Opticospinal Multiple Sclerosis Research Articles

MR imaging findings of the corpus callosum region in the differentiation between multiple sclerosis and neuromyelitis optica

PurposeTo evaluate MR imaging findings in corpus callosum region for the discrimination between opticospinal multiple sclerosis (OSMS) and neuromyelitis optica (NMO). Materials and methodsForty-two definite OSMS with seronegative NMO-IgG and 23 NMO with seropositive NMO-IgG, and 27 age-matched normal controls (NC) were recruited. Sagittal T2-FLAIR images with 2-mm slice thickness were obtained. Subcallosal dot-dash (SCDD) sign and subcallosal striations (SCS) sign were reviewed. ResultsSCDD was more commonly detected in OSMS (28 of 42 patients) than in NMO (5 of 23 patients) (P<0.05). SCS showed no difference between OSMS (31 of 42 patients) and NMO (12 of 23 patients) (P>0.05). For comparing ROC analysis among SCDD, SCS, and SCDD+SCS for predicted probability through binary logistic regression analysis, SCDD+SCS had the largest area under ROC curve (0.777) than SCDD (0.725) and SCS (0.608). ConclusionSCDD may be helpful in distinguishing OSMS from NMO. The regression equation may also be a simple and effective method of choice for the differentiation between OSMS and NMO.

Aquaporin 4 Antibodies in the Cerebrospinal Fluid Are Helpful in Diagnosing Chinese Patients with Neuromyelitis Optica

Objective: It was the aim of this study to compare the diagnostic efficiency of anti-aquaporin 4 (AQP4) antibody detection between serum and cerebrospinal fluid (CSF) samples in Chinese patients with central nervous system demyelinating diseases. Methods: Anti-AQP4 antibodies were detected by a cell-based assay. We calculated the sensitivity, specificity and coherence in 118 patients with neuromyelitis optica (NMO, n = 39), multiple sclerosis (n = 34), longitudinally extensive transverse myelitis (LETM, n = 22), optic neuritis (ON, n = 6), opticospinal multiple sclerosis (n = 8) and acute partial transverse myelitis (n = 9). Results: Forty-four serum samples (33.8%) were positive for anti-AQP4 antibodies. Anti-AQP4 antibody seropositivity was 76.9, 59.1 and 16.7% in patients with NMO, LETM and ON, respectively. Sixty-five CSF samples (50%) were positive for anti-AQP4 antibodies. Anti-AQP4 antibody positivity was 87.1, 81.8, 83.3, 62.5 and 11.8% in patients with NMO, LETM, ON, opticospinal multiple sclerosis and multiple sclerosis, respectively. The ĸ value of the coherence test was 0.585 (p < 0.0001) between the two types of samples. The antibody positivity rate was significantly different between the two body fluids (p = 0.0008, McNemar test). The sensitivity and specificity were 74.3 and 100% in serum, 85.7 and 88.2% in CSF, and 94.3 and 88.2% for serum and CSF combined, respectively. Conclusion: The sensitivity of anti-AQP4 antibodies in the CSF was higher than that in the serum, and their combined use is helpful in diagnosing Chinese patients with NMO.

Seroprevalence of NMO-IgG among patients with neuromyelitis optica and opticospinal multiple sclerosis

Objectives In this study we sought to compare the seropositivity of NMO-IgG in patients presenting with demyelinative involvement of optic nerve and spinal cord with and without longitudinally extensive spinal cord lesion (LESCL). Methods Patients who were referred to Isfahan Multiple Sclerosis Clinic and Isfahan Devic's Disease Clinic at Al-Zahra Hospital in Iran were screened for this study. Patients with signs and symptoms indicating the demyelinating involvement of optic nerve(s) and spinal cord were included. Patients were evaluated by a neurologist and spinal cord and brain magnetic resonance imaging (MRI) were obtained. Patients with normal first brain MRI and with spinal cord demyelinative lesions visible on spinal MRI were included. Patients were then put into two groups: (i) patients with LESCL [neuromyelitis optica (NMO)] and (ii) patients with spinal plaques which do not extend over three vertebrae [opticospinal multiple sclerosis (OSMS)]. NMO-IgG was measured in the serum of the included patients. Results Totally we recruited 33 patients with LESCL and 32 patients without LESCL. The mean age of patients without LESCL was 34.61 ± 10.98 and it was 33.48 ± 11.93 for the NMO patients. In both groups there were 24 females and the rest were males. Among the NMO patients 16 (48.5%) were positive for NMO-IgG, while in the OSMS group there were none. Conclusion The results of this study are in line with previous observations, and imply that the presence of LESCL is associated with the presence of NMO-IgG and thus an indicator of NMO.

