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Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Objective Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220(+) B cells, IgG1(+) cells, CD138(+) plasma cells, CD3(+) T cells, F4/80(+) macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-beta 1 was produced preferentially in B cells and macrophages while TGF-beta receptor I (TGF-beta RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-beta 1, TGF-beta RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-beta RI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-beta 1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation TGF-beta 1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.

Objectives Studies of longitudinally extensive spinal cord lesions (LESCLs) in neuromyelitis optica (NMO) have focused on gray matter, where the relevant antigen, aquaporin-4 (AQP4), is abundant. Because spinal white matter pathology in NMO is not well characterized, we aimed to clarify spinal white matter pathology of LESCLs in NMO. Methods We analyzed 50 spinal cord lesions from eleven autopsied NMO/NMO spectrum disorder (NMOSD) cases. We also evaluated LESCLs with three or fewer spinal cord attacks by 3-tesla MRI in 15 AQP4 antibody-positive NMO/NMOSD patients and in 15 AQP4 antibody-negative multiple sclerosis (MS) patients. Results Pathological analysis revealed seven cases of AQP4 loss and four predominantly demyelinating cases. Forty-four lesions from AQP4 loss cases involved significantly more frequently posterior columns (PC) and lateral columns (LC) than anterior columns (AC) (59.1%, 63.6%, and 34.1%, respectively). The posterior horn (PH), central portion (CP), and anterior horn (AH) were similarly affected (38.6%, 36.4% and 31.8%, respectively). Isolated perivascular inflammatory lesions with selective loss of astrocyte endfoot proteins, AQP4 and connexin 43, were present only in white matter and were more frequent in PC and LC than in AC (22.7%, 29.5% and 2.3%, Pcorr = 0.020, and Pcorr = 0.004, respectively). MRI indicated LESCLs more frequently affected PC and LC than AC in anti-AQP4 antibody-seropositive NMO/NMOSD (86.7%, 60.0% and 20.0%, Pcorr = 0.005, and Pcorr = 0.043, respectively) and AQP4 antibody-seronegative MS patients (86.7%, 73.3% and 33.3%, Pcorr = 0.063, and Pcorr = 0.043, respectively). PH, CP and AH were involved in 93.3%, 86.7% and 73.3% of seropositive patients, respectively, and in 53.3%, 60.0% and 40.0% of seronegative patients, respectively. Conclusions NMO frequently and extensively affects spinal white matter in addition to central gray matter, especially in PC and LC, where isolated perivascular lesions with astrocyte endfoot protein loss may emerge. Spinal white matter involvement may also appear in early NMO, similar to cerebral white matter lesions.

Objective To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Methods Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. Results A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti–aquaporin-4 antibody or had significantly lower titers than those without CNV. Interpretation Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

Objective Neuromyelitis optica (NMO) is an inflammatory disease in which NMO-immunoglobulin G (IgG) targeting aquaporin-4 (AQP4) is specifically detected. Although the main subclass of AQP4 antibody was reported to be in the IgG1 subclass, other subclasses have also been described, including IgG2 AQP4 antibody, as a second common subclass. NMO patients were analyzed to clarify the clinical features of NMO patients with IgG2 AQP4 antibody. Methods Serum samples from 58 NMO patients, who met the revised 2006 criteria for NMO, were analyzed for AQP4 antibody subclass expression using an established flow cytometric assay, and clinical features were compared according to the main AQP4 antibody subclasses. Results A total of 50 patients (86.2%) had IgG1 AQP4 antibodies, while eight (13.8%) expressed IgG2 AQP4 antibody as the main subclass. Those eight individuals exhibited younger age of onset (P = 0.0089), lower AQP4 antibody titers (P = 0.0024) and a more common fulfillment of Barkhof's criteria (P = 0.0466) than patients with IgG1 AQP4 antibody expression. Conclusions Results from the present study suggest that the characteristics of individuals with IgG2 AQP4 antibody as a main subclass are more similar to multiple sclerosis and somewhat distinct from NMO patients with IgG1 AQP4 antibody.

