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Background: The risk of stroke after cardiac and carotid surgery is well established. In contrast, stroke risk in association with non-cardiac and non-carotid surgery and its time course are insufficiently known. We investigated the prevalence of recent and planned surgery among patients with stroke and transient ischemic attack (TIA), time dependency of stroke risk, stroke etiology, and interruption of antithrombotic medication in association with surgery. Methods: Data on type and date of surgery and similar interventions within the last year or planned for the next 2 weeks were anonymously collected together with demographic data, vascular risk factors, stroke severity, handicap before stroke and stroke etiology within a state-wide, mandatory, hospital-based acute stroke care quality monitoring project (Rhineland-Palatinate, Germany) for 1 year (2010). Results: Non-carotid and non-cardiothoracic surgery was reported as performed within 1 year before the index event or as planned for the next 2 weeks thereafter in 532 out of 12,120 patients with ischemic stroke/TIA (4.4%). Compared to 91-365 days before stroke/TIA as reference period, risk of cerebral ischemia (per day analysis) was increased for surgery within 61-90 days before ischemia (rate ratio 2.0, 95% CI 1.5-2.8) and continuously increased along shorter intervals between stroke and surgery (31-60 days: rate ratio 3.6, 95% CI 2.9-4.5; 15-30 days: rate ratio 8.2, 95% CI 6.7-10.1; 8-14 days: rate ratio 13.2, 95% CI 10.3-16.8; 4-7 days: rate ratio 16.5, 95% CI 12.2-22.1) peaking at an interval of 1-3 days before ischemia (rate ratio 34.0, 95% CI 26.9-42.8). On the day of surgery, rate ratio was 14.8 (95% CI 7.8-27.9) and for planned surgery it was 2.7 (95% CI 1.8-4.0). Results were similar for first-ever and for recurrent ischemic stroke. Perioperative stroke/TIA was positively associated with atrial fibrillation and cardioembolic stroke etiology, higher mortality, more severe neurological deficits at discharge, and longer hospital stay; and it was inversely associated with microangiopathic etiology and discharge at home. In 34.5% of patients with recent/planned surgery, prior antithrombotic or anticoagulant medication had been interrupted. Conclusions: Recent or planned surgery imposes a considerable short-term stroke risk particularly by cardioembolism with cessation of medication as an important contributor. Stroke after surgery is associated with poor outcome and high mortality. Better strategies to reduce the burden of perioperative stroke are urgently required.

We report a novel heteroplasmic point mutation G8299A in the gene for mitochondrial tRNA Lys in a patient with progressive external ophthalmoplegia complicated by recurrent respiratory insufficiency. Biochemical analysis of respiratory chain complexes in muscle homogenate showed a combined complex I and IV deficiency. The transition does not represent a known neutral polymorphism and affects a position in the tRNA acceptor stem which is conserved in primates, leading to a destabilization of this functionally important domain. In vitro analysis of an essential maturation step of the tRNA transcript indicates the probable pathogenicity of this mutation. We hypothesize that there is a causal relationship between the novel G8299A transition and progressive external ophthalmoplegia with recurrent respiratory failure due to a depressed respiratory drive.

Background: Socioeconomic conditions may strongly influence the risk of stroke. We tested the hypotheses that indexes of social status in different life periods including childhood are inversely associated with stroke risk and that there is a cumulative effect of social conditions during lifetime on the risk of stroke. Furthermore, we investigated whether social advancement compared to the parental generation is associated with reduced stroke risk. Methods: In a case-control study, we assessed parental professional status, highest school degree, professional education and the last professional activity in 370 consecutive patients with ischemic or hemorrhagic stroke or transient ischemic attack [TIA; age 60.7 ± 12.8 years (mean ± standard deviation); 31.1% women] and 370 age- and sex-matched control subjects randomly selected from the general population of the same area. Results: Higher level of school exams [odds ratio (OR) 0.58, 95% confidence interval (CI) 0.39–0.86], university or polytechnic high school degrees (OR 0.39, 95% CI 0.24–0.63), nonmanual (last or current) professional activity (OR 0.51, 95% CI 0.37–0.71) and father’s nonmanual professional activity (OR 0.64, 95% 0.43–0.97) were associated with a lower risk of stroke/TIA. Adjustment for vascular risk factors including current smoking and alcohol consumption reduced the strength of these associations and rendered them nonsignificant except for university or polytechnic high school degrees (OR 0.49, 95% CI 0.27–0.87). Additional adjustment for regular sports activity further attenuated the association between academic degrees and risk of stroke/TIA (OR 0.56, 95% CI 0.31–1.02). A score summarizing 4 lifetime social indexes was not independently associated with stroke risk (OR 0.67, 95% CI 0.39–1.16). Social advancement as assessed by changes from paternal manual work to nonmanual work in the index generation was more common among control subjects (23.5%) than patients (15.3%; p = 0.0097), but such advancement was not independently associated with stroke/TIA after adjustment for all covariables (OR 0.82, 95% CI 0.50–1.33). Conclusions: Socioeconomic conditions were inversely linked to the risk of stroke/TIA. These associations were strongly influenced by lifestyle factors such as smoking, alcohol consumption and mainly sports activity. Stroke preventive strategies may have a particularly large potential if they focus on such lifestyle habits in socially disadvantaged groups.

Purpose. A transient painless monocular visual loss due to a decrease in retinal circulation—also known as “amaurosis fugax”—often precedes acute territorial cerebral ischaemia. The case we present underlines the importance of a comprehensive diagnostic workup in patients with amaurosis fugax.Case Report. A 44-year-old man who had suffered from a dissection of the ascending aorta (Stanford Type A) five months ago presented with recurrent monocular vision problems. Episodes with sectional vision loss mainly occurred in combination with low blood pressure levels. Furthermore, the haemoglobin level was chronically low (Hb 9.7 mg/dL), and the patient was by mistake on a simultaneous therapy with phenprocoumon and unfractionated heparin. Carotid artery duplex scanning revealed a high-grade stenosis of the proximal right common carotid artery. MR imaging corroborated hypoperfusion in brain area corresponding to the right MCA.Conclusion. Our patient is an example in whom transient retinal ischaemic attacks may originate from haemodynamic reasons.

Background and Purpose— We compared among young patients with ischemic stroke the distribution of vascular risk factors among sex, age groups, and 3 distinct geographic regions in Europe. Methods— We included patients with first-ever ischemic stroke aged 15 to 49 years from existing hospital- or population-based prospective or consecutive young stroke registries involving 15 cities in 12 countries. Geographic regions were defined as northern (Finland, Norway), central (Austria, Belgium, France, Germany, Hungary, The Netherlands, Switzerland), and southern (Greece, Italy, Turkey) Europe. Hierarchical regression models were used for comparisons. Results— In the study cohort (n=3944), the 3 most frequent risk factors were current smoking (48.7%), dyslipidemia (45.8%), and hypertension (35.9%). Compared with central (n=1868; median age, 43 years) and northern (n=1330; median age, 44 years) European patients, southern Europeans (n=746; median age, 41 years) were younger. No sex difference emerged between the regions, male:female ratio being 0.7 in those aged Conclusions— Primary preventive strategies for ischemic stroke in young adults—having high rate of modifiable risk factors—should be targeted according to sex and age at continental level.

