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Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathic disease of the central nervous system characterized by severe optic neuritis and transverse myelitis. The antibody against aquaporin 4 (AQP4), a water channel mainly expressed in astrocytes, is specific to NMOSD and may be detected in >70% of all cases. Inebilizumab is a humanized IgG1 monoclonal antibody against CD19. Anti-AQP4 antibodies are produced by CD19-positive plasmablasts, and inebilizumab administration significantly reduces the number of CD19-positive B cells and has therapeutic effects on NMOSD. The efficacy and safety of inebilizumab have been verified in the N-MOmentum trial, an international double-blind, placebo-controlled phase II/III study, in which Japanese patients also participated. Inebilizumab was approved for the treatment of NMOSD with AQP4-IgG in Japan in March 2021. In this review, we summarize the efficacy and safety of inebilizumab in the treatment of NMOSD and, focus on findings from the primary and additional analyses of the N-MOmentum trial. These results suggest that inebilizumab is effective and safe in preventing the recurrence of NMOSD in populations with different backgrounds and that long-term treatment with inebilizumab is beneficial.

Neuromyelitis optica (NMO) is clinically characterized by severe optic neuritis and long myelitis; and is associated with aquaporin-4 immunoglobulin-G (AQP4-IgG), an autoantibody directed against aquaporin-4 (AQP4), which is an astrocytic water channel protein. Until recent years, the treatment of NMO has mainly focused on the suppression of lymphocytes and depletion of autoantibodies. However, several studies on the pathogehesis of the disease in human pathology, cultured cells, and animal models have revealed that astrocyte injury in NMO is mainly caused by the complement-dependent cytotoxicity following AQP4-IgG binding to AQP4. Moreover, complement-targeting therapy has recently been translated into practical applications in several hematological disorders. and similary, also in the cases of NMO. In this article, we review the relevance of the complement system in the pathogenesis of NMO. Additionally, we review the current status and prospects of the complement-targeting therapy for NMO, including the clinical trials of eculizumab and C1 inhibitor for NMO, and the experimental studies on C1 inhibition by monoclonal antibodies.

FreeSurfer is open source software used to process and analyze magnetic resonance imaging of the human brain. It is a convenient tool that helps elucidate various structural characteristics the brain. In this review, we introduce the various structural indices of the brain, analyzed using FreeSurfer and magnetoencephalography, which can evaluate neural activity with high temporal and spatial resolution. We consider that the FreeSurfer has great potential as a platform for multimodal neuroimaging studies.

A 10-year-old boy developed bilateral optic neuritis and myelitis after a suspected viral infection and appendicitis. Magnetic resonance imaging (MRI) showed multiple lesions in both optic nerves, the optic chiasm, and the spinal cord. Several small lesions were also observed in the cerebellum and cerebral white matter. The serum tested negative for anti-aquaporin (AQP)-4 antibody and positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibody. The diagnosis was neuromyelitis optica spectrum disorder (NMOSD). Two courses of high-dose methylprednisolone were administered; however, only a small improvement in his visual acuity was achieved. He underwent 3 courses of plasma exchange to achieve sufficient visual acuity. After the serum anti-MOG antibody titer decreased to the cut-off level, oral prednisolone and azathioprine administration were also stopped, 10 months after onset. Recently, NMO and NMOSD cases positive for anti-MOG antibodies have been reported, which showed clinical features different from those of NMO cases positive for anti-AQP4 antibody. Although most of the reported cases responded to steroid therapy, plasma exchange was required in our case. Further analysis on larger numbers of cases is needed to establish treatments for anti-MOG antibody-positive NMO and NMOSD.

More than a century has passed since the first description of neuromyelitis optica (NMO) or Devic's disease. The relation between NMO and multiple sclerosis (MS) had long been debated, but the discovery of anti-aquaporin-4(AQP4) antibody, an NMO-specific autoantibody has accelerated clinical and experimental research of NMO, and contributed to estabilishing NMO spectrum disorder(NMOSD), a wider disease spectrum than a prototypic opticospinal phenotype and a new disease concept: autoimmune astrocytopathic disease. Clinical, MRI and laboratory findings and therapeutic response in NMOSD are different from those in MS. On the other hand, anti-AQP4 antibody-seronegative NMOSD has some distinct features from seropositive cases, and anti-myelin oligodendrocyte glycoprotein(MOG) antibody is detected in a fraction of cases of seronegative NMOSD. Unlike anti-AQP4 antibody-associated NMOSD, anti-MOG antibody-seropositive NMOSD may be a demyelinating desease. In this review, we provide an overview of how the concept of NMOSD has evolved in association with accumulated scientific evidences.