Autoimmunity in neuromyelitis optica and opticospinal multiple sclerosis: Astrocytopathy as a common denominator in demyelinating disorders

Neuromyelitis optica (NMO) selectively affects the optic nerves and spinal cord. In Asians, multiple sclerosis (MS) is rare; however, when it appears, the selective and severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal multiple sclerosis (OSMS), has similar features to the relapsing form of NMO in Westerners. The discovery that NMO-IgG, an NMO-specific IgG, targets aquaporin-4 (AQP4), suggested that NMO is a distinct disease entity with a fundamentally different etiology from MS. Because NMO-IgG is present in 30–60% of OSMS patients, OSMS in Asians is suggested to be the same entity as NMO. Pathologically, perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions are reported hallmarks of NMO. However, we found that some autopsied NMO cases showed selective AQP4 loss while others showed preservation of AQP4, despite extensive tissue destruction. Vasculocentric deposition of complement and immunoglobulin was detected only in NMO patients, with less than 30% of actively demyelinating lesions showing AQP4 loss. Such heterogeneity of AQP4 expression and immunoglobulin deposition suggests a heterogeneous disease process in NMO. We recently reported that AQP4 was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of actively demyelinating lesions in Baló's disease, a variant of MS. We also found that in some acute MS lesions, AQP4 was lost extensively far beyond the areas of myelin loss. Active demyelinating lesions involved perivascular lymphocyte cuffings, consisting mainly of T cells in Baló's disease and MS, while the same was true for approximately half of the active lesions in NMO. This review proposes that anti-AQP4 antibody-dependent AQP4 loss occurs in some NMO patients while antibody-independent AQP4 astrocytopathy can occur in heterogeneous demyelinating conditions, including Baló's disease, NMO and MS. The latter may be mediated by T cells and other cell-mediated mechanisms, and should be tested in future experimental studies.

IFNβ-1b may severely exacerbate Japanese opticspinal MS in neuromyelitis optica spectrum: Japanese optic-spinal MS: Is it MS or neuromyelitis optica and does the answer dictate treatment?

# {#article-title-2} To the Editor: Shimizu et al.1 report increased demyelination and inflammation following interferon-β-1b (IFNβ-1b) therapy in patients with opticospinal multiple sclerosis (OSMS) and neuromyelitis optica (NMO). In the accompanying editorial, Drs. Weinshenker and Wingerchuk2 discuss whether a shift of immune response secondary to treatment with IFNβ-1b may account for the unpredictable response. We contend that the offset of immune response capable of unpredictable demyelinating attacks is unknown and not necessarily confined to B-cell activity or Th2 shift. A 42-year-old Caucasian woman had, over the course of 6 months, 2 episodes of optic neuritis—one in each eye—and 2 attacks to the spinal cord consistent with acute recurrent myelitis. The MRI brain showed no signs of demyelination and, despite negative NMO–immunoglobulin G (IgG), the patient was started on rituximab. Within 2 weeks, she developed a left hemispheric brain lesion similar to the one shown in figure 1A.1 The brain lesion continued to expand and after 6 courses of monthly cyclophosphamide the active process was suppressed. The pathology obtained via brain biopsy revealed reactive hypercellularity with …

Therapeutic efficacy of double filtration plasmapheresis in patients with anti-aquaporin-4 antibody-positive multiple sclerosis

Multiple sclerosis (MS) in Asian countries, including Japan, is classified into two types: conventional MS (C–MS), characterized mainly by cerebral lesions, and opticospinal MS (OS–MS) or neuromyelitis optica (NMO), characterized by selective involvement of the optic nerve and spinal cord. Recently, a serum immunoglobulin-G-antibody was discovered in patients with NMO that targets aquaporin-4 (AQP4). The existence of the anti-AQP4 antibody shows the pathogenetic role of humoral immune factors in OS–MS/NMO. We treated eight patients with anti-AQP4 antibody-positive MS with double filtration plasmapheresis (DFPP) to remove the antibody. Improvement of vision was observed in two patients. Motion improvement was seen in seven patients. Sensory improvement was observed in four patients. In total, six out of eight patients (75%) showed therapeutic improvement after DFPP treatment. We propose that DFPP might be an effective therapeutic option for patients with anti-AQP4 antibody-positive MS.