Background: Stroke etiology in ischemic stroke guides preventive measures and etiological stroke subgroups may show considerable differences between both sexes. In a population-based stroke registry we analyzed etiological subgroups of ischemic stroke and calculated sex-specific incidence and mortality rates. Methods: The Ludwigshafen Stroke Study is a prospective ongoing population-based stroke registry. Multiple overlapping methods of case ascertainment were used to identify all patients with incident stroke or transient ischemic attack. Modified TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria were applied for subgroup analysis in ischemic stroke. Results: Out of 626 patients with first-ever ischemic stroke in 2006 and 2007, women (n = 327) were older (73.5 ± 12.6 years) than men (n = 299; 69.7 ± 11.5 years; p < 0.001). The age-adjusted incidence rate of ischemic stroke was significantly higher in men (1.37; 95% CI 1.20–1.56) than in women (1.12; 95% CI 0.97–1.29; p = 0.04). Cardioembolism (n = 219; 35.0%), small-artery occlusion (n = 164; 26.2%), large-artery atherosclerosis (n = 98; 15.7%) and ‘probable atherothrombotic stroke’ (n = 84; 13.4%) were common subgroups of ischemic stroke. Stroke due to large-artery atherosclerosis (p = 0.025), current smoking (p = 0.008), history of smoking (p < 0.001), coronary artery disease (p = 0.0015) and peripheral artery disease (p = 0.024) was significantly more common in men than in women. Overall, 1-year survival was not different between both sexes; however, a significant age-sex interaction with higher mortality in elderly women (>85 years) was detected. Conclusions: Cardioembolism is the main source for ischemic stroke in our population. Etiology of ischemic stroke differs between sexes, with large-artery atherosclerotic stroke and associated diseases (coronary artery disease and peripheral artery disease) being more common in men.

Background and Purpose— Quality monitoring projects are useful tools to improve the quality and to assess temporal trends of stroke care in larger populations. Methods— In Rhineland-Palatinate, Germany, a statewide, hospital-based, acute stroke care quality monitoring project was started in 2001. Initially, participation was mandatory for all hospitals with dedicated stroke units and from 2006 onward was mandatory for all hospitals. Quality monitoring included a structured data assessment and quality indicators for procedural measures. Results— Between 2001 and 2006, the numbers of patients registered annually (N=6389 vs N=10 610), admission P P P P Conclusions— Although these results reflect high standards of acute stroke care and improvements regarding early admission, thrombolytic therapy, and several secondary preventive measures, there is still the potential for further improvement regarding thrombolysis, use of oral anticoagulation and statins, and admission to stroke units, for example.

There is increasing evidence that acute bacterial and viral infection represent trigger factors that temporarily elevate the risk of ischemic stroke. During and after influenza epidemics vascular death rates and hospitalizations for stroke are increased. Influenza vaccination is an effective measure to reduce hospitalization and mortality in the elderly and work incapacity in adults of working age. Results of several observational studies support the hypothesis that influenza vaccination is associated with reduced odds of stroke. As randomized studies are lacking, a causal role of influenza vaccination in stroke prevention is not proven, however. According to current guidelines in many countries, that recommend the vaccination in all patients with chronic vascular disease, all patients with a history of stroke or TIA should receive an influenza vaccination annually. Furthermore, patients with diabetes mellitus or with a combination of risk factors that increase stroke risk should obtain the vaccination. In addition, there is evidence from observational data that the neuraminidase inhibitor oseltamivir reduces the risk of stroke within 6 months after influenza infection.

Background: Churg–Strauss syndrome (CSS) is a rare systemic vasculitis. Case series with a focus on neurologic involvement are not common. With this study, we intended to evaluate the frequency and types of neurologic manifestations and complications at time of diagnosis and during follow-up of patients with CSS. Methods: In this monocentric study, consecutive patients of our hospital with first diagnosis of CSS based on the criteria of the American College of Rheumatology were included between 2001 and 2007. Each patient underwent a periodic follow-up with clinical and electrophysiologic examination. Data were obtained prospectively. Results: Fourteen patients were included. All patients had a hypereosinophilia and a history of asthma. Twelve of 14 patients had a neurologic involvement, mainly as an acute or subacute multiplex mononeuropathy (eight patients) or an axonal polyneuropathy (three patients). Three patients suffered from a neuropathy of cranial nerves, and two patients had a cerebral infarct. Mean follow-up period was 31 months. With immunosuppressive therapy, 13 patients had no additional neurologic complications, one patient suffered from a cerebral infarct. Initial neurologic symptoms as a result of peripheral neuropathy improved, but sequelae of axonal damage were persistently detectable. Conclusions: Even at time of diagnosis of a CSS, neurologic manifestations are common, especially as a multiplex mononeuropathy. With a consequent immunosuppressive therapy, new neurologic complications can be avoided for the most part.

Background/Aims: Inflammation plays an important role in atherosclerosis and stroke. Acute infections are recognized as trigger factors for ischemic stroke. Methods: In this whole genome expression profile study of 15 patients and 15 control subjects, we tested the hypothesis that patients with a history of atherothrombotic stroke show enhanced transcription of inflammatory genes in circulating leukocytes. RNA from unstimulated or lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) was analyzed with Affymetrix U133A GeneChips using a pooling design. Expression of single genes and functional groups of genes was analyzed by global statistical tests. Results: A total of 10,197 probe sets showed positive calls. After correction for multiple testing no single probe set revealed significant differences either without or with LPS stimulation. However, significant global expression differences were found upon LPS stimulation for the group of genes that are involved in cell–cell signaling. Conclusion: LPS stimulation of PBMCs, a condition mimicking bacterial infection, induces differential expression of a group of cell–cell signaling genes in patients with previous atherothrombotic stroke. This finding can be caused by genetic differences between both groups, but acquired risk factors, medication and technical factors may also have contributed to the result.

Background and Purpose: Oxidative stress has been proposed as a major contributing factor for vascular disease, that acts independently from its participation in predisposing disorders such as diabetes and arterial hypertension. A functionally relevant C242T polymorphism of the CYBA gene encoding the NAD(P)H oxidase p22phox subunit, is supposed to lead to an abnormal reduction in the generation of reactive oxygen species in vascular smooth-muscle and endothelial cells. Methods: We investigated the p22phox C242T single-nucleotide polymorphism by polymerase chain reaction in consecutive patients with ischemic stroke or transient ischemic attack under the age of 50 (n = 161) and in population-based control subjects (n = 136). Results: Homozygosity for the T variant was associated with an enhanced risk for cerebral ischemia (odds ratio 3.85, confidence interval 1.39–10.64) after adjusting for classical risk factors. Risk for cerebral ischemia was not increased in heterozygous subjects. Conclusion: The p22phox C242T single-nucleotide polymorphism is associated with stroke risk. This finding supports the hypothesis that oxidative stress may contribute to stroke pathogenesis.

Acetylsalicylic acid (ASA; Aspirin) has a neuroprotective potential by its anti-excitotoxic and anti-inflammatory effects. A temporary middle cerebral artery occlusion (tMCAO) model was used in 80 Wistar rats to evaluate whether a high dose of Aspirin (40 mg/kg) applied with different initiation time points after stroke onset (30 min, 3 h, 6 h, 12 h, 20 rats for each time group) and followed by repeated administration (1, 2 and 3 days) is neuroprotective. Neurological score and brain infarct volume were analyzed and indicated that postischemic therapy initiation at 30 min and as late as 6 h led to better neurological recovery (6 h, p = 0.0046) and significant smaller infarct size (6 h, 57 ± 9 mm 3 , n = 10, p = 0.0043) compared to the saline control group (110 ± 13 mm 3 , n = 10). Thus, there may be a relatively wide time window for acute stroke therapy with high dose Aspirin.

