Cerebral Microvascular Erdheim-Chester Disease: A Perivascular Hematopoietic Vasculopathy.

Erdheim-Chester disease (ECD) is a rare and elusive hematopoietic malignancy that may involve the nervous system in various ways. Cerebrovascular ECD involves the perivascular infiltration and compromise of any cervicocranial vessel by transformed proliferating histiocytes. Presented is the novel case of a patient with pathologically proven perivascular microangiopathy, manifesting in multifaceted fashion with ischemia, hemorrhage, mass lesions, and edema.

Critique on the Use of Early Short-Term Dual Antiplatelet Therapy Following Minor Acute Cerebral Ischemic Events.

BACKGROUND: Two recent cerebrovascular studies, Clopidogrel (Clo) in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT), have purportedly demonstrated the superiority of early dual antiplatelet therapy (DAPT), using aspirin (ASA) plus Clo, in comparison to ASA alone following the occurrence of acute minor cerebral infarction or transient ischemic attack. However, limitations to these trials exist that may not have been adequately explored and presented in the literature, and which may impact the overall efficacy and benefit of DAPT in these situations. Herein we provide a detailed and extensive critique of these 2 trials and of a combined analysis, with particular attention to study data and analyses pertaining to hemorrhagic complications. SUMMARY: DAPT may be superior to ASA alone in preventing recurrent cerebral ischemic events, but exclusively during the first 7-10 days of treatment, and probably only in the presence of acute infarction on cerebral imaging. The impact of minor hemorrhages, which are often clinically consequential and which frequently lead to permanent DAPT discontinuation, has not been adequately considered in the available analyses. Based on data from the trials, DAPT use causes more major and minor hemorrhages than ASA use alone or Clo alone, and Clo use results in fewer hemorrhages than the use of ASA alone. Analyses that include hemorrhage data from the period of Clo alone use as part of the DAPT data may provide inaccurate and erroneous conclusions regarding the relative safety and overall net benefit of DAPT use over ASA alone.

Red blood cell transfusion increases the risk of thrombotic events in patients with subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Red blood cell transfusion (RBCT) may increase the risk of thrombotic events (TE) in patients with subarachnoid hemorrhage (SAH) through changes induced by storage coupled with SAH-related hypercoagulability. We sought to investigate the association between RBCT and the risk of TE in patients with SAH. METHODS: 205 consecutive patients with acute, aneurysmal SAH admitted to the neurovascular intensive care unit of a tertiary care, academic medical center between 3/2008 and 7/2009 were enrolled in a retrospective, observational cohort study. TE were defined as the composite of venous thromboembolism (VTE), myocardial infarction (MI), and cerebral infarction noted on brain CT scan. Secondary endpoints included the risk of VTE, poor outcome (modified Rankin score 3-6 at discharge), and in-hospital mortality. RESULTS: 86/205 (42 %) received RBCT. Eighty-eight (43 %) had a thrombotic complication. Forty (34 %) of 119 non-transfused and 48/86 (56 %) transfused patients had a TE (p = 0.002). In multivariate analysis, RBCT was associated with more TE by [OR 2.4; 95 % CI (1.2, 4.6); p = 0.01], VTE [OR 2.3; 95 % CI (1.0, 5.2); p = 0.04], and poor outcome [OR 5.0; 95 % CI (1.9, 12.8); p < 0.01]. The risk of TE increased by 55 % per unit transfused when controlling for univariate variables. Neither mean nor maximum age of blood was significantly associated with thrombotic risk. CONCLUSIONS: RBCT is associated with an increased risk of TE and VTE in SAH patients. A dose-dependent relationship exists between number of units transfused and thrombosis. Age of blood does not appear to play a role.

Hospital mortality in primary admissions of septic patients with status epilepticus in the United States*.