Objectives Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, and is generally considered to be mediated by T helper (Th) 1/Th17 cells. Interferon-β (IFNβ) is widely used as a disease-modifying MS drug, but its effects on Th17 cells are still disputed. Furthermore, the effects of IFNβ on Th9 cells have not been elucidated. The present study aimed to clarify the effects of IFNβ on cytokines/growth factors in cerebrospinal fluid (CSF) and cytokine-producing Th cells in peripheral blood. Methods First, the frequency of IFNγ, interleukin (IL)-17A, IL-9, and IL-4-producing Th cells in peripheral blood lymphocytes was analyzed by flow cytometry in 34 MS patients and 15 healthy volunteers enrolled in the cytokine-producing Th cell study. Second, levels of 27 cytokines/growth factors in the CSF were measured using a multiple fluorescence bead-based immunoassay in 34 MS patients enrolled in the cytokines/growth factors study. Results We found a significantly higher frequency of IL-4−IL-9+CD4+ T cells and lower frequency of IFNγ+IL-17A−CD4+ cells in peripheral blood lymphocytes in the 10 MS patients who had received IFNβ than in the 24 MS patients who had not received IFNβ or the 15 healthy controls (P

Objective Recent evidence has suggested the importance of an aberrantly activated monocyte system in amyotrophic lateral sclerosis (ALS) pathogenesis. However, the roles of each monocyte subset, namely CD14+CD16− classical monocytes, CD14dimCD16+ non-classical monocytes and CD14+CD16+ intermediate monocytes, in ALS remain unknown. We aimed to clarify the alterations in the monocyte subset proportions and the surface marker expressions on each monocyte subset in ALS. Methods Blood samples were collected from 19 ALS patients and 28 healthy controls (HC). The surface expressions of CCR2, CX3CR1, CD64 and CD62L were measured in the three monocyte subsets (classical, non-classical and intermediate) by flow cytometry. Results The percentages of CCR2 and CD62L on CD14+CD16− classical monocytes were significantly lower in ALS patients than in HC (P = 0.0012 and P = 0.0296, respectively). No differences were found in CX3CR1 and CD64 on each monocyte subset. The percentage of intermediate monocytes showed a significant negative correlation with the revised ALS functional rating scale score (r = −0.631, P = 0.0038). Conclusions Reductions in chemotaxis- and adhesion-related molecules on classical inflammatory monocytes are present in ALS, further suggesting the involvement of an aberrant innate immune system in ALS pathogenesis.

Objectives To clarify the prevalence, frequent causes and distinct features of hypertrophic pachymeningitis (HP) according to background conditions in a nationwide survey in Japan. Methods The study began with a preliminary survey to determine the approximate number of HP patients diagnosed from 1 January 2005 to 31 December 2009, and was followed by a questionnaire survey for clinical and laboratory findings. HP was defined as a condition with thickening of the cranial or spinal dura mater with inflammation, evidenced by MRI or histology. Results Crude HP prevalence was 0.949/100 000 population. The mean age at onset was 58.3±15.8 years. Among 159 cases for whom detailed data were collated, antineutrophil cytoplasmic antibody (ANCA)-related HP was found in 54 cases (34.0%) and IgG4/multifocal fibrosclerosis (MFS)-related HP in 14 cases (8.8%). Seventy cases (44.0%) were classified as ‘idiopathic’ and 21 (13.2%) as ‘others’. ANCA-related HP cases showed a female preponderance, a higher age of onset, and higher frequencies of otological symptoms and elevated systemic inflammatory biomarkers, but lower frequencies of diplopia compared with idiopathic HP. IgG4/MFS-related HP cases showed a marked male predominance; all had cranial HP while none had isolated spinal HP or decreased sensation. Conclusions HP is not extremely rare. ANCA-related HP is the most frequent form, followed by IgG4/MFS-related HP. Both forms have unique features, which may help to differentiate background causes.

Objectives Human peripheral blood monocytes comprise three different subtypes: CD14+CD16− (classical type), CD14lowCD16+ (non-classical type) and CD14+CD16+ (intermediate type). These subsets are known to have different functions, but little is known about their roles in multiple sclerosis (MS), especially for maintaining remission. We aimed to clarify the alterations in monocyte subsets in patients with MS and neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) in the remission phase. Methods Blood samples were collected from 19 MS patients and 10 NMO/NMOSD patients in the remission phase, and 42 healthy controls (HC). The surface expressions of CCR2, CX3CR1, CD64 (FcγR1) and CD62L were analyzed in the monocyte subsets by flow cytometry. Results CCR2 expression was significantly decreased in classical monocytes from MS patients, regardless of interferon-β (IFN-β) treatment, but not in those from NMO/NMOSD patients. CX3CR1 expression was also decreased in all monocyte subsets from MS patients receiving IFN-β, whereas CX3CR1 expression in classical monocytes was only decreased in NMO/NMOSD patients receiving prednisolone. In NMO/NMOSD patients on prednisolone, the percentages of CD14+CD16+ intermediate monocytes, CD14lowCD16+ non-classical monocytes and CD64+CD14+CD16+ monocytes among total monocytes were significantly lower than in HC. CD62L expression on the monocyte subsets showed no significant differences among the patients and HC. Conclusions Our findings suggest that alterations in chemokine receptor expressions on peripheral blood monocytes can occur in MS and NMO/NMOSD during the remission phase. Down-modulation of CCR2 in MS, and CX3CR1 in MS and NMO/NMOSD could partly contribute to sustained remission by preventing monocyte infiltration into the central nervous system.

