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We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.

New diagnostic criteria for multiple sclerosis (MS) were recently proposed from the international panel on the diagnosis of MS, and they include exclusion criteria, such as lesions extending over more than two vertebral segments on spinal MRI and CSF pleocytosis of more than 50/mm3. We reviewed the clinical features of 158 patients who satisfied the diagnostic criteria for MS except for having the above atypical paraclinical findings. All patients exhibited two or more clinical attacks and objective clinical evidence of multiple lesions without any evidence of other disorders. Thirty-three (20.9%) patients had one or both atypical paraclinical findings. Twenty-one out of the 33 patients were classified as having optico-spinal MS (OSMS), and the other 12 as non-OSMS patients with atypical large expanding or destructive cerebral, cerebellar or brainstem lesions on MRI as well as one or both atypical paraclinical findings. Based on this heterogeneity in clinical findings in MS, there is an urgent need to develop a common general concept of the "MS" syndromes, and the ethnic-related heterogeneity should be considered in the revised criteria for the diagnosis of MS.

We evaluated the association of the platelet-activating factor receptor (PAFR) gene polymorphism (A224D) with the susceptibility and severity of multiple sclerosis (MS) in a Japanese population. DNA was collected from 162 Japanese patients with clinically definite 'conventional' MS (MS) and 245 healthy controls. The missense mutation A224D that impairs PAF-PAFR signaling was determined by polymerase chain reaction restriction fragment length polymorphism. The frequency of the AD/DD genotypes was significantly higher in MS patients (21.0%) than in healthy controls (13.5%) (p=0.045; odds ratio (OR), 1.71; 95% confidence interval (CI), 1.01-2.89). Moreover, the frequency of D allele in MS patients (11.7%) was also significantly higher than those in healthy controls (6.9%) (p=0.019; OR, 1.78; 95% CI, 1.10-2.89). These findings suggest that the PAFR gene missense mutation has a relation to the susceptibility for MS.

Understanding the spectrum of idiopathic inflammatory demyelinating disorders (IIDD) is a fundamental issue for the diagnosis and treatment of these disorders as well as for the approach to their pathogenesis. The spectrum of IIDD is usually classified according to clinical course and lesion distribution. We compared the demographic features, clinical characteristics, laboratory findings, and genetic backgrounds between 193 Japanese patients with and without clinically or radiographically fulminant attacks who all satisfied the diagnostic criteria for multiple sclerosis (MS). "Fulminant attacks" in the current study represent attack-related clinically or radiologically severe relapses but do not necessarily mean severe disability. Patients with fulminant attacks were clinically and immunogenetically distinct from those free of such attacks, and the previously described characteristics of the opticospinal form of MS (OSMS) or neuromyelitis optica (NMO) were mostly shared by patients with fulminant attacks. HLA profiles were similar among patients with fulminant attacks irrespective of the lesion distributions. The GG homozygous and G alleles of the CTLA4 gene A/G coding SNP at position 49 in exon 1 were significantly more common in patients with fulminant attacks than in those without. Attack-related severity may be an important factor if validated by prospective studies defining criteria and establishing relationships to disease course and treatment regimens.

We evaluated the association of the plasma platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphism (G(994)-->T) and PAF-AH activity with susceptibility and severity of multiple sclerosis (MS) in Japanese. DNA was collected from 216 patients with clinically definite MS (65 opticospinal MS (OS-MS) and 151 conventional MS (C-MS)) and from 213 healthy controls. The missense mutation G(994)-->T that disrupts the PAF-AH activity was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No statistically significant difference in the frequency of genotypes and alleles of the plasma PAF-AH polymorphism was observed among OS-MS patients, C-MS patients and healthy controls. However, the missense mutation tended to be associated with the severity of OS-MS, especially in females (GT/TT genotypes; 51.7% in female rapidly progressive OS-MS vs. 26.6% in female controls, p=0.0870). Moreover, PAF-AH activities were significantly lower in MS than in controls, irrespective of clinical subtypes, among those carrying the identical polymorphism in terms of nucleotide position 994 of the PAF-AH gene. These findings suggest that the PAF-AH gene missense mutation has no relation to either susceptibility or severity of C-MS, yet its activity is down-regulated, and that the mutation has no relation with susceptibility of OS-MS, yet it may confer the severity of female OS-MS.

C-C chemokine receptor 2 (CCR2) is a receptor for chemoattractant protein-1 (MCP-1) and associated with infiltrating lymphocytes in chronic active multiple sclerosis (MS) lesions. To study the role of CCR2 gene in the development of MS, we investigated the CCR2-64I polymorphism in 122 MS patients and 112 healthy controls in a Japanese population. We also analysed the influence of CCR2-64I polymorphism on the clinical course, age at disease onset, and severity. The distribution of the CCR2-64I allele was significantly different between patients and controls (p=0.0187), and the 64I/64I homozygote was significantly less common in MS than in control. Logistic analysis, adjusted for HLA-DRB1*1501-positivity, revealed negative association between the CCR2-64I and MS (p=0.0204). There were no significant associations between CCR2 polymorphism and the clinical features of MS. Our results indicate that the presence of CCR2-64I allele seems to provide protection against the development of MS.

