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.

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.

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.

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.

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.

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.

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.

Imaging of vertebral artery stenosis: a systematic review.

BACKGROUND AND PURPOSE: Posterior circulation stroke accounts for 20% of ischaemic strokes. Recent data suggest that the early stroke recurrence risk is high and comparable with carotid artery disease. Vertebral artery stenosis accounts for approximately 20% of posterior circulation stroke, and with endovascular treatment available accurate diagnostic imaging is important. We performed a systematic literature review to validate the accuracy of the non-invasive imaging techniques Duplex ultrasound (DUS), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) in detecting severe vertebral artery stenosis, with intra-arterial angiography (IAA) as the reference standard. METHODS: We identified studies that used non-invasive imaging and IAA as the reference standard to determine vertebral artery stenosis and provided adequate data to calculate sensitivity and specificity. We analysed the quality of these studies, looked for evidence of heterogeneity and performed subgroup analysis for different degrees of stenosis. RESULTS: 11 studies categorised stenosis into 50-99%. The sensitivity of CTA (single study) and pooled sensitivities of contrast enhanced MRA (CE-MRA) and colour duplex were 100% (95% CI 15.8 to 100), 93.9% (79.8 to 99.3) and 70.2% (54.2 to 83.3), respectively. The specificities for CTA, CE-MRA and colour duplex were 95.2% (83.8 to 99.4), 94.8% (91.1 to 97.3) and 97.7% (95.2 to 99.1). However, specificities for CE-MRA and colour duplex demonstrated significant heterogeneity (p = 0.003 and p = 0.002, respectively). CONCLUSIONS: CE-MRA and possibly CTA may be more sensitive in diagnosing vertebral artery stenosis than DUS. However, data are limited and further high quality studies comparing DUS, MRA and CTA with IAA are required.

The relationship between white matter brain metabolites and cognition in normal aging: the GENIE study.

Magnetic resonance spectroscopy (MRS) has demonstrated age-related changes in brain metabolites that may underlie micro-structural brain changes, but few studies have examined their relationship with cognitive decline. We performed a cross-sectional study of brain metabolism and cognitive function in 82 healthy adults (aged 50-90) participating in the GENIE (St GEorge's Neuropsychology and Imaging in the Elderly) study. Absolute metabolite concentrations were measured by proton chemical shift imaging within voxels placed in the centrum semiovale white matter. Cognitive abilities assessed were executive function, working memory, information processing speed, long-term memory and fluid intelligence. Correlations showed that all cognitive domains declined with age. Total creatine (tCr) concentration increased with age (r=0.495, p<0.001). Regression analyses were performed for each cognitive variable, including estimated intelligence and the metabolites, with age then added as a final step. A significant relationship was observed between tCr and executive function, long-term memory, and fluid intelligence, although these relationships did not remain significant after age was added as a final step in the regression. The regression analysis also demonstrated a significant relationship between N-acetylaspartate (NAA) and executive function. As there was no age-related decline in NAA, this argues against axonal loss with age; however the relationship between NAA and executive function independent of age and estimated intelligence is consistent with white matter axonal integrity having an important role in executive function in normal individuals.

EFNS guideline on neuroimaging in acute stroke. Report of an EFNS task force.

Neuroimaging techniques are necessary for the evaluation of stroke, one of the leading causes of death and neurological impairment in developed countries. The multiplicity of techniques available has increased the complexity of decision making for physicians. We performed a comprehensive review of the literature in English for the period 1965-2005 and critically assessed the relevant publications. The members of the panel reviewed and corrected an initial draft, until a consensus was reached on recommendations stratified according to the European Federation of Neurological Societies (EFNS) criteria. Non-contrast computed tomography (CT) scan is the established imaging procedure for the initial evaluation of stroke patients. However, magnetic resonance imaging (MRI) has a higher sensitivity than CT for the demonstration of infarcted or ischemic areas and depicts well acute and chronic intracerebral hemorrhage. Perfusion and diffusion MRI together with MR angiography (MRA) are very helpful for the acute evaluation of patients with ischemic stroke. MRI and MRA are the recommended techniques for screening cerebral aneurysms and for the diagnosis of cerebral venous thrombosis and arterial dissection. For the non-invasive study of extracranial vessels, MRA is less portable and more expensive than ultrasonography but it has higher sensitivity and specificity for carotid stenosis. Transcranial Doppler is very useful for monitoring arterial reperfusion after thrombolysis, for the diagnosis of intracranial stenosis and of right-to-left shunts, and for monitoring vasospasm after subarachnoid hemorrhage. Currently, single photon emission computed tomography and positron emission tomography have a more limited role in the evaluation of the acute stroke patient.

Chlamydia pneumoniae infection and early asymptomatic carotid atherosclerosis.