We report a 44-year-old woman who had anti-aquaporin 4 (AQP4) antibody-positive myelitis and immune thrombocytopenic purpura (ITP). She was admitted to our hospital with paraparesis, dysesthesia below the Th8 dermatome level on her right side and lower extremities, constipation and urinary retention. Magnetic resonance imaging revealed a longitudinally extending lesion at the level of Th4-Th10. Her serum sample was positive for anti-AQP4 antibody. Corticosteroid therapy was initiated, and her symptoms were largely ameliorated. Furthermore, concurrently with the myelitis, her platelet count dropped (99 × 10(9)/l). A diagnosis of ITP was made with positive serum platelet-associated IgG (PA-IgG) and negative work-up for blood malignancies by bone marrow aspiration. Since a causal relationship between Helicobacter pylori (H. pylori) and ITP is suggested by several studies, she was also examined and diagnosed with H. pylori-positive ITP. After the bacteria eradication therapy, her platelet count and PA-IgG returned to normal range. Furthermore, the anti-AQP4 antibody titer declined and her symptoms were almost resolved. We considered that H. pylori might influence progression of the myelitis as well as induction and development of ITP.

Neuromyelitis optica (NMO) is a disease characterized by severe optic neuritis and transverse myelitis with autoantibody against aquaporin 4 (AQP4), mainly localized at astrocyte foot processes. Loss of AQP4 and glial fibrillary acidic protein with relatively preserved myelin is the pathological hallmarks of active NMO lesions. Several experimental studies suggested the crucial role of AQP4 antibody with diverse mechanisms including antibody- and complement-induced cytotoxicity against astrocytes. In vivo studies demonstrated that T cell-mediated CNS inflammation is necessary for the access of AQP4 antibody into CNS. NMO patients often develop medullary lesions including area postrema, which lacks the blood-brain-barrier and is sensitive to emetic agents. NMO is now considered to be an autoimmune astrocytopathy, and is distinct from multiple sclerosis.

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and transverse myelitis. The proposed relationship between NMO and multiple sclerosis (MS) has long been controversial. However, after the discovery of an NMO-specific antibody against aquaporin-4 (AQP4), a water channel mainly expressed in astrocytes, clinical, MRI, and laboratory features, including longitudinally extensive spinal cord lesions and unique brain lesions, were identified in NMO. Analyses of AQP4 antibody-positive cases have shown that the clinical spectrum of NMO is wider than just optic myelitis. Neuropathological studies have demonstrated extensive loss of AQP4 and glial fibrillary acidic protein (GFAP) in NMO lesions, especially in perivascular areas of acute inflammatory lesions where immunoglobulins and activated complements are deposited. In contrast, myelin basic protein (MBP)-positive myelinated fibers are relatively preserved, suggesting that myelin damage is secondary to astrocyte destruction. The GFAP level in the cerebrospinal fluid is remarkably elevated during relapse of NMO, but not in MS. Experimental studies strongly suggest that AQP4 antibodies are pathogenic; they activate complements and destroy AQP4-expressing cells. Between two AQP4 isoforms, M1 and M23, AQP4 antibody has a higher affinity to M23 because it forms an orthogonal array of particles that appears to be specifically recognized by AQP4 antibodies. Immunosuppression is the mainstay of NMO management. High-dose intravenous methylprednisolone and plasma exchange are employed during acute exacerbation, and corticosteroids and immunosuppressants are efficacious in reducing NMO relapse. Importantly, some disease-modifying drugs for MS, such as interferon-beta and fingolimod, can exacerbate NMO; therefore, early differentiation between NMO and MS is important in selecting an appropriate treatment strategy. In conclusion, NMO is now classified as an autoimmune astrocytopathic disease targeting AQP4, rather than a demyelinating disease like MS. Further studies are warranted to clarify disease pathogenesis and develop a molecular target treatment for NMO.

Recently, the disease-specific neuromyelitis optica (NMO) autoantibody NMO-IgG was detected in the sera of NMO patients, as the specific immunohistochemical pattern of human IgG on mouse brain slices. Aquaporin-4 (AQP4), mainly expressed in astroglial foot processes, was identified as the target for NMO-IgG. For diagnosing NMO, serological tests are mainly performed using a cell-based assay with HEK293 cells transfected with AQP4; this assay has the highest sensitivity (>70%) and specificity (>90%) for diagnosing NMO. However, several assays, such as immunoprecipitation assay, and ELISA systems, for detecting the AQP4 antibody have been reported. Several papers focus on inflammatory and pathological biomarkers, including cytokines, chemokines, and astrocyte markers, for NMO. Pleocytosis in the cerebrospinal fluid (CSF) and an increased CSF IgG: serum IgG/albumin ratio are useful markers of inflammation and blood-brain barrier leakage in NMO patients. Increased concentrations of cytokines such as IL-17, IL-6, and BAFF in the CSF may be key factors that induce the formation of NMO lesions, mainly by promoting the infiltration of neutrophils or plasma cells. Astrocytic damage, reflected by a marked increase in CSF-GFAP levels, was evident in NMO patients, but not in classical multiple sclerosis (MS) patients, indicating that CSF-GFAP is a good marker of lysis during autoimmune astrocytopathy. Therefore, the assessment of such useful biomarkers may become a supportive criterion for diagnosing NMO and NMO spectrum disorders.