Objectives: We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD). Methods: We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barre syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells. Results: At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barre syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody–positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms. Conclusion: Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.

Objectives The frequency of brain lesions that fulfil the Barkhof criteria (Barkhof brain lesions) is low in Asian patients with multiple sclerosis (MS). Several genes are associated with MS in the Japanese, but their influence on brain lesion development is unknown. Here, we clarified the genetic profiles of Barkhof brain lesion-positive and -negative MS in the Japanese. Methods We genotyped the HLA-DRB1 and -DPB1 alleles, the NOTCH4 missense mutation rs422951, and the IL-7RA single nucleotide polymorphism rs6897932 in 123 non-neuromyelitis optica/neuromyelitis optica spectrum disorder MS patients and 367 healthy controls by annealing of sequence-specific oligonucleotide probes to polymerase chain reaction-amplified genomic DNA (for the HLA alleles), DNA sequencing (for rs422951), and real-time polymerase chain reaction using TaqMan genotyping assays (for rs6897932). Results Compared with the healthy controls, the frequency of DRB1*0405 was significantly higher in the Barkhof brain lesion-negative group, that of DPB1*0301 was significantly higher in the Barkhof brain lesion-positive group, and those of DRB1*0901 and DPB1*0401 were significantly lower in the Barkhof brain lesion-positive group. The frequency of NOTCH4 rs422951 G allele carriers was significantly lower in both groups compared with the healthy controls, whereas the frequency of the IL-7RA rs6897932 CC genotype was significantly higher in the Barkhof brain lesion-positive group. Haplotype analyses identified one susceptibility and three resistance haplotypes for Barkhof brain lesion-positive MS, and two susceptibility and three resistance haplotypes for Barkhof brain lesion-negative MS. Conclusions The genetic profiles of Japanese MS patients are distinct according to the presence or absence of Barkhof brain lesions.

Objectives To clarify the differences in multimodality evoked potential findings between patients with atopic myelitis (AM) and those with multiple sclerosis (MS). Methods A retrospective chart review of 70 consecutive AM patients and 93 MS patients was carried out. All patients were negative for serum anti-aquaporin-4 antibody. Visual- (VEP), somatosensory- (SEP) and motor-evoked potentials (MEP) recorded at first examination, and magnetic resonance imaging (MRI) findings from the first examination were compared between AM and MS patients. Results Compared with MS patients, AM patients showed male preponderance, lower the Expanded Disability Status Scale scores and less frequent spinal cord MRI lesions. Visual impairment and muscle weakness were also less severe in AM patients. Frequencies of abnormal VEP and prolonged central conduction time on lower limb MEP were significantly lower in AM patients than in MS patients (AM vs MS: 9.5% vs 55.6%, and 28.2% vs 54.4%, respectively), whereas frequencies of peripheral nerve involvement in upper and lower limb MEP and upper limb SEP were significantly higher in AM than in MS patients (AM vs MS: 12.8% vs 2.9%, 17.9% vs 2.9% and 33.3% vs 4.4%, respectively). When patients whose EP were examined within 5 years of disease onset were compared, lower frequencies of abnormal VEP and higher peripheral nerve involvement detected by MEP and SEP were observed in AM patients. Conclusions AM patients have distinct physiological features compared with MS patients, even at the first examination of evoked potentials, which might suggest distinct immunological mechanisms between the two conditions. Multimodality evoked potentials might contribute to the early discrimination of these two disorders.

Neuromyelitis optica (NMO) is an inflammatory disease that selectively affects the optic nerves and spinal cord. The discovery of NMO-IgG targeting aquaporin-4 (AQP4) in NMO patients suggested that NMO is a distinct entity, with a fundamentally different etiology from that of multiple sclerosis (MS). Although NMO usually leads to grave disability because of the more severe tissue destruction compared with classical MS, there have been several reports describing a benign form of NMO over a long disease term. NMO-IgG/AQP4 antibodies show high specificity but medium sensitivity for NMO, while the clinical relevance of AQP4 antibody titers remains to be determined. We aimed to clarify the clinical relevance of AQP4 antibody levels determined by a bridging enzyme-linked immunosorbent assay in 38 patients with NMO or NMO spectrum disorder. The AQP4 antibody levels were higher in patients with optic neuritis (ON) than in those without ON (p = 0.0164). Among the 12 patients examined in a longitudinal study, four showed an increase in the ELISA values during some relapses, and eight showed no clear correlation between the ELISA values and relapse. Of the four patients who demonstrated a steady rise in the antibody levels over time, two patients had no concomitant relapses, despite elevation of the AQP4 antibody levels. We conclude that high AQP4 antibody levels are associated with the occurrence of ON, but that the antibody levels themselves are not closely correlated with the onset of relapse.

