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.

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.

Lymphocyte alpha-glucosidase in late-onset glycogenosis type II.

We describe the biochemical characterization of lymphocyte alpha-glucosidase in a 23-year-old man with intermediate clinical features between the childhood and adult forms of glycogenosis type II (Pompe's disease). Acid alpha-glucosidase activity was markedly reduced, but immunologic cross-reactive material against human liver acid alpha-glucosidase protein could be detected, and its amount was normal. In this patient, the disorder was induced by the catalytically inactive enzyme with a normal amount of enzyme protein.

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.

Neuropathy and IgM paraproteinemia: differential binding of IgM M-proteins to peripheral nerve glycolipids.

Two patients with neuropathy and IgM paraproteinemia displayed different immunoreactivity to acidic peripheral nerve glycolipids. In one patient, immunostaining on thin-layer chromatographic plate revealed binding of the IgM to sulfated glucuronosyl paragloboside (SGPG) and sulfated glucuronosyl lactosaminyl paragloboside (SGLPG). The other IgM bound SGPG, SGLPG, and a new third glycolipid. Immunoreactivity of the IgM varies in this syndrome.

A new mitochondrial DNA mutation associated with mitochondrial myopathy: tRNA(Leu)(UUR) 3254C-to-G.

We investigated a patient with mitochondrial myopathy accompanied by cardiomyopathy. Molecular analysis disclosed a C-to-G substitution at nucleotide position 3254 of the mitochondrial tRNA(Leu)(UUR). Pedigree analysis revealed that this mutation was inherited maternally. Mutation C3254G may also be a candidate for genetic defects in mitochondrial myopathy.

Antibodies to sulfated glucuronic acid containing glycosphingolipids in neuropathy associated with anti-MAG antibodies and in normal subjects.

Serum of patients with neuropathy and IgM monoclonal antibodies (M-proteins) that bind to the myelin-associated glycoprotein (MAG) were tested for binding to the major cross-reactive sulfated glucuronic acid containing glycosphingolipid, sulfated glucuronic acid paragloboside (SGPG). IgM binding to the glycolipid was detectable at serum dilutions of 1:10,000 and reactivity was greatest at 4 degrees C. Low titers of IgM binding to the glycolipid were also detected in sera from normal subjects and from patients with neurologic or rheumatologic diseases without serum M-proteins. Binding activity was present in 25% of the sera tested, and titers ranged between 1:25 and 1:400. One patient with peripheral neuropathy, however, had a measurable titer of 1:12,800 in the absence of monoclonal gammopathy. The study indicates that cold reacting anti-SGPG IgM antibodies are frequent constituents of the normal human antibody repertoire, and that monoclonal or polyclonal expansion of B cells that secrete these antibodies, is associated with peripheral neuropathy.

CAG repeat length and disease duration in Machado-Joseph disease: a new clinical classification.

To evaluate the clinical characteristics of Machado-Joseph disease (MJD) with reference to CAG repeat length and disease duration, we analyzed neurologic findings in 108 patients from 84 families. The majority of MJD patients presented with an ataxic gait as the initial symptom. Dysarthria and nystagmus were observed from an early stage. Bulging eyes, muscle atrophy and bradykinesia developed later. Patients with a shorter CAG repeat length or later onset had more frequent involvement of proprioceptive sensory deficit. Incidence of abnormal reflexes, tones, and proprioceptive sensation was not associated with disease duration, but with CAG repeat length. Based on these results, we propose a new clinical classification: type A (juvenile type), with hyperreflexia and dystonia, but without a proprioceptive sensory deficit; type C (adult type), with hyporeflexia and a proprioceptive sensory deficit, but without dystonia; and type B (intermediate type), the remaining patients with a mixed presentation.

Association between carotid atherosclerosis and hemostatic markers in patients with cerebral small artery disease.