Neuromyelitis optica (NMO) or Devic's disease is an inflammatory neurologic disease characterized by severe optic neuritis and transverse myelitis. Other features of NMO include female preponderance, higher onset age, severe functional disability, longitudinally extensive spinal cord lesions (longer than 3 vertebral segments), and oligoclonal IgG bands negativity. Brain lesions are not uncommon in NMO. The relation between NMO and multiple sclerosis (MS) has long been a matter of controversy, but since the discovery of anti-aquaporin 4 (AQP4) antibody (NMO-IgG), an NMO-specific autoantibody, the clinical, MRI, and laboratory features that distinguish NMO from MS have been clarified. Anti-AQP4 antibody binds to the extracellular domain of AQP4, which is highly expressed in endfeet of astrocytes. Recent neuropathological studies, analysis of CSF-GFAP levels during relapse and experimental studies strongly suggest that NMO is an anti-AQP4 antibody-mediated astrocytopathic disease and that T cell-mediated CNS inflammation is necessary to develop NMO. Also, IL-6 is remarkably elevated in the CSF and appears to regulate plasmablasts to produce anti-AQP4 antibody. Therefore, from the therapeutic point of view, depletion of anti-AQP4 antibody, suppression of T cell response to trigger relapse and anti-IL-6 therapy seem to be pivotal. High-dose intravenous methylprednisolone is the first-line therapy for acute exacerbations of NMO. But plasma exchange should be started soon if corticosteroid is not efficacious. If untreated, AQP4 antibody-positive patients are highly likely to experience relapses within a year. Thus, immunosuppressive therapy (corticosteroids, immunosuppressants, rituximab) should be initiated without delay. Preliminary results suggest that eculizumab, an anti-C5 monoclonal antibody, can also prevent relapse in NMO, Meanwhile, interferon-beta, a first-line disease modifying drug of MS, is not effective in NMO. Symptomatic therapy for pain, paresthesia, spasticity, dysuria and constipation which commonly occur in the chronic stage of NMO is also important to improve patients' quality of life.

We produced a Japanese translation of the 15-item myasthenia gravis (MG)-specific quality of life (QOL) scale (MG-QOL15), assessed its reliability and validity, and examined clinical factors affecting the self-perceived QOL in MG. Consecutive 327 patients with MG seen at six neurological centers were evaluated. All patients completed an MG-QOL15 Japanese version (MG-QOL15-J), the Beck Depression Inventory-Second Edition (BDI-II), and a generic health-related QOL questionnaire, the SF-36. Disease severity was determined according to the MG Foundation of America (MGFA) quantitative MG score and the MG composite. The MG-QOL15-J exhibited adequate internal reliability, test-retest repeatability, and concurrent validity with SF-36, disease severity, and known-patient groups categorized by MGFA postintervention status. Multivariate analysis revealed severity, dose of oral corticosteroids, and BDI-II as independent factors negatively affecting QOL. The MG-QOL15-J is anticipated to be a valuable clinical measure of QOL in Japanese patients with MG.

Numbers of tonsillectomies may be decreasing in Japan due to troublesome bleeding involved in managing in a small viewing field and relatively low national health insurance point for tonsillectomy. We found coblation tonsillectomy to have advantages of less bleeding, shorter operating time, and less postoprerative pain than conventional tonsillectomy. We found that 40% of those on whom a coblator was used reported no postoperative throat pain, and noted a quick learning curve in decreasing postoperative bleeding in coblation tonsillectomy.

Recently, a disease-specific antibody was found in serum from patients with neuromyelitis optica (NMO), and its target antigen was identified as aquaporin 4 (AQP4) water channel protein. There is no clinical picture of pediatric cases with anti-AQP4 antibody, except one report from North America. Here, we report the clinical features of 18 Japanese anti-AQP4-antibody-positive patients with childhood-onset of NMO. Of the 2000 patients who had been examined for anti-AQP4 antibody at Tohoku University Hospital up until 2008, 60 were under 15 years of age at onset, and 18 of them were positive for anti-AQP4 antibody. We analyzed the clinical information on those patients. There were 14 girls and 4 boys (M:F ratio = 1:3.5). The age of onset ranged from 3 to 15 years old (median 13). The clinical diagnoses of the 18 patients before the anti-AQP4 antibody tests were: NMO in 8 (44%), MS in 7 (39%), and opticospinal MS (OSMS) in 3 (17%). Nine patients developed only optic neuritis at onset. At the last follow-up, brain magnetic resonance imaging (MRI) was abnormal in 14 patients, nine had monocular or binocular blindness, and the expanded disability status scale score was 6.0 or higher (cannot walk without support) in eight patients. NMO has a poor prognosis, as seen in adult cases, suggesting the importance of an early diagnosis using the anti-AQP4 antibody test to institute effective immunosuppressive treatment.

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by relapses of optic neuritis and acute myelitis. The disease was referred to as the optic-spinal form of multiple sclerosis (OSMS) in Japan for a long period. A specific auto-antibody, NMO-IgG, was detected in the serum of NMO patients, and aquaporin-4 water channel protein was detected as its target antigen; aquaporin-4 water channel protein is localized at the end-feet of astrocytes. Because of the presence of this specific serum auto-antibody, most OSMS patients in Japan were found to exhibit a disease that was identical to NMO that affects individuals of the Western countries. Since the discovery of NMO-IgG, various clinical and histopathological features of this condition have been recognized; in addition the concept of NMO has been established in Japan as well as in many other countries.

