[Cerebrovascular events, headache and livedoracemosa - diagnosis at a glance?] / Zerebrovaskuläre Ereignisse, Kopfschmerzen und Livedo racemosa ­ Blickdiagnose?

Sneddon's syndrome is a rare disease characterized by cerebrovascular events and livedo racemosa. There are often autoimmunological comorbidities, especially antiphospholipid antibody syndrome. The underlying pathophysiology is still not fully clarified. A causal therapy does not exist. The reported case shows a patient with a thrombophilic form of Sneddon's syndrome with the main symptoms of headache and thromboembolic events. Symptoms, laboratory parameters, histology and differential diagnoses are explained.

Educational campaign on stroke in an urban population in Northern Germany: influence on public stroke awareness and knowledge.

BACKGROUND: Public stroke awareness and knowledge may be supportive for stroke prevention and emergency care-seeking behavior after the acute event, which is highly important for early treatment onset. AIMS: In an urban population in Northern Germany (Hannover), a six-month stroke educational campaign was conducted. We expected an increase in stroke knowledge and awareness thereafter. METHODS: Computer-assisted telephone interviews were randomly conducted among 1004 representative participants before and 1010 immediately after the educational multimedia campaign. The computer-assisted telephone interviews focused on questions about stroke knowledge and interventions remembered. RESULTS: Knowledge of stroke risk factors increased during the campaign for overweight, physical inactivity, old age, and stroke in family (P < 0·05). The knowledge of stroke warning signs was low, although it significantly increased during the campaign (P < 0·001) as paresis/weakness (46%) and speech problems (31%) were most frequently named. The majority of respondents indicated that the first action after suffering from stroke should be calling emergency care (74% before vs. 84% after campaign, P < 0·001). CONCLUSIONS: Our data indicate that stroke knowledge and awareness, which could provide earlier presentation to the emergency unit for timely treatment onset, are still low in urban Northern Germany but may decisively be increased by educational campaigns.

An extended association screen in multiple sclerosis using 202 microsatellite markers targeting apoptosis-related genes does not reveal new predisposing factors.

Apoptosis, the programmed death of cells, plays a distinct role in the etiopathogenesis of Multiple sclerosis (MS), a common disease of the central nervous system with complex genetic background. Yet, it is not clear whether the impact of apoptosis is due to altered apoptotic behaviour caused by variations of apoptosis-related genes. Instead, apoptosis in MS may also represent a secondary response to cellular stress during acute inflammation in the central nervous system. Here, we screened 202 apoptosis-related genes for association by genotyping 202 microsatellite markers in initially 160 MS patients and 160 controls, both divided in 4 sets of pooled DNA samples, respectively. When applying Bonferroni correction, no significant differences in allele frequencies were detected between MS patients and controls. Nevertheless, we chose 7 markers for retyping in individual DNA samples, thereby eliminating 6 markers from the list of candidates. The remaining candidate, the ERBB3 gene microsatellite, was genotyped in additional 245 MS patients and controls. No association of the ERBB3 marker with the disease was detected in these additional cohorts. In consequence, we did not find further evidence for apoptosis-related genes as predisposition factors in MS.

Association of the HLA region with multiple sclerosis as confirmed by a genome screen using >10,000 SNPs on DNA chips.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with a complex genetic background. Here, we present a genome screen for association in small scale, employing 11,555 single nucleotide polymorphisms (SNPs) on DNA chips for genotyping 100 MS patients stratified for HLA-DR2+ and 100 controls. More than 500 SNPs revealed significant differences between cases and controls before Bonferroni correction. A fraction of these SNPs was reanalysed in two additional cohorts of patients and controls, using high-throughput genotyping methods. A marker on chromosome 6p21.32 (rs2395182) yielded the highest significance level, validating the established HLA-DR association.

Refining the results of a whole-genome screen based on 4666 microsatellite markers for defining predisposition factors for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a complex genetic background. In order to identify loci associated with the disease, we had performed a genome screen initially using 6000 microsatellite markers in pooled DNA samples of 198 MS patients and 198 controls. Here, we report on the detailed reanalysis of this set of data. Distinctive features of microsatellites genotyped in pooled DNA causing false-positive association or masking existing association were met by improved evaluation and refined correction factors in the statistical analyses. In order to assess potential errors introduced by DNA pooling and genotyping, we resurveyed the experiment in a subset of microsatellite markers using de novo-composed DNA pools. True MS associations of markers were verified via genotyping all individual DNA samples comprised in the pools. Microsatellites share characteristically superb information content but they do not lend themselves to automation in very large scale formats. Especially after DNA pooling many artifacts of individual marker systems require special attention and treatment. Therefore, in the near future comprehensive whole-genome screens may rather be performed by typing single nucleotide polymorphisms on chip-based platforms.

Role of chemokines and their receptors in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the human central nervous system (CNS) of unknown etiology that causes demyelination and associated tissue injury. Trafficking of inflammatory T cells into the CNS is a crucial event in the pathogenesis of MS, a process in which chemokines and their receptors have been demonstrated to play an important role. Chemokines are key mediators of inflammation and have major effects on migration of cells to the sites of inflammation as well as activation of recruited and resident CNS cells. This paper summarizes recent and new information about the expression and function of elements of the chemokine system in MS and its animal model experimental allergic encephalomyelitis. Analysis of the chemokine system provides insights into mechanisms of CNS inflammatory reactions and may lead to new targets of therapeutic intervention in MS.

The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy.