Hintergrund Ziel dieser Studie war es, Hinweise auf die Haufigkeit extrakardialer, v. a. pulmonaler Rechts-links-Shunts (RLS) bei Patienten mit akuter zerebraler Ischamie unklarer Ursache zu erlangen.

Background and Purpose— The widespread preference of anticoagulants over antiplatelets in patients with cervical artery dissection (CAD) is empirical rather than evidence-based. Summary of Review— This article summarizes pathophysiological considerations, clinical experiences, and the findings of a systematic metaanalysis about antithrombotic agents in CAD patients. As a result, there are several putative arguments in favor as well as against immediate anticoagulation in CAD patients. Conclusions— A randomized controlled trial comparing antiplatelets with anticoagulation is needed and ethically justified. However, attributable to the large sample size which is required to gather meaningful results, such a trial represents a huge venture. This comprehensive overview may be helpful for the design and the promotion of such a trial. In addition, it could be used to encourage both participation of centers and randomization of CAD patients. Alternatively, antithrombotic treatment decisions can be customized based on clinical and paraclinical characteristics of individual CAD patients. Stroke severity with National Institutes of Health Stroke Scale score ≥15, accompanying intracranial dissection, local compression syndromes without ischemic events, or concomitant diseases with increased bleeding risk are features in which antiplatelets seem preferable. In turn, in CAD patients with (pseudo)occlusion of the dissected artery, high intensity transient signals in transcranial ultrasound studies despite (dual) antiplatelets, multiple ischemic events in the same circulation, or with free-floating thrombus immediate anticoagulation is favored.

Persisting disability requiring professional healthcare or help in daily life activities can be expected in a third to a half of all stroke survivors. It is mainly the elderly that are affected. For the increasingly aging population of Western societies, stroke represents an increasing social and economic burden. Besides the existing therapeutic options, additional treatment and prevention strategies are needed. Traditional risk factors do not explain all clinical and epidemiological features of stroke. Recently, the association between infectious and inflammatory processes and the occurrence of vascular disease has been established. This review summarizes the current evidence of infections as stroke risk factors and of potential anti-infective strategies as future methods of stroke prevention.

Background and Purpose— The association between socioeconomic status in adulthood and the risk of stroke is well established; however, the independent effects of socioeconomic conditions in different life phases are less understood. Methods— Within a population-based stroke registry, we performed a case–control study with 470 ischemic stroke patients (cases) aged 18 to 80 years and 809 age- and sex-matched stroke-free controls, randomly selected from the population (study period October 2007 to April 2012). We assessed socioeconomic conditions in childhood, adolescence, and adulthood, and developed a socioeconomic risk score for each life period. Results— Socioeconomic conditions were less favorable in cases regarding paternal profession, living conditions and estimated family income in childhood, school degree, and vocational training in adolescence, last profession, marital status and periods of unemployment in adulthood. Using tertiles of score values, low socioeconomic conditions during childhood (odds ratio 1.77; 95% confidence interval 1.20–2.60) and adulthood (odds ratio 1.74; 95% confidence interval 1.16–2.60) but not significantly during adolescence (odds ratio 1.64; 95% confidence interval 0.97–2.78) were associated with stroke risk after adjustment for risk factors and other life stages. Medical risk factors attenuated the effect of childhood conditions, and lifestyle factors reduced the effect of socioeconomic conditions in adolescence and adulthood. Unfavorable childhood socioeconomic conditions were particularly associated with large artery atherosclerotic stroke in adulthood (odds ratio 2.13; 95% confidence interval 1.24–3.67). Conclusions— This study supports the hypothesis that unfavorable childhood socioeconomic conditions are related to ischemic stroke risk, independent of established risk factors and socioeconomic status in adulthood, and fosters the idea that stroke prevention needs to begin early in life.

Background Stroke in patients with acute cervical artery dissection may be anticipated by initial transient ischemic or nonischemic symptoms. Aim Identifying risk factors for delayed stroke upon cervical artery dissection. Methods Cervical artery dissection patients from the multicenter Cervical Artery Dissection and Ischemic Stroke Patients study were classified as patients without stroke ( n = 339), with stroke preceded by nonstroke symptoms (delayed stroke, n = 244), and with stroke at onset ( n = 382). Demographics, clinical, and vascular findings were compared between the three groups. Results Patients with delayed stroke were more likely to present with occlusive cervical artery dissection ( P < 0·001), multiple cervical artery dissection ( P = 0·031), and vertebral artery dissection ( P < 0·001) than patients without stroke. No differences were observed in age, smoking, arterial hypertension, hypercholesterolemia, migraine, body mass index, infections during the last week, and trauma during the last month, but patients with delayed stroke had less often transient ischemic attack ( P < 0·001) and local signs (Horner syndrome and cranial nerve palsy; P < 0·001). Conclusions Occlusive cervical artery dissection, multiple cervical artery dissection, and vertebral artery dissection were associated with an increased risk for delayed stroke. No other risk factors for delayed stroke were identified. Immediate cervical imaging of cervical artery dissection patients without ischemic stroke is needed to identify patients at increased risk for delayed ischemia.

Acute infections, mainly of the respiratory tract, have consistently been demonstrated to considerably increase the risk of stroke. At present, prospective interventional trials are lacking and there is no proof of the effectiveness of any therapeutic anti-infective strategy in stroke prevention. However, some new evidence from observational studies lends support to the idea that influenza vaccination may contribute importantly to fighting stroke. Although final proof of efficacy is still missing, patients with previous cerebral ischemia and subjects of any age at high risk of stroke should be encouraged to receive annual influenza vaccination.

There is increasing evidence that, in addition to conventional risk factors, acute and chronic infectious diseases increase the risk of stroke. Acute infection, mainly respiratory, and both bacterial and viral infection, represent temporarily active trigger factors for cerebral ischemia. Chronic infectious diseases that may increase the risk of stroke include periodontitis, chronic bronchitis and infections with microbial antigens, such as Helicobacter pylori and Chlamydia pneumoniae. From observational studies, there is evidence that vaccination against influenza is associated with a reduced risk of stroke, myocardial infarction and all-cause mortality. This report provides an overview on the influence of infection on stroke risk and potential anti-infective strategies that may play a future role in stroke prevention.

Erratum in: Familial occurrence and heritable connective tissue disorders in cervical artery dissection. [Neurology. 2016]; International audience; In a large series of patients with cervical artery dissection (CeAD), a major cause of ischemic stroke in young and middle-aged adults, we aimed to examine frequencies and correlates of family history of CeAD and of inherited connective tissue disorders. We combined data from 2 large international multicenter cohorts of consecutive patients with CeAD in 23 neurologic departments participating in the CADISP-plus consortium, following a standardized protocol. Frequency of reported family history of CeAD and of inherited connective tissue disorders was assessed. Putative risk factors, baseline features, and 3-month outcome were compared between groups. Among 1,934 consecutive patients with CeAD, 20 patients (1.0%, 95% confidence interval: 0.6%-1.5%) from 17 families (0.9%, 0.5%-1.3%) had a family history of CeAD. Family history of CeAD was significantly more frequent in patients with carotid location of the dissection and elevated cholesterol levels. Two patients without a family history of CeAD had vascular Ehlers-Danlos syndrome with a mutation in COL3A1. This diagnosis was suspected in 2 additional patients, but COL3A1 sequencing was negative. Two patients were diagnosed with classic and hypermobile Ehlers-Danlos syndrome, one patient with Marfan syndrome, and one with osteogenesis imperfecta, based on clinical criteria only. In this largest series of patients with CeAD to date, family history of symptomatic CeAD was rare and inherited connective tissue disorders seemed exceptional. This finding supports the notion that CeAD is a multifactorial disease in the vast majority of cases.

