Heritable and non-heritable uncommon causes of stroke.

Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.

Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology.

BACKGROUND AND PURPOSE: Guidelines on monogenic cerebral small-vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and type IV collagen (COL4)A1/2. METHODS: We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. RESULTS: We have proposed 'red-flag' features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus. CONCLUSIONS: The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.

Musculoskeletal injuries in real tennis.

Introduction: Real tennis is a growing, unique, and well-established sport. To date, there has been no epidemiological data on real tennis injuries. The primary aim of this retrospective study is to record the incidence and document any trends in real tennis musculoskeletal injuries, so as to improve injury awareness of common and possibly preventable injuries. Methods: A surveillance questionnaire e-mailed to 2,036 Tennis & Rackets Association members to retrospectively capture injuries sustained by amateur and professional real tennis players over their playing careers. Results: A total of 485 (438 males and 47 females) questionnaires were fully completed over 4 weeks. A total of 662 musculoskeletal injuries were recorded with a mean of 1.4 injuries per player (range 0-7). The incidence of sustaining an acute real tennis musculoskeletal injury is 0.4/1000 hrs. The three main anatomical locations reported injured were elbow 15.6% (103/662), knee 11.6% (77/662), and face 10.0% (66/662). The most common structures reported injured were muscle 24% (161/661), tendon 23.4% (155/661), ligament 7.0% (46/661), soft tissue bruising 6.5% (43/661), and eye 6.2% (41/661). The majority of the upper limb injuries were gradual onset (64.7%, 143/221), and the lower limb injuries were sudden onset (72.0%, 188/261). Conclusion: This study uniquely provides valuable preliminary data on the incidence and patterns of musculoskeletal injuries in real tennis players. In addition, it highlights a number of reported eye injuries. The study is also a benchmark for future prospective studies on academy and professional real tennis players.

Neuropathologic evidence of endothelial changes in cerebral small vessel disease.

OBJECTIVES: Cerebral small vessel disease (SVD) is common in aged brains and causes lacunar stroke, diffuse white matter lesions (leukoaraiosis), and vascular cognitive impairment. The pathogenesis is unknown. Endothelial dysfunction is a possible causal factor, and circulating markers of endothelial activation (intercellular adhesion molecule-1, thrombomodulin) and inflammation (interleukin [IL]-6) are elevated in patients with SVD. In this case-control study, we tested whether brain endothelial ICAM1, thrombomodulin, and IL-6 are altered in SVD. METHODS: We examined small penetrating cerebral arteries of pathologically diagnosed SVD cases, aged controls without SVD, young control cases with no brain pathology, and cases with early-onset hereditary SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]). All tissues had minimal cerebral amyloid angiopathy or other Alzheimer pathology. RESULTS: Thrombomodulin immunoreactivity was present in all aged SVD, aged control, and CADASIL cases, primarily in small artery endothelium. Thrombomodulin was augmented in aged SVD cases compared with aged controls (p = 0.012) and in vessels with higher sclerotic index (an indicator of SVD severity; p < 0.01). Thrombomodulin was sparse/absent in young controls. Endothelial ICAM1 and IL-6 were rarely seen, and were not related to SVD. CONCLUSIONS: Our data suggest that cerebral endothelial activation in deep penetrating arteries is not associated with SVD. Endothelial thrombomodulin increased with SVD severity, and CADASIL data suggest that this may be a cerebral response to SVD. Elevated thrombomodulin may be a protective agent in SVD. Our data confirm endothelial involvement in SVD.

Ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis.

OBJECTIVES: Better methods are required to identify patients with asymptomatic carotid stenosis (ACS) at risk of future stroke. Two potential markers of high risk are echolucent plaque morphology on carotid ultrasound and embolic signals (ES) in the ipsilateral middle cerebral artery on transcranial Doppler ultrasound (TCD). We explored the predictive value of a score based on these 2 measures in the prospective, observational, international multicenter Asymptomatic Carotid Emboli Study. METHODS: A total of 435 recruited subjects with ACS ≥70% had baseline ultrasound images and TCD data available. Subjects were prospectively followed up for 2 years. RESULTS: A total of 164 (37.7%) plaques were graded as echolucent. Plaque echolucency at baseline was associated with an increased risk of ipsilateral stroke alone (hazard ratio [HR] 6.43, 95% confidence interval [CI] 1.36-30.44, p = 0.019). A combined variable of plaque echolucency and ES positivity at baseline was associated with a markedly increased risk of ipsilateral stroke alone (HR 10.61, 95% CI 2.98-37.82, p = 0.0003). This association remained significant after controlling for risk factors, degree of carotid stenosis, and antiplatelet medication. CONCLUSIONS: Plaque morphology assessed using a simple, and clinically applicable, visual rating scale predicts ipsilateral stroke risk in ACS. The combination of ES detection and plaque morphology allows a greater prediction than either measure alone and identifies a high-risk group with an annual stroke risk of 8%, and a low-risk group with a risk of <1% per annum. This risk stratification may prove useful in the selection of patients with ACS for endarterectomy.