HLA allele frequencies in Iranian opticospinal multiple sclerosis patients&amp;lt;br&amp;gt;——HLA in Opticospinal MS

Background: In Iranian patients with opticospinal multiple sclerosis (OSMS), a paucity of brain lesions and short spinal cord lesions extending less than three spinal segments are characteristic findings on magnetic resonance imaging (MRI). It also shows a relatively benign course with negative CSF oligo-coonal bands. Objective: We aimed to clarify the possible relationship between clinical phenotype and MRI features of OSMS and human leucocyte antigen (HLA) system in Iran. Methods: Genotyping of HLA class II allele frequencies in 20 patients with OSMS were done, using polymerase chain reaction sequence-specific primer amplification method. Blood samples were extracted and typed for HLA-DRB, DQA, and DQB loci and compared with 100 controls. Results: Significant positive association was observed in DRB1*03, DQA1*0201, DQA1*03, DQB1*0201, and DQB1*0611, while DQB1*0602 was absent in our patients. Conclusion: These finding suggest that HLA-DRB association pattern in OSMS is different from conventional MS in Iran which is mostly associated with DRB1*1501 and from similar Japanese OSMS who are negative for brain lesions fulfilling the Barkhof criteria and negative for the presence of longitudinally extensive spinal cord lesions who carries the DRB*0405 allele. OSMS is immunogenetically heterogeneous. Also absence of DQB1*0602 allele may negatively be associated with the absence of Barkhof brain lesion.

Clinical outcome of autologous peripheral blood stem cell transplantation in opticospinal and conventional forms of secondary progressive multiple sclerosis in a Chinese population

To evaluate clinical outcomes of autologous peripheral blood stem cell transplantation (APBCST) between opticospinal multiple sclerosis (OSMS) and conventional multiple sclerosis (CMS) during disease progressive stage in a Chinese population. Thirty-six secondary progressive MS patients, among whom 21 were with OSMS and 15 with CMS, underwent APBSCT and were followed up for an average of 48.92months (range, 10-91months). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. Modified BEAM conditioning regimen (Tiniposide, melphalan, carmustin, and cytosine arabinoside) were administered. Outcomes were evaluated using the expanded disability status scale (EDSS). No maintenance treatment was administered if there was no disease progression. No treatment-related mortality occurred. Among the 36 patients, one OSMS patient dropped during the follow-up. Among the 22 relapse-free patients, 20 were with continuous neurological improvement without any relapse events, and two remained in neurologically stable states. Among the 13 relapse patients, seven had experienced of neurological relapse, but with no progression during the follow-up period; and six experienced neurological deterioration after transplantation and needed further immunosuppressant treatment. The confirmed relapse-free survival rate was 62.9% and progression-free survival rate was 83.3% after 91months according to Kaplan and Meier survival curves. Eleven of the 20 OSMS patients (55%) and two of the 15 CMS patients (13.3%) stayed in disease active group (P = 0.014). For the 20 OSMS patients, the overall EDSS score decreased significantly after transplantation (P = 0.016), while visual functions had no significant improvement (P = 0.716). Progressive OSMS has a higher relapse rate than CMS following APBSCT.