Multiple lines of evidence support the role of genetic factors for susceptibility to multiple sclerosis (MS), although unknown environmental factors must play an important role in developing MS. In this paper, we review the reports studied for the possible associations between Japanese MS and candidate genes by using case-control method. As for HLA alleles, HLA-DRB1*1501 and -DPB1*0501 allele have been confirmed to be associated with conventional MS and opticospinal MS, respectively. Some polymorphisms of vitamin D receptor gene, estrogen receptor gene, CTLA-4 gene, and osteopontin gene were reported to be associated with conventional MS. Appropriate case ascertainment and collection as well as proper statistical method are needed to isolate the susceptibility genes for MS.

In Japan, there is a low prevalence rate (PR) of multiple sclerosis (MS; 0.8-4.0/100,000) but a relatively high frequency of "optic-spinal form" MS (OS-MS). There have been no intensive epidemiologic frequency studies, however, in over 30 years. We performed a province-wide prevalence study of MS in the Tokachi province of Hokkaido, the northernmost island of Japan, and compared the observed clinical features with other populations in Japan and Western countries. Prevalence was determined on March 31, 2001. The primary sources for the case ascertainment were 13 hospitals that treated patients with neurologic diseases including MS in Tokachi. Patients were classified according to Poser's criteria. The prevalence rate of clinically definite or laboratory-supported definite MS (LSDMS) was 8.57 per 100,000 [31/361,726; male/female ratio=1:2.9, and age at onset=29.1+/-14.2 (mean+/-SD) years]. Out of the 31 patients, 5 (16%) were classified as OS-MS. The prevalence rate of MS in the Tokachi province was the highest reported in Orientals to date, although still low in comparison with Western communities at a similar latitude. In contrast to the previous reports in Japan, there was a relatively low frequency of OS-MS in Hokkaido.

Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN are present in brains of patients with multiple sclerosis (MS). The aim of this study was to investigate the role of OPN genes in the pathogenesis of MS. Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C genotype at the 8090th position in exon 6 was more prevalent in MS than in control (p<0.0001), and C allele was more prevalent in MS than in control (p<0.0001, OR=2.57, 95% CI=1.65-4.00). For the 9583rd position polymorphism in exon 7, patients with G/G genotype (age; 32.1+/-12.5 years, mean+/-S.D.) showed a later disease onset than G/A (age; 25.9+/-7.8 years, p=0.01) and A/A (age; 25.2+/-8.9 years, p=0.01) genotypes. There were no significant correlations between OPN gene polymorphisms and disease progression. Our results suggest that the 8090th polymorphism might be associated with susceptibility to MS, while the 9583rd polymorphism might be associated with age of onset of MS.

Background: Oligoclonal IgG bands (OCB) are present in most patients with MS in Western countries; however, in Japanese MS patients, the OCB-positive rate is not as high. A relationship between immunogenetic backgrounds, namely, human leukocyte antigen (HLA) DR2 and DR4 positivity, and OCB production in MS patients from Hokkaido, the northernmost island of Japan, has been previously suggested by the authors., Objectives: To investigate the role of OCB in Japanese MS and to verify the interaction between immunogenetic backgrounds and OCB positivity., Methods: OCB, DR2(15), and DR4 positivity were studied in 45 patients with newly diagnosed MS. In addition to confirming the authors' previous findings, the clinical and demographic features, MRI findings, OCB positivity, and DRB1*15 and DRB1*04 polymorphisms of an expanded data set of 99 MS patients were investigated by using multivariate analysis. Patients with opticospinal MS (OS-MS) were excluded from this study., Results: A relatively low OCB-positive rate (53.3%), HLA-DR15 association with OCB-positive MS (p = 0.0044), and DR4 association with OCB-negative MS (p = 0.0410) were confirmed. DR15 was not associated with OCB-negative MS. Demographic features, disease course, and disability were similar in the OCB-negative and OCB-positive group, whereas there was a preponderance of women in the OCB-positive group. An independent negative association of DRB1*0405 (p = 0.0021, adjusted odds ratio = 0.21) with OCB positivity was found., Conclusions: MS is heterogeneous in its association with HLA alleles, and based on the immunogenetic differences, the MS patients in this population include at least two HLA-related subpopulations with and without OCB.

Interleukin-2 (IL-2) is a cytokine intimately involved with both the function and regulation of the immune system. Genetic analysis of experimental autoimmune encephalomyelitis (EAE) provides strong evidence supporting the candidacy of IL-2 as a susceptibility gene. We investigated the association of two single nucleotide polymorphisms (SNPs) at position -384 in the promoter region and +114 in the first exon of the IL-2 gene through a case-control study involving 113 Japanese patients with multiple sclerosis (MS) and 118 healthy controls. Our results showed no significant differences in the distribution of the two polymorphisms between MS patients and controls. Furthermore, no association was observed between IL-2 gene polymorphisms and clinical characteristics, such as clinical course and age at disease onset. Together, our findings suggest that IL-2 gene polymorphisms do not influence the susceptibility to MS or the clinical characteristics of MS in Japanese patients.