Objective To clarify whether genetic and common infectious backgrounds are distinct, according to anti-aquaporin 4 (AQP4) antibody status in Japanese patients with neuromyelitis optica (NMO). Methods We analysed human leucocyte antigen (HLA)-DRB1 and HLA-DPB1 alleles, and IgG antibodies against Helicobacter pylori , Chlamydia pneumoniae , varicella zoster virus and Epstein–Barr virus nuclear antigen (EBNA) in 116 patients with NMO, including 39 patients with neuromyelitis optica spectrum disorder (NMOSD), 145 multiple sclerosis (MS) patients and 367 unrelated healthy controls. 77 NMO/NMOSD patients were seropositive for AQP4 antibody while 39 were seronegative. Results Compared with healthy controls, NMO/NMOSD patients showed a significantly lower frequency of DRB1*0901 and significantly higher frequencies of DRB1*1602 and DPB1*0501 , which conferred susceptibility to anti-AQP4 antibody positive NMO/NMOSD, but not antibody negative NMO/NMOSD. DRB1*0901 was a common protective allele, irrespective of the presence or absence of anti-AQP4 antibody. Anti- H pylori and anti- C pneumoniae antibodies were more commonly detected in anti-AQP4 antibody positive NMO/NMOSD patients than healthy controls. Antibody negative NMO/NMOSD patients did not differ from healthy controls regarding the presence of these antibodies. The presence or absence of antibodies against varicella zoster virus and EBNA did not vary among the groups. The frequencies of antibodies against these four pathogens were not significantly different between MS patients and healthy controls. Conclusions Our results suggest that HLA-DRB1*1602 and DPB1*0501 alleles and H pylori and Chlamydia pneumonia infection are risk factors only for anti-AQP4 antibody positive NMO/NMOSD but not for anti-AQP4 antibody negative NMO/NMOSD.

Objective To establish the first evidence-based diagnostic criteria for atopic myelitis (AM) enabling it to be discriminated from myelitis-onset multiple sclerosis (MS), which is a difficult differential diagnosis. Methods Sixty-nine consecutive AM patients examined from 1996 to 2010 at Kyushu University hospital, who fulfilled the empirical definition of AM (2003), and 51 myelitis-onset MS patients in whom allergen-specific IgE was measured, were enrolled. The first available brain MRI findings were compared between the two. Then, we compared the clinical and laboratory features between the 16 AM cases who did not meet the Barkhof brain MRI criteria for MS after more than 5 years follow-up and 51 myelitis-onset MS cases. Based on the discriminative findings, we established diagnostic criteria for AM and calculated the sensitivity and specificity. Results AM patients had a significantly lower frequency of Barkhof brain lesions on baseline MRI than myelitis-onset MS patients. AM patients had a significantly higher frequency of present and/or past history of atopic disease and hyperIgEemia, and higher cerebrospinal fluid levels of interleukin 9 and CCL11/eotaxin, but a lower frequency of oligoclonal IgG bands than myelitis-onset MS patients. Our proposed diagnostic criteria for AM demonstrated 93.3% sensitivity and 93.3% specificity for AM against myelitis-onset MS, with 82.4% positive predictive value and 97.7% negative predictive value. Conclusion Our first evidence-based criteria for AM show high sensitivity and specificity, and would be useful clinically.