Neuromyelitis optica and opticospinal multiple sclerosis: Mechanisms and pathogenesis

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. In Asians, MS is rare; however, when it appears, the selective and severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal MS (OSMS), has similar features to the relapsing form of NMO in Western populations. Recently, a specific IgG against NMO, designated NMO-IgG, was discovered, and the relevant antigen was found to be aquaporin-4 (AQP4), one of the major water channel proteins in the CNS. Because NMO-IgG has been reported to be present in 30–60% of OSMS patients, OSMS in Asians has been suggested to be the same entity as NMO. The sensitivity of NMO-IgG/anti-AQP4 antibody for NMO varies from 30% to 80%, while the specificity is 90–100%. Pathological studies on NMO have revealed perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions, where myelin basic protein (MBP) staining was relatively preserved. IgG from NMO-IgG-seropositive NMO patients induces astrocyte death in culture in the presence of complements, and reproduces astrocyte loss in vivo when MBP-specific T cells are co-transferred to cause experimental autoimmune encephalomyelitis. It is thus postulated that the complement-activating anti-AQP4 antibody plays a pivotal role in the development of NMO lesions through astrocyte necrosis, and that demyelination is a secondary event. However, in autopsied cases of NMO, we and others found that some demonstrated selective AQP4 loss while others showed preservation of AQP4, even in the acute lesions. We also found that, in some MS lesions, AQP4 was lost extensively far beyond the areas of myelin loss. In the CSF, proinflammatory cytokines such as IL-17, IL-8, IFNγ, and G-CSF are markedly elevated in OSMS patients, irrespective of the presence or absence of anti-AQP4 antibody. In OSMS and NMO patients, T cells reactive to myelin proteins show intra- and inter-molecular epitope spreading, suggesting that T cells are already stimulated with myelin antigens in vivo. These findings suggest that mechanism of NMO and OSMS in Asians is heterogeneous, anti-AQP4 antibody-related and -unrelated, and that not only anti-AQP4 antibody but also myelin-autoreactive Th17 or Th1 cells may also play a role in triggering CNS inflammation. Possible mechanisms for NMO and OSMS are discussed in this review.

Recent progress in multiple sclerosis research: astrocytopathy in demyelinating diseases

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. Recently, a specific IgG against NMO, designated NMO-IgG, was discovered, and the relevant antigen was found to be aquaporin 4 (AQP4), one of the major water channel proteins in the CNS. The sensitivity of NMO-IgG/anti-AQP4 antibodies for NMO varies from 30% to 80%, while specificity is 90-100%. Pathological studies on NMO patients have revealed perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions, while myelin basic protein (MBP) staining was relatively preserved. IgG from NMO-IgG-seropositive NMO patients induces astrocyte death in culture in the presence of complement, and reproduces astrocyte loss in vivo when MBP-specific T cells are co-transferred to cause experimental autoimmune encephalomyelitis. Therefore, it is postulated that the complement-activating anti-AQP4 antibodies have a pivotal role in the development of NMO lesions through astrocyte necrosis, and that demyelination is a secondary event. Baló's disease is characterized by alternating rings of demyelination and preserved myelin. As additional MS-like lesions often coexist in Baló's cases, Baló's disease is regarded as a variant of MS. However, Baló's concentric rings are also observed in NMO cases and in Asian opticospinal MS patients in the cerebral white matter, spinal cord and optic chiasm. In demyelinated areas, many hypertrophic astrocytes are present, in close contact with oligodendrocytes that often show apoptotic features. In the outermost layer of preserved myelin, stress proteins involved in tissue preconditioning are abundant in oligodendrocytes. The peri-plaque white matter is thus assumed resistant to subsequent attack, thereby leaving a layer of preserved myelin. In some patients, Baló's concentric rings develop systematically in a centrifugal direction, while other patients show simultaneous enhancement of multiple rings. Therefore, tissue preconditioning and successive ring formation does not fully explain the mechanism of the disease. We recently reported that AQP4 was extensively lost in glial fibrillary acidic protein-positive hypertrophic astrocytes, both in demyelinated and myelinated layers of all actively demyelinating lesions in four Filipino Baló's patients. None of six other patients with magnetic resonance imaging-confirmed Baló's disease was seropositive for anti-AQP4 antibodies. I therefore propose that AQP4 astrocytopathy, in the absence of anti-AQP4 antibodies, is characteristic of Baló's disease. Since a similar loss of AQP4 without perivascular deposition of immunoglobulin and complement is also observed in autopsied CNS tissues from NMO and MS cases, I consider that autoantibody-independent astrocytopathy may widely occur in human CNS demyelinating diseases, including Baló's disease, MS and NMO.