OBJECTIVE: To determine the prevalence of status epilepticus, associated factors, and relationship with in-hospital mortality in primary admissions of septic patients in the United States. DESIGN: Cross-sectional study. SETTING: Primary admissions of adult patients more than 18 years old with a diagnosis of sepsis and status epilepticus from 1988 to 2008 identified through the Nationwide Inpatient Sample. PARTICIPANTS: A total of 7,669,125 primary admissions of patients with sepsis. INTERVENTIONS: None. RESULTS: During the 21-year study period, the prevalence of status epilepticus in primary admissions of septic patients increased from 0.1% in 1988 to 0.2% in 2008 (p < 0.001). Status epilepticus was also more common among later years, younger admissions, female gender, Black race, rural hospital admissions, and in those patients with organ dysfunctions. Mortality of primary sepsis admissions decreased from 20% in 1988 to 18% in 2008 (p < 0.001). Mortality in status epilepticus during sepsis decreased from 43% in 1988 to 28% in 2008. In-hospital mortality after admissions for sepsis was associated with status epilepticus, older age, and Black and Native American/Eskimo race; patients admitted to a rural or urban private hospitals; and patients with organ dysfunctions. CONCLUSION: Our analysis demonstrates that status epilepticus after admission for sepsis in the United States was rare. Despite an overall significant reduction in mortality after admission for sepsis, status epilepticus carried a higher risk of death. More aggressive electrophysiological monitoring and a high level of suspicion for the diagnosis of status epilepticus may be indicated in those patients with central nervous system organ dysfunction after sepsis.

Candida cerebral abscesses: a case report and review of the literature.

Cerebral abscess caused by Candida spp. is a rare disease, with a nonspecific presentation, little data on treatment, and generally poor outcomes. We present a case of this type of Candida infection in a 57-year-old man with a history of uncontrolled diabetes mellitus and intravenous drug abuse, and review the literature on this disease. Our patient had a good treatment outcome with liposomal amphotericin B and flucytosine, followed by oral fluconazole. Comorbidities include prior antibiotic use (52%), prior surgery (28%), malignancy (28%), stem cell or solid organ transplant (20%), prior corticosteroid use (16%), central venous catheter (CVC) insertion (10%), and burns (7%). Diagnosis requires a high index of suspicion, as clinical presentations and laboratory data can be nonspecific and difficult to differentiate from bacterial cerebral abscesses. In reviewed cases, 55% of blood cultures and 23% of cerebrospinal fluid (CSF) cultures were positive for Candida spp. and outcomes were poor, as the mortality rate of the non-autopsy cases reviewed was 69%.

Association between sympathetic response, neurogenic cardiomyopathy, and venous thromboembolization in patients with primary subarachnoid hemorrhage.

INTRODUCTION: Sympathetic activation promotes hemostasis, and subarachnoid hemorrhage (SAH) is associated with pronounced sympathetic activation. This investigation will assess whether catecholaminergic activity relates to venous thrombotic events in patients with acute SAH. METHODS: Observational study of consecutive SAH grade 3-5 patients requiring ventriculostomy insertion who did not undergo open surgical treatment of cerebral aneurysm. Cerebrospinal fluid (CSF) samples were obtained within 48 h of hemorrhage for assay of catecholamines, which were related to occurrence of deep venous thrombosis (DVT) and pulmonary embolization (PE). RESULTS: Of the 92 subjects, mean age was 57 years, 76% were female, and 57% Caucasian; 11% experienced lower extremity (LE) DVT, 12% developed upper extremity (UE) or LE DVT, and 23% developed any DVT/PE. Mean time to occurrence of UE/LE DVT was 7.8 days (+/-5.9 days), and mean time to development of PE was 8.8 days (+/-5.4 days). In hazards analysis models, independent predictors of LE DVT included neurogenic cardiomyopathy (NC) [HR 4.97 (95%CI 1.32-18.7)], norepinephrine/3,4-dihydroxyphenylglycol ratio (NE/DHPG) [3.81 (2.04-7.14)], NE [5.91 (2.14-16.3)], and dopamine (DA) [2.27 (1.38-3.72)]. Predictors of UE/LE DVT included NC [5.78 (1.70-19.7)], cerebral infarction [4.01 (1.18-13.7)], NE [3.58 (1.40-9.19)], NE/DHPG [3.38 (1.80-6.33)] and DA [2.01 (1.20-3.35)]. Predictors of DVT/PE included Hunt-Hess grade (H/H) [3.02 (1.19-7.66)], NE [2.56 (1.23-5.37)] and 3,4-dihydroxyphenylalanine (DOPA) [3.49 (1.01-12.0)]. CONCLUSIONS: In severe SAH, central sympathetic activity and clinical manifestations of (nor)adrenergic activity relate to the development of venous thromboemboli. Catecholamine activation may promote hemostasis, or may represent a biomarker for venous thromboses.

