Search

Introduction Progressive brain atrophy, development of T1-hypointense areas, and T2-fluid-attenuated inversion recovery (FLAIR)-hyperintense lesion formation in multiple sclerosis (MS) are popular volumetric data that are often utilized as clinical outcomes. However, the exact clinical interpretation of these volumetric data has not yet been fully established. Methods We enrolled 42 consecutive patients with MS who fulfilled the revised McDonald criteria of 2010. They were followed-up for more than 3 years from onset, and cross-sectional brain volumetry was performed. Patients with no brain lesions were excluded in advance from this study. For the brain volumetric data, we evaluated several parameters including age-adjusted gray-matter volume atrophy, age-adjusted white-matter volume atrophy, and T2-FLAIR lesion volume. The numbers of T1-hypointense and T2-FLAIR-hyperintense areas were also measured along the same timeline. The clinical data pertaining to disease duration, expanded disability status scale (EDSS), and MS severity score (MSSS) at the timing of volumetry were collected. Results Among the 42 patients with MS and brain lesions, the number of T1-hypointensity (rho = 0.51, p

Introduction Neuromyelitis optica spectrum disorder (NMOSD) is characterized by the presence of serum anti-aquaporin 4 (AQP4) antibody. However, the significance of changes in the serum titer as a marker of disease severity or relapse prediction is unknown. Methods We collected clinical data and serum antibody titers by cell-based assay from 45 NMOSD patients for whom more than one titer measurement taken in 6–12 month interval periods was available. The AQP4-IgG titer was measured by a live cell-based assay method, and the serum titer levels between the acute phase and preceding chronic phase were compared. In addition, we evaluated the correlation between the serum titer and relapse frequency while following the clinical course of the enrolled NMOSD patients. Results Serum AQP4-IgG titer was not elevated in the acute phase, compared to that of the preceding chronic phase, irrespective of the clinical phenotypes. Moreover, there was no correlation between the titer at onset and relapse frequency in 10 years post-onset or neurological disability at 5 and 10 years after onset. The titer was slightly elevated several months before relapses in about half of the cases, but the change was trivial and may not be applicable for clinical use. Conclusion Although evaluating the positivity of serum AQP4-IgG at the onset is necessary, the titer level does not reflect the ongoing disease activity or the following neurological prognosis. Repeated follow-up of titer levels may not be useful for the management of NMOSD patients.

We aimed in this study to elucidate the impact of serum AQP4-IgG titer before starting treatments to the clinical manifestation of neuromyelitis optica spectrum disorders (NMOSD). Serum titer at the onset, measured using live cell-based assay method, did not correlate to the subsequent relapse rate or neurological prognosis. Patients with optic neuritis as the first attack showed significantly higher serum titer than patients with acute myelitis or area postrema syndrome, although the titer did not correlate to the visual prognosis. The result implies that the pathological mechanism of optic neuritis and acute myelitis could be different in NMOSD.

It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses. We further demonstrate that the established tissue-destructive lesions trigger the formation of additional lesions by short and far reaching effects on blood vessels and their branches, and that AQP4-abs have profound effects on the AQP4 expression in peripheral tissues which counter-act possible titer loss by antibody absorption outside the CNS. Cumulatively, these data indicate that directly induced pathological changes caused by AQP4-abs inside and outside the CNS are efficient drivers of disease evolution in seropositive organisms. Electronic supplementary material The online version of this article (10.1007/s00401-018-1950-8) contains supplementary material, which is available to authorized users.

Immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) are detected in the serum of some patients with demyelinating diseases. These patients are known to show repeated clinical episodes of inflammatory demyelinating attacks in the central nervous system. Although the associated pathogenicity and mechanism of inflammatory demyelination remains inconclusive, it is known that patients with MOG-IgG antibodies have a different clinical spectrum from those with other demyelinating diseases, such as multiple sclerosis. Based on our database of 85 MOG-IgG positive (+) cases, the most frequently associated clinical episodes were isolated optic neuritis (67.5%), encephalitis (26.5%), and myelitis (19.3%). Optic neuritis in MOG-IgG (+) disease usually involves the long segment of optic nerves and sometimes happens bilaterally, but visual acuity usually recovers with proper treatment in the acute phase. Brain and brainstem lesions usually present vague and focal appearances with irregular margins, typically in subcortical or brainstem regions, but occasionally in the cortex or corpus callosum. Due to these characteristics, MOG-IgG (+) cases with brain or brainstem lesions are sometimes diagnosed with acute disseminated encephalomyelitis, meningitis, or symptomatic epilepsy. The myelitis in MOG-IgG (+) typically shows longitudinally extensive lesions as seen in neuromyelitis optica spectrum disorders. Acute treatment to reduce attack-related disability is recommended in MOG-IgG (+) disease, and long-term immunosuppression may be considered in patients with a high frequency of relapses and/or high risk of neurological disability.

Neuromyelitis optica was previously considered a subtype of multiple sclerosis until a specific serum antibody, NMO-IgG, was discovered in 2004. In 2012, anti-MOG antibody was found specifically in the serum of patients whose presentation was similar to those with neuromyelitis optica. These autoantibodies are pathogenic and are important disease markers when reaching a diagnosis.

