Koichi Narikawa

Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG

This study investigates the relation between the serological status of NMO (neuromyelitis optica)-IgG and the clinical and MRI features in Japanese patients with multiple sclerosis. Serum NMO-IgG was tested in 35 Japanese patients diagnosed with multiple sclerosis, including 19 with the optic–spinal form of multiple sclerosis (OSMS), three with the spinal form of multiple sclerosis (SMS), and 13 with the conventional form of multiple sclerosis (CMS), which affects the brain. NMO-IgG was detected in 14 patients, 12 with OSMS and 2 with CMS. In these patients, longitudinally extensive (>3 vertebral segments) spinal cord lesions (93% v 57%) and permanent, complete blindness (no perception of light) in at least one eye (50% v 0%) were the noticeable features as compared with NMO-IgG-negative OSMS. The two patients having CMS with NMO-IgG had unusual brain lesions, but in other respects had features suggesting OSMS. NMO-IgG was detected in more than half the number of patients with OSMS and in some patients with CMS. This newly discovered serum autoantibody was markedly associated with longitudinally extensive spinal cord lesions and with complete blindness, suggesting severe optic–spinal disease.

CSF chemokine levels in relapsing neuromyelitis optica and multiple sclerosis

The pathogenesis of relapsing neuromyelitis optica (RNMO) remains unknown. We, for the first time, studied the levels of four chemokines in the cerebrospinal fluid in RNMO with ELISA and compared the data with those in multiple sclerosis (MS) and control. CXCL10/IP-10 and CCL17/TARC were significantly elevated in both RNMO and MS. Conversely, CCL2/MCP-1 was significantly lower in MS, but not in RNMO, than in control. CCL11/Eotaxin was not different between groups. None of the four chemokines studied was significantly different between RNMO and MS.

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.

Periodic episodes of aphasia as an unusual manifestation of partial status epilepticus

Recurrent episodes of aphasia due to partial status epilepticus is an uncommon clinical entity. We report here a 78-year-old-woman with episodic aphasia which occurred periodically. During the ictal period, she was conscious, but had difficulty in speech and could not comprehend verbal commands. The ictal EEG showed continuous spike and sharp waves over the left frontotemporal area. After the administration of antiepileptic drugs, her language activity returned to near the baseline level and the epileptic discharges were significantly reduced. Nonconvulsive partial status epilepticus should be considered in the differential diagnosis of recurrent aphasia, even if the symptoms occur periodically.

Importance of the quotient of albumin, quotient of immunoglobulin G and Reibergram in inflammatory neurological disorders with disease‐specific patterns of blood–brain barrier permeability

There are still insufficient quantitative comparisons of phase‐dependent blood–brain barrier permeability among inflammatory central nervous system disorders.

Soluble CD26 and CD30 levels in CSF and sera of patients with relapsing neuromyelitis optica

Sirs: Relapsing neuromyelitis optica (RNMO) is a rare demyelinating disease in which the optic nerves and spinal cord are selectively and repeatedly targeted [8, 12, 15]. The immuno-pathogenesis of RNMO, distinct from classical multiple sclerosis (MS), remains unknown although recently a serum autoantibody highly specific to NMO (NMO-IgG) was discovered [4] and its diagnostic and pathogenetic roles are being investigated. Since there is evidence that MS is a helper T cell type 1 (Th1)-dominant disease [9, 14], it is of interest to compare Th1/ Th2 balance between RNMO and MS, but such studies are few. CD26 is a dipeptidyl peptidase-IV highly expressed on Th1 cells [2], and CD30 is a member of the tumor necrosis factor/nerve growth factor receptor superfamily preferentially expressed on Th2 cells [1]. Upregulation of CD26 during relapse and CD30 during remission have been reported in MS [3, 7, 13]. We quantified soluble CD26 (sCD26) and sCD30 in the cerebrospinal fluid (CSF) and sera of 13 patients (all women) with RNMO and 17 patients (14 women and 3 men) with MS by sandwich ELISA. The diagnosis was made based on the proposed criteria [6, 15]. The CSF and sera were obtained during relapse of acute myelitis and before methylprednisolone therapy was started. Fourteen patients with non-inflammatory neurological diseases (10 women and 4 men) were also analyzed as controls. RNMO and control patients were older than MS patients. The present study conformed to the guidelines of the institutional ethics committee, and patients gave spoken consent prior to the study. We used a sCD26 ELISA kit (Chemicon International, Temecula, CA) and a sCD30 ELISA kit (Bender Medsystem, Vienna) according to the manufacturers’ instructions. The minimum detectable levels of sCD26 and sCD30 were 11 ng/ml and 0.5 U/ml, respectively. Samples were analyzed undiluted in duplicate. The data in the three patient groups were compared with the KruskalWallis test and post hoc Scheffe test. Correlations were tested by Spearman rank correlation test. P < 0.05 was considered statistically significant. Data in RNMO, MS, and control patients and the statistics are shown in Table 1. The CSF-sCD26 levels were significantly elevated in RNMO and MS compared with control, but those in RNMO and MS were not different (Fig. 1A). Meanwhile, the serum-sCD26, CSFsCD30 and serum-sCD30 were not different between the 3 groups (Fig. 1B–D). There was no difference in CSFor serum-sCD26/ sCD30 ratios between the groups, either (Fig. 2A, B). The CSF-sCD26 levels were significantly correlated with the CSF-total protein levels in RNMO and MS. Our study suggests that a significant intrathecal Th1 response associated with CD26 expression develops during relapse in RNMO and MS but that overall Th1/Th2 balances in these diseases are not very different. Alternatively, it is also possible that differences in blood-CSF integrity have influenced the results as sCD26 and sCD30 levels were higher in serum than in CSF, and sCD26 and sCD30 indices were higher in RNMO and MS than in control but the differences did not reach statistical significance. We recently reported that CXCL10/IP-10, a Th1 chemokine, was significantly elevated in CSF of both RNMO and MS as compared with controls [11]. As for Th2 chemokines, CCL17/TARC was slightly higher in CSF in both demyelinating diseases, but the levels were much lower than the serum levels [11]. CCL2/MCP-1 capable of inducing Th2 polarization was significantly lower in CSF in MS but not in RNMO as compared with the level in controls [11]. These chemokine data are consistent with the present study that revealed a significant Th1 response in both RNMO and MS, though their Th2 responses may differ to some extent. We reported that RNMO lacked an IgG1 response seen in MS and other Th1-dominant diseases [10], and another group has suggested a pathogenic role of humoral immunity, mainly controlled by Th2, in their neuropathological study of NMO [5], suggesting less Th1-dominance in RNMO than in MS. NMO-IgG [4] may also imply the importance of humoral immunity or Th2 response in NMO as compared with MS. The present analysis did not detect such a difference, but further comparative studies on Th1 and Th2 components are needed to clarify unique pathomechanisms in RNMO. LETTER TO THE EDITORS