Background and objective: The objective of this study is to clarify clinical, immunological, and neuroimaging features in anti-aquaporin-4 (AQP4) antibody-positive and antibody-negative Sjögren’s syndrome (SS) patients with central nervous system (CNS) involvement. Methods: Medical records and MRI scans were retrospectively analyzed in 22 consecutive SS patients with CNS manifestations. Results: Seven (31.8%) patients were positive for anti-AQP4 antibodies. The frequency of visual impairment was higher in anti-AQP4 antibody-positive patients than in antibody-negative patients (71.4% vs. 0.0%, p = 0.0008). Brain MRI showed that discrete lesions were more commonly found in the cerebrum, brainstem, and optic nerve in anti-AQP4 antibody-positive patients than in antibody-negative patients ( p = 0.002, p = 0.006, and p = 0.004, respectively), while spinal cord MRI showed that posterior column lesions in the cervical spinal cord were more frequent in anti-AQP4 antibody-positive patients than in antibody-negative patients (71.4% vs. 14.3%, p = 0.01). SS-A antibody titers were higher in anti-AQP4 antibody-positive patients than in antibody-negative patients ( p = 0.012) and were also higher in patients with longitudinally extensive spinal cord lesions (LESCLs) than in those without LESCLs ( p = 0.019). Conclusions: In SS, the presence of anti-AQP4 antibodies is associated with involvement of the optic nerve, cerebrum and brainstem, and with cervical posterior column lesions in the spinal cord.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by systemic vascular diseases mainly shown as arterio-visnous fistula (AVF). Here, we presented a 29-year-old woman with HHT complicated with migraine with aura (MWA) and vertigo. At the age of twelve years, she developed migraine with visual aura. At that time, migraine attacks were seen three times a year. At the age of 29 years, she also developed speech disturbance as migraine aura. At the ages of 20 and 29 years, she repeatedly suffered from positional vertigo attacks for a month. Physical examination revealed dilation of the capillary vessels at tongue, soft palate, and nasal mucosa and AVFs were located in the upper cervical cord, parietal lobe, and bilateral lungs. These clinical findings were consistent with the diagnostic criteria of HHT. Embolization of pulmonary AVF decreased the frequency of migraine attacks during 2-year follow-up after the embolization. The frequency of migraine in patients with HHT is higher than that of general population as well as the prevalence of vertigo. Therefore, MWA and vertigo presented in the patient with HHT suggests that there is a common pathological mechanism of dysfunction of endothelial cells and R-L shunt, among HHT, MWA, and vertigo.

Rationale Only few cases of myasthenia gravis (MG) associated with small-cell lung cancer (SCLC) have been reported, and cases positive for acetylcholine receptor antibody (AChR-ab) are even rarer. The efficacy of standard MG treatment, such as cholinesterase inhibitor therapy, immunosuppressive therapy using steroids and immunosuppressive drugs, plasma exchange, and intravenous immune globulin (IVIg), for these cases is unclear. Patient concerns and diagnoses A 71-year-old man complained of bilateral eyelid ptosis. He also presented with dysphagia and masticatory muscle fatigue after chewing. The edrophonium test was positive, and the serum AChR-ab level was increased; therefore, the patient was diagnosed with MG. Computed tomography scan showed a nodule on the left upper lobe of the lung and mediastinal lymphadenopathy. Further examination revealed the lesion as SCLC. Finally, he was diagnosed with AChR-ab-positive MG associated with SCLC. Interventions and outcomes Oral pyridostigmine and tacrolimus were administered to treat MG; however, his symptoms worsened. Therefore, methylprednisolone and IVIg were administrated, which temporarily improved his symptoms. However, they remained uncontrolled. Meanwhile, chemotherapy with carboplatin and etoposide was administered to treat his SCLC. The lesions shrunk, and the MG symptoms and serum AChR-ab level also improved. Lessons AChR-ab-positive MG may develop as a comorbidity of SCLC. In such cases, management might require treatment for SCLC in addition to the standard MG treatment to stabilize the MG symptoms.

To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases.Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays.A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV.Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) while neuromyelitis optica (NMO) is an inflammatory disease of the CNS that selectively affects the optic nerves and spinal cord. An antibody for aquaporin-4 (AQP4), which is a water channel located in astrocyte foot process, is specifically positive for NMO and antibody and complement dependent astrocytic damage is thought to be a main cause of NMO. Baló's disease is characterized by alternating rings of demyelination and preserved myelin. We pathologically compared the astrocytic changes among autopsied cases with these CNS demyelinating diseases. NMO, MS and Baló's disease shared with reduced AQP4 immunoreactivity independent of antibodies and complements. The pathological finding was accompanied with a reduced immunoreactivity of connexin 43 and perivascular lymphocytic cuffing predominantly composed by T cells. The loss of astrocytic proteins such as AQP4 and connexin 43 preceded the loss of myelin proteins in some lesions. These features suggest astrocyte damages resulting in the loss of connexin 43 cause demyelination through the impairment of interaction between astrocytes and oligodendrocytes and the pathomechanism involves a T cell reaction.