Genetic thrombophilic conditions such as those associated with Factor V Leiden (FVL) and the prothrombin mutant (PT G20210A) have been identified as risk factors for cerebral venous thrombosis (CVT). Recently, a single nucleotide polymorphism (SNP) of the thrombin activatable fibrinolysis inhibitor (TAFI G-438A) has been shown to be associated with lower TAFI levels and to decrease the risk for peripheral venous thrombosis. Furthermore, a protective role in juvenile stroke was shown for a SNP of the vitamin K dependent protein Z (PZ Intron F G79A) which is linked with low PZ levels.In 77 consecutive patients with CVT and in 203 randomly selected population controls from the same region of Southern Germany, we investigated the following functional SNPs using PCR and restriction fragment analysis techniques: TAFI G-438A, PZ Intron F G79A, FVL and PT G20210A.The prevalence of FVL tended to be higher (OR 2.08, 95 % CI 0.91-4.75, p = 0.06) and that of PT G20210A (OR 4.57, 95 % CI 1.45-14.44, p = 0.007) was significantly higher in patients with CVT than in controls. The A-allele frequency of the TAFI G-438A polymorphism did not significantly differ between patients (21.3 %) and controls (26.9%; OR 0.71, 95 % CI 0.45-1.12; p = 0.17). For the PZ G79A SNP, the frequency of the A-allele was 19.5% in CVT and 24.6% in controls (OR 0.77, 95 % CI 0.49-1.21; p = 0.31).In this large series of CVT patients, a positive association with established thrombophilic risk factors FVL and especially the PT G20210A mutation was confirmed. In contrast, our study found no significant association of CVT with SNPs of the TAFI and the PZ genes. Other than testing for FVL and the PT G20210A mutation, exploration of these potential thrombophilic variants seems to be of limited value in the investigation of CVT.

Studies suggest that there is an association between weather patterns and ischemic stroke risk. Exposure to a sudden decrease in temperature may increase stroke risk through altering blood viscosity and/or by triggering infections. We investigated the association between ischemic stroke risk and change in temperature. We used a case-crossover study design with 303 consecutive patients admitted to Heidelberg University, Department of Neurology over a one and a half year period (Aug 1998-Jan 2000). We used one day before stroke as the hazard (case) period matched to two control periods 2-7 days before and after stroke onset and took both ambient maximum temperature and the 24-hour difference in maximum temperature as exposure. There was no risk associated with ambient maximum temperature at all lag times and in all subgroup analyses. For the 24-hour difference, large changes in temperature (>5 degrees C) were associated with an increased risk of acute ischemic stroke regardless of whether the change was negative or positive. The odds ratio for temperature increases >5 degrees C compared to no change in temperature was 2.0 (95% confidence interval (CI): 0.7-5.9) at a lag time of 3 days. We found no relevant relation between temperature and stroke risk. The results suggest that the risk of ischemic stroke may increase with large day-to-day variations upwards or downwards in temperature.

Case-control studies and a few prospective studies have indicated that chronic infections may add to the risk of stroke and that acute infections may act as trigger factors for stroke. Such chronic infections include periodontal disease, infection with Chlamydia pneumoniae or Helicobacter pylori, and chronic bronchitis. A causal role of these infectious diseases has not been proved, given conflicting study results, possible residual confounding in observational studies, and the lack of evidence from interventional trials. Therefore, special treatment regimens for stroke prevention based on serologic or genomic evidence of infection are not indicated outside of randomized studies at present. However, the preliminary available evidence suggests that in patients with previous cerebral ischemia, clinically diagnosed chronic infections should be taken seriously and should receive the treatment that is indicated according to current guidelines. This may include appropriate treatment of moderate or severe periodontitis and of chronic bronchitis. Inflammatory parameters (eg, C-reactive protein, leukocyte count, fibrinogen) are independently associated with the risk of first or recurrent stroke. The question of whether these indexes are causally related to stroke or merely represent risk markers is not sufficiently clarified. Their use in monitoring individual risk in daily clinical practice is limited at present by the lack of clearly defined therapeutic strategies to modify these parameters, although statins and other drugs can influence inflammatory markers. Observational studies have shown that influenza vaccination is significantly and independently associated with a reduced risk of stroke and myocardial infarction. Although interventional studies in stroke are lacking, it is recommendable that in accordance with current guidelines patients with previous vascular disease, including stroke, patients with high risk of stroke, and all subjects above age 60, receive an influenza vaccination annually.

The aim of this study was to assess the associations of different periodontal parameters with cerebral ischemia.In a case-control study, 303 consecutive patients with ischemic stroke or transient ischemic attack, and 300 representative population controls received a complete clinical and radiographic dental examination. Patients were examined on average 3 days after ischemia. The individual mean clinical attachment loss measured at four sites per tooth was used as indicator variable for periodontitis.Patients had higher clinical attachment loss than population (p0.001). After adjustment for age, gender, number of teeth, vascular risk factors and diseases, childhood and adult socioeconomic conditions and lifestyle factors, a mean clinical attachment loss6 mm had a 7.4 times (95% confidence interval 1.55-15.3) a gingival index1.2 a 18.3 times (5.84-57.26) and a radiographic bone loss a 3.6 times (1.58-8.28) higher risk of cerebral ischemia than subjects without periodontitis or gingivitis, respectively.Periodontitis is an independent risk factor for cerebral ischemia and acute exacerbation of inflammatory processes in the periodontium might be a trigger for the event of cerebral ischemia.

Background and Purpose— Chronic infectious diseases may increase the risk of stroke. We investigated whether periodontal disease, including periodontitis and gingivitis, is a risk factor for cerebral ischemia. Methods— We performed a case-control study with 303 patients examined within 7 days after acute ischemic stroke or transient ischemic attack, 300 population controls, and 168 hospital controls with nonvascular and noninflammatory neurological diseases. All subjects received a complete clinical and radiographic dental examination. The individual mean clinical attachment loss measured at 4 sites per tooth served as the main indicator for periodontitis. Results— Patients had higher clinical attachment loss than population ( P P =0.010) controls. After adjustment for age, sex, number of teeth, vascular risk factors and diseases, childhood and adult socioeconomic conditions, and lifestyle factors, the risk of cerebral ischemia increased with more severe periodontitis. Subjects with severe periodontitis (mean clinical attachment loss >6 mm) had a 4.3-times-higher (95% confidence interval, 1.85 to 10.2) risk of cerebral ischemia than subjects with mild or without periodontitis (≤3 mm). Severe periodontitis was a risk factor in men but not women and in younger ( Conclusions— Our study indicates that periodontal disease, a treatable condition, is an independent risk factor for cerebral ischemia in men and younger subjects.

Niemann-Pick disease type C (NPC) is a rare, neurovisceral lipid storage disorder caused by genetic defects in lipid transporting proteins. It is distinct from Niemann-Pick types A and B (sphingomyelin lipidoses) and displays genetic (mutations in the NPC1 or NPC2[=HE1] gene), biochemical, and clinical heterogeneity. Late infantile to juvenile forms of NPC predominate and are characterised by atypical behaviour, ataxia, dysarthria, dysphagia, dystonia, cataplexy, vertical gaze palsy, splenomegaly, and dementia. In adult variants, psychosis and dementia are common, and dysarthria, ataxia, splenomegaly, and vertical gaze palsy are further facultative signs. Routine laboratory results including serum cholesterol are normal. In bone marrow smears, sea-blue histiocytes are often demonstrated and foam cells sometimes seen. The diagnosis is confirmed by detecting free cholesterol accumulation in perinuclear granules (lysosomes) and reduced cholesterol esterification after challenge with exogenous low-density lipoprotein in fibroblasts. Alternatively or additionally, mutational analysis can be performed. Treatment is restricted to symptomatic measures, since there is no specific therapy.