Objectives We investigated the clinical characteristics and treatment response in myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease and looked for evidence of subclinical disease. Methods We prospectively evaluated the frequency and pattern of relapse, tested afferent visual function and monitored treatment response in 42 south Asian patients from a single centre. Results Eighteen patients (42.9%) had monophasic and 24 (57.1%) a relapsing course. Disease duration was longer ( PConclusion Our study highlighted the tendency for stereotypical attacks in MOG-IgG-associated disease, heterogeneity in clinical course among subtypes, subclinical visual impairment and the need for early and sustained immunosuppressive therapy.

Chloride imbalance between the serum and the cerebrospinal fluid (CSF) has been recently shown to exist in the acute phase of neuromyelitis optica (NMO). In this report, we studied the relation between the quotient of chloride (QCl) and the severity of optic neuritis (ON) in NMO patients. There was a positive correlation (R = 0.67; p

Multiple sclerosis (MS) is a demyelinating disease which characteristically shows repeated relapses and remissions irregularly in the central nervous system. At present, the pathological mechanism of MS is unknown and we do not have any theories or mathematical models to explain its disseminated patterns in time and space. In this paper, we present a new theoretical model from a viewpoint of complex system with chaos model to reproduce and explain the non-linear clinical and pathological manifestations in MS. First, we adopted a discrete logistic equation with non-linear dynamics to prepare a scalar quantity for the strength of pathogenic factor at a specific location of the central nervous system at a specific time to reflect the negative feedback in immunity. Then, we set distinct minimum thresholds in the above-mentioned scalar quantity for demyelination possibly causing clinical relapses and for cerebral atrophy. With this simple model, we could theoretically reproduce all the subtypes of relapsing-remitting MS, primary progressive MS, and secondary progressive MS. With the sensitivity to initial conditions and sensitivity to minute change in parameters of the chaos theory, we could also reproduce the spatial dissemination. Such chaotic behavior could be reproduced with other similar upward-convex functions with appropriate set of initial conditions and parameters. In conclusion, by applying chaos theory to the three-dimensional scalar field of the central nervous system, we can reproduce the non-linear outcome of the clinical course and explain the unsolved disseminations in time and space of the MS patients.

Over the last decade, knowledge regarding antibodies (Abs) associated with inflammatory disorders of the CNS has revolutionized diagnosis and clinical care. Examples of highly specific Ab assays that are now widely used to diagnose and make rapid treatment decisions in this area include those for Abs directed at the aquaporin-4 water channel and NMDA receptor. This has resulted in the acceleration of knowledge regarding treatment and has decidedly improved outcomes among these patient populations. Challenging the field is the vast majority of patients who have syndromes that lack a specific biomarker.

The serum diagnosis of anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) associated diseases can be confirmed by the presence of the MOG-Ab, yet its levels in cerebrospinal fluid (CSF) are of unknown significance. We report the case of a 59-year-old woman with a history of 12 recurrent central nervous system lesions in the optic nerve, cerebrum, and spinal cord. The woman's condition improved by each steroid therapy. She tested seronegative for MOG-Ab, yet CSF-positive, leading to a diagnosis of MOG-Ab-associated encephalomyelitis. Our experience suggests measuring MOG-Ab in CSF and serum to prevent the underdiagnosis of MOG-Ab-associated diseases.

Background Myelin-oligodendrocyte glycoprotein and aquaporin-4 have been extensively analyzed as targets for humoral immune reactions in central nervous system (CNS) demyelinating diseases, and the results indicated a possible role of these antibodies in the pathogenesis of various demyelinating diseases. Objective To investigate the antibody titer levels against myelin-oligodendrocyte glycoprotein and aquaporin-4 in pediatric patients with inflammatory CNS disorders, and to evaluate clinical significance to study anti-myelin-oligodendrocyte glycoprotein antibodies. Methods Sera at onset from patients with acute disseminated encephalomyelitis (ADEM) in 7, optic neuritis (ON) in 5, pediatric MS in 4 and neuromyelitis optica in one were tested for myelin-oligodendrocyte glycoprotein and aquaporin-4 antibodies using cell-based assays with live transfected cells. The duration of the observation periods ranged from 1 to 21 years (median, 10 years). We also described clinical course of patients with positive anti-myelin-oligodendrocyte glycoprotein antibodies. Results Among 17 patients diagnosed with inflammatory CNS demyelinating diseases nine (52%) were positive to anti-myelin-oligodendrocyte glycoprotein antibodies. Of note, all cases with positive anti-myelin-oligodendrocyte glycoprotein antibodies showed seronegativity against anti-aquaporin-4 antibodies and had a favorable prognosis. Conclusions This preliminary report showed that anti-myelin-oligodendrocyte glycoprotein antibodies testing at onset could be a useful tool predicting clinical outcome of children with ADEM, ON, and MS.