Background Interleukin 2 receptor α subunit (IL2RA) is a genetic risk for multiple sclerosis (MS) in Caucasians. However, the association between MS and IL2RA in Japanese idiopathic demyelinating diseases of the central nervous system has not been examined. Objective To determine whether IL2RA gene polymorphisms confer risks of developing MS or neuromyelitis optica (NMO) in a Japanese population. Methods DNA samples were obtained from 115 MS patients, 75 NMO/NMO spectrum disorder (NMOSD) patients, and 238 healthy controls. The single nucleotide polymorphisms (SNPs) rs2104286, rs12722489, and rs7090512 were genotyped by real-time PCR using TaqMan SNP genotyping assays. Results No significant associations of the three IL2RA SNPs with the development of the diseases were observed. In MS patients only, the annualized relapse rates were significantly higher for the rs2104286-TT genotype than for the non-TT (CT+CC) genotype and for the rs12722489-CC genotype than for the non-CC genotype in females (p = 0.0138 for both), but not in males. Conclusions Although the possibility that IL2RA is a risk factor for MS development was not confirmed in this Japanese population, IL2RA gene polymorphisms were able to modify the disease activity in female MS patients, but had no influence on either susceptibility or disease phenotype in NMO/NMOSD patients.

Background:The G allele of NOTCH4 rs422951 is protective against demyelinating disease in Japanese.Objectives:The purpose of this study was to assess the relation of the G allele to neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) and multiple sclerosis (MS) and the interaction between the G allele and HLA-DRB1 alleles, and to clarify any association of the G allele with clinical features.Methods:DNA sequencing was used to genotype 106 NMO/NMOSD patients, 118 MS patients and 152 healthy controls (HCs) for rs422951.Results:G allele frequency in MS patients, but not that in NMO/NMOSD patients, was lower than that in HCs (8.9% vs 21.7%, pcorr=0.0380) while DRB1*0901 was negatively associated (OR=0.32, pcorr=0.0114). Logistic regression analyses revealed that, after adjusting for gender and either HLA-DRB1*0405 or DRB1*0901, rs422951 was associated with MS in the dominant model (OR=0.37, 95% confidence interval (CI)= 0.20–0.66, p=0.0012). Haplotype analyses identified two susceptible and three resistant haplotypes formed from rs422951 and either HLA-DRB1*0405 or DRB1*0901. There were no statistically significant differences in clinical features between G allele carriers and non-G allele carriers.Conclusion:This NOTCH4 missense mutation decreased the risk for developing MS in Japanese, but did not affect clinical features of those who had already developed the disease.

Background: To clarify the clinical relevance of anti-aquaporin-4 (anti-AQP4) antibody titers and immunoglobulin (IgG) subclass. Methods: Using a bridging enzyme-linked immunosorbent assay (ELISA), a flow cytometric assay (FCMA) and an immunofluorescence assay (IFA) for anti-AQP4 antibodies, sera from 142 patients with multiple sclerosis (MS) as defined by the McDonald criteria (2005), 29 with neuromyelitis optica (NMO) who fulfilled the 1999 criteria, 19 with recurrent and/or longitudinally extensive myelitis (RM/LM), 86 with other non-inflammatory neurological diseases (OND) and 28 healthy controls (HC) were studied. Results: Anti-AQP4 antibody positivity rates by IFA, FCMA, and ELISA were 41.4%, 51.7% and 48.3%, respectively, in NMO (1999) patients, and 0% in the OND and HC groups. Twenty-six MS patients (18.3%) were positive for the antibody; 17 met the 2006 NMO criteria, including positivity for anti-AQP4 antibody, and five had longitudinally extensive myelitis (LM). Among the cases with anti-AQP4 antibody detected by FCMA, IgG1, 2, 3, and 4 anti-AQP4 antibodies were found in 97.8%, 37.0%, 6.5% and 6.5% respectively. There was no association of either antibody positivity or level of anti-AQP4 antibody IgG subclasses with clinical parameters after adjustment of p values for multiple comparisons. Conclusions: FCMA and bridging ELISA are useful for detecting and quantifying anti-AQP4 antibodies.

Extensive aquaporin-4 (AQP4) loss without perivascular deposition of either activated complement or immunoglobulins is a characteristic of Baló's disease. Our aim in this study was to investigate the relationship between astrocytopathy and demyelination in Baló's disease, focusing on connexins (Cx), which form gap junctions among glial cells and myelin. Autopsied specimens from four cases that provided seven actively demyelinating concentric lesions infiltrated with numerous CD68(+) macrophages were immunohistochemically examined for the astrocyte markers glial fibrillary acidic protein (GFAP), AQP4, Cx43, Cx30 and megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1). Specimens were also stained for oligodendrocyte/myelin markers, namely Cx32, Cx47, myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP) and Nogo-A. Serum samples from six patients that had undergone magnetic resonance imaging, confirming a diagnosis of Baló's disease, were assayed for the presence of anti-Cx43, -Cx32 and -AQP4 antibodies. Despite the presence of numerous GFAP- and MLC1-positive astrocytes, there was a marked decrease in the levels of Cx43, Cx32 and Cx47. At the leading edges, Cx43 and AQP4 were mostly absent despite positive GFAP, MLC1, Cx32, Cx47, MOG, MAG, and OSP immunoreactivity. Of the six Baló's disease patients, none were positive for anti-Cxs or -AQP4 antibodies. Baló's disease is characterized by extensive loss of Cxs and AQP4, and a lack of auto-antibodies to Cxs and AQP4. Loss of Cx43 and AQP4 in the presence of other oligodendrocyte/myelin proteins at the leading edges suggests the possibility that auto-antibody-independent astrocytopathy may contribute to disease pathology via the disruption of astrocyte-oligodendrocyte/myelin interactions.

