SNP-based analysis of the HLA locus in Japanese multiple sclerosis patients.

Although several major histocompatibility complex (MHC)-wide single-nucleotide polymorphism (SNP) studies have been performed in populations of European descent, none have been performed in Asian populations. The objective of this study was to identify human leukocyte antigen (HLA) loci associated with multiple sclerosis (MS) in a Japanese population genotyped for 3534 MHC region SNPs. Using a logistic regression model, two SNPs (MHC Class III SNP rs422951 in the NOTCH4 gene and MHC Class II SNP rs3997849, susceptible alleles A and G, respectively) were independently associated with MS susceptibility (204 patients; 280 controls), two (MHC Class II SNP rs660895 and MHC Class I SNP rs2269704 in the NRM gene, susceptible alleles G and G, respectively) with aquaporin-4- (AQP4-) MS susceptibility (149 patients; 280 controls) and a single SNP (MHC Class II SNP rs1694112, susceptible allele G) was significant when contrasting AQP4+ against AQP4- patients. Haplotype analysis revealed a large susceptible association, likely DRB1*04 or a locus included in the DRB1*04 haplotype, with AQP4- MS, which excluded DRB1*15:01. This study is the largest study of the HLA's contribution to MS in Japanese individuals.

Positional relationship between recurrent intracerebral hemorrhage/lacunar infarction and previously detected microbleeds.

BACKGROUND AND PURPOSE: Although MBs, ICH, and LI are secondary to cerebral microangiopathy, it remains unclear whether the location of subsequent ICH/LI corresponds to the previous location of MBs. We performed this study to clarify the positional relationship between recurrent ICH/LI and previously detected MBs. MATERIALS AND METHODS: We evaluated patients with recurrent ICH/LI who had MBs, as shown on prior T2*-weighted MR imaging. We assessed retrospectively whether the location of recurrent ICH/LI corresponded to that of the prior MB. Patients with ICH were divided into the deep ICH group and the lobar ICH group, and the positional relationship between hematoma and previously detected MBs was evaluated. RESULTS: A total of 55 patients, including 34 with recurrent ICH and 21 with recurrent LI were evaluated. Although the location of the LI corresponded to prior MBs in only 1 patient (4.8%), the location of ICH corresponded to prior locations of MBs in 21 patients (61.8%) (OR, 32.3; 95% CI, 3.86-270.3; P < .001). Among the patients with ICH, the correspondence ratio was higher in the deep ICH group (19 of 24 patients, 79.2%) than in the lobar ICH group (2 of 10 patients, 20%) (OR, 15.2; 95% CI, 2.42-95.3; P < .002). CONCLUSIONS: The close positional association between recurrent ICH and prior MBs suggests that MBs represent hemorrhage-prone microangiopathy. In addition, different correspondence ratios between the deep ICH group and the lobar ICH group may be attributable to their different pathogenesis.

Temporal changes and geographical differences in multiple sclerosis phenotypes in Japanese: nationwide survey results over 30 years.

BACKGROUND: There are two distinct phenotypes of multiple sclerosis (MS) in Asians, manifesting as optic-spinal (OSMS) and conventional (CMS) forms. In Japan, four nationwide surveys of MS have been conducted. The first three were in 1972, 1982, and 1989, and we performed the fourth in 2004. RESULTS: The recent survey showed six main findings as follows: (1) a four-fold increase in the estimated number of clinically definite patients with MS in 2003 (9900; crude MS prevalence, 7.7/100,000) compared with 1972; (2) a shift in the peak age at onset from early 30s in 1989 to early 20s in 2003; (3) a successive proportional decrease in optic-spinal involvement in clinically definite patients with MS; (4) a significant north-south gradient for the CMS/OSMS ratio; (5) after subdivision of the mainland (30-45 degrees North) into northern and southern parts at 37 degrees N, northern-born northern residents (northern patients) showed a significantly higher CMS/OSMS ratio and higher frequency of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) than southern-born southern residents (southern patients); (6) among northern patients, the absolute numbers of patients with CMS and those with Barkhof brain lesions rapidly increased with advancing birth year. CONCLUSIONS: These findings suggest that MS phenotypes are drastically altered by environmental factors, such as latitude and "Westernization."

Association between cerebral microbleeds on T2*-weighted MR images and recurrent hemorrhagic stroke in patients treated with warfarin following ischemic stroke.