Depression and chronic fatigue are frequently present in multiple sclerosis (MS); however, the prevalence rates have not been investigated in neuromyelitis optica (NMO). Thirty-nine consecutive NMO and 75 MS patients were compared using self-rating questionnaires for depressive states, daily activity, and fatigue, as well as serum carnitine levels. A subgroup of patients with low carnitine levels were re-evaluated regarding depression and fatigue after levocarnitine treatment. Depression and fatigue were equally prevalent in MS and NMO and were strongly correlated with one another. Measurement of the serum carnitine levels and the administration of levocarnitine did not appear to be beneficial.

Multiple sclerosis (MS) is relatively common in the West, but rare in Japan. In the literature, there are few comparative data regarding disease severity throughout the world. The objective of this study was to compare disability in patients from a UK and a Japanese MS cohort. We retrospectively analysed the clinical features of patients with MS from a UK and Japanese MS centre. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Expanded Disability Status Scale score according to disease duration, was used as a marker of disease severity. One thousand one hundred forty-eight UK patients and 104 Japanese patient were identified representing the relative national prevalence. Demographics and disease duration did not differ between the groups. Median MSSS was significantly different between the two groups (Japan 3.34 vs. UK 5.87, p

Background There are still insufficient quantitative comparisons of phase-dependent blood–brain barrier permeability among inflammatory central nervous system disorders. Aim By using the Reibergram (2-D diagram of the quotient of albumin and quotient of immunoglobulin G), we visually compared the extent of blood–brain barrier permeability among inflammatory central nervous system disorders. Methods Both the quotient of albumin and that of immunoglobulin G in the acute and chronic phase were calculated in non-herpetic meningitis, septic meningitis, multiple sclerosis and neuromyelitis optica, and were plotted on the Reibergram. As controls, samples from non-inflammatory patients without pleocytosis were collected. The correlation coefficient between each cerebrospinal fluid biomarker and disease severity index in each disorder was also studied. Results In the controls, the distribution differed between males and females, suggesting a sex-dependent difference in blood–brain barrier-function, in addition to the age-related compromise. A compromised blood–brain barrier was confirmed in the acute phase of meningitis and neuromyelitis optica, but not in the acute phase of multiple sclerosis. However, blood–brain barrier permeability significantly correlated with the severity and disability in multiple sclerosis. In meningitis, a compromised blood–brain barrier correlated well with the length of hospitalization rather than cerebrospinal fluid cell count. Conclusion Visualization of the blood–brain barrier permeability with a Reibergram indicated distinct pathophysiology in each disorder. The quotient of albumin and quotient of immunoglobulin G would be useful for estimating the pathophysiology in each disorder, and the severity of ongoing inflammation or damage in the central nervous system.

To elucidate the etiology and clinical significance of periventricular lesions (PVLs) and oligoclonal bands (OB) in multiple sclerosis (MS).We enrolled a total of 97 MS patients (67 OB-positive and 30 OB-negative) who were negative both for anti-aquaporin-4 (AQP4) autoantibody and anti-myelin oligodendrocyte glycoprotein (MOG) antibody. In these patients, comprehensive data including clinical, laboratory, and MRI were collected to investigate the significance of OB and PVLs.Within the MS patients, OB-positivity and the number of PVLs were associated each other. Both of OB-positivity and PVLs did not affect clinical severity or relapse rate, though the patients with ≥3 PVLs showed faster cerebral atrophy than those with3 PVLs. The patients with OB or ≥3 PVLs showed lower values of quotient of albumin (QAlb), a biomarker of blood-brain barrier (BBB)-permeability and possibly reflects the ongoing disease activity, and lower protein levels in cerebrospinal fluid (CSF). The causal relationship between the decreased QAlb and OB or ≥3 PVLs was not determined.OB and PVLs were associated each other, but they did not affect the clinical course or increased the BBB-permeability within MS patients.

The anti-MOG antibody is an autoantibody that induces inflammatory demyelinating lesions in the central nervous system in diseases such as optic neuritis, encephalitis, and myelitis. The recent development of a cell-based assay that can detect specific autoantibodies, which recognize conformational epitopes of membrane proteins, revealed the clinical features of diseases associated with the anti-MOG antibody. Because the disease spectrum of anti-MOG antibody-associated diseases is different from that of conventional demyelinating diseases, a new disease classification would be established in the near future.

We collected serum-cerebrospinal fluid (CSF)-paired samples during the acute phase of clinical episodes in MS and NMO patients, together with paired samples from non-MS/NMO patients, to compare the quotients of proteins and electrolytes among them. In NMO, the quotient of chloride was significantly higher in the acute phase of optic neuritis and brain lesions, but it was significantly lower in the acute phase of myelitis. Such findings were not observed in MS or in non-MS/NMO cases. With the coexistence of serum anti-AQP4-Ab, chloride imbalance between serum and CSF could be associated with the clinical episodes in NMO.

Myelin oligodendrocyte glycoprotein immunoglobulin G (anti-MOG-IgG) has been recently found to be associated with some forms of idiopathic inflammatory demyelinating CNS disorders. In a preliminary study from India, recurrent optic neuritis and isolated longitudinally extensive transverse myelitis were identified as the common phenotypes.1 The clinical and radiologic features of this newly discovered subset of autoimmune disorders are only beginning to be understood. In this context, we would like to draw attention to an unusual and hitherto unreported association noticed in a patient with anti-MOG-IgG–associated myelitis.