This report describes, for the first time, an occurrence of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a 19-year-old female with neuromyelitis optica (NMO) spectrum disorder, who had anti-aquaporin-4 (AQP4) antibody. A high signal intensity lesion on T2-weighted MRI was detected in the midbrain tegmentum adjacent to the aqueduct, and presumably involved the medial longitudinal fasciculus bilaterally at the caudal levels. Plasma exchange resolved both WEBINO syndrome and the midbrain lesion. Although WEBINO syndrome is occasionally reported in multiple sclerosis patients, diagnosis of NMO should not be excluded in patients with WEBINO syndrome, because AQP4 is expressed abundantly around the periaqueductal region.

Objectives To clarify the clinical features of combined central and peripheral demyelination (CCPD) via a nationwide survey. Methods The following characteristics were used to define CCPD: T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials; conduction delay, conduction block, temporal dispersion or F-wave abnormalities suggesting demyelinating neuropathy based on nerve conduction studies; exclusion of secondary demyelination. We conducted a nationwide survey in 2012, sending questionnaires to 1332 adult and paediatric neurology institutions in Japan. Results We collated 40 CCPD cases, including 29 women. Age at onset was 31.7±14.1 years (mean±SD). Sensory disturbance (94.9%), motor weakness (92.5%) and gait disturbance (79.5%) were common. Although cerebrospinal fluid protein levels were increased in 82.5%, oligoclonal IgG bands and elevated IgG indices were detected in 7.4% and 18.5% of cases, respectively. Fifteen of 21 patients (71.4%) had abnormal visual-evoked potentials. Antineurofascin 155 antibodies were positive in 5/11 (45.5%). Corticosteroids, intravenous immunoglobulins and plasmapheresis resulted in an 83.3%, 66.7% and 87.5% improvement, respectively, whereas interferon-β was effective in only 10% of cases. CCPD cases with simultaneous onset of central nervous system (CNS) and peripheral nervous system (PNS) involvement exhibited greater disability, but less recurrence and more frequent extensive cerebral and spinal cord MRI lesions compared to those with temporarily separated onset, whereas optic nerve involvement was more common in the latter. Conclusions CCPD shows different characteristics from classical demyelinating diseases, and distinctive features exist between cases with simultaneous and temporarily separated onset of CNS and PNS involvement.

BACKGROUND: Interferon-beta (IFNbeta) regulates the expression of a complex set of pro- as well as anti-inflammatory genes. In cohorts of MS patients unstratified for therapeutic response to IFNbeta, normal vaccine-specific immune responses have been observed. Data capturing antigen-specific immune responses in cohorts of subjects defined by response to IFNbeta-therapy are not available. OBJECTIVE: To assess antigen-specific immune responses in a cohort of MS patients responding clinically and radiologically to IFNbeta. METHODS: In 26 MS patients, clinical and MRI disease activity were assessed before and under treatment with IFNbeta. Humoral and cellular immune response to influenza vaccine was prospectively characterized in these individuals, and 33 healthy controls by influenza-specific Enzyme-Linked Immunosorbent Assay (ELISA) and Enzyme Linked Immuno Spot Technique (ELISPOT). RESULTS: Related to pre-treatment disease activity, IFNbeta reduced clinical and radiological MS disease-activity. Following influenza vaccination, frequencies of influenza-specific T cells and concentrations of anti-influenza A and B IgM and IgG increased comparably in MS-patients and in healthy controls. CONCLUSIONS: By showing in a cohort of MS-patients responding to IFNbeta vaccine-specific immune responses comparable to controls, this study indicates that antigen-specific immune responses can be preserved under successful IFNbeta-therapy.

Background Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO), relapsing remitting multiple sclerosis (RRMS), and primary progressive MS (PPMS), and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis. Methods/Principal Findings We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND) by multiplexed fluorescent bead-based immunoassay. Interleukin (IL)-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF) and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-γ, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients. Conclusions Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell and macrophage/microglia inflammation in the central nervous system. In RRMS, only a mild elevation of proinflammatory cytokines/chemokines was detectable at relapse.