Carotid intima-media thickness is greater but carotid plaque prevalence is lower in black compared with white subjects.

BACKGROUND AND PURPOSE: Carotid IMT is widely used as a surrogate marker for atherosclerosis. Prospective studies in largely white populations demonstrate that it is strongly associated with carotid plaque and is an independent predictor of stroke. There are few data from black populations. In a previous study, we showed that carotid IMT is increased in black individuals in the UK. The purpose of this study was to confirm this with a larger sample size and to establish whether raised IMT in black stroke-free individuals is associated with increased carotid plaque. MATERIALS AND METHODS: High-resolution sonography was used to measure the CCA-, BIF-, and ICA-IMT and plaque in 306 black and 281 white healthy individuals recruited by random community sampling from London, U.K. Mean CCA-IMT was determined by using a semiautomated computer program that detects the blood/intima borderline and the media/adventitia borderline with the use of a gray-value algorithm. RESULTS: CCA-IMT was higher in black compared with white individuals after controlling for cardiovascular risk factors and socioeconomic status (ß = 0.050; 95%CI, 0.024-0.076; P < .001). BIF- and ICA-IMT were also increased in black subjects. In contrast, carotid plaque was more common in white individuals (OR, 2.90; 95%CI, 1.41-5.96; P = .004). CONCLUSIONS: The lack of correlation between increased IMT and carotid plaque in black individuals implies that IMT should not currently be used as a surrogate marker of atherosclerosis in black populations. It suggests that the increased IMT seen in black individuals may not represent early atherosclerosis.

The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis.

OBJECTIVES: To review the evidence for an association of white matter hyperintensities with risk of stroke, cognitive decline, dementia, and death. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed from 1966 to 23 November 2009. STUDY SELECTION: Prospective longitudinal studies that used magnetic resonance imaging and assessed the impact of white matter hyperintensities on risk of incident stroke, cognitive decline, dementia, and death, and, for the meta-analysis, studies that provided risk estimates for a categorical measure of white matter hyperintensities, assessing the impact of these lesions on risk of stroke, dementia, and death. DATA EXTRACTION: Population studied, duration of follow-up, method used to measure white matter hyperintensities, definition of the outcome, and measure of the association of white matter hyperintensities with the outcome. DATA SYNTHESIS: 46 longitudinal studies evaluated the association of white matter hyperintensities with risk of stroke (n=12), cognitive decline (n=19), dementia (n=17), and death (n=10). 22 studies could be included in a meta-analysis (nine of stroke, nine of dementia, eight of death). White matter hyperintensities were associated with an increased risk of stroke (hazard ratio 3.3, 95% confidence interval 2.6 to 4.4), dementia (1.9, 1.3 to 2.8), and death (2.0, 1.6 to 2.7). An association of white matter hyperintensities with a faster decline in global cognitive performance, executive function, and processing speed was also suggested. CONCLUSION: White matter hyperintensities predict an increased risk of stroke, dementia, and death. Therefore white matter hyperintensities indicate an increased risk of cerebrovascular events when identified as part of diagnostic investigations, and support their use as an intermediate marker in a research setting. Their discovery should prompt detailed screening for risk factors of stroke and dementia.

Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis.

BACKGROUND AND AIM: The pathogenesis of cerebral small-vessel disease (SVD) is incompletely understood. Endothelial dysfunction has been implicated and may result in increased blood-brain barrier (BBB) permeability with leakage of blood constituents into the vessel wall and white matter. We used contrast-enhanced MRI to determine whether there was any evidence for BBB permeability in the white matter of patients with SVD, and whether this was present not only in areas of leucoaraiosis (white-matter lesions) but also in normal-appearing white matter (NAWM). METHODS: Subjects underwent T1 volumetric MRI before and after bolus injection of contrast. Scanning was continued for 30 min postinjection to determine the contrast-enhancement time course. The mean signal intensity change was plotted against time to calculate the area under the curve values, a parameter related to BBB permeability. Automated brain segmentation and regions of interest analysis were performed to determine 'permeability' in different brain compartments. RESULTS: Compared with controls (n=15), the SVD patient group (n=24) had signal changes consistent with increased BBB permeability in NAWM (p=0.033). Multivariate regression analyses identified leucoaraiosis grade as an independent predictor of these permeability related signal changes in NAWM after adjustment for age, gender, weight, brain volume, area under the curve in the internal carotid arteries and cardiovascular risk factors. CONCLUSION: This study provides evidence for increased BBB permeability in SVD, and this is particularly seen in SVD with leucoaraiosis. Its presence in NAWM would be consistent with it playing a causal role in disease pathophysiology.