In multiple sclerosis (MS), beta-adrenergic receptor densities on peripheral blood mononuclear cells are enhanced, while the astrocytes present in plaques lack beta2 adrenergic receptor (beta2AR) expression. This differentially altered expression suggests that beta2ARs may influence the pathogenesis of MS. In the present study, we investigated the association of polymorphisms of the beta2AR gene with the occurrence of MS. Our results showed no significant differences in the distribution of the polymorphisms between MS patients overall and control subjects. Furthermore, no association was observed between the presence of beta2AR gene polymorphisms and clinical characteristics, such as age at disease onset and disease severity. While a trend towards an increase of the Gly allele frequency in codon 16 was observed in the secondary-progressive MS, this result was not significantly different from that observed in relapsing-remitting MS patients or control subjects. Together, our findings suggest that the presence of beta2AR gene polymorphisms may be inconclusive in the susceptibility to MS or in the clinical characteristics of Japanese patients with MS and, therefore, need further studies.

Background: The Apo-1/Fas (CD95) molecule is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor (TNF) receptor family. Both Fas and Fas ligand (FasL) are expressed in activated mature T cells, and prolonged cell activation induces susceptibility to Fas-mediated apoptosis. The Apo-1/Fas gene is located in a chromosomal region that shows linkage in multiple sclerosis (MS) genome screens, and studies indicate that there is aberrant expression of the Apo-1/Fas molecule in MS., Methods: Mva I polymorphism on the Apo-1/Fas promoter gene was detected by PCR-RFLP from the DNA of 114 Japanese patients with conventional MS and 121 healthy controls. We investigated the association of the Mva I polymorphism in Japanese MS patients using a case-control association study design., Results: We found no evidence that the polymorphism contributes to susceptibility to MS. Furthermore, there was no association between Apo-1/Fas gene polymorphisms and clinical course (relapsing-remitting course or secondary-progressive course). No significant association was observed between Apo-1/Fas gene polymorphisms and the age at disease onset., Conclusions: Overall, our findings suggest that Apo-1/Fas promoter gene polymorphisms are not conclusively related to susceptibility to MS or the clinical characteristics of Japanese patients with MS.

We investigated PvuII and XbaI polymorphism in the estrogen receptor gene (ERG) and HLA-DRB1*1501 positivity in 116 conventional multiple sclerosis (MS) patients and 101 healthy controls in a Japanese population. Logistic analysis revealed independent associations of [P] allele in the profiles for PvuII (p=0.0005, adjusted odds ratio (aOR)=3.17) and DRB1*1501 (p=0.0089, aOR=2.61) with conventional MS. Synergistic elevated risk of MS due to interaction between the [P] allele and HLA-DRB1*1501 allele was found among female patients (odds ratio=16.0; 95% CI=3.99-63.8, p<0.0001). The [P] allele-positive patients with disease duration of more than 5 years had a significantly higher progression index (PI) of disability (p=0.0230) and a worse ranked MS severity score (p=0.0152) than their non-[P] counterparts.

Vitamin D-binding protein (DBP) is known to function as an immunomodulatory factor, as well as the main carrier of vitamin D. We analyzed the frequencies of two polymorphisms (codon 416 and codon 420) in the DBP gene through a case-control study involving 107 Japanese patients with multiple sclerosis (MS) and 109 healthy controls. None of these polymorphisms showed any association with the occurrence of MS. Furthermore, no association was observed between the DBP polymorphisms and the age at disease onset. These results suggest that DBP does not contribute to the development of MS in Japanese.

In the present study, we have investigated the association of specific polymorphisms of the interleukin (IL)-1beta and IL-1 receptor antagonist (ra) gene with both the susceptibility to and the clinical characteristics of multiple sclerosis (MS) in Japanese patients. We collected and analyzed DNA from 98 MS patients and 104 healthy controls for distribution of IL-1beta or IL-1ra polymorphisms. Our results show no significant differences in the distribution of the polymorphisms between MS patients and controls. Furthermore, no association was observed between IL-1beta or IL-1ra polymorphisms and clinical characteristics, such as age at disease onset, clinical course and severity. Together, our findings suggest that IL-1beta or IL-1ra gene polymorphisms may not be relevant in the susceptibility to MS or the clinical characteristics of Japanese patients with MS.

Despite the strength of the association of multiple sclerosis (MS) and human leukocyte antigen (HLA)-DR2, other genetic elements could have a role in the pathophysiology of MS. We investigated possible associations with polymorphic susceptibility genes located within the HLA complex, i.e., heat-shock protein (HSP)70-1, HSP70-2, and HSP70-hom in Japanese patients with MS. Furthermore, we analyzed the influence of HSP70 gene polymorphisms on the severity of the disease, clinical course, magnetic resonance imaging findings, and oligoclonal bands in the cerebrospinal fluid, and HLA in MS patients. The results of the present study indicated that there were no significant differences in the distribution of all HSP70 genotypes and allele frequencies between Japanese MS patients and controls. In MS patients, there were no associations between HSP70 gene polymorphisms and the clinical data. Moreover, there were no significant differences in HSP70 genotype or allele frequencies between MS patients positive for HLA-DRB1*1501 alleles and matched controls. Our data indicate that HSP70 gene polymorphisms are not relevant in the susceptibility to or the severity of Japanese MS patients.

