDSS) scores. The aim of this study was to compare clinical and laboratory features between MS and neuromyelitis optica (NMO) patients with and without autoantibodies and to investigate the prognosis of NMO in patients with and without autoantibodies.

Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption:

Background: Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood–brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown. Objective: We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO. Methods: The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients. Results: NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions. Conclusion: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).

Epstein-Barr virus persistence and reactivation in neuromyelitis optica

Objective Epstein-Barr virus (EBV) infection has been thought to be a key environmental factor in the development of multiple sclerosis (MS). The aim of this study is to investigate the association of EBV infection with neuromyelitis optica (NMO). Methods We measured levels of serum antibodies against EBV antigens, including anti-viral capsid antigen (VCA) IgM, anti-VCA IgG, anti-early antigen (EA) IgM, anti-EA IgG and anti-EBV nuclear antigen-1 IgG, in 50 patients with NMO (including 12 partial form with antiaquaporin 4 antibodies), 51 patients with MS, and 52 healthy controls, and cerebrospinal fluid (CSF) antibodies in 37 patients with NMO and 33 patients with MS with ELISA. Result Compared with patients with MS and normal participants, patients with NMO more frequently had serum anti-EA IgG antibodies (52%), indicating more active viral replication than patients with MS (26%) and controls (25%). The antibody titres were significantly higher in the NMO group than in the MS (p=0.005) and control (p=0.005) groups. The CSF antibody titres were also higher in patients with NMO than in those with MS (p=0.03). Conclusions Our results raise the hypothesis that persistent, active EBV replication is present in NMO, and may contribute to the immunological alterations that play a pathogenetic role in the disorder.

Soluble CD40 ligand contributes to blood–brain barrier breakdown and central nervous system inflammation in multiple sclerosis and neuromyelitis optica spectrum disorder

Soluble CD40 ligand (sCD40L) is reported to disrupt the blood-brain barrier (BBB). Cerebrospinal fluid (CSF) and serum sCD40L levels were measured in 29 multiple sclerosis (MS), 29 neuromyelitis optica spectrum disorder (NMOSD), and 27 disease control (DC) patients. In MS, serum sCD40L levels were higher than in DCs and positively correlated with the CSF/serum albumin ratio (Qalb). In NMOSD, CSF sCD40L levels were significantly increased compared to DCs, and were correlated to Qalb, CSF cell counts, protein concentrations, and interleukin-6 levels. sCD40L could be involved in BBB disruption in MS, whereas it may contribute to CNS inflammation in NMOSD.

Antemortem detection of colonic α-synuclein pathology in a patient with pure autonomic failure.

Dear Sirs, Pure autonomic failure (PAF) is a degenerative disorder of the autonomic nervous system and a clinical phenotype of Lewy body (LB) disease as well as Parkinson’s disease (PD) and dementia with Lewy bodies. It usually occurs in middle-aged and elderly individuals and progresses slowly. a-Synuclein, the main constituent of LB, in sympathetic ganglia neurons is a postmortem diagnostic hallmark of PAF [1]. On the contrary, a-synuclein deposition has been observed in the colonic tissue of patients with PD, and the identification of colonic a-synuclein aggregates in vivo could be a diagnostic marker for PD [2]. However, the presence of a-synuclein in the colonic tissue of patients with PAF has not been reported. Here, we describe a patient who was definitely diagnosed with PAF based on pathological evidence of a-synuclein in his surgically resected colon specimen. A 70-year-old Japanese man began experiencing orthostatic dizziness at 55 years of age. His postural symptoms gradually deteriorated, and he began experiencing recurrent syncope. At 56 years of age, an episode of syncope resulted in a cerebral contusion, which caused moderate cognitive dysfunction, and he noticed olfactory loss. He suffered from constipation since 60 years of age. At 67 years of age, the head-up tilt test revealed orthostatic hypotension (OH). At 70 years of age, neurological examination revealed normal findings, except for severe autonomic failure and moderate cognitive dysfunction without fluctuations and hallucinations. Routine hematological and serological studies revealed normal findings. M protein was not detected by serum immunofixation electrophoresis. Serum anti-ganglionic acetylcholine receptor antibodies were not analyzed. Brain MRI (Fig. 1) revealed no cerebellar, putaminal, or hippocampal atrophy. Hyperintensities on T2-weighted images were observed in the bilateral frontal lobes and the central pontine. These lesions were also observed in the brain CT scan performed at 59 years of age. Brain perfusion singlephoton emission computed tomography with intravenously injected I-iodoamphetamine identified hypoperfusion in the bilateral frontal lobes, but not in the temporal, parietal, posterior cingulate, and occipital regions (Fig. 1). Myocardial I-metaiodobenzylguanidine (MIBG) accumulation was decreased, and his delayed heart-to-mediastinum was 1.03 (normal,\2.09 in our institution). ECG showed normal findings. His blood pressure was 108/63 mmHg (heart rate, 60/min) in the supine position and 58/37 mmHg (75/min) during the head-up tilt test (70 ). His plasma norepinephrine levels were 97 pg/mL in the supine position (normal, C100 pg/ mL) and 162 pg/mL after 5 min in the head-up tilt position. The coefficient of variation for the R–R intervals, an index of heart rate variability, was 0.96 % (normal, C1.14 %). Nerve conduction studies in the right extremities revealed normal findings, excluding slightly prolonged distal latency in the median nerve. Abdominal skin biopsy did not identify amyloid or a-synuclein deposition. The patient underwent colon fiberscopy because of persistent anorexia, and cancer was suspected in the transverse sigmoid colon. Transverse colon resection was subsequently performed, and immunostaining of the H. Masuda (&) M. Asahina H. Wakita Y. Sekiguchi N. Araki S. Kuwabara Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan e-mail: hiroki_masuda@msn.com