Recently, the disease-specific antibody was found in the sera from neuromyelitis optica (NMO) patients, and its target was identified as aquaporin-4 (AQP4), mainly expressed in astroglial foot processes. In our immunohistochemical studies, loss of AQP4 and glial fibrillary acidic protein (GFAP) was evident in about 90% of NMO lesions, especially in perivascular areas of acute inflammatory lesions where immunoglobulins and complements were deposited. In contrast, myelin basic protein (MBP)-stained myelinated fibers were relatively preserved in those lesions, which probably suggested the secondary damage of myelin sheaths following astrocytic damage. Recently, there are developing evidences of the effect of AQP4 antibody in vitro or in vivo. In HEK293 cells transfected with AQP4, AQP4 antibody could bind to the membrane AQP4, and induced the degradation and endocytosis of AQP4 in complement-dependent manner. In vitro experiments by primary cultured astrocytes, AQP4 antibody had cytotoxic effects with complement, and also could impair the astrocytic function such as the maintenance of the blood brain barrier or glutamate homeostasis. In vivo study, the lesions lacking AQP4 and GFAP was appeared by passive-transferred Lewis rats with human purified IgG from NMO patients. Furthermore, in cerebrospinal fluid (CSF) biomarker study, astrocytic damage reflected by marked increase of CSF-GFAP, far severe than demyelination (CSF-MBP), was evident in NMO but not in classical multiple sclerosis (MS). These evidences suggested the pathogenic role of AQP4 antibody with astrocytopathy in NMO. Now it is indispensable to check the AQP4 antibody,and is important to reconsider the role of astrocyte in demyelinating disorders.

Neuromyelitis optica (NMO) is an inflammatory disease mainly affecting the optic nerve and spinal cord. There has been prolonged controversy over whether NMO is a subtype of multiple sclerosis (MS) or a distinct disease. Recently, a highly specific serum autoantibody marker, NMO-IgG, was exclusively found in the sera of NMO, and the target antigen was identified as the water channel protein aquaporin (AQP) 4. In our immunocytochemical assay using HEK293 cells transfected with human AQP4, we found that the sensitivity and specificity of AQP4 antibody in NMO were as high as 91 and 100%, respectively. Our histopathological studies of NMO revealed that AQP4 and GFAP, an astrocytic marker protein, were completely lost in the acute inflammatory lesions surrounding immunoglobulin and complement-deposited dilated vessels, but the staining of myelin basic protein was relatively preserved. These results suggest that astrocytic damage associated with autoimmunity to AQP4 is involved in the pathogenesis of NMO, which is distinct from MS, a primary demyelinating disease. Growing evidence for the in vitro cytotoxic or functional effects of AQP4 antibody on astrocytes support its pathogenic implications in NMO. Regarding the treatment of NMO, there are refractory patients which can be treated with interferon beta, so immunosuppressive agents such as low-dose oral prednisolone and/or azathioprine reduce the rate of relapse, while, unlike in MS, the therapeutic efficacy of interferon beta is unclear in NMO. Therefore, AQP4 antibody is indispensable in the diagnosis and treatment of NMO.

Recent findings on the etiology and pathogenesis of multiple sclerosis (MS) and neuromyelitis optica (NMO) were reviewed. As new MS-susceptibility genes, IL-7Ralpha and IL-2Ralpha genes were identified. Among environmental factors, Epstein-Barr virus, vitamin D and smoking appear to play a role in developing MS. As opposed to previous reports on the lesion heterogeneity, a recent study showed antibody-, complement-mediated myelin phagocytosis is the dominant mechanism of demyelination in MS. Clinical trials of monoclonal antibodies demonstrated that targeting such immune molecules as CD52, CD25, VLA-4 and CD20, is therapeutically effective. Aquaporin-4 (AQP4) antibody is a diagnostically useful biomarker of NMO, and a recent study revealed severe astrocytic damage in NMO probably caused by AQP4-targeting is a pathological finding distinct from that in MS.

Neuromyelitis optica (NMO) is an inflammatory disease mainly affecting optic and spinal cords, and was originally described by Devic in 1894. There has been long controversy about whether NMO is a subtype of multiple sclerosis (MS) or a distinct disease. In Japan and other Asian countries, relapsing NMO has been called as optic-spinal form of MS (OSMS), but we reported in 2002 that OSMS was heterogeneous and it comprised both typical NMO and MS with optic spinal presentation. Recently, a highly specific serum autoantibody marker, NMO-IgG, was found in the sera of Caucasian NMO and Japanese OSMS cases, and the target antigen was identified as the water channel protein aquaporin (AQP) 4. So in NMO and OSMS, similar autoimmune backgrounds were revealed. In our anti-AQP4 antibody assay using HEK293 cells transfected with human AQP4, we found that the sensitivity and specificity of anti-AQP4 antibody was 91% and 100%, respectively, which was superior to the original immunohistological assay using mouse brain slices (NMO-IgG). The titre of AQP4 antibody correlated with the length of spinal cord lesions and relapse rate. We also studied the expression of AQP4 in autopsied cases of NMO and MS and revealed that AQP4 and GFAP, an astrocytic marker protein, were completely lost at the acute inflammatory lesions surrounding immunoglobulin and complement-deposited dilated vessels, but the myelin basic protein was relatively preserved. Those results suggest that astrocytic damage associated with autoimmunity to AQP4 may be involved in the pathogenesis of NMO, which is distinct from MS, primarily demyelinating disease. After the long history of confusion, NMO became clearly discriminated disease from MS. In this review, we focus on the historical changes of the disease concept and new knowledge gained from the clinical or immunological analyses of NMO.