The purposes of this study were to investigate the association between carotid atherosclerosis and hemostatic markers, and to elucidate the difference in hemostatic markers between intima-media thickening and plaque formation in patients with cerebral small artery disease. We investigated carotid atherosclerosis by assessing diffuse intima-media thickness measurements and localized plaque using B-mode ultrasonography, and we measured the concentrations of plasma fibrinogen, beta-thromboglobulin and platelet factor 4 as markers for platelet activation, and the activity of plasma von Willebrand factor as a marker for endothelial damage. The intima-media thickness was significantly associated with age, male sex, the concentrations of plasma beta-thromboglobulin and platelet factor 4, and the activity of plasma von Willebrand factor. The plaque score showed a significant association with male sex, the concentration of fibrinogen, and the activity of plasma von Willebrand factor. These results may indicate that underlying mechanisms are not the same between the intima-media thickness and plaque formation. We suggest that hemostatic markers could reflect the severity of carotid atherosclerosis in patients with cerebral small artery disease, and that preventive antiplatelet therapies against brain infarction might be necessary for patients with severe carotid atherosclerosis.

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.

Ratios of nerve conduction parameters in proximal to distal limbs remain constant through the second to the eighth decades.

We investigated the effect of age on nerve conduction parameters to establish a diagnostic validity in demyelinating neuropathies of the aged. We evaluated 257 subjects (age 10-76 years old) with no history or signs of peripheral neuropathies. The CMAP amplitude ratio (proximal CMAP/distal CMAP), duration ratio, and area ratio were almost the same throughout the second to eighth decades. The respective lower limits of the normal CMAP amplitude ratio (mean-3 SD) were 0.79 (median nerve), 0.75 (ulnar nerve), 0.57 (peroneal nerve), and 0.45 (tibial nerve). The upper limits of the normal CMAP duration ratio (mean +3 SD) were 1.21 (median nerve), 1.22 (ulnar nerve), 1.37 (peroneal nerve), and 1.35 (tibial nerve). The lower limits of the normal CMAP area ratio (mean-3 SD) were 0.81 (median nerve), 0.78 (ulnar nerve), 0.60 (peroneal nerve), and 0.57 (tibial nerve). No age-related changes were observed in the amplitude ratio or duration ratio SNAP, although the standard deviation increased with age. Since the amplitude, duration and area ratios are easily calculated and age-independent, they can provide useful and reliable information on aged patients with demyelinating neuropathies by conventional nerve conduction studies.

[Early-onset parkinsonism with diurnal fluctuation--clinical and pathological studies].

The literature regarding parkinsonism of early-onset indicates that it encompasses several diseases differing in their clinical and pathological features. Since 1968 we have reported cases of early-onset parkinsonism with diurnal fluctuation of symptoms (abbrev. as EPDF). Attention has been focused on its similarities to or differences from Parkinson's disease (PD), juvenile parkinsonism of Yokochi, and hereditary progressive dystonia (HPD) of Segawa et al. In this paper we report the clinical and pathological characteristics of EPDF to facilitate its nosological identification. We examined the pathological features of EPDF in two cases. Case 1 was a 52-year-old female with consanguineously related parents and two other affected sisters. The disease began at the age of 20, and she had marked diurnal fluctuation of symptoms. With the assistance of L-dopa and bromocriptine, she was able to enjoy relatively satisfactory daily life activity until the age of 50. In the last two years she was bed-ridden with advanced parkinsonism. Case 2 was a 56-year-old man without any contributing family history. His disease started at age 26 and his symptoms showed slight fluctuation during the earlier stages of the disease. Treatment with L-dopa and bromocriptine was associated with marked up-and-down phenomenon and choreatic dyskinesia. Pathological study in the two cases revealed marked cell loss in the substantia nigra zona compacta, especially in the area A9, while the neuronal cell population of the ventral tegmental area (A10), locus caeruleus, superior raphae nucleus, and substantia innominata was relatively well preserved. There were no Lewy bodies.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of optic-spinal form of multiple sclerosis with lobar type large cerebral hemorrhage].