Increased levels of CSF CD59 in neuromyelitis optica and multiple sclerosis

BACKGROUND Complement activation is important in multiple sclerosis (MS) and is essential for anti-aquaporin 4 antibodies to damage the central nervous system in neuromyelitis optica (NMO). Little is known about the role of cerebrospinal fluid (CSF) regulators of complement activation in NMO and MS. We determined whether CSF CD59, which is a complement regulator and C5b-9 formation inhibitor, is involved in the pathogenesis of NMO and MS. METHODS We analyzed CSF levels of CD59 in 30 patients with NMO, 22 patients with MS, and 24 patients with non-inflammatory neurological disorders (NINDs). Possible correlations between CSF CD59 levels and the clinical and laboratory variables in patients with NMO and MS were also reviewed. RESULTS CSF CD59 levels in patients with NMO and MS were higher than those in patients with NINDs (p<0.001), and those in patients with NMO decreased after treatment. No significant correlations were found between CSF CD59 levels and clinical and laboratory parameters in NMO and MS. CONCLUSION High CSF CD59 levels in NMO and MS may reflect inflammation, damage, and/or complement activation in the central nervous system.

Interleukin-6 analysis of 572 consecutive CSF samples from neurological disorders: A special focus on neuromyelitis optica

BACKGROUND Elevation of cerebrospinal fluid (CSF) interleukin (IL)-6 has been reported in various neurological disorders but has never been systematically analyzed. Our main objectives are to compare the CSF IL-6 levels among various neurological disorders and to evaluate the significance of CSF IL-6 measurements for the diagnosis of neuromyelitis optica (NMO). METHODS We retrospectively investigated the IL-6 levels of 572 consecutive CSF samples in patients with various neurological disorders. Additionally, the associations between clinical manifestations in NMO patients and CSF IL-6 levels were closely investigated. RESULTS Among the neurological disorders, patients with NMO had the highest CSF IL-6 level. Receiver operating characteristic analysis found the optimal cutoff CSF IL-6 value for diagnosing NMO as 7.8pg/ml, and the sensitivity and specificity were 0.7317 and 0.7694, respectively. In NMO, CSF IL-6 levels were correlated with the length of the spinal cord lesion and anti-aquaporin-4 antibody-positivity and decreased after treatment. CONCLUSION CSF IL-6 can be high in various inflammatory and non-inflammatory CNS disorders, but its upregulation appears to be the most remarkable in NMO.

Trigeminal root entry zone involvement in neuromyelitis optica and multiple sclerosis

Trigeminal root entry zone abnormality on brain magnetic resonance imaging has been frequently reported in multiple sclerosis patients, but it has not been investigated in neuromyelitis optica patients. Brain magnetic resonance imaging of 128 consecutive multiple sclerosis patients and 46 neuromyelitis optica patients was evaluated. Trigeminal root entry zone abnormality was present in 11 (8.6%) of the multiple sclerosis patients and two (4.3%) of the neuromyelitis optica patients. The pontine trigeminal root entry zone may be involved in both multiple sclerosis and neuromyelitis optica.

Seronegative neuromyelitis optica spectrum disorder patients diagnosed using new diagnostic criteria

Background: Recently, new diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD) were published. Objective: Our primary aim was to evaluate the usefulness of the new diagnostic criteria in anti-aquaporin 4 (AQP4) antibody-negative cases. Methods: Consecutive 471 patients whose anti-AQP4 antibody was measured at Chiba University were reviewed. Results: Four anti-AQP4 antibody negative-patients, who fulfilled the new diagnostic criteria for NMOSD but not 2006 diagnostic criteria for neuromyelitis optica (NMO), were identified. They showed high cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels, an absence of oligoclonal bands and/or cloud-like enhancement on magnetic resonance imaging, which are compatible findings for NMO. Conclusion: The new diagnostic criteria are clinically useful in seronegative NMOSD.

Recovery from optic neuritis attack in neuromyelitis optica spectrum disorder and multiple sclerosis.

BACKGROUND Both neuromyelitis optica spectrum disorder (NMOsd) and multiple sclerosis (MS) patients experience optic neuritis (ON) attacks characterized by rapidly reduced best-correct visual acuity (BCVA) and slow recovery. Prognosis and effects of recurrence on recovery may differ between disorders but remain unclear. OBJECTIVE To compare ON severity, time and degree of recovery and effects of previous ON between NMOsd and MS patients. METHODS Retrospective chart review was performed. BCVA measurements acquired before ON, at nadir and during recovery were retrospectively reviewed. Records were obtained on 69 ON attacks in 36 NMOsd patients and 43 attacks in 28 MS patients, including first episodes and recurrences. RESULTS NMOsd patients exhibited significantly lower BCVA values at all time points after attack (P<0.05), reached nadir earlier (P=0.014) and regained a smaller fraction of baseline BCVA than MS patients (P<0.001). In NMOsd, relapsed ON resulted in worse recovery and tended to reach nadir earlier than first-episode ON (P=0.030 and 0.059, respectively). In MS, relapsed ON also reached nadir earlier (P=0.042); however, there was no difference in recovery. CONCLUSIONS Recovery from ON was poorer in NMOsd than in MS and was negatively affected by previous ON attacks.