BACKGROUND AND PURPOSE: Although accumulating evidence suggests the presence of microbleeds as a risk factor for intracerebral hemorrhage (ICH), little is known about its significance in anticoagulated patients. The aim of this study was to determine whether the presence of microbleeds is associated with recurrent hemorrhagic stroke in patients who had received warfarin following atrial fibrillation-associated cardioembolic infarction. MATERIALS AND METHODS: A total of 87 consecutive patients with acute recurrent stroke, including 15 patients with ICH and 72 patients with cerebral infarction, were enrolled in this study. International normalized ratios (INRs), vascular risk factors, and imaging characteristics, including microbleeds on T2*-weighted MR images and white matter hyperintensity (WMH) on T2-weighted MR images, were compared in the 2 groups. RESULTS: Microbleeds were noted more frequently in patients with ICH than in patients with cerebral infarction (86.7% versus 38.9%, P = .0007). The number of microbleeds was larger in patients with ICH than in patients with cerebral infarction (mean, 8.4 versus 2.1; P = .0001). INR was higher in patients with ICH than in patients with cerebral infarction (mean, 2.2 versus 1.4; P < .0001). The frequency of hypertension was higher in patients with ICH than in patients with cerebral infarction (86.7% versus 45.8%, P = .0039). Multivariate analysis revealed that the presence of cerebral microbleeds (odds ratio, 7.383; 95% confidence interval, 1.052-51.830) was associated with ICH independent of increased INR and hypertension. CONCLUSION: The presence of cerebral microbleeds may be an independent risk factor for warfarin-related ICH, but more study is needed because of strong confounding associations with elevated INR and hypertension.

Plasma total homocysteine levels are associated with advanced leukoaraiosis but not with asymptomatic microbleeds on T2*-weighted MRI in patients with stroke.

Both leukoaraiosis and asymptomatic microbleeds are associated with small-artery diseases. Although an association between hyperhomocysteinemia and leukoaraiosis has been reported, no studies have evaluated the association between total homocysteine (tHcy) level and presence of microbleeds in stroke patients. We evaluated the association between tHcy level and leukoaraiosis or microbleeds in stroke patients. In 102 patients with stroke (69.5 +/- 10.3 years old, 54 men and 48 women), microbleeds on T2*-weighted MR images were counted, leukoaraiosis on T2-weighted images was graded and fasting plasma tHcy concentrations were measured. Plasma tHcy level was significantly higher in patients with advanced leukoaraiosis than in those without advanced leukoaraiosis (13.9 +/- 4.6 micromol/l vs. 10.2 +/- 3.4 micromol/l, P < 0.0001). Plasma tHcy level was not significantly different in patients with microbleeds and those without microbleeds (11.3 +/- 4.1 micromol/l vs. 11.4 +/- 4.3 micromol/l, P = 0.9441). Elevated tHcy level is significantly and independently associated with advanced leukoaraiosis [odds ratio (OR), 1.330; 95% CI, 1.130-1.565] but not with the presence of microbleeds. Elevated tHcy level appears to be associated with ischemic small-artery disease rather than with bleeding-prone small-artery disease.

Combinations of the presence or absence of cerebral microbleeds and advanced white matter hyperintensity as predictors of subsequent stroke types.

BACKGROUND AND PURPOSE: Previous studies have shown microbleeds to be a risk factor for intracerebral hemorrhage and white matter hyperintensity (WMH) to be a risk factor for ischemic stroke. This study was performed to determine whether combinations of the presence or absence of microbleeds and advanced WMH are risk factors for subsequent recurrent stroke types. METHODS: In 266 patients with stroke, microbleeds on T2*-weighted MR images were counted, and WMH on T2-weighted images was graded. Patients were divided into 4 groups by the combinations of the presence or absence of microbleeds and advanced WMH and were followed up for stroke recurrence. RESULTS: During a mean follow-up period of 564.8 +/- 220.5 days, 26 patients developed recurrent strokes, including 10 intracerebral hemorrhages and 16 ischemic strokes. Patients with microbleeds without advanced WMH (n = 42) developed only intracerebral hemorrhages (n = 8), and the recurrence rate of intracerebral hemorrhage in those patients estimated by the Kaplan-Meier method was the highest in the 4 groups (14.3% in 1 year and 21.2% in 2 years). In contrast, patients with advanced WMH without microbleeds (n = 39) developed only ischemic strokes (n = 6), and the estimated recurrent rate of ischemic stroke in those patients was the highest in the 4 groups (10.5% in 1 year and 17.4% in 2 years). Cox proportional hazards regression analysis revealed that microbleeds were associated with intracerebral hemorrhage (hazard ratio [HR], 85.626; 95% confidence interval [CI], 6.344-1155.649) and that advanced WMH was negatively associated with intracerebral hemorrhage (HR, 0.016; 95% CI, 0.001-0.258). Advanced WMH was associated with ischemic stroke (HR, 10.659; 95% CI, 2.601-43.678). CONCLUSION: It appears that patients at high risk of subsequent intracerebral hemorrhage or ischemic stroke can be identified by combinations of the presence or absence of microbleeds and advanced WMH.

Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease.

BACKGROUND: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. OBJECTIVE: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. METHODS: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. RESULTS: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. CONCLUSION: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Significance of serum soluble thrombomodulin level in acute cerebral infarction.

The purpose of the present study was to investigate sequential changes in serum soluble thrombomodulin (sTM) concentrations in patients with acute cerebral infarction (ACI), and to correlate sTM concentrations with the severity of ACI evaluated by Japan Stroke Scale. Eighty-three consecutive patients with ACI were enrolled, and blood examinations were carried out soon after admission and 1 month after. sTM concentrations at admission in patients with cardioembolic infarction (3.2 +/- 1.2 ng/ml) were significantly lower than those of lacunar infarction (3.9 +/- 1.2) (P < 0.05). Serial examinations revealed that sTM concentrations increased significantly 1 month after admission (3.8 +/- 1.2), compared with those at admission (3.6 +/- 1.2) (P = 0.02). Of three ACI subtypes, sTM concentrations during 1 month significantly increased in atherothrombotic infarction (P = 0.002) or, not significantly, in cardioembolic infarction (P = 0.09). The sTM concentrations at admission showed a significant inverse correlation with the severity of ACI (P = 0.04). Although sTM concentrations serve as a useful marker for endothelial cell damage, they are decreased in patients with severe ACI, especially in atherothrombotic and cardioembolic infarctions. Lower sTM concentrations may play some important role in disease progression or in the recurrence following ACI, although the exact mechanism of this unique result should be clarified.

Folic acid-responsive neurological diseases in Japan.

Folic acid (folate) levels were measured in the serum of patients with various neurological diseases in Japan. Thirty-six patients showed decreased serum folate levels among 343 consecutive neurological patients (10.5%). Folate administration (15 mg/d) to folate-deficient patients improved neurological symptoms in 24 of 36 cases (67%). Serum folate levels were significantly lower in female than in male folate-deficient patients. Folate-deficient patients showed predominantly axonal neuropathy, which responded to folate supplementation more markedly. Male patients more frequently exhibited neuropathy, especially demyelinating and motor-dominant neuropathy, than females. Anemia was correlated with male sex and low serum folate levels. Male patients were more responsive than females to folate treatment. More male patients had taken excess alcohol or received gastrectomies than females. Neurological symptoms were more frequently improved by folate supplementation in patients with neuropathy than exclusive encephalopathy. Serum folate levels were lower in patients with encephalopathy, especially those with dementia, while folate therapy was more effective in neurological patients without dementia. Dysgeusia and anemia improved in all patients after folate administration. Neurological patients with malabsorption or treated with continuous drip infusion were resistant to folate therapy. Since folate-responsive neuroencepahlopathies are not rare among patients with neurological diseases in Japan, the serum folate level would serve as a valuable indicator for folate supplement therapy.

Sequential changes in von Willebrand factor and soluble thrombomodulin in acute ischemic stroke.

The purposes of the present study were to investigate sequential changes in plasma von Willebrand factor (vWf) activities and serum soluble thrombomodulin (sTM) concentrations, compared with white blood cell (WBC) counts, and to disclose the different roles of vWf and sTM in acute ischemic stroke. Forty-three acute ischemic stroke patients admitted to our hospital within 48 hours from onset were enrolled. Plasma vWf activities, serum sTM concentrations, and WBC counts were measured at the acute stage and 1 and 6 months after admission. The time course study revealed that vWf activities increased more markedly 1 month after admission than at the acute stage. However, sTM concentrations were low at the acute stage and increased sequentially at 1 month (not significantly) and 6 months (significantly) after admission. In contrast, elevated WBC counts at the acute stage decreased significantly at 1 and 6 months after admission. Raised vWf activities 1 month after admission were suggested to occur through continuous endothelial dysfunction or repair and platelet activation, compared with the acute stage, and decreased sTM at the acute stage through down-regulation of sTM synthesis by acute inflammatory response after acute ischemic stroke, compared with the chronic stage.

Elevation of serum soluble E-selectin and antisulfoglucuronyl paragloboside antibodies in amyotrophic lateral sclerosis.