We report a 57-year-old woman with optic-spinal form of active multiple sclerosis, who developed a large lobar type hemorrhage of the brain. She initially suffered from left visual loss, and three month later, she was hospitalized with paraplegia and total sensory loss up to the fourth thoracic level accompanied by sphincteric disturbance. Diagnosis of clinically probable multiple sclerosis was based on the relapsing-remitting clinical course and laboratory findings. Five months after admission, she developed sudden consciousness loss. Brain CT scan showed a massive hemorrhage in the right frontal to parietal lobe. The patient had no risk factors for cerebral hemorrhage including hypertension. Histopathological study of brain tissues obtained at surgical evacuation of hematoma did not reveal any malignancy, and congo-red staining of this specimen was negative. We analyzed coagulation, fibrinolytic, and endothelial parameters during the follow-up period. von Willebrand factor (vWF) as a marker for endothelial damages was elevated persistently. Moreover, thrombin-antithrombin III complex (TAT) as a marker for activation of coagulation was also elevated constantly throughout the clinical course. The findings suggest that fragility of the vascular walls and permeability changes associated with immunological mechanisms might have resulted in the cerebral hemorrhage. Although there are few reports of cerebral hemorrhage in patients with multiple sclerosis, it has been reported that vascular wall damage is an important aspect of the pathology of multiple sclerosis and acute cerebral vascular damage may sometimes occur in multiple sclerosis. We propose that coagulation studies including the endothelial marker such as vWF would provide a useful information regarding the risk of cerebrovascular complication in multiple sclerosis.

[Antiplatelet therapy in patients with cerebral thrombosis at the chronic phase--assessment of its effect on coagulation and fibrinolytic parameters].

We studied the effect of antiplatelet therapy not only on the secondary prevention of stroke but also on the suppression of vascular damages in patients with cerebral thrombosis at the chronic phase. We measured von Willebrand factor (vWF) as a marker for the endothelial system, and coagulation and fibrinolytic parameters in addition to platelet functions. The platelet aggregation and markers for platelet activation were monitored for the adequate inhibition of platelets. Twenty-one patients were treated with 200 mg ticlopidine. 9 patients with 100 mg ticlopidine and 60-150 mg acetylsalicylic acid, and 18 patients with 200 mg cilostazol daily. The mean duration of follow up was 8.4 +/- 3.0 months. A patient was attacked by a recurrent stroke, but no fatal vascular events occurred during the period. A significant decrease was observed in the collagen- and ADP-induced platelet aggregation and markers for platelet activation such as platelet factor 4 (PF4) and beta-thromboglobulin (beta TG) by the antiplatelet therapy. In addition, the activities of coagulation factor VIII (FVIII) and vWF, markers for vascular damages, showed a significant decrease. The results suggest that the antiplatelet therapy could ameliorate the vascular damage through the inhibition of platelet function. Moreover, thrombin-antithrombin III complex (TAT) and alpha 2-plasmin inhibitor-plasmin complex (PIC), markers for the activation of coagulation and fibrinolytic systems, decreased significantly, suggesting that the treatment inhibits the activation of coagulation and fibrinolytic systems induced by the platelet activation. The activities of FVIII and vWF decreased significantly when the level of beta TG or that of PF4 lowered sufficiently by the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Endothelial cell activation and/or injury in multiple sclerosis: analysis with von Willebrand factor and thrombomodulin].

Breakdown of the blood-brain barrier, which consists of endothelial cells, is implicated essential in the pathogenesis of multiple sclerosis (MS). To examine the endothelial cell damage, we determined the von Willebrand factor and thrombomodulin, markers for endothelial cell activation and/or injury, in the peripheral blood of patients with MS. The subjects were 26 patients with relapsing-remitting MS and 35 control subjects (mean age +/- standard deviation, 44.8 +/- 9.6 years). Patients with systemic vasculitis were excluded. The plasma activity of von Willebrand factor was significantly higher in patients with MS in the active phase (n = 23; 44.6 +/- 9.6 years) than in the age-matched controls. This suggests that von Willebrand factor could be a useful marker for evaluating the breakdown of blood-brain barrier resulting from endothelial damage in MS. In contrast, the serum level of thrombomodulin was not significantly different between patients with active MS and the controls. In MS patients (n = 15; 44.2 +/- 2.2 years), the plasma activity of von Willebrand factor was significantly lowered after immunosuppressive treatment. This suggests that von Willebrand factor could be used as a parameter for assessing the effect of treatment in MS.

[Coagulation and fibrinolytic parameters as predictors for small-vessel disease revealed by magnetic resonance imaging of the brain].