Fabry's disease is an x-linked, recessive, lysosomal storage disorder that results from deficient alpha-galactosidase A activity with pathological sphingolipid deposition mainly in endothelium, smooth muscle cells, kidneys, central and peripheral nervous system, and myocardium. Clinical manifestation mostly occurs during childhood and adolescence with severe pain attacks or chronic pain mainly in hands and feet, hypohydrosis, and skin lesions (angiokeratoma). In more advanced disease stages, renal and cerebrovascular complications develop with proteinuria and later renal failure and cerebral ischemia caused by cerebral microangiopathy, dilatative arteriopathy, or cardiac embolism. Heterozygote female carriers are severely affected more often than was previously considered. The diagnosis is based on the detection of deficient alpha-galactosidase A activity in leukocytes, fibroblasts, or tissue biopsies. Two randomised placebo-controlled studies showed that enzyme replacement is effective by demonstrating either reduced pain or reduced tissue sphingolipid deposition. Early diagnosis of Fabry's disease is important in view of these new causal therapeutic options.

With ischemic heart disease (IHD) and stroke sharing many risk factors, one could presume a similar geographic pattern of stroke and IHD; however, Kim and Johnston described remarkable worldwide variations in disability-adjusted life-years (DALY) loss for both diseases.1 For stroke, much of Asia, eastern Europe, and Africa had DALY loss of ≥120/100 000 in contrast to North America, western Europe, and Australia having DALY loss rates ≤60/100 000. Eastern Europe and northern Asia also had strikingly high DALY loss (≥240/100 000) from IHD. Overall, there were 62 of 192 countries with higher DALY loss from stroke than for IHD, particularly for China, but also in many countries in Africa and South America. There were only marginally more countries (74 of 192) with higher DALY loss from IHD, particularly the Middle East, but also North America, Australia, and western Europe. Countries with lower national income, lower prevalence of diabetes, higher average alcohol intake, and less obesity tended to have higher DALY loss from stroke than IHD.1 The contributors to the substantial variations in stroke incidence within countries have been examined by reports including that by Grimaud and colleagues, who showed stroke incidence was as much as one third higher in regions of France with lower levels of socioeconomic status and/or higher levels of income inequality.2 A similar one third difference (32%) in stroke risk was observed between high socioeconomic status and low socioeconomic status neighborhoods in the United States.3 Attenuation of these neighborhood differences was larger with adjustment for biological risk factors (mediated to a 16% excess) than for behavioral risk factors (mediated to a 30% excess), suggesting that biological risk factors …

Adult-onset autosomal dominant leukodystrophy (ADLD, OMIM accession number 169500) is a slowly progressive neurological disorder involving early autonomic dysfunction, cognitive impairment, pyramidal lesions, and cerebellar dysfunction. Onset is usually in the fourth or fifth decade of life. The disease is caused by a duplication of a region on chromosome 5q23.2 including the Lamin B1 gene (LMNB1) [1]. Neuroradiological characteristics are symmetrical extensive white matter changes predominantly in the frontal and parietal lobes, middle cerebellar peduncles, and specific brain stem tracts. Furthermore, atrophy of the corpus callosum and the brain stem develop. Sparing or less severe alteration of the periventricular white matter is a typical finding [2]. We report on a 47-year-old male patient with a 2-year history of gait disturbance and micturition problems with imperative strangury and, as mentioned by family members, personality changes and depression. On examination he had moderately severe gait ataxia, symmetrical appendicular ataxia, mild spastic paraparesis, brisk deep tendon reflexes, and bilaterally positive Babinski signs. MR imaging of the brain showed extensive bilateral T2hyperintense lesions in the subcortical and deep cerebral white matter with relative sparing of a periventricular rim and the corpus callosum. The middle cerebellar peduncles, the pyramidal tracts, and medial lemniscus in the midbrain, pons, and medulla, and the decussation of the superior cerebellar peduncles were also affected (Fig. 1). Neuropsychological testing yielded results below average regarding the following domains: verbal fluency and flexibility, verbal memory, verbal recall, working memory, several executive functions, and general working velocity. Lumbar puncture, evoked potentials, nerve conduction studies, and electromyography were without abnormal findings. Blood and urine analysis of amino acids, long-chain fatty acids, and lysosomal enzymes (arylsulfatase A, galactocerebrosidase, alpha-galactosidase) were normal. The pedigree showed numerous affected members of father’s family within three generations. Four out of five uncles and aunts and in the grandparents’ generation, six out of eight family members were affected, mainly by gait disturbance but also by neuropsychiatric symptoms (Fig. 2). Seven affected siblings had died; age at death varied between 46 and 71 years. Because of the mode of inheritance and the clinical and MRI findings, ADLD was supposed and the lamin B1 gene was analyzed. Genomic DNA was extracted from venous blood and hybridized on Affymetrix GeneChip Human Mapping SNP6.0 arrays, following the manufacturer’s instructions. M. M. Dos Santos (&) A. J. Grau Department of Neurology, Klinikum Ludwigshafen, Bremserstrasse 79, 67063 Ludwigshafen, Germany e-mail: santosm@klilu.de

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis which can be clinically diagnosed and specifically treated. It is is an underdiagnosed disorder worldwide. Here, we describe two women who were diagnosed with CTX during their forties after symptoms had already developed 15 years earlier. Both patients showed gait ataxia, spastic paraparesis, polyneuropathy, bilateral premature cataracts, tendon xanthomas,and cognitive deficits. One of the patients had also chronic diarrhea.The deficiency of the mitochondrial enzyme sterol 27-hydroxylase results in a virtual absence of chenodeoxycholic acid. This leads to excessive production of cholestanol and cholesterol and accumulation of these sterols in many tissues, especially the eye lens, central nervous system, and tendons.The determination of a high cholestanol serum level allows the diagnosis, which can be confirmed through genetic analysis. Early diagnosis of CTX is important, since an effective therapy is available. Long-term therapy with chenodeoxycholic acid is effective for CTX, mainly in prevention of further deterioration.

Background and Purpose— The aim of this study was to evaluate the time course of platelet activation after ischemic stroke and to investigate whether platelet activation and inflammation are correlated with each other. Methods— We serially determined expression of p-selectin (CD62p) and lysosome-associated membrane protein (CD63) by platelets using flow cytometry at 10 time points between days 1 and 90 in patients after ischemic stroke (n=50), in healthy subjects (n=30), and in risk factor control subjects (n=20). Furthermore, we correlated leukocyte count, C-reactive protein, and fibrinogen levels with platelet activation markers. Results— CD62p and CD63 expression was higher on day 1 after stroke than in both control groups ( P Conclusions— The initial increase in both CD62p and CD63 expression by platelets is followed by a differential regulation of both parameters after stroke. The rapid decrease in CD62p expression may be caused by shedding from the cell surface. Its persistent elevation makes CD63 a good candidate for studies on predictors for stroke recurrence. Our findings suggest that the expression of CD62p and CD63 by platelets is regulated independently from inflammatory indexes.