Immunological abnormality is often found in amyotrophic lateral sclerosis (ALS). Antibodies to sulfoglucuronyl paragloboside (SGPG) were reported in ALS, although the pathogenetic significance of the antibodies is still unknown. We have already demonstrated that SGPG, a unique glycolipid, is present in both peripheral nerve and vascular endothelial cells. To investigate whether serum anti-SGPG antibodies would participate in activation and/or injury of endothelial cells in ALS, we examined serum anti-SGPG antibodies in association with serum soluble E- and P-selectins, which are markers of activated endothelial cells, in 25 patients with ALS and 14 age-matched patients with other neurological diseases (ONDs) using the microtiter-ELISA method. Seven out of 25 ALS patients had anti-SGPG antibodies. Levels of sE-selectin were significantly higher in patients with ALS (48.5 +/- 23.4 ng/ml) compared with ONDs (24.0 +/- 11.8 ng/ml) (P < 0.005). Four out of seven ALS patients with anti-SGPG antibodies had concomitantly high sE-selectin levels. The mean sE-selectin levels were higher in patients with anti-SGPG antibodies (61.9 +/- 25.2 ng/ml) than in those without anti-SGPG antibodies (43.3 +/- 21.1 ng/ml). Anti-SGPG antibodies may take part in the activation and/or injury of endothelial cells. The increased expression of E-selectin may be related to an immunological process in some ALS patients.

Gallyas-positive argyrophilic and ubiquitinated filamentous inclusions in rapidly progressive motor neuron disease: immunohistochemical and electron microscopic studies.

In an autopsy case of sporadic rapidly progressive lower motor neuron disease (MND), Gallyas-positive argyrophilic and ubiquitinated filamentous intracytoplasmic inclusions were found in the neurons. Clinically, 7 months prior to death, a 68-year-old woman experienced a history of rapidly progressive muscle weakness of all four extremities and bulbar sign, without sensory and autonomic disturbance. Two months later, she became unable to stand or walk. Four months after onset, she needed respiratory support, and subsequently died due to cardiorespiratory arrest. Neuropathological examinations revealed neuronal loss and associated gliosis in the lower motor neurons, except for ocular motor nuclei, Clark's column, and accessory cuneate nucleus, and tract degeneration was observed in the middle root zone of the posterior column and spinocerebellar tract. No Bunina bodies or Lewy body-like hyaline inclusions were found in the anterior horns. Gallyaspositive argyrophilic filamentous inclusions were found in the lower motor neurons and in nerve cells of the Clark's column, intermediate zone, posterior horn and accessory cuneate nucleus. These were positive with anti-ubiquitin antibody but negative with anti-tau (tau-2 and AT8) and neurofilament antibodies. Electron microscopic examinations disclosed randomly arranged tubular-like filamentous profiles, with a diameter of 12-14 nm, sometimes with amorphous granules in the perikaryon. This is the first report on the Gallyas-positive argyrophilic and ubiquitinated filamentous inclusions in neurons in MND.

[An autopsy case of catastrophic antiphospholipid syndrome presenting with recurrent multiple cerebral infarction associated with lung cancer].

We reported an autopsy case of cerebral infarction with primary lung cancer. The patient was a 50-year-old man. Despite having been treated with warfarin potassium and ticlopidine hydrochloride, he relapsed cerebral infarction. His laboratory data on admission showed that lupus anticoagulant was positive, together with a high value of beta-thromboglobulin, thrombin-antithrombin III complex, markers of platelet and coagulation activation, CEA and CA 19-9. The autopsy finding revealed a primary papillary adenocarcinoma in the right lower lung, multiple cerebral infarction, renal infarction, pulmonary infarction and splenic infarction. The atherosclerotic changes were mild in the whole tissues and findings of vasculitis were not observed. Recurrence of cerebral infarction was effectively suppressed with the addition of steroid therapy to antithrombotic therapy. This case was considered as catastrophic antiphospholipid syndrome. It is necessary to differentiate antiphospholipid syndrome in case of the abnormal coagulation and fibrinolytic factors with recurrent cerebral infarction. Moreover, systemic examinations are important, because malignant tumor may exist on the background of the case.

[An analysis of characters and changes of the blood pressure in 29 cases on recurrence of cerebral infarction].

We investigated changes of the blood pressure in 29 stroke patients before stroke recurrence and after recurrence. Additional antihypertensive drugs were not administered to all patients after stroke recurrence. Twenty-five lacunar infarct patients and 4 atherothrombotic infarct patients were included in this study. A significant difference was observed between the systolic blood pressure(SBP) within 4 weeks before recurrence and that just after recurrence(132.8 +/- 17.2 mmHg vs. 157.4 +/- 21.3 mmHg, Wilcoxon rank sum test, p < 0.001), or between the SBP just after and 2 weeks after stroke recurrence(157.4 +/- 21.3 mmHg vs. 138.0 +/- 18.3 mmHg, Wilcoxon rank sum test, p < 0.001). The similar difference was found in the diastolic blood pressure(DBP) or in the mean arterial blood pressure(MABP). There was no significant difference in the SBP, the DBP or the MABP between the patients before and 2 weeks after the stroke recurrence. These results suggested that the elevation of the blood pressure at recurrence decreased spontaneously to the pre-recurrence level of the blood pressure in about 2 weeks.