Background Approximately 55% of patients with neuromyelitis optica spectrum disorder (NMOSD) show cognitive impairment as evaluated using the Rao Brief Repeatable Neuropsychological Battery (BRBN), but this frequency appears to be higher than the frequency of specific brain lesions in NMOSD. Objective We studied whether cognitive impairment could be observed in NMOSD patients with no or minor non-specific brain lesions. Methods We evaluated cognitive function in 12 NMOSD and 14 MS patients using the Wechsler Adult Intelligence Scale-III (WAIS-III), the Wechsler Memory Scale-Revised (WMS-R), and the BRBN. We judged as cognitively impaired patients whose scores were below the average by 2 standard deviations or greater in 2 or more cognitive domains. Results Cognitive impairment was observed in 5 MS patients (35.7%) and in the only NMOSD patient (8.3%) with symptomatic brain lesions, but not in the other NMOSD patients who had no or minor non-specific brain lesions. Meanwhile, 5 NMOSD (41.7%) and 4 MS (28.6%) patients who had normal cognition according to the WAIS-III and WMS-R were assessed as cognitively impaired by the BRBN (which is not standardized for age). Conclusions Cognitive function in NMOSD patients with no or mild non-specific brain lesions was preserved according to the WAIS-III and WMS-R., Highlights • NMOSD patients without symptomatic brain lesions were cognitively intact. • BRBN may misevaluate cognitive functions in NMOSD patients over 55 years old. • WAIS and WMS are suitable for the cognitive assessments in older NMOSD patients.

Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein exclusively expressed on the surface of the myelin sheath in the central nervous system (CNS). Although the precise function of MOG is yet unknown, it is possibly related to the maintenance of the myelin structure. MOG has been of great interest because of its association with demyelinating diseases, particularly in multiple sclerosis (MS). It has also been used as an antigen to induce experimental autoimmune encephalomyelitis (EAE) in rodents as an animal model of MS. EAE induced by MOG peptides may develop inflammatory demyelinating CNS lesions dominantly in the optic nerves and the spinal cord. Although …

Background Anti-Myelin oligodendrocyte glycoprotein (MOG) antibodies are detected in various demyelinating diseases, such as pediatric acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, and aquaporin-4 antibody-seronegative neuromyelitis optica spectrum disorder. We present a patient who developed anti-MOG antibody-positive ADEM following infectious mononucleosis (IM) due to Epstein–Barr virus (EBV) infection. Case presentation A 36-year-old healthy man developed paresthesia of bilateral lower extremities and urinary retention 8 days after the onset of IM due to primary EBV infection. The MRI revealed the lesions in the cervical spinal cord, the conus medullaris, and the internal capsule. An examination of the cerebrospinal fluid revealed pleocytosis. Cell-based immunoassays revealed positivity for anti-MOG antibody with a titer of 1:1024 and negativity for anti-aquaporin-4 antibody. His symptoms quickly improved after steroid pulse therapy followed by oral betamethasone. Anti-MOG antibody titer at the 6-month follow-up was negative. Conclusions This case suggests that primary EBV infection would trigger anti-MOG antibody-positive ADEM. Adult ADEM patients can be positive for anti-MOG antibody, the titers of which correlate well with the neurological symptoms.

Background Myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis (ON) and myelitis are recognized as important differential diagnosis of aquaporin-4 (AQP4) antibody-positive neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD). Similar to NMO/NMOSD associated with AQP4 antibodies, preceding infections have been reported in patients with MOG antibody-positive ON. This is the first report of bilateral ON following a herpes simplex virus (HSV) infection associated with a positive MOG antibody. Case presentation A 41-year-old man who initially presented with genital herpes developed allodynia in the Th2-Th5 and Th8-L2 areas, urinary retention, and painful visual loss in the left eye. Ophthalmological evaluation and brain magnetic resonance imaging (MRI) revealed bilateral ON. A spinal MRI showed leptomeningeal enhancement from the thoracic to lumbar vertebrae and abnormal enhancement of the L3 to S3 dorsal root ganglia without a change in intramedullary signals. Following treatment with acyclovir and steroid pulse, he fully recovered. Serum anti-AQP4 antibodies were negative, but anti-MOG antibodies were positive. Finally, he was diagnosed with MOG antibody-positive bilateral ON and meningoganglionitis following an HSV infection. Conclusion Our case supports a relationship between anti-MOG antibodies and ON triggered by an HSV infection. Clinicians should thus consider testing for MOG antibodies in patients with post-infectious neurological symptoms due to an HSV infection.