Background Nationwide surveys conducted in Japan over the past thirty years have revealed a four-fold increase in the estimated number of multiple sclerosis (MS) patients, a decrease in the age at onset, and successive increases in patients with conventional MS, which shows an involvement of multiple sites in the central nervous system, including the cerebrum and cerebellum. We aimed to clarify whether genetic and infectious backgrounds correlate to distinct disease phenotypes of MS in Japanese patients. Methodology/Principal Findings We analyzed HLA-DRB1 and -DPB1 alleles, and IgG antibodies specific for Helicobacter pylori, Chlamydia pneumoniae, varicella zoster virus, and Epstein-Barr virus nuclear antigen (EBNA) in 145 MS patients and 367 healthy controls (HCs). Frequencies of DRB1*0405 and DPB1*0301 were significantly higher, and DRB1*0901 and DPB1*0401 significantly lower, in MS patients as compared with HCs. MS patients with DRB1*0405 had a significantly earlier age of onset and lower Progression Index than patients without this allele. The proportion and absolute number of patients with DRB1*0405 successively increased with advancing year of birth. In MS patients without DRB1*0405, the frequency of the DRB1*1501 allele was significantly higher, while the DRB1*0901 allele was significantly lower, compared with HCs. Furthermore, DRB1*0405-negative MS patients were significantly more likely to be positive for EBNA antibodies compared with HCs. Conclusions Our study suggests that MS patients harboring DRB1*0405, a genetic risk factor for MS in the Japanese population, have a younger age at onset and a relatively benign disease course, while DRB1*0405-negative MS patients have features similar to Western-type MS in terms of association with Epstein-Barr virus infection and DRB1*1501. The recent increase of MS in young Japanese people may be caused, in part, by an increase in DRB1*0405-positive MS patients.

Objective: To clarify the genetic and infectious profiles of MS and neuromyelitis optica (NMO). Background The prevalence of multiple sclerosis (MS) is rapidly increasing and the age of onset is becoming younger in Japanese patients. Design/Methods: We analysed HLA-DRB1 and -DPB1 alleles, and IgG antibodies against helicobacter pylori, chlamydia pneumonia, varicella-zoster virus, and Epstein-Barr virus nuclear antigen in 145 MS patients, 122 NMO patients, and 367 healthy controls (HC). Results: As compared with HC, frequencies of DRB1*0405 and DPB1*0301 were significantly higher in MS patients, while those of DRB1*0901 and DPB1*0401 were significantly lower. By contrast, NMO patients showed significantly higher frequencies of DRB1*1602 and DPB1*0501 and a significantly lower frequency of DRB1*0901 compared with HC. MS patients with DRB1*0405 had a significantly earlier age of disease onset, and lower Kurtzke9s Expanded Disability Status Scale score, Progression Index and frequency of brain MRI lesions that met the Barkhof criteria than patients without this allele. The proportions and absolute numbers of DRB1*0405 showed a successive increase with advancing year of birth. Among individuals without DRB1*0405, the frequency of DRB1*1501 was significantly higher and that of DRB1*0901 was significantly lower in MS patients than in HC. DRB1*0405-negative MS patients showed a significantly higher frequency of anti-Epstein-Barr virus nuclear antigen antibodies as compared with HC, while anti-helicobacter pylori and anti-chlamydia antibodies were significantly higher only in anti-aquaporin-4 antibody-positive NMO patients. Conclusions: These findings suggest that the susceptibility genes vary according to the disease phenotype and that DRB1*0901 is a common protective allele, irrespective of the phenotype. DRB1*0405-positive MS patients showed an earlier age of disease onset and a relatively benign course with low brain lesion loads, while DRB1*0405-negative MS patients had similar trends to Caucasian MS patients in terms of high frequency of Epstein-Barr virus infection and presence of DRB1*1501. Disclosure: Dr. Yoshimura has nothing to disclose. Dr. Yonekawa has nothing to disclose. Dr. Isobe has nothing to disclose. Dr. Masaki has nothing to disclose. Dr. Satou has nothing to disclose. Dr. Matsushita has nothing to disclose. Dr. Kira has received personal compensation for activities with Bayer Pharmaceuticals Corporation and Biogen Idec as a speaker and/or consultant.Dr. Kira has received research support from Ministry of Health, Labour and Welfare, Japan, the Japan Science and Technology Agency, and the Ministry of Education, Science, Sports and Culture, Japan. Dr. Kira has received personal compensation in an editorial capacity for Multiple Sclerosis, The Open Neurology Journal, and Journal of the Neurological Sciences.