[A patient of myasthenia gravis complicated by lichen planus 9 years after thymectomy].

We report a 39-year-old woman with myasthenia gravis (MG) complicated by lichen planus, elevated liver enzymes of unknown cause and mucosal lesions of the colon and anus. Although the etiology of lichen planus is uncertain, an autoimmune abnormality is considered to be a possible cause. Lichen planus is sometimes associated with thymoma. This patient had hyperplasia of the thymus which was surgically removed nine years prior to lichen planus development. Myasthenic symptoms worsened when the lichen planus appeared and the liver enzymes were elevated. Steroid therapy was effective for the above symptoms. The clinical course suggests that MG, lichen planus and elevated liver enzymes in this patient results from common underlying autoimmune abnormality.

Age-related change in peripheral nerve conduction: compound muscle action potential duration and dispersion.

BACKGROUND: We investigated the effect of age on nerve conduction parameters with special reference to the compound muscle action potential (CMAP) duration and duration ratio. METHOD: We examined 295 subjects (aged 15-85 years old) with no previous history or present signs of peripheral neuropathy. The subjects were divided into 3 groups: young (15-34 years old); intermediate (35-64 years old), and old (65-85 years old). RESULTS: CMAP amplitude was lower in the old group than in the young group; however, the CMAP ratio (proximal CMAP/distal CMAP) did not change with age. The CMAP duration and duration ratio did not differ among the 3 groups. The CMAP area was smaller in the old group, but the area ratio was almost constant among the 3 groups. CONCLUSION: We suggest that age-related changes in CMAP amplitude, duration or area may occur uniformly, at least in the forearm and the calf segment, in routine nerve conduction studies. The present findings also provide useful and reliable information, regardless of age, in diagnosing peripheral neuropathy.

Characteristic magnetic resonance imaging findings in spinocerebellar ataxia 6.

OBJECTIVE: To clarify the characteristic magnetic resonance imaging (MRI) findings in patients with spinocerebellar ataxia 6 (SCA6) diagnosed by genetic analysis. PATIENTS AND METHODS: Using MRI, we examined 10 patients genetically diagnosed as having SCA6 and 40 control subjects. RESULTS: The mean (+/-SD) CAG repeat length in 10 patients with SCA6 was 22.9 +/- 1.3. There was a significant inverse correlation between the CAG repeat size and age at onset in the SCA6 group (r = -0.86, P = .003). In patients with SCA6, the areas of the cerebellar vermis and hemispheres in sagittal MRI were significantly smaller than those in the control subjects. In transaxial MRI, the anteroposterior diameter of the pons and the diameter of the middle cerebellar peduncle were mildly decreased and the red nucleus was slightly atrophied in patients with SCA6. There was no significant difference in the diameter of the midbrain, medulla oblongata, fourth ventricle, superior cerebellar peduncles, dentate nucleus, or globus pallidus between the SCA6 and control groups. A high-signal intensity in the transverse pontine fibers was not observed in any of the patients with SCA6 on T2-weighted and/or proton-weighted axial MRI. CONCLUSIONS: The cerebellum and its afferent and efferent systems were affected in patients with SCA6. These results seem to distinguish the MRI findings of SCA6 from those of other forms of spinocerebellar ataxia.

QTc interval, and autonomic and somatic nerve function in diabetic neuropathy.

QTc intervals were measured using an electrocardiogram and other autonomic function tests, in 66 neuropathy patients with non-insulin-dependent diabetes mellitus (59.0 +/- 12.5 years; mean +/- SD). The change in R-R interval did not influence the QTc interval, as calculated by the equation: QTc = QT + (1000 - R-R)/7 (ms), compared with the conventional Bazett's equation which appeared to overcompensate in the case of a small R-R interval. The QTc interval in the diabetic patients was significantly longer than that in age-matched controls. The QTc interval showed an inverse correlation with the coefficient of variation of the R-R interval and skin blood flow at rest. However, no correlation was found between QTc interval and blood pressure change, change in heart rate on standing, or results of the sympathetic skin response. The QTc interval did not correlate significantly with motor or sensory nerve conduction parameters. We conclude that the QTc interval can be a simple and useful autonomic indicator for diabetic neuropathy relatively independent of other abnormalities of autonomic and somatic nervous system function.