Macrophage migration inhibitory factor (MIF) is becoming increasingly recognized as an important regulator of immune and inflammatory responses. It is released by activated T lymphocytes and macrophages and up-regulates the proinflammatory activity of these cells. MIF is required for antigen- and mitogen-driven T cell activation, and stimulates macrophages to release cytokines and nitric oxide. On the basis of the recent suggestion that pharmacological modulation of MIF production and neutralization of its activity may have important implications for treatment of a variety of autoimmune or inflammatory conditions, we determined the level of MIF in the cerebrospinal fluid (CSF) of patients with conventional-form multiple sclerosis (C-MS) and optic-spinal form multiple sclerosis (OpS-MS), and neuro-Behçet's disease (NBD). As control, the CSF of patients with non-inflammatory neurological diseases (NIND) was used. The concentration of MIF in CSF samples was significantly elevated in relapsed cases of C-MS (4.13+/-1.07 ng/ml) (mean+/-S.D.) compared with control samples (2.38+/-0.60 ng/ml) (P<0.0001), whereas MIF in the CSF of C-MS patients in remission was not elevated (2.65+/-0.67 ng/ml). The concentration of MIF in the CSF of OpS-MS patients in relapse (5.53+/-1.74 ng/ml) was higher than that of patients with C-MS in relapse (P<0.05). In NBD patients, the concentration of MIF in CSF was significantly elevated (7.47+/-5.61 ng/ml) compared with control samples (P<0.01) and correlated well with cell count in these samples (r=0.910, P<0.005). These results suggest that MIF may play a pivotal role in immune-mediated diseases of the central nervous system, and that MIF may be useful in the study of differences between C-MS and OpS-MS.

Estrogen has been reported to have immunosuppressive functions, and to inhibit the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Since estrogen shows its biological effects via estrogen receptors (ER), we investigate the possible role of ER genes (ERG) in the pathogenesis of MS. PvuII and XbaI polymorphisms in ERG were detected by PCR-RFLP from the DNA of 79 conventional MS patients and 73 healthy controls. The [P] allele in the profiles in PvuII was significantly more prevalent in MS patients than in the controls (P<0.0005). In the study of XbaI polymorphism, the onset age of MS patients with the Xx genotype was earlier than that of the xx genotype group (mean age+/-S.D.; 22.60+/-8.04, and 27.49+/-9.14, respectively) (P<0.05) by ANOVA followed by Fisher's PLSD. Although the Xx genotype group tended to earlier onset age than the XX genotype group (29.60+/-11.10), this difference did not reach. On the basis of these results, PvuII polymorphism might be associated with susceptibility to MS, and XbaI polymorphism with onset age of MS. ERG polymorphism should be further studied in other populations to improve strategies for treatment of MS.

We have previously reported that the association between Bsm I polymorphism, one of the vitamin D receptor genes (VDRG) polymorphism, and multiple sclerosis (MS). In this report, we investigated the further possible role or relevance of VDRG in the pathogenesis of MS. Apa I polymorphism was detected by PCR-RFLP from the DNA of 77 conventional MS patients and 95 healthy controls. The study of the Bsm I and Apa I haplotypes was carried out by employing previously reported Bsm I data. The AA genotype and the [A] allele in the profiles were significantly more prevalent in MS patients than in controls (P=0.0070 and P=0.0321, respectively). In the [A] allele-positive MS patients, the positive rate of DPB1*0501 in HLA was significantly higher than that of the [A] allele-positive controls and that of the [A] allele-negative MS patients even when the corrected P value (P(corr)) was applied (P(corr)=0.0220 and P(corr)=0.0077, respectively). The frequency of DRB1*1501 was higher in the [A] allele-positive patients than in the [A] allele-positive controls and the [A] allele-negative patients (P(uncorr)=0.0431 and P(uncorr)=0.0089, respectively), but the P values did not reach statistical significance after P corrections. The rate of Bsm I and Apa I haplotypes was much higher in bA/bA-positive MS patients than in the controls (P=0.0003), and in the bA positive MS patients, the positive rate of DPB1*0501 was higher than that of the bA-positive controls and that of the bA-negative MS patients (P(corr)=0.0308 and P(corr)=0.0033, respectively). These results indicate that VDRG polymorphism may be associated with susceptibility to MS, and HLA alleles may correlate with risk for MS together with VDRG.

