Juichi Fujimori

Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and transverse myelitis. The relationship of NMO to multiple sclerosis (MS) has long been debated, but NMO has been classified as a demyelinating disease. Since the discovery of an NMO‐specific autoantibody to aquaporin 4 (AQP4), a dominant water channel in the central nervous system densely expressed on end‐feet of astrocytes, the clinical, magnetic resonance imaging and laboratory findings to distinguish NMO from MS have been clarified. Furthermore, pathological studies showed an extensive loss of immunoreactivities to astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), and perivascular deposition of immunoglobulins and activated complements with a relative preservation of the staining of myelin basic protein (MBP) in acute NMO lesions, but not in MS. In support of these pathological findings, the GFAP levels in the cerebrospinal fluid (CSF) during acute exacerbation of NMO are remarkably elevated compared with MBP and neurofilament, whereas the CSF‐GFAP in MS is not different from those in controls. Additionally, recent experimental studies have convincingly shown that AQP4 antibody is pathogenic in causing astorocytic destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that damage of astrocytes is far more severe than those of myelin and neurons, and that autoimmune astrocytopathy is the primary pathology in NMO. Based on these accumulated data, we propose that NMO should be classified as an astrocytopathic disease rather than a demyelinating disease.

CSF-chemokines in HTLV-I-associated myelopathy: CXCL10 up-regulation and therapeutic effect of interferon-α

We measured four chemokines in the cerebrospinal fluid (CSF) in human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) with ELISA. CXCL10/IP-10, a T cell type 1 (Th1)-associated chemokine, was significantly elevated in HAM/TSP compared with controls, and the values were even significantly higher in HAM/TSP than in multiple sclerosis (MS) in which CXCL10/IP-10 up-regulation was previously reported. Among Th2-associated chemokines, CCL17/TARC and CCL11/Eotaxin in HAM/TSP were not different from those in controls. As shown in MS, CCL2/MCP-1 was significantly lower in HAM/TSP than in control. Following interferon (IFN)-alpha therapy in HAM/TSP, CCL2/MCP-1 became significantly higher than that before therapy, which may reflect a Th2 induction, while CXCL10/IP-10 remained elevated.

Absence of IgG1 response in the cerebrospinal fluid of relapsing neuromyelitis optica

The authors studied immunoglobulin (Ig) G subclasses in the CSF and sera of patients with relapsing neuromyelitis optica (RNMO) and typical multiple sclerosis (MS). Although the total IgG concentrations were elevated in the CSF of patients with RNMO and MS, IgG1% and IgG1 index were significantly elevated only in patients with MS. The absence of the CSF IgG1 responses in the patients with RNMO may suggest less Th1 immunity and may also explain the rarity of oligoclonal IgG bands in patients with this disease.

Chemokine profile in the cerebrospinal fluid and serum of Vogt–Koyanagi–Harada disease

We analyzed the concentrations of four chemokines in the cerebrospinal fluid (CSF) and sera in Vogt-Koyanagi-Harada disease (VKH), an autoimmune uveomeningitis syndrome against melanocyte-associated proteins, with ELISA. CSF-CXCL10/IP-10 and CSF-CCL17/TARC were significantly elevated in VKH than in controls. In the majority of VKH cases and controls, CSF-CXCL10 was higher than serum-CXCL10, and CSF-CCL17 was lower than serum-CCL17. CCL11/Eotaxin was not different between groups. CSF-CCL2/MCP-1 was significantly lower in VKH than in control. The changes in VKH were essentially similar to those in multiple sclerosis, a known Th1-dominant condition.

Relevance of callosal and periventricular MRI lesions to oligoclonal bands in multiple sclerosis

Objectives –  To evaluate the association between callosal or periventricular lesions, and the presence of oligoclonal IgG bands (OB) or the IgG index in Japanese patients with multiple sclerosis (MS).

Bilateral frontal cortex encephalitis and paraparesis in a patient with anti-MOG antibodies.