Monoclonal antibody therapy is a new treatment strategy for many types of diseases including cancers and autoimmune diseases, realizing a high efficacy and tolerability. In multiple sclerosis (MS) and neuromyelitis optica (NMO) spectrum disorders, several monoclonal antibodies have been suggested to decrease the incidence of clinical relapse and the disease activity. In MS, anti-α4 integrin (natalizumab), anti-CD52 (alemtuzumab), anti-CD25 (daclizumab) and anti-CD20 (ocrelizumab) have been shown to effectively reduce the relapses in randomized controlled trials and have been approved by the Food and Drug Administration. Specifically, ocrelizumab is the first drug that has shown significant suppression of brain volume loss and suppression of chronic disability progression. In NMO, though there have yet to be any approved monoclonal antibodies, rituximab, anti-complement C5 (eculizumab), anti-IL-6 receptor (tocilizumab), anti-CD19 (inebilizumab) and non-pathogenic anti-aquaporin 4 (aquaporumab) have been suggested to be effective, and some of these are now under clinical trials. Aquaporumab is a non-pathogenic recombinant human monoclonal antibody that competitively inhibits the binding of the pathogenic auto-antibody against aquaporin 4 in NMO patients; thus, it is expected to be highly disease specific with less non-specific adverse events. Some of these monoclonal antibodies in MS and NMO are known to cause several notable adverse events. Natalizumab and rituximab increase the risk of progressive multifocal leukoencephalopathy. Eculizumab increases the risk of meningococcal infection. Tocilizumab is known to cause intestinal diverticulitis that can cause intestinal perforation. In this review, we summarize the characteristics of, evidence for and notable adverse events of each monoclonal antibody in MS and NMO.

Purpose An autoantibody against aquaporin-4 (AQP4 Ab) is highly specific for neuromyelitis optica spectrum disorder and plays a pathogenic role in this disease. The purpose of this study was to investigate the impact of AQP4 Ab on inner retinal structure, function, and the structure−function relationships in eyes with optic neuritis. Methods Thirty five eyes from 25 cases who had received visual function tests and RTVue optical coherence tomography (OCT) measurement at least six months after the latest episode of optic neuritis were enrolled. Patients with multiple sclerosis were excluded. AQP4 Ab was measured using a cell-based assay. Visual acuity, mean deviation (MD) of the Humphrey visual field SITA standard 30–2 tests, retinal nerve fiber layer (RNFL), ganglion cell complex (GCC) thicknesses, and other clinical variables were compared between the AQP4 Ab-positive and -negative groups. Parameters associated with visual functions were evaluated by generalized estimating equation (GEE) models. Results The AQP4 Ab-positive group (20 eyes from 12 cases) had a higher proportion of bilateral involvement and longer duration of follow-up than the AQP4 Ab-negative group (15 eyes from 13 cases). Linear mixed effect models revealed worse MD and visual acuity in AQP4 Ab-positive eyes than those in AQP4 Ab-negative eyes after adjusting for within-patient inter-eye dependence, whereas there were no differences in RNFL and GCC thickness between the two groups. In seropositive eyes, GEE regression analyses revealed that depending on age and the number of recurrences of ON episodes, OCT parameters correlated strongly with MD and more weakly with visual acuity. Conclusions Reductions in RNFL and GCC thickness were proportional to the visual field defect in eyes with AQP4 Ab but not in eyes without AQP4 Ab. The presence of AQP4 Ab probably plays a critical role in retinal ganglion cell loss in optic neuritis.

We report a patient with neuromyelitis optica (NMO) presenting anti-myelin-oligodendrocyte glycoprotein (MOG)-seropositive, in whom biomarkers of demyelination and astrocyte damage were measured during an acute attack. A 31-year-old man developed right optic neuritis followed by longitudinally extensive transverse myelitis, fulfilling the criteria for definite NMO. He was anti-MOG-seropositive and anti-aquaporin-4 seronegative. The myelin basic protein level was markedly elevated whereas glial fibrillary acidic protein was not detectable in cerebrospinal fluid during an acute attack. His symptoms quickly improved after high-dose methylprednisolone therapy. This case suggests that NMO patients with anti-MOG may have severe demyelination in the absence of astrocyte injury.

More than 80% of patients with the demyelinating disorder neuromyelitis optica (NMO) experience pain from this condition, which severely affects their quality of life. NMO-associated pain is largely refractory to contemporary pain therapy, suggesting that the mechanisms underlying pain in NMO differ from those underlying other causes of pain. In this article, Bradl and colleagues explore the mechanisms underlying pain in patients with NMO, and attempt to identify molecular and cellular targets for therapy. Terrible, agonizing, wretched, sickening and unbearable—these are words frequently used by patients with neuromyelitis optica (NMO) to describe a very common symptom of their disease: pain. More than 80% of patients with NMO experience pain from this condition, which severely affects their quality of life. At present, there is no known therapy that produces satisfactory relief from NMO-associated pain. In fact, contemporary pain therapy is largely ineffective in these patients, suggesting that the mechanisms underlying pain in NMO differ substantially from those of other treatable causes of pain. Until now, the near-complete neglect of research into pain mechanisms in NMO has precluded rational pain therapy. In this Perspectives article, expertise from the fields of neuroimmunology, neurology and pain research is combined to explore, for the first time, the mechanisms underlying pain in patients with NMO, and to identify molecular and cellular targets for therapy.