The etiology of spontaneous cervical artery dissection (sCAD) is unknown. An underlying connective tissue disorder has been suggested. As a collagen disease is conceivable several genes encoding fibrillar collagens have been condsidered as candidate genes for sCAD. We analysed the COL3A1 gene in patients with spontaneous cervical artery dissection (sCAD) and in healthy controls, using three different genetic methods. 1) The promoter region, the 5' and 3' untranscribed regions and the N- and C- peptide encoding regions were studied by direct sequencing analysis of DNA from 12 patients. 2) A possible association of sCAD and the COL3A1 gene was tested for with 5 different DNA polymorphisms in 45 patients and 50 healthy control subjects. 3) DNA samples from a father and his two daughters, all suffering from spontaneous dissections of a cervical artery, were analysed with CA-repeat markers that flank the COL3A1 locus. No disease-causing mutations were found in an extended sequence analysis of the COL3A1 gene in patients with sCAD. However, we identified a single nucleotid polymorphism (SNP) in the promotor region in 2 patients and a 2 bp deletion in the 3' UTR in 7 patients. These sequence variants were also found among 50 healthy subjects. An analysis of multiple DNA polymorphisms of the COL3A1 locus in patients and healthy control persons did not indicate a significant association of sCAD with COL3A1. A deletion polymorphism in the 3' UTR was, however, found more often amongst patients with sCAD. The possible linkage of a hypothetical disease mutation with the COL3A1 locus was tested in a small family with three affected patients. As the affected daughters did not inherit the same COL3A1 allele from their affected father (LOD < - 2.3) COL3A1 was excluded as a disease gene in this family. This study confirms and extends earlier work which suggests that COL3A1 mutations are not a major cause for isolated sCAD.

Survival in amyotrophic lateral sclerosis varies considerably. About one third of the patients die within 12 months after first diagnosis. The early recognition of fast progression is essential for patients and neurologists to weigh up invasive therapeutic interventions. In a prospective, population-based cohort of ALS patients in Rhineland-Palatinate, Germany, we identified significant prognostic factors at time of diagnosis that allow prediction of early death within first 12 months. Incident cases, diagnosed between October 2009 and September 2012 were enrolled and followed up at regular intervals of 3 to 6 months. Univariate analysis utilized the Log-Rank Test to identify association between candidate demographic and disease variables and one-year mortality. In a second step we investigated a multiple logistic regression model for the optimal prediction of one-year mortality rate. In the cohort of 176 ALS patients (mean age 66.2 years; follow-up 100%) one-year mortality rate from diagnosis was 34.1%. Multivariate analysis revealed that age over 75 years, interval between symptom onset and diagnosis below 7 months, decline of body weight before diagnosis exceeding 2 BMI units and Functional Rating Score below 31 points were independent factors predicting early death. Probability of early death within 12 months from diagnosis is predicted by advanced age, short interval between symptom onset and first diagnosis, rapid decline of body weight before diagnosis and advanced functional impairment. ClinicalTrials.gov ( NCT01955369 , registered September 28, 2013)

Background: The possibility to survive with amyotrophic lateral sclerosis (ALS) varies considerably and survival extends from a few months to several years. A number of demographic and clinical factors predicting survival have been described; however, existing data are conflicting. We intended to predict patient survival in a population-based prospective cohort of ALS patients from variables known up to the time of diagnosis. Methods: Incident ALS patients diagnosed within three consecutive years were enrolled and regularly followed up. Candidate demographic and disease variables were analysed for survival probability using the Kaplan-Meier method. The Cox proportional hazard regression model was used to assess the influence of selected predictor variables on survival prognosis. Results: In the cohort of 193 patients (mean age 65.8, standard deviation 10.2 years), worse prognosis was independently predicted by older age, male gender, bulbar onset, probable or definite ALS according to El Escorial criteria, shorter interval between symptom onset and diagnosis, lower Functional Rating Scale, diagnosis of frontotemporal dementia, and living without a partner. Conclusions: Taking into account these predictor variables, an approximate survival prognosis of individual ALS patients at diagnosis seems feasible.

Background and Purpose: A recent surgery may be one of the trigger factors precipitating stroke and transient ischemic attack (TIA). While stroke in cardiac and carotid surgery has been well studied, less is known on stroke risk after surgery outside the heart and brain supplying arteries. We tested the hypothesis that preceding non-neurosurgical, non-cardiothoracic, and non-carotid surgery and other interventions temporarily increase the risk of stroke and transient ischemic attack (TIA) and investigated the risk related to different time periods between interventions and stroke/TIA. Methods: In the Ludwigshafen Stroke Study, a population-based stroke registry, we assessed surgery and other interventions within the year preceding stroke and TIA. The risk factor profiles of patients with and without prior intervention were compared and rate ratios (RR) were calculated for different time periods with 91-365 days before stroke and TIA serving as reference period. Results: In 2006 and 2007, 803 patients without and 116 patients with non-neurosurgical, non-cardiothoracic, and non-carotid intervention within the preceding year were identified. Elective (n = 21) and posttraumatic orthopedic (n = 14), eye (n = 14), and visceral surgery (n = 11) dominated. Interventions within 0-30 days (n = 34; RR 4.72; 95% confidence interval (CI) 2.70-8.26) but not within 31-60 or 61-90 days before stroke/TIA were observed more often than in the reference period. Interventions were more common within day 8-30 before stroke/TIA (RR 3.26; 95% CI 1.66-6.39), particularly common within the preceding week (RR 9.52; 95% CI 3.77-24.1) and most common in the preceding 2 days (RR 27.1; 95% CI 5.97-123) as compared to the reference period. Atrial fibrillation (AF) but not other risk factors was more common in patients with interventions within 30 days (n = 15; 44.1%) as compared to patients with more antecedent interventions (n = 19; 23.2%, p = 0.022) and those without surgery (n = 222; 27.6%, p = 0.031). Interventions within 30 days before stroke/TIA, were associated with total ischemic stroke (RR 6.11; 95% CI 3.32-11.2), first-ever in a lifetime ischemic stroke (RR 5.62; 95% CI 2.83-11.1) and recurrent ischemic stroke (RR 7.50; 95% CI 2.88-19.6). Conclusion: Recent non-cardiothoracic, non-carotid, and non-neurosurgical interventions are associated with an increased risk of stroke lasting for about 1 month and being particularly high within the first days. AF may be among the mechanisms linking interventions and stroke besides induction of a procoagulant state and interruption of medication.

There is a lack of prospective and population based epidemiological data on amyotrophic lateral sclerosis in Germany to date. The ALS registry Rhineland-Palatinate was established to investigate the incidence, course and phenotypic variety of ALS in this south-west German state of about 4 million inhabitants. During the period 2010-2011, consecutive incident patients with amyotrophic lateral sclerosis according to the revised El Escorial criteria were included and followed up using multiple overlapping sources of case ascertainment. One hundred and forty-six patients were enrolled. The annual crude incidence for amyotrophic lateral sclerosis in Rhineland-Palatinate was 1.8/100,000 person-years (95% CI 1.6-2.2). Male to female ratio was 1.1:1. Incidence increased with age reaching a peak in the 70-74 years age group and declined thereafter. Late-onset ALS (≥ 75 years) was found in 14.4% of patients. About 32% of patients presented with bulbar onset. In conclusion, incidence rate of amyotrophic lateral sclerosis in Rhineland-Palatinate is within the range of other prospective population based registers in Europe and North America. Gender ratio is nearly balanced.