The purpose of this study was to clarify the association of HLA-DRB1 and -DPB1 alleles with multiple sclerosis (MS) in Japanese, to determine whether optico-spinal MS (OS-MS) and conventional MS are immunogenetically distinct, and to verify the role of gender difference in HLA associations of MS. We studied HLA-DRB1 and -DPB1 polymorphisms in 166 Japanese patients with MS. Forty-seven patients were classified as having the optico-spinal MS (OS-MS) and 119 as having conventional MS. A lack of DPB1*0301 and a higher frequency of DPB1*0501 compared with controls (corrected P<0.0074; odds ratio=9.48) were found in OS-MS. By contrast, we found for the first time an association of DPB1*0301 with conventional MS in Japanese (corrected P=0.0444; odds ratio=3.28). Logistic analysis, adjusted for sex and age, revealed independent associations of DPB1*0301 (P=0.0004, adjusted odds ratio (aOR)=4.70), DPB1*0501 (P=0.0081, aOR= 2.50) and DRB1*1501 (P=0.0252, aOR=2.21) with conventional MS. However, the frequencies of DRB1*1501 and DPB1*0501 in male patients with conventional MS were equal to those in male controls while the DPB1*0301 frequency was increased in both male and female patients. We did not find any association of these HLA alleles with disease course and severity. In conclusion, OS-MS is a DPB1*0501-associated distinct subtype of MS, and DPB1*0301 is the most strongly associated allele with conventional MS in Japanese. In addition, gender plays an important role in HLA association with MS.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Although environmental risk factors are clearly involved in MS, the importance of genetic factors has been strongly supported by the results of studies on multiplex families, though a weak association with major histocompatibility complex (MHC) has been the only genetic feature of MS consistently observed to date. Other candidates genes have been pointed out, but none has been confirmed. Recent genome scans suggest that no single MS susceptibility locus is necessary or sufficient to cause MS, and this finding is compatible with a polygenic etiology. Furthermore, MS is a heterogeneous disorder, and thus different genes may influence its course or presentation. Actually, some candidate genes have been proposed, which contribute to the genotype-phenotype interactions in MS.

The polymorphism of the HLA class II genes was investigated in 97 patients with multiple sclerosis (MS) in Hokkaido, the northernmost main island of Japan. Of these, 80 patients were classified as having conventional MS and 17 as having opticospinal MS (OS-MS). Our findings confirmed a previous report that the DPB 1*0501 allele is positively associated with OS-MS (P = 0.0043). The frequency of DPB 1*0501 was also found to be higher in conventional MS patients than in controls (79% vs. 58%, P = 0.0084), although the differences were not statistically significant. Our results indicate that OS-MS is a DPB 1*0501-associated subgroup of MS, and that DPB1*0501 is also correlated with risk of conventional MS in Japanese.

Multiple sclerosis (MS) is widely believed to have a T-cell-mediated autoimmune etiology. The CTLA-4 gene is a strong candidate for involvement in autoimmune diseases because it plays an important role in the termination of T-cell activation. To examine the genetic association of the CTLA-4 gene locus with MS, we analyzed the CTLA-4 gene exon 1 A/G polymorphism in 74 Japanese MS patients and 93 controls. We also investigated the possible interactions of the CTLA-4 gene polymorphism with clinical course and severity, with MRI findings, with another genetic marker-HLA antigens, and with oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). The CTLA-4 exon 1 polymorphism was similar between MS patients and controls. Conversely, clinical disability was significantly more severe in AA homozygous patients than in the other patients, and the allele frequency and the phenotype frequency of the A allele were significantly higher in patients with severe-grade MRI findings of cerebral white matter than in patients with mild-grade MRI findings. The allele frequency and the phenotype frequency of the A allele were significantly higher in patients with OCB than in patients without. This CTLA-4 polymorphism may modulate the prognosis of patients with MS and may be relevant to generation of OCB in the CSF.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active form of vitamin D, exerts an immunosuppressive effect and can completely prevent experimental autoimmune encephalomyelitis (EAE). 1,25(OH)2D3 exerts most of its actions only after it has bound to its specific nuclear receptors. To investigate the possible role of vitamin D receptor gene (VDRG) polymorphism in susceptibility to or disease-modulation of MS, we evaluated 77 Japanese patients with 'conventional' MS and 95 controls. A VDRG allelic polymorphism was assessed by Bsm1 endonuclease restriction after specific PCR amplification. Genotypic polymorphism was clearly defined as BB (absence of restriction site on both alleles), bb (presence of restriction site on both alleles), or Bb (heterozygous). We found overexpression of the b allele (92.9 vs. 84.2%: P=0.0138) and homozygote bb (85.7 vs. 71.6%; P=0.0263) in MS patients compared with controls. The results indicate for the first time an association of MS with VDRG polymorphism, which may be involved in pathogenesis of MS, or in the linkage disequilibrium of VDRG to another pathogenic gene loci. The role of VDR gene polymorphism should be further studied in other populations, and the distribution of other polymorphism, such as Apa I, Taq I, should be also analyzed to confirm another susceptibility gene for MS and to obtain more adequate strategies for treatment of MS.