Neuromyelitis optica (NMO) is clinically characterized by severe optic neuritis and transverse myelitis. Recurrent NMO has been described as optic-spinal multiple sclerosis (OSMS) in Japan, but it has been known that NMO has distinct clinical and laboratory findings (female preponderance, severe disability, longitudinally extensive myelitis, CSF-pleocytosis, negative oligoclonal IgG bands, etc) from those in typical MS. In addition, anti-aquaporin-4 (AQP4) antibody and loss of AQP4 in the active perivascular NMO lesions with deposition of immunoglobulins and activated complements were recently found to be NMO-specific, strongly suggesting that NMO is a clinical entity that should be separated from MS. In accordance with these unique features of NMO, different therapeutic responses between NMO and MS have been observed, that is, interferon-beta, a disease-modifying therapy (DMT) for MS, is less effective in NMO, while long-term administration of corticosteroid and immunosuppressive agents reduce relapses of NMO. Efficacy of plasma exchange for acute exacerbation in NMO supports the pathogenetic importance of humoral immunity in the disease. Meanwhile, in clinical practice, it is important to differentiate "genuine OSMS" characterized by short spinal cord lesions and anti-AQP4 antibody-negative status from NMO, because such cases with "genuine OSMS" are expected to respond to DMT for MS.

Optic-spinal multiple sclerosis (OSMS) is characterized by the selective and severe involvement of the optic nerves and spinal cord. Typical OSMS is similar to neuromyelitis optica (NMO) in many respects. NMO has distinct laboratory findings from those in classical MS, which are important to understand the unique pathogenesis of NMO. In the cerebrospinal fluid (CSF) examination, oligoclonal IgG bands are negative, and IgG1% is not elevated in NMO. Both Th1- and Th2-associated chemokines are altered in the CSF of NMO as well as classical MS. Neurofilament heavy chain levels in the CSF are elevated in NMO, but not in classical MS, suggesting severer axonal damage in NMO. Unique neuropathological findings in NMO include tissue necrosis, gray matter involvement, and perivascular deposition of immunoglobulins and complements. NMO-IgG is a disease-specific autoantibody for NMO. Complete blindness and longitudinally extensive (> 3 vertebral segments) myelitis are commonly seen in NMO-IgG-positive cases. Some NMO-IgG-positive patients develop such brain lesions as hypothalamic, periaque-ductal, and bilateral extensive ones, and they appear to be different from typical lesions of classical MS. A recent multi-center study in Japanese OSMS has revealed that OSMS is classified into two subtypes, 1) NMO and 2) MS with optic-spinal presentation.

Magnetic resonance imaging(MRI) is very useful as a method form confirming the lesion distribution of multiple sclerosis(MS). Although MS should be diagnosed primarily on clinical grounds, MRI aids the diagnosis by providing paraclinical evidence for the dissemination in both time and space. Recently, a new guideline for MS diagnosis was proposed by International Panel. This guideline set out to integrate MRI into the overall diagnostic scheme because of its unique sensitivity to pathological changes. In Japanese, however, the so-called optic-spinal form of MS, which is characterized by the selective involvement of the optic nerves and the spinal cord, is relatively common. Moreover, most of Japanese MS patients without oligoclonal bands show atypical brain lesions which do not fulfill the MRI criteria for brain abnormality.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). MS is classified into clinical subtypes, such as relapsing-remitting MS, primary and secondary progressive MS, benign MS and malignant MS. In Japan, the classification based on the lesion distribution is also commonly used. There are two subtypes in this classification, conventional MS, in which demyelinating plaques are disseminated within CNS, and optic spinal MS, or relapsing neuromyelitis optica, characterized by the selective involvement of the optic nerves and spinal cord. Clinical manifestations and MRI findings of the clinical subtypes and their immuno-pathology are reviewed with emphasis on the unique features of Japanese MS.

Findings of chemokines and chemokine receptors in multiple sclerosis(MS) are reviewed. MS is a T-helper type 1 (Th1) dominant condition, and Th1-associated chemokine receptors(CCR5 and CXCR3) on CD4- and CD8-positive T cells and their ligands are upregulated in the CNS of the patients with active disease. Meanwhile, Th2-associated chemokine receptors(CCR3 and CCR4) on CD4- and CD8-positive T cells are suppressed during relapse. Their expressions are useful immunological measures of disease activity, clinical subtypes and therapy. CCR7 and the ligands are expressed in the CNS of MS and may be important for the recruitment of immune cells committed to immunological memory and antigen presentation.