The population burden of stroke mortality continues to plummet in developed countries. For example, in the United States, among the 30 leading causes of death the 37% decline in age-adjusted stroke deaths between 1990 and 2010 was only exceeded by a 68% decline from HIV/AIDS, a 44% decline from ischemic heart disease, and a 39% decline from lower respiratory tract infections.1 However, data from the US Greater Cincinnati/Northern Kentucky Study suggest that between 1993/1994 and 2005 stroke rates are falling only for those aged ≥55 years, and there has been a 55% (83/100 000→128/100 000) increase for blacks aged 20 to 54 years, and a 92% (26/100 00→48/100 000) increase for whites of the same age.2 Although declines in stroke mortality and incidence in the United States are encouraging, disparities exist for Hispanics3 (perhaps because of a higher stroke risk in native born than first-generation Hispanics)4 and blacks.5 ### Traditional Risk Factors (Defined by the Framingham Stroke Risk Function) Advances have been made to further understand the impact of the well-established risk factors. Not only the presence of diabetes mellitus, but also its duration may be an important factor. Compared with those free from diabetes mellitus, the risk of stroke was 1.7× greater for persons with diabetes mellitus of duration

Activated monocytes may contribute to the pathogenesis of ischemic stroke. We tested the hypothesis that release products and procoagulant activity of monocytes are increased in acute ischemic stroke. In patients on days 1, 3 and 7 after ischemic stroke and in age- and sex-matched healthy control subjects, we assessed plasma levels of interleukin 8 (IL-8) and neopterin (enzyme linked immunosorbent assay, ELISA) and investigated superoxidanion release (ferricytochrome C reduction), procoagulant activity (one-stage clotting assay) and tissue factor (TF) gene transcription (reverse transcriptase polymerase chain reaction) by monocytes. As compared to control subjects (n=23), IL-8 levels were increased on day 1 after stroke (n=22; p=0.005) and remained elevated on days 3 and 7. Neopterin levels were elevated on days 3 and 7 (p0.05, respectively) but not on day 1. Neopterin and IL-8 were not correlated with monocyte counts. Superoxid anion production by stimulated and unstimulated monocytes was not different between groups. TF mRNA could neither be detected in monocytes from patients investigated within 12 h after ischemia (n=12) nor in control subjects (n=10) and procoagulant activity of cells was similar in both groups. Our results indicate increased monocyte activation after ischemic stroke although not all activation parameters were elevated. We found no support for the hypothesis that circulating monocytes express TF and possess increased procoagulant activity. Elevated IL-8 may contribute to stroke pathophysiology by activating polymorphonuclear leukocyte (PMNL) activation early after ischemia.

Background Enhanced stimulus-induced release of pro-inflammatory cytokines by leucocytes may contribute to the pathogenesis of ischaemic stroke. Design We investigated the lipopolysaccharide-induced release of interleukin-1β (IL-1β), IL-6, IL-8, and tumour necrosis factor-α (TNF-α) in whole blood from 20 patients with a history of ischaemic stroke under the age of 50, 20 patients with a history of cervical artery dissection (CAD) and 21 age- and sex-matched healthy control subjects. Results Release of IL-8 was higher (P = 0.006) and release of TNF-α and IL-6 tended to be higher (P < 0.1) in young stroke patients than in control subjects. No increased release existed in CAD patients. Vascular risk factors or history of infection before stroke did not modify IL-8 production. A common T(250) → A polymorphism in the IL-8 gene promotor was newly identified but did not correlate with the variability of IL-8 release. The C(260) → T polymorphism in the gene of the monocytic LPS-receptor CD14 - a risk factor for myocardial infarction - was not associated with increased cytokine release. Conclusions We conclude that high inducible release of IL-8 - and possibly of TNF-α and IL-6 - may contribute to the odds of ischaemic stroke in young adults.

Data on risk factors for etiologic subtypes of ischemic stroke are still scant. The aim of this study was to characterize stroke subtypes regarding risk factor profile, outcome, and current treatment strategies.We analyzed data from 5017 patients with acute ischemic stroke (42.4% women, aged 65.9+/-14.1 years) who were enrolled in a large multicenter hospital-based stroke data bank. Standardized data assessment and stroke subtype classification were used by all centers.Sex and age distribution, major risk factors and comorbidities, recurrent stroke, treatment strategies, and outcome were all unevenly distributed among stroke subtypes (P0.001, respectively). Cardioembolism, the most frequent etiology of stroke (25.6%), was particularly common in the elderly (those aged70 years) and associated with an adverse outcome, a low rate of early stroke recurrence, and frequent use of thrombolytic therapy and intravenous anticoagulation. Large-artery atherosclerosis (20.9%), the most common cause of stroke in middle-aged patients (those aged 45 to 70 years), showed the highest male preponderance, highest rate of early stroke recurrence, and highest prevalence of previous transient ischemic attack, current smoking, and daily alcohol consumption among all subtypes. The highest prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and obesity was found in small-vessel disease (20.5%), which, in turn, was associated with the lowest stroke severity and mortality.Our results foster the concept of ischemic stroke as a polyetiologic disease with marked differences between subtypes regarding risk factors and outcome. Therefore, studies involving risk factors of ischemic stroke should differentiate between etiologic stroke subtypes.

Background: The etiology of spontaneous cervical artery dissection (CAD) is largely unknown. An underlying connective tissue disorder has often been postulated. Objective: To further assess the association of CAD with ultrastructural abnormalities of the dermal connective tissue. Methods: In a multicenter study, skin biopsies of 65 patients with proven nontraumatic CAD and 10 control subjects were evaluated. The ultrastructural morphology of the dermal connective tissue components was assessed by transmission electron microscopy. Results: Only three patients (5%) had clinical manifestations of skin, joint, or skeletal abnormalities. Ultrastructural aberrations were seen in 36 of 65 patients (55%), consisting of the regular occurrence of composite fibrils within collagen bundles that in some cases resembled the aberrations found in Ehlers–Danlos syndrome type II or III and elastic fiber abnormalities with minicalcifications and fragmentation. A grading scale according to the severity of the findings is introduced. Intraindividual variability over time was excluded by a second biopsy of the skin in eight patients with pronounced aberrations. Recurrent CAD correlated with connective tissue aberrations. In addition, similar connective tissue abnormalities were detected in four first-degree relatives with familial CAD. Conclusion: CAD is associated with ultrastructural connective tissue abnormalities, mostly without other clinical manifestations of a connective tissue disease. A structural defect in the extracellular matrix of the arterial wall leading to a genetic predisposition is suggested. The dermal connective tissue abnormalities detected can serve as a phenotypic marker for further genetic studies in patients with CAD and large families to possibly identify the underlying basic molecular defect(s).

Chronic infection may increase the risk for ischemic stroke. Presently, it is insufficiently established whether Helicobacter pylori infection represents a risk factor for ischemic stroke. We analyzed IgG antibodies against H. pylori in 109 patients with acute cerebral ischemia and 82 age- and sex-matched control patients with non-vascular and non-inflammatory neurological diseases. Antibody titers were significantly higher in patients than in control subjects ( p =0.007). H. pylori seropositivity tended to be more common in patients (odds ratio (OR) 1.55, 95% confidence interval (ci) 0.87–2.76), but this trend was further attenuated in multivariate analysis (OR 1.42; 95% 0.75–2.67) with hypertension, diabetes mellitus, current or previous smoking, previous cerebral ischemia and low socioeconomic status. H. pylori seropositivity increased the odds for cerebral ischemia of atherothrombotic origin in univariate (OR 3.63; 95% ci 1.37–9.65) and multivariate analysis (OR 3.53; 95% ci 1.09–11.4). H. pylori seropositivity may be an independent risk factor for stroke of atherothrombotic origin.