We compared clinical and demographic features, MRI findings, and HLA profiles of 57 Japanese patients with multiple sclerosis (MS) between groups with and without oligoclonal IgG bands (OCB) in the cerebrospinal fluid (CSF). Patients with the optic-spinal form of MS (OpS-MS) or acute transverse myelopathy (ATM), which are distinctive and relatively common in Japanese MS, were excluded in this study. The OCB-positive rate was only 56.1% (32/57) among these 57 'conventional' MS patients, of whom clinical features were similar to those of Western MS patients. The demographic features, clinical course, disability, and cerebral abnormalities seen on MRI were similar in the OCB-negative and OCB-positive patient groups. HLA-DR2 antigen, which has been confirmed to be associated with MS in many populations, was more common in the OCB-positive than in the OCB-negative and control groups. Furthermore, DR4 antigen was statistically more common in the OCB-negative patient group. These results raise the possibility that the presence of OCB is related to the immunogenetic background of the patient, and that there may be at least two subpopulations in Japanese patients with 'conventional' MS from the viewpoint of immunogenetics. In one subpopulations, MS is associated with the DR2 antigen, and shows a stronger humoral immune response in the CSF, while in the other MS is associated with DR4, which has a milder humoral response. Further investigations involving more patients are warranted.

Facial palsy occurred in 21 (19.6%) of 107 Japanese patients with multiple sclerosis (MS) during a mean follow-up period of 4.3 years. We observed residual signs of facial palsy in five other patients in whom acute onset was confirmed from medical records. Facial palsy began on average 7.6 years after the onset of MS but in five patients (4.7%) was the first symptom of MS, preceding the next MS symptom by 0.5-3 years. Facial palsy was usually associated with other brainstem signs, while two patients showed only facial palsy 1 and 3 years after the onset of MS. Twenty-one (84.0%) of the 25 patients who underwent brain magnetic resonance imaging (MRI) showed brainstem lesions in the pontine tegmentum ipsilateral to the facial palsy. However, the two patients without other symptoms or signs had no apparent causal lesion on MRI, which suggests difficulty in differentiating idiopathic Bell's palsy from MS- associated facial palsy by MRI, although it has an excellent capacity to detect causal lesions of facial palsy associated with MS.

We found anti-nuclear antibodies (ANA) (1:20 or higher) in sera from 11 of 16 patients with a diagnosis of the optic-spinal form of multiple sclerosis (OpS-MS) and 13 of 59 patients with other forms of MS (other MS), both rates being significant (P = 0.0004). Six of the OpS-MS patients had a high level of ANA (1:80 or higher), while levels were high in only three of the other MS patients, showing a significant difference (P = 0.0022). Titres of ANA were significantly higher in OpS-MS patients than in other MS patients (P < 0.0001). There was no relationship between the presence of ANA and age in OpS-MS patients, while patients with were older than those without high ANA levels among other MS patients. ANA-positive rate and titres were significantly higher in OpS-MS patients than in sex- and age-matched other MS patients. These results support the concept that OpS-MS constitutes a distinct subgroup among patients with a clinical diagnosis of MS and may indicate that systemic dysregulation of the inflammatory or immune response is more common in OpS-MS patients; the possible pathogenetic relevance of ANA-associated vasculopathy to some patients with a clinical diagnosis of OpS-MS should be considered.

The serum concentrations of total, free and acylcarnitine were compared in 25 patients with multiple sclerosis (MS) and among age- and sex-matched normal controls by the new enzymatic cycling method in order to clarify whether the fatigue in MS might be due to possible carnitine-related fatty acid metabolic abnormalities in the mitochondria of skeletal muscles. Patients with MS were divided into those with and those without excessive fatigue. Levels of total and free carnitine were not significantly different between MS patients and normal controls. Levels of acylcarnitine, whose decrease in chronic fatigue syndrome has been reported, were also similar between MS patients and normal controls. There was no difference in these carnitine levels between MS patients with and without excessive fatigue. We argue that acylcarnitine deficiency and fatty acid metabolic dysfunction in mitochondria are not relevant to the excessive fatigue in patients with MS, and further explanatory investigations are to be sought.

The level of macrophage inflammatory protein-1 alpha (MIP-1 alpha), a newly discovered cytokine of chemokine family, was determined in cerebrospinal fluid (CSF) from 18 patients with multiple sclerosis (MS) and from control patients with other neurological disorders by an enzyme-linked immunosorbent assay (ELISA). The concentration of MIP-1 alpha in CSF was significantly elevated in MS in relapse (4.4 pg/ml) compared with non-inflammatory neurological disease control samples (0.3 pg/ml) (p < 0.0002). These concentrations in MS patients correlated well with leukocyte cell counts and protein content in CSF (r = 0.845, p < 0.0001; r = 0.853, p < 0.0001, respectively). In other inflammatory neurological disorders such as Behçet's disease and HTLV-1 associated myelopathy, significantly increased CSF levels of MIP-1 alpha were also observed. Chemokines are reported to play an important role in an early event of inflammation such as lymphocyte traffic. This report is the first study which confirmed the involvement of a chemokine in MS and other inflammatory neurological disorders.