Encephalitis seldom causes paraparesis as the initial symptom. Here, we report a case of steroid-responsive bilateral frontal cortical encephalitis involving leg motor areas in a patient who presented with paraparesis on admission. Interestingly, the initial paraparesis evolved into an acute disseminated encephalomyelitis (ADEM)-like illness and optic neuritis, and the patient was found to be positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. A 46-year-old man experienced transient dizziness in early September 2008. Brain MRI retrospectively showed a slight fluid attenuation inversion recovery (FLAIR) high-intensity lesion involving the left frontal cortex (figure 1). One week later, the patient experienced a focal motor seizure in the right leg that subsequently generalised. Thereafter, he gradually developed headache and paraparesis over the course of a week. On admission, he presented with paraparesis without other neurological deficits, but the spinal MRI was normal. An electroencephalogram revealed that there were no epileptic discharges. A cerebrospinal fluid (CSF) examination revealed elevated leucocytes (56 /µL; 93% mononuclear cells, 3% polymorphonuclear leucocytes) and normal protein (36 mg/dL) and glucose (59 mg/dL) levels. The myelin basic protein (MBP) and glial fibrillary acidic protein levels in the CSF were not elevated. Cell-based assays for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, anti-voltage-gated potassium channel (VGKC) antibodies, anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibodies and anti-γ-aminobutyric acid-B receptor (GABA(B)R) antibodies in the CSF were negative. Blood and CSF examinations for infectious central nervous system (CNS) CNS diseases, collagen diseases, vasculitis, Behcet disease, sarcoidosis, lymphoma, paraneoplastic syndrome, vitamin B deficiency and Hashimoto encephalopathy were unremarkable. Figure 1 Upper panel: axial fluid attenuation inversion recovery (FLAIR) images (1.5 T; TR 6000 ms, TE 105 ms). (A) Brain MRI at …

Validation of the Brief International Cognitive Assessment for Multiple Sclerosis in Japan

Background The Brief International Cognitive Assessment for MS (BICAMS) is a practical battery for measuring cognitive function in multiple sclerosis (MS). Objectives We aimed to validate a Japanese version of the BICAMS in patients with MS and healthy controls. Methods The Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-Second Edition (CVLT2) and the Brief Visuospatial Memory Test Revised (BVMTR) were administered to 156 patients with MS and 126 healthy controls (HCs). The BICAMS was re-administered in a subset of 27 MS patients and 30 HCs. Results The mean (±SD) raw scores in the MS and HC groups were as follows: SDMT: MS 47.9 ± 14.0, HC 61.0 ± 9.5; CVLT2: MS 48.6 ± 12.6, HC 55.7 ± 10.5; BVMTR: MS 23.5 ± 8.4, HC 28.3 ± 5.4, respectively, and significant differences were found between the two groups on all tests (p < 0.0001). Cohen’s d values were 1.07, 0.60, and 0.67 in SDMT, CVLT2, and BVMTR, respectively. The test-retest reliability coefficients for each test were as follows: SDMT: r = 0.93; CVLT2: r = 0.82; and BVMTR: r = 0.77 (p < 0.0001). Conclusions This study provides results that support the reliability and validity of the BICAMS in Japan.

Cerebrospinal fluid CXCL13 is a prognostic marker for aseptic meningitis

In exceptional cases, patients with aseptic meningitis eventually develop aseptic meningoencephalitis. To find a candidate marker for the development of aseptic meningoencephalitis in adult patients diagnosed with aseptic meningitis, we compared 12 different cytokines/chemokines in cerebrospinal fluid (CSF) from 5 patients with aseptic meningoencephalitis, 8 patients with aseptic meningitis, and 8 patients with control disease. Only the CXCL13 concentration was significantly elevated in the CSF of the group with aseptic meningoencephalitis compared with the group with aseptic meningitis. Thus, CSF CXCL13 may be a useful marker for predicting the prognosis of aseptic meningitis.

Retrospective analysis of Guillain–Barré syndrome and Fisher syndrome after the Great East Japan Earthquake

Guillain‐Barré syndrome (GBS) and Fisher syndrome (FS) are immune‐mediated peripheral neuropathies, and most of these cases were known to be associated with a preceding infection. Recent reports evidenced an increase in the number of infectious disease cases after the earthquake. The aim of this report is to investigate the incidence and clinical features of GBS and FS after the Great East Japan Earthquake. We found GBS and FS patients had markedly increased in 2011, the year of the earthquake. In regard to an antecedent illness, gastrointestinal infection was significantly increased in GBS patients after the earthquake. These results suggest environmental factors including infectious agents and stress caused by the earthquake might have been involved in the outbreak of the diseases.

Epitope Analysis of Cerebrospinal Fluid IgG in Japanese Multiple Sclerosis Patients Using Phage Display Method

To investigate the antigen recognized by cerebrospinal fluid (CSF) high affinity IgG in patients with multiple sclerosis (MS), the phage display method was applied to the CSF from 15 MS and 10 control patients. Peptide sequences recognized by MS and control CSF IgG were individual specific, and no common motif was found. Peptide sequences frequently showed homology to various kinds of amino acid sequences of ubiquitous viruses such as epstein barr virus (EBV) and herpes simplex virus (HSV), although the frequency was not specific to MS patients. MS CSF IgG may recognize various types of ubiquitous viral antigen and may be increased by a bystander response.