Objective The aim of the present study was to investigate the association of magnetic resonance imaging (MRI) findings and social activity with cognitive function in Japanese patients with multiple sclerosis (MS). Methods The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was carried out in 184 Japanese patients with MS, and 163 controls matched for age, sex and education. MRI findings of cerebral, brainstem, and cerebellar lesions and social activities of MS patients were further examined. Results MS patients with higher numbers of cerebral lesions on MRI had lower scores in most BRB-N tests. BRB-N scores in the majority of tests were significantly lower in patients with brainstem and cerebellar lesions. Data from an analysis of variance model in which only the main effects of cerebral, brainstem and cerebellar lesions were hypothesized showed an association of cerebral lesions with decreased scores in all BRB-N tests, except symbol digit modalities test (SDMT) and paced auditory serial addition test (PASAT). In contrast, cerebellar lesions were associated with decreased SDMT and PASAT scores. Patients categorized as “unemployed because of MS” had lower BRB-N scores than other social activity groups. Lower SDMT scores had an effect on the “unemployed because of MS” group, whereas the Expanded Disability Status Scale had a significantly greater negative impact on patients in this social category. Conclusions Higher numbers of brain lesions on MRI could have an impact on cognitive function in patients with MS, and impairment of information processing appears significantly associated with cerebellar lesions. Cognitive impairment affects the employment status of patients with MS.

To elucidate immunopathogenetic roles of aquaporin-4 antibodies in the cerebrospinal fluid (CSF) of neuromyelitis optica spectrum disorders (NMOSD), we analyzed aquaporin-4 antibody titers, cellular and inflammatory markers in the CSF collected from 11 aquaporin-4 antibody seropositive patients. The CSF aquaporin-4 antibody levels during attacks (but not in sera) closely correlated with pleocytosis, inflammatory cytokines including interleukin-6 that can regulate antibody-producing plasmablasts, and glial fibrillary acidic protein levels in the CSF. The amount of aquaporin-4 antibodies present in the central nervous system may have therapeutic implications, as it is associated with astrocyte injury and inflammatory responses during NMOSD attacks. Ann Neurol 2014;76:305–309

Objective The aim of this study is to investigate the unique features of seronegative neuromyelitis optica spectrum disorders (NMOSD) in Thailand. Background It remains unknown whether seronegative NMOSD patients possess clinical and paraclinical features that are distinct from those with seropositivity. Methods In a Thai cohort of idiopathic inflammatory CNS disorders (n = 122), 52 patients fulfilled the Wingerchuk 2007 criteria for NMOSD. We determined anti-AQP4 antibody statuses using three different assays (an in-house cell-based assay [CBA], a commercially available CBA and a tissue-based indirect immunofluorescence [IIF] assay). Results Among the NMOSD patients, the percentage of seropositive cases was 54.5% based on the in-house and commercial CBAs and 30.8% based on the IIF assay. Using the in-house CBA, seronegative NMOSD patients exhibited distinct features compared with seropositive patients, such as a lack of female preponderance (F/M = 1.2 vs. 6.0), frequent simultaneous bilateral optic involvement (33.3% vs. 0.04%), a lower annual relapse rate (0.4 ± 0.3 vs. 0.7 ± 0.6), fewer spinal cord lesions (1.0 ± 4.3 vs. 1.4 ± 0.6), and lower CSF cell counts (20 ± 72 vs. 80 ± 285). Use of the commercial CBA yielded essentially similar results, but some of these differences were not significant using IIF. Conclusions Sensitive anti-AQP4 antibody assays reveal features of seronegative NMOSD patients that differ from those of seropositive patients from Thailand.

Fingolimod has demonstrated efficacy in patients with multiple sclerosis (MS), and patients become gradually lymphopenic after a few days of treatment, with selective reductions in CD4+ subsets. We observed an increase in the frequencies of circulating regulatory T cells after fingolimod administration. However, we also found that half of patients had increased proportion of circulating Th17 cells in CD4+ T cells after treatment (including a patient with MS relapses), whereas the others showed lower frequencies of Th17 cells, indicating some variability among patients. Further studies may confirm if slower reduction of circulating Th17 cells following fingolimod initiation predisposes to relapses.

Neuromyelitis optica (NMO) is an autoimmune inflammatory, neurodestructive disease primarily targeting the optic nerve and spinal cord. An autoantibody against water channel protein aquaporin-4 (AQP4), which is expressed at endofeet of astrocytes has been implicated in the pathogenesis of NMO. We evaluated the impact of sera of seropositive patients with NMO spectrum disorders (NMOSDs) on the rodent optic nerve and retina. Serum was obtained either from patients with seropositive NMOSD (AQP4+), seronegative patient with idiopathic optic neuritis (AQP4-), and healthy volunteers (control). Anti-AQP4 antibody in a serum was measured by a previously established cell-based assay. The patients' sera were applied on the optic nerve after de-sheathed. Immunohistochemistry showed that at 7 days after the treatment, the area of the optic nerve exposed to the AQP4+ sera lost expression of both AQP4 and glial fibrillary acidic protein. Also, Human-IgG immunoreactivity and marked invasion of inflammation cells were observed in the optic nerve treated with AQP4+ serum. Immnoreactivity of neurofilament was reduced at 14 days after the treatment, not 7 days. Real-time polymerase chain reaction revealed the reduced gene expression of neurofilament in retina from the eye that was exposed to the AQP4+ sera at 14 days. Retrograde fluorogold-labeling on the retinal flatmount disclosed the significantly reduced number of retinal ganglion cells when the AQP4+ sera were applied. The present model has demonstrated that the sera from patients with seropositive NMOSDs led to the regional astrocytic degeneration and inflammatory cell invasion in the optic nerve, resulting in the ultimate loss of RGCs and their axons at areas beyond the injury site.