A case of multiple sclerosis (MS) associated with granulomatous panuveitis was reported. A 45-year-old woman developed diplopia in 1972, at age 24, optic neuritis in 1974 and acute transverse myelopathy in 1981. Subsequently, while being under our care with the clinical diagnosis of MS, right abducens palsy in 1989, deterioration of paraparesis with remission in 1991, and weakness of left arm in 1992 occurred. CSF study revealed high IgG index and brain MRI showed multiple abnormal intensity areas in the deep white matter and periventricular areas bilaterally. On the beginning in March, 1993, she noticed left hazy vision and the ophthalmological examinations revealed marked mutton-fat like keratic precipitates, posterior synechiae, cells and flare in anterior chamber, retinal phlebitis and snow ball vitreous opacity. Granulomatous panuveitis was diagnosed and treated by topical steroid with improvement within two months. During this episode, no neurological deterioration was seen. Granulomatous uveitis in MS was rarely documented in the literatures, but this seems to be more common in women, mildly symptomatic or asymptomatic and responds well to topical steroid treatment.

We evaluated circulating anticardiolipin antibodies (aCL) in 38 Japanese patients who fulfilled the criteria of clinically definite multiple sclerosis (MS), using a newly developed EIA system with aCL-cofactor. Two of 38 patients (5.3%) had a aCL-cofactor-dependent positive serology, and differences compared with findings in controls were statistically significant. The 2 aCL-positive patients had similar clinical features with acute transverse myelopathy (ATM), optic neuropathy (OPN), normal cranial MRI and negative oligoclonal IgG bands (OCBs) in the cerebrospinal fluid (CSF). Among the 38 patients, 3 had ATM, OPN, normal cranial MRI and negative OCBs, hence, in a significant number of the patients (2/3; 67%) with these distinctive features, serology for aCL was positive. Therefore, they may have another condition associated with aCL, masquerading as MS. Serological testing for aCL with aCL-cofactor is recommended for the patients with clinical diagnosis of MS, especially for those showing OPN and ATM during the clinical course, and in Asian peoples where the incidence of ATM and OPN is relatively high among the patients with diagnosis of MS.

We analyzed the cerebrospinal fluid (CSF) IgG profiles of 46 Japanese patients with relapsing and remitting types of multiple sclerosis (MS). There were 12, 13 and 21 patients, with inactive, active and both clinical conditions, respectively. The values for IgG, IgG/Alb ratio, IgG index and IgG synthesis rate were significantly higher during active than during inactive stages, but the patients with high values for these IgG profiles during active stages tend to also have high values during inactive stages. None of 33 (0%) and 2 of 34 patients (5.9%) exhibited abnormal IgG levels, 3 (9.1%) and 8 (23.5%) an abnormal IgG/Alb ratio, 9 (27.3%) and 18 (52.9%) an abnormal IgG index, and 5 (15.2%) and 14 (41.2%) an abnormal IgG synthesis rate, during inactive and active stages, respectively. Some of HLA antigen frequencies were significantly different between the patients with and without abnormal CNS IgG profiles. Increased CSF IgG was of lesser diagnostic value for MS in Japan, and seemed to be a function of immunogenetics rather than clinical activity.

We studied HLA haplotypes in 43 consecutive clinically definite MS patients in Hokkaido. The patients were classified into Group A, 12 patients with acute transverse myelopathy (ATM) during the course of illness, and Group B, 31 without ATM. We found an association with HLA-DQw7 in Group A, and with DR4 and DRw8 in Group B. The frequency of DQw7 and DR4 were significantly different between Groups A and B. This study may indicate the different genetic backgrounds between the groups. DRw8 and DRw52 antigens were significantly more common in MS than in controls. Our result is inconsistent with previous Japanese studies, and ethnic variation might be considered as a possible cause of the contradiction.

We classified clinically definite multiple sclerosis (MS) patients who underwent brain MRI with superconductive magnet into 2 subgroups: group A, consisting of 14 patients who had shown acute transverse myelopathy (ATM) during the course of illness; and group B, 35 patients without ATM, and the same neuroradiologist, blinded to clinical profiles of the patients, investigated the MR scans. We analyzed some parameters such as distribution, size, shape and number of the lesions. Although the total number of lesions were similar in each group, and the number of small size or patchy shape solitary lesions were not different, the moderate, large, ovoid or confluent lesions were lower in number in group A, compared with group B. The degree of cerebral white matter lesions and periventricular lesions were higher in group B. Brainstem lesions were significantly less common in group A. These results show characteristic differences in MR-detected, possibly pathological, changes between these 2 groups, and support our previous report that group A may constitute a distinct subgroup in patients with MS.

We analyzed the clinical features of multiple sclerosis (MS) prospectively seen between July 1986 and October 1989 on Hokkaido island, the northernmost part of Japan. Clinical features were generally considered to be intermediate between the previous Japanese reports and those of Western countries. Devic's disease was rare and simultaneous bilateral visual loss at on set was not too common this series, differing from that previously reported of Japanese MS. The high incidence of acute transverse myelopathy and lesser involvement of the cerebellum, however, support the previous view. Further clinical and epidemiological studies will be necessary on this island.

