Herpes zoster peripheral nerve complications: Their pathophysiology in spinal ganglia and nerve roots.

Varicella zoster virus (VZV) causes chickenpox at the primary infection and then becomes latent in the spinal dorsal root ganglia; VZV can reactivate with aging, immunosuppression, stress, and other factors, occurring as herpes zoster (HZ) at 1-2 skin segments. HZ peripheral nerve complications caused by VZV reactivation include Hunt syndrome, segmental HZ paresis, post-herpetic neuralgia, and Guillain-Barré syndrome (GBS). We have encountered the rare HZ complications of upper-limb paresis, myeloradiculitis, and polyradiculoneuritis: an adult woman with upper-limb paresis consistent with the nerve root on segments above the thoracic HZ dermatome; another woman exhibiting ascending myeloradiculitis originating at the Th11-12 roots; an elderly woman with ascending VZV polyradiculoneuritis resembling GBS; an adult with VZV quadriplegia with disseminated HZ; and an elderly patient with VZV-associated polyradiculoneuritis. The three polyradiculoneuritis cases may be a new subtype of HZ peripheral neuropathy, but the pathophysiology for these HZ peripheral nerve complications unrelated to HZ dermatomes is unclear. We analyzed host factors, skin lesions, neurological and virological findings, and MRI results including 3D NerveVIEW in 15 Japanese patients treated at our facility for HZ peripheral neuropathy, including six differing from the HZ dermatome. Based on the clinical findings including MRI results of spinal ganglia and roots, we identified four possible routes for the patterns of VZV spread: (i) ascending spinal roots, (ii) ascending spinal cord, (iii) polyradiculopathy, and (iv) intrathecal spread. The incidence of HZ is increasing with the aging of many populations, and clinicians should be aware of these HZ neuropathies.

An elderly case with late carotid stent thrombosis: possible role of antiphospholipid antibodies.

The case study speculates that the antiphospholipid antibodies acquired during the follow-up period of carotid artery stenting may cause late stent thrombosis that is resistant to direct oral anticoagulants. A 73-year-old man was hospitalized with complaints of weakness in the right lower extremity. The patient had undergone carotid artery stenting for symptomatic stenosis of the left internal carotid artery 6 years prior and had received antiplatelet therapy with clopidogrel 75 mg/day. As the patient had developed atrial fibrillation without stent stenosis at the age of 70 years, anticoagulation therapy with rivaroxaban15 mg/day was initiated while discontinuing clopidogrel. On admission, diffusion weighted imaging (DWI) revealed acute brain infarcts in the territory of the left middle cerebral artery. Contrast-enhanced computed tomography and cerebral angiography exposed severe stenosis in the left carotid artery accompanied by a filling defect caused by a floating thrombus. Laboratory examination revealed the presence of three types of antiphospholipid antibodies, with marked prolongation of activated partial thromboplastin time (APTT). Replacement of rivaroxaban with warfarin eliminated the thrombus without recurrent stroke. In conclusion, late stent thrombosis may be associated with antiphospholipid antibodies acquired during the follow-up period of carotid artery stenting.

Varicella zoster virus associated-polyradiculoneuritis in an elderly woman: A new subtype of varicella zoster virus neuropathy.

An 82-year-old Japanese woman without underlying disease was admitted to our hospital 3 days after she noticed lower-limb weakness. At presentation, she had lower-leg motor paralysis with mild upper-limb paresis and left Ramsay Hunt syndrome. Cerebrospinal fluid (CSF) findings revealed moderate pleocytosis. A polymerase chain reaction for varicella zoster virus (VZV) DNA in CSF was positive. MRI using 3D Nerve-VIEW (Philips) and contrast T1 images showed high-intensity lesions on the L2-5 and S1-2 spinal roots. A new subtype of VZV-associated polyradiculoneuritis was diagnosed in this patient. We provide the case details and compare three similar reported cases.

[A case of pneumococcal meningitis with reversible arterial stenosis].

A 72-year-old male was diagnosed pneumococcal meningitis and we started treatment with antibacterial drugs and corticosteroids. On the 6th day, his consciousness level decreased. On the 7th day DWI of MRI showed a new infarction in bilateral cerebellar, and MRA showed multiple arterial stenosis. On the 12th day, CT angiography showed expansion of cerebral infarction and progress of diffuse stenosis. After that the stenosis improved over time, it disappeared on the 39th day. These results suggest that vasospasm is involved in the pathology of vascular stenosis.