We correlated coagulation and fibrinolytic parameters with small-vessel disease revealed by magnetic resonance imaging (MRI) of the brain. One hundred and eleven patients with asymptomatic or symptomatic cerebral infarction were randomly selected for the study; 57 males and 54 females with an average age of 66.6 +/- 9.6, age range 40 to 85, years old. Among them, 76 patients had a history of symptomatic cerebral infarction; 38 patients hypertension; and 24 patients diabetes mellitus. Patients with large cortical infarction, cerebral hemorrhage, demyelinating disease or mass lesions were excluded from the present study. The MRI scans were reviewed for areas with increased signal intensity on T2-weighted images. The small infarction was defined as a lesion less than 10mm in diameter. The activity of von Willebrand factor (vWF) correlated significantly with the grade of caps at the anterior and posterior horns of the lateral ventricle, and the number of small infarctions in the subcortical white matter and basal ganglia, suggesting vWF could be a predictor for these small-vessel disease. The grade of caps at posterior horn of the lateral ventricle and the number of small infarctions in the subcortical white matter were associated significantly with the concentration of plasma fibrinogen and reversely with the activity of antithrombin III, an inhibitory factor in coagulation system. These results indicate that hypercoagulable state may causatively relate with small-vessel disease in the territory of medullary artery branching from cortical artery. On the contrary, these coagulation parameters did not correlate significantly with small ischemic lesions in the territory of perforating artery. No correlation was observed between the level of marker proteins for platelet activation and the degree of small-vessel disease, indicating the activation of platelet could not associate with the etiology of small-vessel disease.

[Significance of the coagulation and fibrinolytic parameters as predictors for carotid atherosclerosis].

We investigated the relation between atherosclerosis of common carotid artery measured by B-mode ultrasound sonography and vascular risk factors, in particular the coagulation and fibrinolytic parameters. A total of 118 patients without either hematological disease or symptomatic brain infarction are enrolled in this study. Vascular risk factors associated with increased intima-media thickness (IMT) of common carotid artery were advancing age, sex (male), systolic blood pressure and diastolic blood pressure. There was a significant correlation of IMT with the activity of von Willebrand factor (vW factor) which had a significant correlation with concentration of beta-thromboglobin (beta TG) and platelet factor 4 (PF4). It has been reported that vW factor is a useful parameter for the evaluation of the extent of vascular involvement. vW factor in plasma and in the vessel wall is known to contribute appreciably to the platelet adherence, and to play a major role in the platelet aggregation particularly at high shear stress. In this study, we showed that plasma vW factor might enhance platelet aggregation. In addition, we revealed that plasma vW factor might reflect the injury of carotid artery wall and serve as a significant predictor of carotid atherosclerosis. There was a significant correlation of IMT with concentration of fibrinogen (Fbg), suggesting Fbg may play a role in atherogenesis by affecting local blood flow especially at the bifurcation. We reconfirmed that Fbg is a significant indicator of carotid atherosclerosis. Concentrations of beta TG and PF4 were significantly correlated with IMT. They are useful parameters of platelet activation and elevated in various angiopathies. These results, therefore, indicate that beta TG and PF4 also reflect the injury of carotid artery wall, and could be markers for carotid atherosclerosis.

[Vasomotor impairment in patients with diabetic neuropathy--evaluation by laser Doppler flowmetry].

Using laser Doppler flowmetry, we evaluated cutaneous microcirculation in 28 patients with diabetic neuropathy and 18 control subjects. Skin blood flow in the hand was significantly reduced in the patients compared with that in age-matched controls. Skin blood flow in the hand of the patients correlated significantly with the amplitude of sensory nerve action potential of the median nerve. Significant correlation was shown in the patients between skin blood flow in the hand and changes in systolic blood pressure on standing from a supine position. However, there was no correlation between skin blood flow in the hand and variation in the R-R interval. These results suggest that the skin blood flow may decrease with the progression of diabetic neuropathy, particularly sympathetic autonomic neuropathy, and that neural control may be an important factor in the regulation of skin blood flow. Cold water immersion test revealed that there was no significant difference in vasoconstrictive response during the cold challenge, while recovery time of vasodilatory response after withdrawal of the thermal challenge was significantly prolonged in the patients as compared with that in the controls. In addition, it is suggested that the patients with a small increase or normal in skin blood flow of the hand may possess abnormalities predominantly in vasoconstrictive tone, whereas the patients with a decrease in skin blood flow of the hand in vasodilatory tone. Consequently, microcirculation in skin of extremities changes under the balance of vasoconstrictive and vasodilatory tones in patients with diabetic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.