Iron may play an important role in the pathogenesis of Parkinson's disease (PD). Recent studies have shown that the iron-transporting glycoprotein lactoferrin (LF) and its receptor are increased in the substantia nigra (SN) in PD. We investigated whether plasma levels of LF are altered in dopa-responsive PD. Plasma LF was not different between patients with PD (n = 23; 306 +/- 116 [mean +/- standard deviation] ng/ml) and age- and sex-matched healthy control subjects (n = 15; 359 +/- 126 ng/ml ). However, LF was inversely correlated with PD severity (r = -0.68, P = 0.002), an association that remained significant after adjustment for treatment with levodopa, monoaminooxidase inhibitors, and dopa agonists (r = -0.53, P = 0.017). Plasma transferrin and ferritin levels were not different between groups and neither correlated with disease severity nor with LF levels. Together with the result of increased nigral lactoferrin, this finding is compatible with the hypothesis of an imbalance between LF levels in blood and SN in progressing PD. Larger and particularly longitudinal studies and measurements of LF in cerebrospinal fluid are warranted to further examine the role of LF in PD.

In a pilot study, we identified Chlamydia pneumoniae in the cerebrospinal fluid by polymerase chain reaction in 5 of 10 patients with definite multiple sclerosis (MS). In a second series, 2 of 20 patients with definite MS and 3 of 17 patients with possible/probable MS or MS variants, but none of 56 patients with other neurological, diseases were polymerase chain reaction-positive. We confirm that C. pneumoniae can be found in the cerebrospinal fluid of MS patients, but our rate of positive results is lower than in a recent report.

This article summarises recommendations for acute management of stroke by the European Stroke Initiative (EUSI), on behalf of the European Stroke Council (ESC), the European Neurological Society (ENS), and the European Federation of Neurological Societies (EFNS).

Previous studies showed that elevated body temperature early after ischemic stroke is associated with severe neurological deficit and a poor outcome. The aim of this study was to analyse the prevalence and putative etiology of febrile body temperature (>/=38.0 degrees C) early after stroke and to investigate the association between body temperature, stroke severity and outcome. We investigated 119 consecutive patients who were admitted within 24 h after ischemic stroke. Patients were examined for infection before ischemia using a standardized questionnaire and received daily clinical examination after stroke. In case of fever, standardized radiological and microbiological examinations were performed. Fever within 48 h after stroke was observed in 30 (25.2%) patients. The probable cause of fever was infective or chemical aspiration pneumonia (n=12), other respiratory tract infection (n=7), urinary tract infection (n=4), viral infections (n=3) or insufficiently defined (n=5). (One patient had two potential causes of fever.) In thirteen of these patients, infection was most probably acquired before stroke. Fever newly developed more often during day 1 to 2 than day 3 to 7 after stroke (P=0.016). Fever was associated with a more severe deficit on admission independent from age, vascular diseases and risk factors (odds ratio 9.6; 95% confidence interval 3.1-29). Fever is a frequent complication early after stroke and in the majority of cases, it can be explained by infection or chemical aspiration pneumonia. In about half of the infected patients, infection was most probably acquired before stroke. Fever was associated with a more severe neurological deficit on admission.

Background and Purpose —It has been recently reported that a G→A transition at nucleotide position 20210 in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of deep venous thrombosis. To date, it is unknown whether this polymorphism also represents a risk factor for cerebral venous thrombosis (CVT). Methods —Venous blood samples were collected from 45 patients with CVT and from 354 healthy blood donors as controls. A second control group consisted of 131 subjects with acute ischemic stroke or transient ischemic attack (TIA). Genomic DNA was isolated from peripheral blood leukocytes. Amplification of DNA was performed by polymerase chain reaction (PCR). The G→A transition at nucleotide position 20210 of the prothrombin gene was detected by allele-specific restriction digestion. Results —The G 20210 →A transition in the prothrombin gene was found in a heterozygous form in 4 of 45 patients with CVT (8.9%) and in 8 of 354 healthy control subjects (2.3%). This difference was statistically significant ( P =0.010). The G 20210 →A transition increased the relative risk for CVT approximately 5-fold (age-adjusted odds ratio 5.7; 95% CI 1.5 to 21.5). In contrast, in the group of patients with acute cerebral ischemia, only 3 of 131 subjects (2.3%) were heterozygous for the G 20210 →A transition, which corresponded to the prevalence in the group of healthy blood donors. Conclusions —The recently described G 20210 →A transition in the 3′-untranslated region of the prothrombin gene is an inherited risk factor for CVT but obviously not for acute ischemic stroke or TIA.

We performed a case-control study to investigate the role of recent infection as stroke risk factor and to identify pathogenetic pathways linking infection and stroke. We examined 166 consecutive patients with acute cerebrovascular ischemia and 166 patients hospitalized for nonvascular and noninflammatory neurologic diseases. Control subjects were individually matched to patients for sex, age, and season of admission. We assessed special biochemical parameters in subgroups of stroke patients with and without recent infection (n = 21) who were similar with respect to demographic and clinical parameters. Infection within the preceding week was a risk factor for cerebrovascular ischemia in univariate (odds ratio [OR] 3.1; 95% confidence interval (CI), 1.57 to 6.1) and age-adjusted multiple logistic regression analysis (OR 2.9; 95% CI, 1.31 to 6.4). The OR of recent infection and age were inversely related. Both bacterial and viral infection contributed to increased risk. Infection elevated the risk for cardioembolism and tended to increase the risk for arterioarterial embolism. Stroke patients with and without preceding infection were not different with respect to factor VII and factor VIII activity, fibrin monomer, fibrin D-dimer, von Willebrand factor, C4b-binding protein, protein S, anticardiolipin antibodies, interleukin-1 receptor antagonist, soluble tumor necrosis factor-α receptor, interleukin-6, interleukin-8, and neopterin. In conclusion, recent infection is an independent risk factor for acute cerebrovascular ischemia. Its role appears to be more important in younger age groups. The pathogenetic linkage between infection and stroke is still insufficiently understood.

Periodontitis is a common infectious disease associated with increased risk for ischemic stroke though presently unclear mechanisms. In a case-control study, we investigated salivary levels of four periodontal pathogens, as well as systemic and local inflammatory markers. The population comprised 98 patients with acute ischemic stroke (mean ± SD, 68.2 ± 9.7 yrs; 45.9% women) and 100 healthy controls (69.1 ± 5.2 yrs; 47.0% women). Patients were more often edentulous and had fewer teeth than controls (13.8 ± 10.8 versus 16.6 ± 10.1). After adjusting for stroke risk factors and number of teeth, controls had higher saliva matrix metalloproteinase-8 (MMP-8), myeloperoxidase (MPO), IL-1β, Aggregatibacter actinomycetemcomitans, and serum LPS activity levels. Patients had higher serum MMP-8 and MPO, and they were more often qPCR-positive for A. actinomycetemcomitans (37.9% versus 19.0%) and for ≥3 periodontopathic species combined (50.0% versus 33.0%). We conclude that controls more often had evidence of current periodontal infection with higher periodontal pathogen amount, endotoxemia, local inflammation and tissue destruction. Stroke patients more often had evidence of end-stage periodontitis with edentulism and missing teeth. They were more often carriers of several periodontopathic pathogens in saliva, especially A. actinomycetemcomitans. Additionally, inflammatory burden may contribute to high systemic inflammation associated with elevated stroke susceptibility.