Brain stem infarction in a 6-year-old boy with Down syndrome.

Infarct locations in children with arterial ischemic stroke have primarily been reported to be lobar or in the basal ganglia, and those in patients with Down syndrome (DS) and antiphospholipid syndrome (APS) are typically wide and multiple. No solitary brain stem infarctions have ever been reported in children with DS until now. Here, we report a case of brain stem infarction in a 6-year-old boy with DS who had no cardiac, renal, or intestinal complications. He exhibited ataxic gait and medial longitudinal fasciculus (MLF) symptoms at first presentation. Neuroimaging revealed a localized and isolated lesion in the midbrain. Although he did not satisfy the diagnostic criteria of APS, he showed persistently elevated levels of anticardiolipin antibody (21 U/mL; normal value <10 U/mL). Although he had the risks of a multiple vascular systems disorder, DS, and persistently elevated levels of antiphospholipid antibodies, his lesion was not similar to any of the previously reported cerebral infarctions in DS or in APS. To our knowledge, this is the first report of limited solitary brain stem infarction in a child with DS.

Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation: a case report.

BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently responsible for MELAS. CASE PRESENTATION: A 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy. CONCLUSION: A T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner.

Association Between Onset-to-Door Time and Clinical Outcomes After Ischemic Stroke.

BACKGROUND AND PURPOSE: The role of early hospital arrival in improving poststroke clinical outcomes in patients without reperfusion treatment remains unclear. This study aimed to determine whether early hospital arrival was associated with favorable outcomes in patients without reperfusion treatment or with minor stroke. METHODS: This multicenter, hospital-based study included 6780 consecutive patients (aged, 69.9±12.2 years; 63.9% men) with ischemic stroke who were prospectively registered in Fukuoka, Japan, between July 2007 and December 2014. Onset-to-door time was categorized as T0-1, ≤1 hour; T1-2, >1 and ≤2 hours; T2-3, >2 and ≤3 hours; T3-6, >3 and ≤6 hours; T6-12, >6 and ≤12 hours; T12-24, >12 and ≤24 hours; and T24-, >24 hours. The main outcomes were neurological improvement (decrease in National Institutes of Health Stroke Scale score of ≥4 during hospitalization or 0 at discharge) and good functional outcome (3-month modified Rankin Scale score of 0-1). Associations between onset-to-door time and main outcomes were evaluated after adjusting for potential confounders using logistic regression analysis. RESULTS: Odds ratios (95% confidence intervals) increased significantly with shorter onset-to-door times within 6 hours, for both neurological improvement (T0-1, 2.79 [2.28-3.42]; T1-2, 2.49 [2.02-3.07]; T2-3, 1.52 [1.21-1.92]; T3-6, 1.72 [1.44-2.05], with reference to T24-) and good functional outcome (T0-1, 2.68 [2.05-3.49], T1-2 2.10 [1.60-2.77], T2-3 1.53 [1.15-2.03], T3-6 1.31 [1.05-1.64], with reference to T24-), even after adjusting for potential confounding factors including reperfusion treatment and basal National Institutes of Health Stroke Scale. These associations were maintained in 6216 patients without reperfusion treatment and in 4793 patients with minor stroke (National Institutes of Health Stroke Scale ≤4 on hospital arrival). CONCLUSIONS: Early hospital arrival within 6 hours after stroke onset is associated with favorable outcomes after ischemic stroke, regardless of reperfusion treatment or stroke severity.

Anti-Cyclic Citrullinated Peptide Antibody-Positive Meningoencephalitis in the Preclinical Period of Rheumatoid Arthritis.

Rheumatoid meningoencephalitis (RM) is a rare complication of rheumatoid arthritis (RA). This report describes a 63-year-old man with complaints of high-grade fever, headache, and vomiting for several days before admission. Both his serum and cerebrospinal fluid were positive for anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor, and contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging (MRI) showed abnormal gadolinium enhancement of the meninges and high-intensity lesions in the subarachnoid spaces. The patient was diagnosed with RM despite lack of signs suggesting RA. His symptoms drastically improved with intravenous infusion of high-dose methylprednisolone. Two months later, he developed RA. The findings in this patient suggest that RM could develop prior to the onset of RA. Anti-CCP antibody and MRI findings may be useful for the diagnosis of RM, regardless of RA history.