Cerebrospinal fluid catecholamine levels as predictors of outcome in subarachnoid hemorrhage.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is associated with marked sympathetic activation at the time of ictus. The purpose of this study is to determine whether early central catecholamine levels measured from cerebrospinal fluid (CSF) relate to outcome in patients with SAH. METHODS: Observational study of consecutive SAH grade 3-5 patients who underwent ventriculostomy placement, but did not undergo open craniotomy for aneurysm obliteration. CSF samples were obtained during the first 48 h following symptom onset and assayed for catecholamine levels. Statistical analyses were performed to determine whether the levels predicted mortality by day 15 or mortality/disability by day 30. RESULTS: For the 102 patients included, mean age was 58, and 73% were female - 21% experienced day-15 mortality, and 32% experienced mortality/disability by day 30. Early mortality was related to Hunt-Hess (H/H) grade (p < 0.001), neurogenic cardiomyopathy (NC) (p = 0.003), cerebral infarction (p = 0.001), elevated intracranial pressure (ICP) (p = 0.029), epinephrine (EPI) level (p = 0.002) and norepinephrine/3,4-dihydroxyphenylglycol (NE/DHPG) ratio (p = 0.003). Mortality/disability was related to H/H grade (p < 0.001), NC (p = 0.018), infarction (p < 0.001), elevated ICP (p = 0.002), EPI (p = 0.004) and NE/DHPG (p = 0.014). Logistic regression identified age [OR 1.09 (95% CI 1.01-1.17)], H/H grade [9.52 (1.19-77)], infarction [10.87 (1.22-100)], ICP elevation [32.26 (2-500)], EPI [1.06 (1.01-1.10)], and (inversely) DHPG [0.99 (0.99-1.00)] as independent predictors of early mortality. For mortality/disability, H/H grade [OR 21.74 (95% CI 5.62-83)], ICP elevation [18.52 (1.93-166)], and EPI [1.05 (1.02-1.09)] emerged as independent predictors. Proportional-hazards analysis revealed age [HR 1.041 (95% CI 1.003-1.08)], H/H grade [6.9 (1.54-31.25)], NC [4.31 (1.5-12.35)], and EPI [1.032 (1.009-1.054)] independently predicted early mortality. CONCLUSIONS: CSF catecholamine levels are elevated in SAH patients who experience early mortality or disability. EPI may potentially serve as useful index of outcome in this population of patients with SAH.

Determinants of central sympathetic activation in spontaneous primary subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) has been associated with pronounced acute sympathetic activation. The purpose of this investigation is to identify demographic, clinical, radiological, and anatomical features of SAH that relate to sympathetic activation. METHODS: Observational study of consecutive Grades 3-5 SAH patients requiring ventriculostomy and undergoing endovascular aneurysmal obliteration. All patients underwent cerebrospinal fluid (CSF) sampling within 48 h of SAH onset, and samples were assayed for various catecholamine compounds and metabolites. Univariate analyses were performed to identify variables associated with catecholamine levels, and to correlate linearity among catecholamine compounds and metabolites. Variables demonstrating a possible association and variables of interest were entered into linear regression models to determine predictors of catecholamine elevations. RESULTS: Of the 102 patients, mean age was 58 years and 74% were female; 42% were Hunt-Hess (H/H) grade 4/5, 61% had a computed tomography (CT) score of 3/4, 57% had anterior cerebral or communicating artery (ACA/ACom) aneursysms, and 23% had aneurysms in the posterior circulation. In the univariate analysis, age, gender, H/H grade, CT score, and aneurysm location demonstrated various associations with catecholamine levels, and substantial positive correlations existed between the various catecholamine compounds and metabolites. Linear regression analyses revealed H/H grade to be an independent predictor of elevated CSF epinephrine (EPI), 3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) levels, and of the norepinephrine/3,4-dihydroxyphenylglycol (NE/DHPG) ratio (p < 0.05 for all analyses). Female gender independently predicted increased dopamine (DA) and DOPAC levels (p < 0.05 for two analyses), as well as possibly DOPA levels (p < 0.1). Age, CT score and aneurysm location demonstrated only inconsistent associations and trends. CONCLUSIONS: Central sympathetic activation relates to clinical severity and female gender. No definitive associations were found for age, hemorrhage amount, or aneurysm location.