Beta-catenin is an undercoat protein of cadherin, a cellular adhesion molecule. Beta-catenin also functions as a transcriptional activator downstream of the Wnt signaling pathway. Intracellular beta-catenin is regulated by the formation of a complex with APC (adenomatous polyposis coli) protein. The activation of this pathway by stabilization with beta-catenin has been shown to be an important step in the development of colorectal carcinoma, which is mainly caused by inactivating mutations in the APC tumor suppressor gene or by activating mutations in exon 3 of the beta-catenin gene. This study was conducted to clarify the contribution of beta-catenin accumulation and the mutation of the beta-catenin gene to the carcinogenesis of head and neck cancer. Beta-catenin accumulation was examined immunohistochemically in 49 frozen or formalin-fixed, paraffin-embedded samples of head and neck tumors. We also performed a direct sequence analysis of APC and beta-catenin to examine the cause of beta-catenin accumulation. Genomic DNA was extracted and purified from fresh tissue samples of head and neck cancers. We examined the APC mutation cluster region in 15 samples and analyzed beta-catenin exon 3 mutations in 31 cases. Twelve out of 49 (24.5%) cases exhibited beta-catenin accumulation in our histochemical study. The 5 year survival rate was 0% in the beta-catenin accumulation group, compared to 50% in the non-accumulation group, (p < 0.01). This finding strongly suggests that beta-catenin may play an important role in the carcinogenesis or progression of head and neck cancer. One of the 15 cases exhibited an APC missense mutation that led to the replacement of amino acids; this case died in 12 months. Regarding the beta-catein mutation, non of the 31 samples exhibited a gene mutation in beta-catenin exon 3. Thus, the rate of APC and beta-catenin mutation in head and neck cancer may be very low.

We reviewed the clinical and immunological features of optic-spinal multiple sclerosis (OSMS), or relapsing neuromyelitis optica. OSMS has collected much attention as to whether it is a distinct entity from conventional MS (CMS). However, OSMS plus minor cerebral and brainstem/cerebellar involvement and the later conversion into CMS had been a diagnostic dilemma. To overcome such problems and delineate the features of OSMS, we analyzed 'Pure OSMS' with which patients had only relapsing optic neuritis and myelitis clinically and consistently normal brain MRI during 5 years or longer follow-ups. As a result, we found that this type of MS was characterized by a definite female preponderance and negative oligoclonal IgG bands (OB), although 'Pure OSMS' was heterogeneous with regards to the clinical severity and HLA class II alleles. Previously reported immunological data in OSMS include negative OB and no elevation of IL-10 or matrix metalloproteinase-9 in the cerebrospinal fluid (CSF) during relapses. In addition, we recently demonstrated that the CCR5+ Th1 cell subset in CSF during relapses, which significantly increased in CMS, remained low in OSMS. These unique clinical and immunological findings probably relate to fundamental differences in the pathogeneses of OSMS and CMS and deserve further characterization.

An 18-year-old woman developed subacute transverse myelopathy with renovascular hypertension, hyperlipidemia, and proteinuria. Spinal magnetic resonance imaging(MRI) showed an intra-spinal cord lesion with severe spinal cord swelling at the C 2-Th 2 level. Increased plasma and cerebrospinal fluid interleukin-8(IL-8) levels and the presence of serum antineutrophil cytoplasmic antibody(ANCA) suggested the existence of an ischemic lesion due to vasculitis. Administration of corticosteroids ameliorated the clinical symptoms and MRI findings. Renovascular angiogram revealed the presence of fibromuscular dysplasia(FMD) at the left renal artery but no malformation was found at the cervical arteries. We discussed the possibility of relationships between myelopathy, FMD, IL-8, and ANCA.

We report a case of fungal meningoencephalitis with steroid-responsive diffuse cerebral white matter lesions. A 49-year-old male developed auditory hallucination, confusion and fever, on April, 1994. He was diagnosed as having cryptococcal meningoencephalitis based on the detection of cryptococcal antigens in the cerebrospinal fluid (CSF). Intravenous administration of fluconazole resulted in improvement of his neurologic symptoms and CSF findings. For the next seven months, he was treated with oral fluconazole and the neurological status was stable. However, soon after the dose of fluconazole was tapered, he became confused and febrile, which made him admitted to our hospital. Neurological examination on admission showed disturbance of consciousness, disorientation and meningeal irritation. The CSF examination revealed mild pleocytosis (mostly lymphocytes), elevated protein and normal glucose levels, although fungus was not detected. The T2-weighted image of brain MRI demonstrated diffuse hyperintense lesions in the bilateral cerebral white matters. GD-DTPA enhanced MRI showed spotty enhanced lesions in the periventricular white matters. The neurologic symptoms were once relieved after intravenous administration of fluconazole was started, but two months later, he became comatose and needed ventilatory support, despite amphotericine B therapy. Then, a needle brain biopsy targeting the white matter lesion was done. Histopathology of the specimen showed chronic inflammation with granuloma formation and T lymphycyte infiltrate around the small vessels, though fungus was not detected in the tissue. Combined therapy with corticosteroid and antifungal agents remarkably improved the neurological symptoms as well as the MRI findings. In the present case, fungal infection possibly induced an altered immune reactions which resulted in the steroid responsive diffuse cerebral white matter lesions.