[Intravascular Large B Cell Lymphoma with Cauda Equina Syndrome: A Case Report and Review of the Literature].

A 62-year-old man complained of gait disturbance, bladder and bowel dysfunction and paresthesia of both legs one month before admission. His symptoms were suggestive of cauda equina syndrome. After admission, he developed rapid progressive numbness and weakness of both legs and a disturbance of consciousness. A random skin biopsy was performed and a histological diagnosis of intravascular large B cell lymphoma (IVLBCL) was reached. His symptoms were improved after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy.

Meta-analysis of published studies identified eight additional common susceptibility loci for Crohn's disease and ulcerative colitis.

BACKGROUND: Both ulcerative colitis (UC) and Crohn's disease (CD) have a complex etiology involving multiple genetic and environmental factors. Many genome-wide association studies (GWAS) and subsequent replication studies revealed that both diseases share some of the susceptibility loci; however, common genetic factors for both diseases are not fully elucidated. This study is aimed to identify the common genetic factors for CD and UC by a meta-analysis of published studies. METHODS: We first reviewed the 10 GWAS for CD to select candidate single nucleotide polymorphisms (SNPs). Next, we performed a PubMed literature search up to June 30, 2010 and carried out a systemic review of published studies that examined the association of CD susceptibility loci in UC patients. Meta-analysis was carried out using the inverse variance-weighted method or the DerSimonian-Laird method after estimating the heterogeneity among the studies. The data for highly linked SNPs were combined. Finally, we performed a meta-analysis of 43 published studies in 45 SNPs located at 33 loci by using a total of 4852 to 31,125 subjects. RESULTS: We confirmed the association of 17 reported common susceptibility loci. Moreover, we found associations at eight additional loci: GCKR, ATG16L1, CDKAL1, ZNF365, LRRK2-MUC19, C13orf31, PTPN2, and SBNO2. The genetic risk of each locus was modest (odds ratios ranged from 1.05-1.22) except IL23R. CONCLUSIONS: These results indicate that CD and UC share many susceptibility loci with small genetic effect. Our data provide further understanding of the common pathogenesis between CD and UC.

Association study of the polymorphisms on chromosome 12p13 with atherothrombotic stroke in the Japanese population.

Recent genome-wide association study using four prospective population-based cohorts identified two single-nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579, to be significantly associated with the incidence of atherothrombotic stroke. To examine the association of these SNPs with atherothrombotic stroke in the Japanese population, we carried out a case-control association study using a total of 3784 cases and 3102 controls. We also examined the effect of these SNPs on the subtypes of ischemic stroke. Association analysis was carried out using logistic regression model after adjustment of age, sex and cardiovascular risk factors. Rs12425791 was significantly associated with atherothrombotic stroke (P=0.0084, odds ratio (OR)=1.15). When we analyzed effects of rs12425791 on ischemic stroke subtypes, rs12425791 was significantly associated with both small-artery occlusion (P=0.015, OR=1.15) and large-artery atherosclerosis (P=0.024, OR=1.19). Rs11833579 showed no association with atherothrombotic stroke or its subtypes in our population. Our data suggest that rs12425791 on chromosome 12p13 is a genetic marker for atherothrombotic stroke in multiethnic population.

Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke.

Although stroke is a common cause of death and a major cause of disability all over the world, genetic components of common forms of ischemic stroke are largely unknown. To identify susceptibility genes of atherothrombotic stroke, we performed a large case-control association study and a replication study in a total of 2775 cases with atherothrombotic stroke and 2839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, we found that a single-nucleotide polymorphism (SNP), rs2280887, in the ARHGEF10 gene was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test [unadjusted P = 1.2 x 10(-6), odds ratio = 1.80, 95% confidence interval (CI) = 1.42-2.28]. This association was replicated in independent 1915 cases and 1979 controls. Subsequent fine mapping found another three SNPs which showed similar association due to strong linkage disequilibrium to rs2280887 (r(2) > 0.95). In the functional analyses of these four highly associated SNPs, using luciferase assay and electrophoretic mobility shift assay we found that rs4376531 affected ARHGEF10 transcriptional activity due to the different Sp1-binding affinity. In small GTPase activity assay, we found that a gene product of ARHGEF10 specifically activated RhoA. A population-based cohort study revealed the subjects with rs4376531 CC or CG to increase the incidence of ischemic stroke (P = 0.033, hazard ratio = 1.79, 95% CI = 1.05-3.04). Our data suggest that the functional SNP of ARHGEF10 confers the susceptibility to atherothrombotic stroke.