Posterior Reversible Encephalopathy Syndrome Presenting as Opsoclonus-Myoclonus.

Opsoclonus-myoclonus may be caused by various neurological conditions and toxic-metabolic states, but typically occurs as a parainfectious or paraneoplastic manifestation. The development of opsoclonus-myo-clonus has been variably attributed to lesions in the pons or cerebellum. Herein the authors describe a case of opsoclonus-myoclonus due to posterior reversible encephalopathy syndrome in which magnetic resonance imaging revealed lesions in the region of the cerebellar dentate nuclei. Clinical and radiological resolution of the opsoclonus-myoclonus and of the posterior reversible encephalopathy syndrome followed antihyperten-sive therapy.

Impact of intraventricular hemorrhage upon intracerebral hematoma expansion.

BACKGROUND: The purpose of this study is to determine whether intraventricular hemorrhage (IVH) exerts a "decompressive" effect that limits intracerebral hemorrhage (ICH) enlargement. METHODS: Retrospective review of patients with spontaneous supratentorial ICH diagnosed within 6 h of onset, who underwent follow-up head CT approximately 48 h later. Digital imaging analysis of CT scans was performed to compare hematoma volume changes between patients with and without IVH. Hemorrhage locations were classified as paraventricular (PV) or non-PV. Regression analyses were employed to identify predictors of IVH, hematoma expansion, and mortality. RESULTS: Of the 70 patients included 57% developed IVH, 85% of which occurred before initial CT. 71% of PV hemorrhages developed IVH, all before initial CT, and 48% of non-PV hemorrhages developed IVH, 29% of which occurred after initial CT. IVH was associated with PV location (P = 0.04), and among IVH patients PV location was associated with early IVH (P = 0.003). Predictors of mortality included age (P = 0.037), initial hematoma volume (P < 0.04), absolute volume change (P = 0.01), and final hematoma volume (P < 0.001). Variables predicting IVH included PV location (P < 0.0001), larger initial hematoma volume (P = 0.002), and greater absolute volume increase (P = 0.01). Hematoma expansion was greatest for non-PV with IVH (P = 0.08), and graphic inspection suggested that ICH volume tended to decrease with PV location and increase with IVH. Final hematoma volume was associated with initial volume (P < 0.0001), non-PV location (P = 0.02), and IVH (P = 0.04). CONCLUSIONS: IVH was not associated with less hematoma volume expansion, and for non-PV hemorrhages IVH was linked to greater volume increase.

CSF catecholamine profile in subarachnoid hemorrhage patients with neurogenic cardiomyopathy.