HTLV-I proviral DNA load is significantly increased in HTLV-I associated myelopathy (HAM) compared with asymptomatic HTLV-I seropositive carriers (SPC), and this spread of HTLV-I infection seems to be critically important in the pathogenesis of HAM. Thus, in this report, cellular immune surveillance against HTLV-I was reviewed. (1) MHC class I-restricted cytotoxic T lymphocytes (CTL) activities are detected in peripheral blood mononuclear cells (PBMC) of HAM. CTL release various proinflammatory and cytotoxic cytokines, chemokines, and proteases. Since CTL are also found in the spinal lesions of HAM, CTL may contribute to the tissue damage. In spontaneous proliferation of PBMC in HAM, CD 4/CD 8 is decreased due to the proliferation of CD 8 + CTL. CD 4/CD 8 is inversely correlated with the clinical severity of HAM. Collectively, CTL may be involved in the pathogenesis of HAM. (2) Activity and subsets of natural killer (NK) cells are lower in HTLV-I-seropositive individuals. Moreover, NK have only a weak cytotoxicity against HTLV-I infected cells. (3) Antibody-dependent cell-mediated cytotoxicity (ADCC) are impaired in HAM compared with SPC due to the suppressed effector cell activity. Since ADCC effectively lyse HTLV-I infected cells in vitro, the impaired ADCC may in part allow the spread of HTLV-I infection in HAM, and potentiation of ADCC may have an anti-HTLV-I therapeutic effect.

To provide histological diagnoses of brain diseases, CT-guided stereotactic brain biopsy (CT-SBB) has been widely used because of its less invasive technique compared with open brain biopsy (OBB). However, CT-SBB is not always diagnostic. We report a case of multiple intracranial tuberculoma whose diagnosis was not made by CT-SBB but by OBB. The patient is a 46-year-old man with insulin-dependent diabetes mellitus who had been receiving immunosuppressive agents (azathioprine, cyclosporin, and prednisolone) after renal transplantation for diabetic renal failure for 9 years. He gradually developed febrile, headache and unsteady gait. Brain MRI demonstrated multiple intracranial lesions involving left fronto-temporal and right parietal lobes, left cerebellar hemisphere, and the fourth ventricle. Although the MRI findings were consistent with those of previously reported cases of intracranial tuberculoma, other conditions, such as malignant lymphoma and toxoplasmosis, were not ruled out. Therefore, CT-SBB targeting the left temporal lobe lesion was done for definitive diagnosis, but it revealed only mild perivascular infiltration of mononuclear cells and hemorrhage. He was transferred to our clinic for further evaluation. On examination, mild truncal and limb ataxia on the left were noted in addition to the neurological findings corresponding to diabetic retinopathy and neuropathy. Despite vigorous laboratory examinations, including repeated bacterial cultures and PCR of cerebrospinal fluid, no evidence of tuberculous infection was obtained. A tentative diagnosis of multiple intracranial tuberculoma was made, and anti-tuberculous drugs (isoniazid 400 mg, ethambutol 750 mg, and pyrazinamide 1.5 g) were administered. Since his symptoms deteriorated because of ventricular dilatation resulting from the enlarged lesion in the fourth ventricle after a temporary clinical improvement, VP-shunting and OBB from the left temporal lobe lesion were done. The excised lesion was firmly encapsulated and the histological examination revealed typical pathology of tuberculoma. Ziehl-Neelsen staining and PCR for Mycobacterium tuberculosis of the biopsied specimen were also positive. Further administration of increased doses of anti-tuberculous drugs (isoniazid 600 mg, ethambutol 500 mg, pyrazinamide 2.0 g and intramuscular injection of streptomycin 0.3 g twice a week) eventually ameliorated the symptoms and shrank the lesions. In case of intracranial tuberculoma, the needle of CT-SBB may not penetrate the firm capsule of tuberculoma and only the surrounding brain tissue may be obtained as in the present case. Therefore, it is recommended to consider OBB from the beginning for definitive diagnosis of intracranial tuberculoma. Paradoxical worsening of the clinical and laboratory findings of tuberculosis in spite of appropriate anti-tuberculous therapy as seen in the present case has been described in both pulmonary and extra-pulmonary tuberculosis. The phenomenon, called transient worsening, could happen and we have to keep it in mind during the treatment of intracerebral tuberculoma.