Diffusion tensor imaging detects age related white matter change over a 2 year follow-up which is associated with working memory decline.

BACKGROUND: Diffusion tensor imaging (DTI) is a sensitive method for detecting white matter damage, and in cross sectional studies DTI measures correlate with age related cognitive decline. However, there are few data on whether DTI can detect age related changes over short time periods and whether such change correlates with cognitive function. METHODS: In a community sample of 84 middle-aged and elderly adults, MRI and cognitive testing were performed at baseline and after 2 years. Changes in DTI white matter histograms, white matter hyperintensity (WMH) volume and brain volume were determined. Change over time in performance on tests of executive function, working memory and information processing speed were also assessed. RESULTS: Significant change in all MRI measures was detected. For cognition, change was detected for working memory and this correlated with change in DTI only. In a stepwise regression, with change in working memory as the dependent variable, a DTI histogram measure explained 10.8% of the variance in working memory. Change in WMH or brain volume did not contribute to the model. CONCLUSIONS: DTI is sensitive to age related change in white matter ultrastructure and appears useful for monitoring age related white matter change even over short time periods.

The relationship between episodic long-term memory and white matter integrity in normal aging.

It has been proposed that episodic long-term memory (LTM) declines in normal aging and may be affected by disruption of white matter networks. This was explored in 104 healthy adults aged 50-90 years in the GENIE study; white matter integrity was assessed using diffusion tensor imaging (DTI) in large regions of interest, with additional measures of white matter hyperintensities (WMH), normalized brain and hippocampal volumes. LTM was compared with executive function, working memory and information processing speed. LTM correlated significantly with DTI, WMH and whole brain volume, but not with hippocampal volume. Using linear regression, only DTI measures explained the variance (approximately 19%) in LTM; mediational analyses explored the extent to which other cognitive functions mediate the association between DTI changes and memory. The results suggest that reduced LTM performance in normal aging is related to reduced integrity of a distributed network dependent on white matter pathways supporting episodic memory.

Hypertension-related cognitive decline: is the time right for intervention studies?

The importance of lowering blood pressure in hypertensive subjects is well known but the relationship between hypertension and cognitive function has been a subject of considerable controversy. Cross-sectional studies investigating the relationship between blood pressure and cognition have shown conflicting relationships whilst the majority of longitudinal studies have demonstrated elevated blood pressure to be associated with cognitive decline. Randomised studies have demonstrated heterogeneous and sometimes conflicting effects of blood pressure lowering on cognitive function and suggested reasons include multiple mechanisms by which hypertension affects the brain, the variety of cognitive instruments used for assessment and differences in antihypertensive treatments. Chronic hypertension accelerates arteriosclerotic changes in the brain with a disproportionate effect on subcortical circuits associated with cerebral small vessel disease. Randomised clinical trials assessing the cognitive consequences of blood pressure reduction in people with small vessel disease are lacking and many of the existing controversies on the cognitive consequences of blood pressure lowering, especially in older people, arise from the design limitations of studies. This article describes the methodological issues in designing such a trial and the results of a pilot evaluation to see if careful selection of subjects and measurements would make undertaking intervention studies feasible. Given the predicted upswing in people with cognitive impairments, the time is right for randomised clinical trials with specific cognitive end-points to examine the relationship between cognitive function and hypertension and guide practice.

CADISP-genetics: an International project searching for genetic risk factors of cervical artery dissections.

BACKGROUND: Cervical artery dissection (CAD) is a frequent cause of ischemic stroke, and occasionally death, in young adults. Several lines of evidence suggest a genetic predisposition to CAD. However, previous genetic studies have been inconclusive mainly due to insufficient numbers of patients. Our hypothesis is that CAD is a multifactorial disease caused by yet largely unidentified genetic variants and environmental factors, which may interact. Our aim is to identify genetic variants associated with an increased risk of CAD and possibly gene-environment interactions. METHODS: We organized a multinational European network, Cervical Artery Dissection and Ischemic Stroke Patients (CADISP), which aims at increasing our knowledge of the pathophysiological mechanisms of this disease in a large group of patients. Within this network, we are aiming to perform a de novo genetic association analysis using both a genome-wide and a candidate gene approach. For this purpose, DNA from approximately 1100 patients with CAD, and 2000 healthy controls is being collected. In addition, detailed clinical, laboratory, diagnostic, therapeutic, and outcome data are being collected from all participants applying predefined criteria and definitions in a standardized way. We are expecting to reach the above numbers of subjects by early 2009. CONCLUSIONS: We present the strategy of a collaborative project searching for the genetic risk factors of CAD. The CADISP network will provide detailed and novel data on environmental risk factors and genetic susceptibility to CAD.

Cerebrovascular reactivity and dynamic autoregulation in ischaemic subcortical white matter disease.