FP21-TU-04 Anti-AQP4 autoimmunity-related and -unrelated opticospinal multiple sclerosis in Japanese

FP21-TU-04 Anti-AQP4 autoimmunity-related and -unrelated opticospinal multiple sclerosis in Japanese

Aquaporin-4 autoimmune syndrome and anti-aquaporin-4 antibody-negative opticospinal multiple sclerosis in Japanese

Background Antibodies to aquaporin-4 (AQP4) are found in a fraction of Japanese opticospinal multiple sclerosis (OSMS) patients. However, it remains unknown whether anti-AQP4 antibody-positive and negative OSMS patients possess an identical disease. Objective The objective of the current study was to clarify immunological differences between the two groups of patients. Methods We studied the serum antibody titers against AQP4 in 191 patients with idiopathic central nervous system demyelinating diseases and clarified their relationships with immunological parameters. Results Anti-AQP4 antibody positivity rate was higher in patients with OSMS (21/58, 36.2%), idiopathic recurrent myelitis (4/17, 23.5%), and recurrent optic neuritis (7/26, 26.9%), than in conventional MS (CMS) patients (6/90, 6.7%) and patients with other diseases (0/87). Anti-AQP4 antibody titer was significantly higher in patients with SS-A/B antibodies than in those without them. Anti-AQP4 antibody-negative OSMS patients showed significantly higher CD4+IFN-γ+IL-4−T cell percentages and intracellular IFN-γ/IL-4 ratios than anti-AQP4 antibody-positive patients, anti-AQP4 antibody-negative CMS patients, and healthy controls, and CD4+IFN-γ+IL-4−T cell percentages were negatively correlated with anti-AQP4 antibody titers. Conclusion Anti-AQP4 antibody-positive patients are immunologically distinct from anti-AQP4 antibody-negative OSMS patients owing to a Th2 shift in the former group in comparison to a Th1 shift in the latter.

Is neuromyelitis optica associated with human leukocyte antigen?

Background To establish whether or not multiple sclerosis (MS) and neuromyelitis optica (NMO) are different pathological entities, we wondered whether MS patients and NMO patients share the same pattern of human leukocyte antigen (HLA) predisposition. Objective To study a putative association between susceptibility to NMO and HLA class I or class II loci in Caucasians. Methods A total of 39 unrelated Caucasian patients with NMO and six patients at a high risk of converting to NMO were studied. DNA genotyping of HLA class I and class II loci was assessed and allelic frequencies were reported at a high-resolution level. A case-control study by comparing the allelic distribution in the NMO patients with that of a French Caucasian MS group and a French Caucasian healthy group was carried out. Results The frequencies of HLA-DQA1, DQB1, and HLA-DRB1 DR2 alleles in the NMO group were intermediate between the healthy control group and the MS group. The DPB1*0501 allele was not increased in the NMO group compared with the healthy control group. The distribution of HLA-DRB1 allele enabled to distinguish between NMO-IgG-positive patients and healthy controls (P = 0.01). NMO-IgG-negative patients presented an HLA II pattern closer to that of the MS group (P = 0.01). Conclusion In contrast to the reported results in Asian opticospinal MS, we found no association between the DPB1*0501 allele and NMO in our Caucasian patients. Moreover, we suggest that NMO-IgG-positive patients could represent a distinct NMO group in terms of their genetic susceptibility.

Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA.

In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons. To determine whether genetic variation influences clinical MS patterns. Retrospective multicenter cohort study. Six hundred seventy-three African American and 717 white patients with MS. Patients with MS were genotyped for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset. Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti-aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1*15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) and risk of cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001). These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes.