A 26-year-old woman developed two separate episodes of myelopathy mainly presenting paraparesis. Neurologic examination disclosed flaccid paraparesis associated with slight spasticity of the right arm. Deep tendon reflexes were generally hyperactive with positive bilateral Babinski and Chaddock reflexes. Arm pronation sign and Barré leg signs were bilaterally positive. Sensory disturbance below T6, and diminished vibration and position sense in both legs were seen. Urinary and fecal disturbances were also present. She could walk, but her gait was unsteady. Brain MRI showed abnormal high signal intensity areas on T2-weighted image at the left fronto-parietal lobe and right temporo-parietal lobe. Spinal MRI disclosed a cavity formation which was delineated low signal intensity on T1-weighted image through T4 to T8 and high signal intensity on T2-weighted image through T3 to T10. From these clinical manifestations and radiological findings, she was able to be diagnosed to have definite MS. The coexistence of syrinx formation in MS has rarely been reported, and only 5 cases including our case were found. These cases are characterized by the central localization of syrinx, and fair prognosis in their neurological features.

Sixty-two consecutive patients with clinically definite multiple sclerosis (MS) were classified into 2 subgroups: group A, consisting of 16 patients who had shown acute transverse myelopathy (ATM) during the course of illness; and group B, 46 patients without ATM. The clinical features of these 2 groups were analysed prospectively for certain periods, and some significant differences were found. There was (1) later onset, (2) less frequent occurrence of brain stem, cerebellar and cerebral symptoms, (3) more frequent and severe involvement of the optic nerve, (4) a smaller proportion of patients with abnormal findings on brain MRI in group A compared with group B. The clinical features of group B were quite similar to those of previous Western series, while group A seemed to constitute a distinct clinical subgroup in patients with MS.

We documented a case of systemic lupus erythematosus with clinical features of multiple sclerosis who developed transverse myelopathy. Magnetic resonance imaging showed the presence of an abnormal high signal intensity in the gray matter of a swollen spinal cord corresponding to the patient's neurological deficits. After two previous episodes of exacerbation and remission consistent with the clinical diagnosis of multiple sclerosis, right hemiparesis and hemisensory disturbances ensued, then lupus nephritis was confirmed by a renal biopsy.

Recent introduction of Computed Tomography (CT) in clinical neurology made it possible to visualize the brain lesion without any invasive procedures. In multiple sclerosis (MS), the demyelinating foci were reported to be observed as low density areas on CT, but occasionally contrast enhanced high density areas were reported also. So far as we know, only a few reports which analysed interrelationship between clinical signs and CT findings were published. In this report we tried to examine the correlation of clinical findings with CT in MS. All scans were performed using an EMI head scanner (EMI 1000) with a 160 X 160 matrix. Contrast material was administered as an intravenous bolus of 60% meglumine iothalamate. In clinically definite 14 MS patients, CT showed localized, circumscribed low density areas in 4 patients, periventricular low density in 1 patient, widening of cortical sulci with ventricular dilatation in 11 patients and no abnormalities in 3 patients. The widening of cortical sulci with ventricular dilatation were noted to be particularly common findings. The periventricular low density was not so frequently seen as we expected. Localized, circumscribed low density areas on CT were well correlated with the neurological findings in 2 patients. In these cases the abnormalities on CT persisted in spite of neurological improvement. As a conclusion, we think CT might be useful as a diagnostic evaluation of MS.

Human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) and tropical spastic paraparesis belong to a new group of neurological diseases associated with retroviral infection. An HTLV-I-like virus has recently been implicated in multiple sclerosis as well. We studied paired cerebrospinal fluid and serum specimens from HAM and multiple sclerosis patients by isoelectric focusing and an isoelectric focusing HTLV-I p24 overlay technique to clarify the role of HTLV-I in these diseases. We detected oligoclonal bands by isoelectric focusing with silver-staining in cerebrospinal fluid, but not serum, from all 5 HAM and all 9 multiple sclerosis patients. An isoelectric focusing HTLV-I p24 overlay technique demonstrated anti-p24 antibody in HAM cerebrospinal fluid at a different pI distribution than that seen in paired serum, indicating local synthesis of anti-p24 antibody within the central nervous system. Oligoclonal bands in HAM cerebrospinal fluid corresponded in pI distribution to anti-p24 antibody activity, suggesting the presence of an ongoing HTLV-I infection in the central nervous system. Multiple sclerosis patients had no evidence of anti-HTLV-I activity by p24 radioimmunoprecipitation assay, Western immunoblots, or isoelectric focusing HTLV-I p24 overlay analysis. Our data support a role for HTLV-I as an etiological agent in HAM, but not in multiple sclerosis.

To test possible association of human T cell leukemia virus type 1 (HTLV-1) with multiple sclerosis (MS), polymerase chain reaction was applied to detect HTLV-1 DNA integrated into peripheral blood mononuclear cell DNA. Nine Japanese MS patients all gave a negative result, indicating no HTLV-1 infection in these MS patients.