Charcot-Marie-Tooth disease comprises a heterogeneous group of hereditary neuropathies which fall into two main groups: demyelinating CMT1 with reduced nerve conduction velocity and axonal CMT2 with normal nerve conduction velocity. The neuropathological features correspond in most cases to this classification. Four genes were recently identified to cause autosomal dominant CMT2, including the neurofilament light gene. Thus far, only few mutations have been reported in neurofilament light involving eight amino acids of the gene. We identified a novel mutation, Glu397Lys, in a conserved motive signaling the end of the rod domain. The affected family members from three generations showed strikingly different clinical phenotypes, including weakness of the lower extremities, foot deformities, and deafness. The mutation was associated with nerve conduction velocities ranging from 27 m/s in a 25-year-old female to 43 m/s in an 82-year-old male in the lower extremity motor nerves. Sural nerve biopsies of two affected subjects were analyzed by light and electron microscopy. The pathological changes consisted of a reduction of predominantly large myelinated nerve fibers and various stages of onion bulb formation as typically seen in CMT1. This correlative study further confirms that neurofilament light gene mutations cause a wide clinical spectrum. Thus, analysis of the neurofilament light gene should not be restricted to pure axonal neuropathies.

Assessment of driving performance in patients with relapsing-remitting multiple sclerosis by a driving simulator.

OBJECTIVE: To compare the driving performance using a driving simulator with physical and cognitive functions as measured by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients suffering from the relapsing-remitting form of multiple sclerosis (RRMS). METHODS: 31 RRMS patients (18 women, 13 men, mean age 35.6 +/- 8.3 years, EDSS 2.8 +/- 1.4) were compared with 10 healthy controls (8 men, 2 woman, age 45.1 +/- 7.8 years). RESULTS: Compared with controls, the accident rate (5.3 +/- 3.8 vs. 1.3 +/- 1.5, p < 0.001) and concentration faults (21.1 +/- 15.5 vs. 7.1 +/- 2.6, p < 0.01) of RRMS patients using the driving simulator were increased. While there was no correlation with the EDSS score, the accident rate was correlated with the MSFC (r = -0.5, p < 0.05). Regarding the three dimensions of the MSFC, accidents were related to the number of correct answers and Z-score in the paced auditory serial addition test (PASAT) as a measure for cognitive function (r = -0.33, p < 0.05). CONCLUSION: The current study demonstrates the need to focus also on driving skills in MS patients. The risk of accidents should be evaluated after relapses in particular. However, there are great interindividual differences. In the MSFC, most deficits could be evaluated in the PASAT. As there was a significant correlation between the accident rate in the driving simulator and the PASAT results, accidents seem to be more influenced by cognitive decline than by physical impairment. This indicates that the MSFC is a broader, more dimensional scale than the EDSS and should be preferred in the case of driving assessment. At the present time, the driving simulator seems to be a useful instrument judging driving ability, especially in cases with ambiguous neuropsychological results.

Expression of chemokine receptor CXCR3 on cerebrospinal fluid T-cells is related to active MRI lesion appearance in patients with relapsing-remitting multiple sclerosis.

We evaluated CXCR3 expression on T-cells and levels of its ligand CXCL10 in blood and cerebrospinal fluid (CSF) of 22 patients with relapsing-remitting multiple sclerosis (RR-MS) in association with magnetic resonance imaging (MRI) disease activity. CXCL10 was strongly released intrathecally, but did not change in association with MRI activity. CXCR3 expression on T-cells was lower in the peripheral blood (PB) of RR-MS patients compared to healthy controls and was increased in the CSF of RR-MS patients undergoing acute attacks, as illustrated by Gd-enhancing lesions on MRI, compared to patients without enhancing lesion. Our results suggest that MRI-documented disease activity is associated with an increase of CXCR3 positive T-cells in the CSF, possibly due to the migration of activated T-cells from the circulation into the CSF.

A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.

PTPRC (CD45) is not associated with multiple sclerosis in a large cohort of German patients.

BACKGROUND: Since contradictory results have been reported, we reanalysed the 77C-->G transition in exon 4 of the protein-tyrosine phosphatase receptor-type C (PTPRC also known as CD45) in a large cohort of German MS patients and controls. Different isoforms of the protein are expressed, depending on alternative splicing of exons 4 (CD45RA), 5 (CD45RB) and 6 (CD45RC) (CD45RO, exons 4-6 spliced out). The 77C-->G transition does not change the amino acid sequence, but it is probably part of a motif necessary for splicing leading to the isoform CD45RA. The expression of CD45RA is increased in 77C/G heterozygous individuals. The aim of the study was to clarify the importance of the PTPRC 77C-->G transition in our German cohort of MS patients. METHODS: PCR products of exon 4 were digested using endonuclease MspI. The resulting restriction fragments of the wildtype C allele are 198 and 62 bp in length. In the G allele an additional restriction site is present yielding fragments of 114 and 84 bp. RESULTS: The G allele was identified in 10 of the 347 controls (1.4%) and in 7 of 454 MS patients (0.8%; Table 1). No homozygous individuals were found either in the control or in the patient group. Genetic association between the PTPRC 77C-->G transition and MS susceptibility was excluded in the MS cohort. In addition, subgrouping patients according to differences in the clinical course of MS or according to HLA-DRB1*15 status did not yield significant differences. CONCLUSIONS: The 77C-->G transition in exon 4 of the PTPRC gene may contribute to MS susceptibility only in very few families, if at all, but it is not relevant for the majority of MS cases, including virtually all German patients.