BACKGROUND: Chronic Chlamydia pneumoniae infection has been implicated in the pathogenesis of atherosclerosis but whether it plays a role at an early stage in the disease is uncertain. An early estimate of atherosclerosis can be obtained by ultrasonic imaging of the carotid artery to determine intima-media thickness (IMT) and the thickness of any atheroma plaques. METHODS AND RESULTS: In 983 normal population individuals aged 30 to 70 years, we measured common carotid artery (CCA) and carotid bulb IMT, and also carotid plaque thickness and the degree of internal carotid artery (ICA) stenosis. C. pneumoniae IgA titers of >/=16 and IgG titers of >/=64 were taken as positive. There was no association between C. pneumoniae IgA or IgG seropositivity with right, left, or mean CCA or bulb IMT, or with the presence of carotid plaques. There was a significant association between IgA seropositivity and >50% mean carotid stenosis with an odds ratio of 5.24 (95% CI 1.24 to 22.21, P=0.0245) after controlling for age and sex; after controlling for other cardiovascular risk factors, this was not significant 3.96 (95% CI 0. 84 to 18.78, P=0.082). No association was found between IgA or IgG seropositivity and markers of fibrinogen, log C-reactive protein, or leukocyte count. CONCLUSIONS: We found no evidence that serological evidence of C. pneumoniae infection is associated with early atherosclerosis. It is possible that IgA seropositivity is associated with more advanced disease but this hypothesis needs to be examined in a population with a higher prevalence of advanced atherosclerosis. We found no evidence that C. pneumoniae results in a chronic systemic inflammatory state.

L-arginine and S-nitrosoglutathione reduce embolization in humans.

BACKGROUND: L-Arginine reduces platelet aggregation and adhesion in ex vivo studies, but there is no evidence as yet that it has a therapeutic effect on clinical end points. Doppler ultrasound can detect cerebral emboli noninvasively. Such embolic signals are common after carotid endarterectomy, and their frequency predicts risk of stroke recurrence. We used this situation to determine the antiplatelet efficacy of L-arginine and S-nitrosoglutathione (GSNO), a physiological nitric oxide donor with possible platelet specificity. METHODS AND RESULTS: Patients undergoing carotid endarterectomy were randomized in a double-blind manner between L-arginine (n=14), GSNO (n=14), or placebo (n=14) administered intravenously for 90 minutes, starting 30 minutes after skin closure. All patients were pretreated with aspirin and given heparin during surgery. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 4 hours after surgery, beginning 30 minutes after skin closure, and also at 6 and 24 hours. There were highly significant reductions in the number of Doppler embolic signals in the L-arginine and GSNO groups; first 4 hours, median (range) number of embolic signals, placebo 44.7 (6 to 778), L-arginine 9.5 (0 to 225), and GSNO 0.8 (0 to 8), both P<0.001 versus control values. The reduction in the signals persisted at the 24-hour recording. CONCLUSIONS: Intravenous L-arginine and GSNO attenuate Doppler embolic signals in humans. Modulation of the NO system with these agents may have applications in the treatment of thromboembolic disease. This study demonstrates the potential application of ultrasonic embolic signal detection to examine the efficacy of new antiplatelet agents in relatively small numbers of patients.

Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis.

BACKGROUND AND PURPOSE: Phosphodiesterase 4D (PDE4D) was identified recently as the first novel stroke gene to predispose to ischemic stroke independently of conventional risk factors. An association was only found with large vessel and cardioembolic stroke, suggesting a mechanism of accelerated atherosclerosis. We sought to replicate this association in ischemic stroke as a whole, and individual stroke subtypes, in a non-Icelandic European population. To assess a role in early atherosclerosis, we also sought associations with underlying asymptomatic atherosclerosis itself, assessed by carotid ultrasound in a community population. METHODS: A total of 737 consecutive white patients with stroke and 933 white community controls free of symptomatic cerebrovascular disease were examined using a case control methodology. For association with atherosclerosis, intima-media thickness (IMT) in a community population (n=1000) was assessed using carotid ultrasound. Nineteen single nucleotide polymorphisms (SNPs) and 1 minisatellite in the PDE4D gene were determined, with haplotyping undertaken using Phase 2.0. RESULTS: No association with ischemic stroke overall was identified. Six of the 19 SNPs were associated with cardioembolic stroke and 2 different SNPs with large vessel disease. There was no association with carotid artery IMT or carotid plaque in the asymptomatic community subjects. CONCLUSIONS: The PDE4D gene is not a major risk factor for ischemic stroke, or early atherosclerosis, within the 2 European population samples studied. On analysis of individual stroke subtypes, there is a possible association with cardioembolic stroke, but the lack of association with carotid IMT and plaque would suggest that this is via a mechanism other than accelerated atherosclerosis.

The effect of the nitric oxide synthase inhibitor L-NMMA on basal CBF and vasoneuronal coupling in man: a PET study.

Nitric oxide (NO) regulates basal CBF. In a number of animal models NO has been implicated in the mediation of the regional changes in CBF (rCBF) that accompany neuronal activation (vasoneuronal coupling). However, some results in animal models have failed to confirm this finding, and the validity of extrapolation to man from animal data is uncertain. To determine the contribution of NO to basal global CBF and activation-induced changes in rCBF, the authors have performed quantitative H2(15)O positron emission tomography (PET) studies before and after administration of the non-isoform-specific NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), in 10 healthy male volunteers. Learning a novel sequence of finger movements was used as a paradigm to induce regional frontal cortex activation. The effect of NO synthase inhibition on the magnitude and pattern of activation was determined. Resting global CBF fell from 33.3 +/- 5.3 mL x 100 g(-1) x min(-1) at rest before L-NMMA, to 26.5 +/- 7.7 mL x 100 g(-1) x min(-1) after L-NMMA (P = 0.001). This fall was reversed by L-arginine administration. Learning sequential finger movements induced increases in rCBF in the left motor, right prefrontal, and bilateral premotor cortices. After NO synthase inhibition with L-NMMA, there was no change in this pattern of activation and no reduction in the magnitude of rCBF responses at the foci of maximal stimulation before and after L-NMMA. These findings confirm that NO production contributes to basal CBF regulation in man, but show that systemic NO synthase inhibition with L-NMMA does not impair regional vasoneuronal coupling.