Fingolimod functions as a modulator of sphingosine-1-phosphate (S1P) receptors expressed on the surface of T and B lymphocytes, leading to their internalization. Loss of S1P receptors results in sequestration of central memory T cells enriched by Th17 cells in lymph nodes. After successful treatment of an animal model of multiple sclerosis (MS), clinical trials of oral fingolimod in patients with relapsing-remitting MS showed a 60% reduction in the annualized rate of relapse. The United States Food and Drug Administration approved fingolimod as a first-line drug for MS treatment in 2010, and data have been accumulated thereafter. However, MS experts recommend that the drug should remain as a second-line option, because the long-term risks for infection and malignancy have not been fully elucidated. Also, because of different genetic backgrounds, Asian MS patients might require special attention regarding other infectious agents and secondary cancer as compared with those reported in Caucasian patients. Furthermore, some Japanese patients who developed severe symptoms were later shown to be positive for the anti-aquaporin-4 antibody. In addition, reports of some Western MS patients have noted worsening after initiation, as well as discontinuation of fingolimod treatment. Finally, the optic spinal type of MS and neuromyelitis optica spectrum disorders are more prevalent in Asian than Western countries. Thus, establishment of criteria for determining which Asian MS patients would benefit from fingolimod treatment is mandatory.

OBJECTIVE: To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin-4 (AQP4) antibodies, or seronegativity for both antibodies. METHODS: Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells. RESULTS: Among the 215 patients with NMOSD, 7.4% (16/215) were positive for MOG antibodies and 64.7% (139/215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG antibodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demonstrated better functional recovery after an attack. CONCLUSIONS: Patients with NMOSD with MOG antibodies have distinct clinical features, fewer attacks, and better recovery than patients with AQP4 antibodies or patients seronegative for both antibodies.

Demyelinating polyneuropathy associated with amyotrophic lateral sclerosis (ALS) is quite rare. We herein present the case of a woman patient with a 12-year history of chronic inflammatory demyelinating polyneuropathy (CIDP)-like polyneuropathy who later developed bulbar palsy and respiratory failure. The autopsy findings revealed neuronal loss in the anterior horn and primary motor cortex with degeneration of the corticospinal tracts. Diffuse phosphorylated TAR DNA-binding protein of 43 kDa inclusions were observed in the anterior horn and cerebral cortices, including the temporal lobe. The final diagnosis was ALS with CIDP-like polyneuropathy. Compared with other reports of ALS with CIDP-like polyneuropathy, the present patient was younger and followed a relatively long clinical course, with no upper motor neuron signs.

Objective:To describe the features of adult patients with benign, unilateral cerebral cortical encephalitis positive for the myelin oligodendrocyte glycoprotein (MOG) antibody.Methods:In this retrospective, cross-sectional study, after we encountered an index case of MOG antibody–positive unilateral cortical encephalitis with epileptic seizure, we tested for MOG antibody using our in-house, cell-based assay in a cohort of 24 consecutive adult patients with steroid-responsive encephalitis of unknown etiology seen at Tohoku University Hospital (2008–2014). We then analyzed the findings in MOG antibody–positive cases.Results:Three more patients, as well as the index case, were MOG antibody–positive, and all were adult men (median age 37 years, range 23–39 years). The main symptom was generalized epileptic seizure with or without abnormal behavior or consciousness disturbance. Two patients also developed unilateral benign optic neuritis (before or after seizure). In all patients, brain MRI demonstrated unilateral cerebral cortical fluid-attenuated inversion recovery hyperintense lesions, which were swollen and corresponded to hyperperfusion on SPECT. CSF studies showed moderate mononuclear pleocytosis with some polymorphonuclear cells and mildly elevated total protein levels, but myelin basic protein was not elevated. A screening of encephalitis-associated autoantibodies, including aquaporin-4, glutamate receptor, and voltage-gated potassium channel antibodies, was negative. All patients received antiepilepsy drugs and fully recovered after high-dose methylprednisolone, and the unilateral cortical MRI lesions subsequently disappeared. No patient experienced relapse.Conclusions:These MOG antibody–positive cases represent unique benign unilateral cortical encephalitis with epileptic seizure. The pathology may be autoimmune, although the findings differ from MOG antibody–associated demyelination and Rasmussen and other known immune-mediated encephalitides.