A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population.

Ulcerative colitis is one of the principal forms of inflammatory bowel disease with complex manifestations. Although previous studies have indicated that there is a genetic contribution to the pathogenesis of ulcerative colitis, the genes influencing susceptibility to the disease have not been fully determined. To identify genetic factors conferring risk of ulcerative colitis, here we conducted a two-stage genome-wide association study and subsequent replication study using 1,384 Japanese individuals with ulcerative colitis and 3,057 control subjects. In addition to the expected strong association with the major histocompatibility complex (MHC) region, we identified three new susceptibility loci: the immunoglobulin receptor gene FCGR2A (rs1801274, P = 1.56 x 10(-12)), a locus on chromosome 13q12 (rs17085007, P = 6.64 x 10(-8)) and the glycoprotein gene SLC26A3 (rs2108225, P = 9.50 x 10(-8)). rs1801274 is a nonsynonymous SNP of FCGR2A that is reported to have a critical effect on receptor binding affinity for IgG and to be associated with other autoimmune diseases. Our findings provide insight into the molecular pathogenesis of ulcerative colitis.

Lack of association between variations of PDE4D and ischemic stroke in the Japanese population.

BACKGROUND AND PURPOSE: After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted. However, the validity of the association has remained controversial because of the heterogeneity of both genetic markers and phenotypes. METHODS: We investigated the association between variations of PDE4D and ischemic stroke by 3 methods: single-marker, haplotype, and tag-single nucleotide polymorphism (SNP) analyses. In the single-marker analysis, we evaluated the association using 2 large case-control samples (1112 cases and 1112 control subjects in a sample obtained from Kyushu, Japan, and 1711 cases and 1786 control subjects in BioBank Japan) and a prospective cohort with 14 years of follow-up. These samples were analyzed both separately and pooled. Haplotype and tag-SNP analyses were performed using the 2 case-control samples together. RESULTS: In single-marker association tests, we found no significant association in the same direction among the 6 SNP reported in the initial study and ischemic stroke subtypes. Haplotype analysis revealed no significant association between the region around the 5'-end of the gene and combined atherothrombotic and cardioembolic infarction. Rs7730070, a SNP located around the 3'-end of PDE4D, showed the lowest nominal probability value by tag-SNP analysis but was not significant after adjustment for multiple testing (adjusted probability value =0.36). CONCLUSIONS: These results suggest that variations in PDE4D are not associated with ischemic stroke risk in the Japanese population.

Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction.

Brain infarction is one of the common causes of death and also a major cause of severe disability. To identify a gene(s) susceptible to brain infarction, we performed a large-scale association study of Japanese patients with brain infarction, using 52608 gene-based single nucleotide polymorphism (SNP) markers. Comparison of allele frequencies between 1112 cases with brain infarction and age- and sex-matched control subjects of the same number found an SNP in the 5'-flanking region of angiotensin receptor like-1 (AGTRL1) gene (rs9943582, - 154G/A) to have a significant association with brain infarction [odds ratio = 1.30, 95% confidence interval (CI) = 1.14-1.47, P = 0.000066]. We also found the binding of Sp1 transcription factor to the region including the susceptible G allele, but not the non-susceptible A allele. Luciferase assay and RT-PCR analysis demonstrated that exogenously introduced Sp1 induced transcription of AGTRL1 and its ligand, apelin, as well, indicating direct regulation of apelin/APJ pathway by Sp1. Furthermore, a 14 year follow-up cohort study in a Japanese community in Hisayama town, Japan revealed that the homozygote of the susceptible G allele of this particular SNP had significantly higher risk of brain infarction (hazard ratio = 2.00, 95% CI = 1.22-3.29, P = 0.006). Our results indicate that the SNP in the AGTRL1 gene is associated with the susceptibility to brain infarction.

A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction.

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 x 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCeta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.