Hypercomplementemia at relapse in patients with anti-aquaporin-4 antibody

Objective Because Asian patients with opticospinal multiple sclerosis (OSMS) frequently have anti-aquaporin-4 (AQP4) antibody, complement-mediated disruption of astrocyte foot processes is proposed but not yet proven. We aimed to clarify whether complement consumption occurs at relapse in anti-AQP4 antibody-positive patients. Methods We analyzed serum CH50, C3, C4, and C-reactive protein (CRP) levels and their relation to clinical phases in 118 MS patients with or without anti-AQP4 antibody. Serum CH50 levels were higher in 24 patients with anti-AQP4 antibody than in 39 OSMS and 54 conventional form of MS (CMS) patients without anti-AQP4 antibody at relapse (Pcorr < 0.05) but not in remission. The frequency of hypercomplementemia at relapse was also higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative CMS patients (70.4% vs 29.0%, Pcorr < 0.05). C3 and C4 levels did not differ significantly among the three groups at relapse. In patients with anti-AQP4 antibody, the coexistence of hypercomplementemia and high CRP values was more common at relapse than in the remission phase (36.0% vs 10.5%, P < 0.05). In patients with extensive central nervous system lesions, hypercomplementemia was significantly more common in anti-AQP4 antibody-positive patients than anti-AQP4 antibody-negative ones (88.9% vs 16.7%, P < 0.01). We consider that hypercomplementemia in anti-AQP4 antibody-positive patients may reflect a systemic inflammatory reaction at relapse.

Neuromyelitis Optica and Asian Phenotype of Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), whereas neuromyelitis optica (NMO) is an inflammatory disease of the CNS selectively affecting the optic nerves and spinal cord. The pathological hallmark in MS is sharply demarcated demyelinating plaque with axons relatively preserved, whereas in NMO both axons and myelin are involved, resulting in necrotic cavitation. The nosological position of NMO has long been a matter of debate. In Asians, MS is rare; however, when it appears, the selective but severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal MS (OSMS), has similar features to those of the relapsing form of NMO in Western populations. Recent discovery of a specific immunoglobulin G (IgG) against NMO, designated NMO-IgG, suggests that NMO is a distinct disease entity with a fundamentally different etiology from that of MS. Because NMO-IgG has been reported to be present in about 50%-60% of OSMS patients with longitudinally extensive spinal cord lesions (LESCLs), OSMS in Asians has been suggested to be the same entity as NMO. About half of the patients with the anti-aquaporin 4 (AQP4) antibody demonstrate brain lesions fulfilling the Barkhof criteria, whereas OSMS patients without the anti-AQP4 antibody show significantly fewer brain lesions. These findings indicate that the mechanism of LESCLs in Asians is heterogeneous, both related and unrelated to anti-AQP4 antibody, and that the disease condition with anti-AQP4 antibody does not completely overlap OSMS in Asians. This review discusses possible mechanisms for OSMS and anti-AQP4 autoimmune syndrome of the CNS.

Distinct CSF cytokine/chemokine profiles in atopic myelitis and other causes of myelitis

We reported the emergence of a distinct myelitis in patients with atopic diathesis (atopic myelitis [AM]) by a nationwide survey throughout Japan. Similar cases have recently been reported in Caucasians. Pathologic studies of biopsied spinal cord specimens revealed chronic active inflammation with eosinophilic infiltration. To clarify the cytokine/chemokine alterations in CSF from patients with AM in comparison to other causes of myelitis. We measured 27 cytokines, chemokines, and growth factors simultaneously in CSF from 22 patients with AM, 20 with opticospinal multiple sclerosis (OSMS), 11 with HTLV-1-associated myelopathy (HAM), 9 with Sjögren syndrome-related myelitis (SM), and 20 with other noninflammatory neurologic diseases (OND), using a fluorescent bead-based immunoassay. In patients with AM, CCL11 and interleukin (IL)-9 were significantly increased as compared with patients with OND and other myelitis while in patients with OSMS interferon-gamma and granulocyte-colony stimulating factor levels were significantly higher than in patients with OND and other causes of myelitis. Significant increase of IL-17 in comparison to patients with OND was found only in patients with OSMS, irrespective of presence or absence of anti-aquaporin-4 (AQP4) antibody. In patients with HAM, CXCL10 and CCL5 were higher than in patients with OND and other myelitis. In patients with SM, CCL3 and CCL4 were higher than in patients with OND. In patients with AM, CCL11, IL-9, and IL-1 receptor antagonist (IL-1ra) showed positive correlations with the final Kurtzke Expanded Disability Status Scale scores while IL-1ra and IL-12(p70) had positive correlations with disease duration. Intrathecal upregulation of CCL11 and Th2 cytokines is characteristic of atopic myelitis, which is distinct from interleukin-17/interferon-gamma-related autoimmune condition of opticospinal multiple sclerosis.