Acute optic neuritis (ON) typically presents with ocular pain and low visual acuity (VA), and there is a risk of permanent vision loss if ON is not managed properly.1 ON may be the first symptom of inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD). Recently, we reported some distinct characteristics between seropositive anti-aquaporin-4 (anti-AQP4) patients and seropositive antimyelin oligodendrocyte glycoprotein (anti-MOG) patients with NMOSD, using our in-house cell-based assays (CBA). However, patients with a single attack of unilateral ON were not included in our previous study. None of the previous studies of anti-MOG+ patients performed orbital MRI or optical coherence tomography (OCT) segmentation analyses, which may have diagnostic and prognostic implications. To address these issues, we evaluated the diagnostic utility of the anti-MOG assay and compared the MRI and OCT findings of anti-MOG+ and anti-AQP4+ patients with isolated ON. ### Patients We investigated 28 affected ON eyes from 21 consecutive anti-AQP4 seronegative patients aged 12 years or older who presented with isolated ON (4 cases with simultaneous bilateral ON, 3 cases with relapsing unilateral ON, and 14 cases with a single attack of unilateral ON) and were admitted to Tohoku University Hospital between 2011 and 2013. We excluded patients with ON already associated with brain and/or spinal cord MRI lesions. We compared anti-MOG+ ON eyes with nine affected ON eyes from eight anti-AQP4+ patients with isolated ON (one simultaneous bilateral ON). Severe VA loss was set at 0.1 in the decimal Japanese chart (equivalent to 20/200).2 ### Orbital MRI All patients performed orbital imaging using a 1.5 T MRI. We measured the short τ inversion recovery (STIR) and/or T2-weighted image hyperintense lesions …

Two patients with longitudinally extensive myelopathy were initially biopsied for suspected spinal cord tumors. Both patients were later diagnosed with neuromyelitis optica spectrum disorders (NMOSD) supported by their AQP4-seropositivity. Pathological review of both biopsies revealed demyelinated lesions with thickened vessel walls and tissue rarefaction. Immunohistochemical staining demonstrated findings compatible with acute NMOSD lesions in one case while the other case exhibited findings consistent with chronic NMOSD lesions. A pre-biopsy differential diagnosis of longitudinally extensive spinal cord tumors should include NMOSD. Specific biopsy features, such as cystic changes with vascular wall thickening and astrocyte injury, should raise suspicion for NMOSD.

An association between the acute or chronic form of inflammatory demyelinating polyneuropathy (IDP) and nephrotic syndrome has occasionally been reported. However, the clinical pictures in IDP of these cases have attracted little attention to date. In the present report, we describe a 50-year-old man with IDP who developed quadriplegia with respiratory impairment followed by a remitting and relapsing course for several months with complete recovery, in which nephrotic syndrome appeared at the nadir and subsided in parallel with the neurological improvement. We also searched for the English-language literature from 1946 to 2012 April and found 32 cases of Guillain–Barre syndrome or chronic inflammatory demyelinating polyneuropathy with nephrotic syndrome. We analyzed the 33 cases including the present case, and found such features as: (i) male preponderance (84.8%); (ii) motor dominant impairments with favorable final outcomes; and (iii) proteinuria occurring simultaneously with neurological symptoms and ameliorating along with neurological improvement in the majority of the cases. Available data of nerve conduction studies consistently showed demyelinating neuropathy. These findings suggest that IDP with nephrotic syndrome might be a distinctive clinical entity possibly caused by immune reactions to antigen(s) shared by peripheral nerves and the glomerulus. As nephrotic syndrome is asymptomatic or transient in some cases, IDP with nephrotic syndrome might be more prevalent than we think.

Guillain–Barre syndrome (GBS) is frequently accompanied by dysautonomia, which potentially leads to a fatal outcome. Pregabalin binds to the α2δ subunit of voltage-gated calcium channels and has been used as a drug for neuropathic pain. We present a 47-year-old woman who had GBS with severe dysautonomia and painful dysesthesia, in whom pregabalin promptly attenuated both symptoms. After symptoms of respiratory infection lasting a week, she showed mydriatic pupils, ophthalmoparesis, weakness in four limbs with areflexia, cerebellar ataxia and limb dysesthesia. Even after intravenous immunoglobulin therapy was started, her neurological symptoms deteriorated; furthermore, she developed severe dysautonomia including intractable hypertension, bradycardia–tachycardia syndrome, paroxysmal facial flushing and paroxysmal nausea. However, promptly after the first dose of pregabalin, both dysautonomia and dysesthesia were attenuated, and her circulatory condition became stable. Thereafter, her neurological symptoms gradually improved. The present case report suggests that pregabalin can be effective in treating dysautonomia, as well as painful dysesthesia in GBS.

Complement is thought to play a pivotal role in neuromyelitis optica (NMO) pathogenesis. Anaphylatoxins (C3a, C4a, and C5a), produced in complement activation, have proinflammatory potential, and thereby may play an important role. We measured concentrations of anaphylatoxins in CSF and sera, obtained from patients with NMO (n=15), multiple sclerosis (MS) (n=15), and other neurological disease (OND) (n=12), and evaluated their clinical implications. The CSF-C5a levels were elevated significantly in NMO patients, especially in patients with multiple enhanced lesions on MRI. The CSF-C5a levels correlated with the severity of exacerbation. Our results may provide a rationale for anti-complement therapies of NMO.