Most of the patients with Lambert-Eaton myasthenic syndrome (LEMS) are over 40 years of age at onset and have a malignant neoplasm, especially pulmonary small cell carcinoma. Juvenile cases of LEMS are rare and have not been reported in Japan. We report a 21-year-old women whose onset of LEMS was at 17 years of age. In the early stage of the disease, she had limb muscle weakness and was diagnosed has having seronegative myasthenia gravis (MG) based on decrementing response in low frequency repetitive nerve stimulation, positive edrophonium test, and negative serum anti-acetylcholin receptor antibodies. Serum anti-voltage-dependent-calcium-channel (VGCC) antibody was negative with an available assay system. She was thymectomized and received anti-cholinesterases, corticosteroids, and cyclophosphamide, but their therapeutic effects were not evident. Two years later, she was confined to bed due to sever emaciation (Her body weight reduced from 47 Kg to 27 Kg.), bulbar palsy, and limb muscle weakness. She needed respiratory support and tube feeding. Type II fiber atrophy, which is non-specific, but is a common finding in LEMS, was seen in the biopsied muscle of the patient. On the other hand, postsynaptic folds and clefts of all seven motor end-plates in the specimen were normal, which is against the diagnosis of MG. Recently, she was found to have anti-VGCC antibody with an improved assay system. Despite vigorous examination, no malignancy or other autoimmune disorders have been found. 3,4-Diaminopyridine was effective to improve limb muscle powers, but she is still bedridden.

A special version of the House-Tree-Person (H-T-P) technique was developed to differentiate organic psychosis from other disorders. H-T-P data of 126 psychiatric inpatients, including 16 patients with organic psychoses, 50 schizophrenics, 50 borderlines and 10 patients with other psychoses, were evaluated for the presence or absence of 29 possible features of houses, trees and persons. These features included those common to all three objects, as well as those specific to each object. Results for patients with organic psychoses were compared with those of patients with other disorders. The comparison disclosed that seven of the original 29 H-T-P features had diagnostical discrimination among treatment groups, giving higher H-T-P organic scores.

It is well known that inflamed human palatine tonsils have many surface crypts showing characteristic lymphoepithelial symbiosis, which play an important role in immune response. The cryptepithelia are rich in blood vessels. This proliferation of blood vessels is said to be the initiation of various kinds of immune responses. We devised a tonsillar cryptscope in order to observe the tonsillar crypt. Scopy with the cryptscope confirmed seven characteristic types of capillary vessels. The cryptscopic figures showed different patterns in tonsillar diseases such as hypertrophic tonsil, recurrent tonsillitis and tonsil with focal infection (palmoplantar pustulosis and psoriasis vulgaris). In this study the significances of tonsillar cryptscopic figures were investigated through the study of three dimensional structures of blood vessels and immuno-histology. In order to understand the structure of capillary vessels in details, human palatine tonsils were studied using corrosion casting techniques with a scanning electron microscope. Horseshoe type capillary vessels corresponded to the curved capillary vessels in the epithelium. This type of capillary vessel was observed in the epithelia covering the interfollicular area. The tonsillar blood vessels, along with closely related substances in the epithelium and the parenchyma, were immuno-histologically examined. Where the lymphocytes had densely infiltrated the epithelium, the basement membrane became thickened and often disrupted; the endothelial cells were also enlarged. Adrian et al reported that lymphocytes invaded from the capillary vessels within the epithelia. Thus it was suggested that the horseshoe type was related to lymphocyte invasion of the epithelia.(ABSTRACT TRUNCATED AT 250 WORDS)

37 year-old man presented to our clinic because of tetany that occurred during driving a car in the morning. He had no anorexia, chronic diarrhea or vomiting. He was normotensive and no edema was noted. On neurological examination, he was rather apprehensive and Trousseau sign was mildly positive. No muscle weakness was noted except for the moderate atrophies of bilateral anterior tibial muscles as a sequela of Guillain-Barré syndrome that he suffered at the age of 7. The results of laboratory studies included hypokalemia, metabolic alkalosis, hyperuricemia, increased plasma renin activity, increased plasma aldosterone concentration, reduced pressor response to infusion of angiotensin II. Based on these clinical and laboratory findings, the diagnosis of Bartter's syndrome was made. As far as we know, it is extremely rare that Bartter's syndrome manifests tetany alone as in the present case. The exacerbation of preexisting alkalosis by hyperventilation during driving might be the cause of tetany. Tetany was easily provoked by hyperventilation, during which serum ionized calcium remained in normal level despite the exacerbation of alkalosis. The results suggest that alkalosis per se can cause tetany in Bartter's syndrome. Indomethacin, 75 mg daily, effectively prevented tetany from recurring for nearly 4 years without any side effect.

A 64-year-old man was admitted with complaints of lethargy, malaise, weight loss and transient left-hemiplegia and aphasia. Initial physical and laboratory findings showed splenomegaly and pericardial effusion. During his hospital stay, his mental status deteriorated progressively. The characteristic pathology of malignant reticulosis was noted at autopsy. Microscopic examination of the brain demonstrated accumulations of malignant histiocytic cells confined within small vessels and subsequent multiple hemorrhages and necroses in the gray matter. Malignant reticulosis with antemortem manifestations of pericardial effusion and central nervous system involvement is rare.