Neuromyelitis optica immunoglobulins as a marker of disease activity and response to therapy in patients with neuromyelitis optica

Objective To determine whether neuromyelitis optica (NMO) immunoglobulin (IgG) antibody status in NMO/Devic’s disease patients followed prospectively is persistent or can change relative to the clinical status and/or response to therapy. Design A cross-sectional group of patients with NMO, relapsing extensive longitudinal transverse myelitis (RLETM) or optico-spinal multiple sclerosis (OSMS) were evaluated for the presence of NMO IgG antibodies. Repeated evaluation was made in all NMO/RLETM patients and in a subgroup of OSMS patients. Setting Baird Multiple Sclerosis Center, Buffalo, New York, an academic multiple sclerosis center. Results Out of a consecutive cohort of 38 patients evaluated for the presence of NMO IgG, 12 had NMO and 26 had OSMS. Five of the 12 NMO/RLETM patients were NMO IgG positive at the time of their initial evaluation. Four of these patients were repeatedly tested for NMO IgG: two of these became negative and two remained positive. One patient who was initially negative became positive during an acute event and again became negative during the stable disease phase following treatment. A positive test result was associated with active disease, whereas a negative NMO IgG result was consistently found in stable, long-term treated patients. None of the OSMS patients were positive for NMO IgG even during acute attacks. Conclusions NMO IgG antibodies are associated with active NMO/RLETM. A well-controlled stable disease usually under effective immunosuppressive therapy can transform the NMO IgG to a negative status. Repeated NMO IgG testing should be considered as a useful biological marker for monitoring NMO/RLETM disease and or response to therapy.

To test or not to test

Neuromyelitis optica (NMO), which includes Devic disease, is widely accepted as a distinct clinical and pathologic entity separate from multiple sclerosis (MS). In NMO, the primary pathologic change is loss of aquaporin 4 water channel protein on astrocytes, occasionally with secondary demyelination.1 NMO is phenotypically similar to optico-spinal MS (OSMS) described in Asian MS populations; particularly in patients with longitudinally extensive transverse myelitis (LETM).2 In 2004, Lennon et al.3 reported a characteristic immunofluorescence autoantibody staining pattern of CNS tissues with serum from patients with NMO; IgG deposition occurred around microvessels of the pia, sub-pia, and Virchow-Robin spaces and colocalized with laminin. This autoantibody was named NMO-IgG and was subsequently shown to bind to the predominant CNS water channel aquaporin-4 (AQP4).4 NMO-IgG positivity (and by inference anti-AQP4 antibody positivity) has now been included as one of the three supportive criteria in the recently revised diagnostic criteria for NMO.5 Inclusion of NMO-IgG positivity as part of the diagnostic criteria for NMO has resulted in phenotypic spread. For example, involvement of the brain, previously …

Clinical Features of Opticospinal Multiple Sclerosis with Anti-Aquaporin 4 Antibody

Background: We have followed 9 Japanese patients with opticospinal multiple sclerosis (OSMS), some of whom showed longitudinally extensive spinal cord lesions, deep sensory disturbances and resistance to treatment. We investigated the patients for anti-aquaporin 4 (AQP4) antibodies and related this to their neuroimaging, clinical and laboratory features. Methods: We studied the clinical course, neurological findings, cerebrospinal fluid (CSF), and electrophysiological findings, and determined the presence of anti-AQP4 antibody and human leukocyte antigen DPB1 and DRB1 alleles. Results: Five patients (56.6%) had anti-AQP4 antibody. Antibody-positive patients displayed female predominance, longitudinally extensive spinal cord lesions, higher frequency of exacerbations, severe disability, and higher cell counts and total protein content without IgG oligoclonal bands in the CSF. They also showed poor steroid responsiveness and poor therapeutic response to interferon β_1b. Conclusions: The presence of anti-AQP4 antibodies correlates with clinical severity and poor prognosis in OSMS.