BACKGROUND: It has been suggested that impaired cerebral autoregulation and vasodilatory capacity may play in role in the pathogenesis of the leukoaraiosis seen in small vessel disease. Adequate perfusion of the deep white matter of the brain depends on the relationships between blood pressure (BP), cerebral vasoreactivity and autoregulation. METHODS: 24 h ambulatory BP measurement, quantitative volumetric MRI analysis of white matter lesion (WML) volume and transcranial Doppler ultrasound assessments of CO(2) reactivity in response to hypercapnia and dynamic cerebral autoregulatory index (ARI) were undertaken in 64 patients with cerebral small vessel disease. RESULTS: Subjects had mean 24 h BP 133/76 mm Hg (SD 13/9), median WML volume 7169 (IQR 20497) mm(3), mean CO(2) reactivity 83.6 (SD 37.4)% and mean ARI 5.6 (SD 1.4) (range 0-9). In multivariate models, after adjusting for age, gender, vascular risk profile and WML volume, ARI correlated with 24 h mean BP levels (R(2) = 0.127, t = 2.440, p = 0.019) and CO(2) reactivity correlated with duration of hypertension (R(2) = 0.085, t = -2.244, p = 0.029). In individuals with hypertension for more than 10 years, ARI also correlated with nocturnal BP dipping (r = 0.806, p = 0.002). ARI and CO(2) reactivity were unaffected by WML volumes, and ARI and CO(2) reactivity were unrelated. CONCLUSION: Cerebral autoregulation and CO(2) reactivity are two distinct processes which are not related to WML volume but are related to BP levels and duration of hypertension, respectively. Greater nocturnal dipping was associated with higher ARI values, suggesting preservation of autoregulation in patients with increased vulnerability to reduced cerebral perfusion.

Cognitive impairment and white matter damage in hypertension: a pilot study.

OBJECTIVES: Hypertension has been associated with impaired cognition. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopy were applied to assess white matter abnormalities in treated vs untreated hypertension and if these correlated with neuropsychological performance. METHODS: Subjects were 40 patients with medically treated hypertension (mean age 69.3 years), 10 patients with untreated hypertension (mean age 57.6 years) and 30 normotensive controls (mean age 68.2 years). Hypertension was defined as a previous diagnosis and taking hypertensive medication, or a resting blood pressure of >140/90 mmHg on the day of assessment. RESULTS: Patients with treated hypertension performed worse on immediate (P = 0.037) as well as delayed memory tasks (P = 0.024) compared with normotensive controls. Cognitive performance was worse in untreated compared with treated hypertension on executive functions (P = 0.041) and psychomotor speed (P = 0.003). There was no significant correlation between cognition and any of the imaging parameters in treated hypertension. However, in untreated hypertension the results revealed a positive correlation between an executive functioning and attention composite score and DTI mean diffusivity values (P = 0.016) and between psychomotor speed and spectroscopy NAA/tCr levels (P = 0.015). CONCLUSIONS: These results suggest there is cognitive impairment in hypertension. Treated hypertension was associated with deficits in memory while untreated hypertension revealed a more 'subcortical' pattern of cognitive impairment.

Treatment of cervical artery dissection: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Cervical dissection is an important cause of stroke in the young. This paper presents a systematic review and a meta-analysis to assess the effectiveness of different treatment approaches: antithrombotic drugs, thrombolysis and stenting. METHODS: Medline and PubMed were searched from 1966 to 8 April 2007. Reference lists were reviewed. Separate searches were performed for treatment with anticoagulation and antiplatelet therapy during the acute phase (within 1 month of symptoms), thrombolysis and stenting. RESULTS: There were only sufficient data for meta-analysis for the comparison of antiplatelet versus anticoagulation therapy. No randomised trials were identified. 34 non-randomised studies included 762 patients. There was no significant difference in risk of death (antiplatelet 5/268 (1.8%), anticoagulation 9/494 (1.8%), p = 0.88); stroke (antiplatelet 5/268 (1.9%), anticoagulant 10/494 (2.0%), p = 0.66), or stroke and death. Four non-randomised studies of thrombolysis provided insufficient data for assessment of efficacy but complication rates were no greater than thrombolysis for other ischaemic stroke. Six studies included 96 patients undergoing stenting for both acute dissection and chronic complications, providing insufficient data for assessment of efficacy, although complication rates appeared similar to those published for carotid atherosclerosic stenosis. CONCLUSIONS: There are no data to support the therapeutic superiority of anticoagulants over antiplatelet agents. Thrombolysis in dissection appears safe but more data on efficacy are required. Stenting is technically possible but there are no data to demonstrate efficacy. There is little evidence to support current treatment approaches in cervical dissection. Randomised controlled prospective trials, particularly assessing anticoagulation versus antiplatelet agents, are required.