BACKGROUND: Patients experiencing apoplectic intracranial processes may develop neurogenic cardiomyopathy (NC). The purpose of this research is to determine whether cerebrospinal fluid (CSF) catecholamine levels are elevated in subarachnoid hemorrhage (SAH) patients with NC when compared to those without NC. METHODS: Observational study of consecutive grades 3-5 SAH patients requiring ventriculostomy. All patients underwent CSF sampling for catecholamine levels, and transthoracic echocardiography (TTE) to assess for NC, within 48 h of SAH onset. Univariate analyses were performed to identify clinical and laboratory variables associated with NC. Clinical variables associated with NC in the univariate analysis were entered into logistic regression models along with the candidate catecholamine variables to identify predictors of NC. RESULTS: The study group contained 100 patients--mean age of study subjects was 58 years, 73% were female, and 15% developed NC. NC patients were more likely to have a worse clinical grade than patients without NC (80 vs. 34%, P = 0.001). NC patients possessed greater DOPA levels (5.83 vs. 4.60 nmol/l, P = 0.044), and a trend toward greater noradrenergic activity as determined by NE/DHPG ratio (0.3799 vs. 0.2519, P = 0.073). Multivariate analysis identified worse clinical grade (OR 7.09, P = 0.005) and possibly NE levels (OR 1.005, P = 0.057) as independent predictors of NC. Bivariate analysis reinforced the findings for NE (OR 1.006, P = 0.022), and also identified DOPA levels (OR 1.001, P = 0.034) and NE/DHPG (OR 22.18, P = 0.019) as predictors of NC. CONCLUSIONS: SAH patients with NC tend to have greater CSF catecholamine levels than those without NC. However, the development of NC may also be related to factors not evaluated by our study.

Restless Legs Syndrome Shows Increased Silent Postmortem Cerebral Microvascular Disease With Gliosis.

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T-cell marker); (3) CD19 (a B-cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease (P=0.015) and gliosis (P=0.003). T cells were increased in RLS compared with controls (P=0.009) and tended to colocalize with microvascular disease (P=0.003). Other markers did not differ. There was no correlation between microvascular lesion load and RLS severity or duration. Conclusions Patients with RLS had statistically significantly more silent cerebral microvascular disease and gliosis than controls compatible with previous magnetic resonance imaging studies and with studies showing a link between RLS and hypertension, clinical stroke, and cardiovascular disease. T-cell invasion may be a secondary phenomenon.

Role of antiplatelet agents in hematoma expansion during the acute period of intracerebral hemorrhage.

BACKGROUND: Oral anticoagulants have been associated with greater hematoma expansion in patients with intracerebral hemorrhage (ICH). The purpose of this study was to determine whether the reported use of antiplatelet agents also results in greater hematoma expansion. METHODS: Retrospective review of patients with spontaneous supratentorial ICH diagnosed within 6 h of onset, who underwent follow-up head CT approximately 48 h later. Digital imaging analysis of initial and second CT scans was performed for comparison of hematoma volume changes between patients reporting and those not reporting antecedent antiplatelet use. Statistical analyses to determine predictors of ICH volume change and in-hospital mortality were also performed via multivariate regression models. RESULTS: Of the 70 patients included, 17 were documented as taking antiplatelet agents. Groups were comparable regarding baseline demographic, clinical and laboratory characteristics, and the timing of CT scans was similar. Patients reporting antiplatelet use experienced greater absolute increase (7.7 ml vs. 5.5 ml) and proportional increase (110% vs. 21%) in ICH volume than those not reporting antiplatelet use, but these differences were not statistically significant (P = 0.94 and 0.61 respectively; Wilcoxon test). Baseline hematoma volume tended to correlate with percentage volume increase (P < 0.1), whereas IVH was inversely associated with percent volume increase (P < 0.05). Age (P < 0.05), absolute volume increase (P < 0.005), and final volume (P < 0.001) were associated with in-hospital mortality, the rates of which were similar between the two study groups (18% vs. 17%). CONCLUSIONS: Patients reporting antiplatelet use experienced similar degrees of hematoma expansion compared to patients not reporting antiplatelet use.

A critical appraisal of bypass surgery in moyamoya disease.

Moyamoya disease (MMD) is a complex cerebrovascular disorder about which little is known. Conventionally, revascularization surgery is recommended for patients, despite an absence of conclusive data from adequate clinical trials. Underscoring the uncertainty that exists in treating MMD patients, investigators continue to present data comparing revascularization with conservative or medical management, most of which originates from East Asia where MMD is most prevalent. The purpose of this manuscript is to review contemporary large case series, randomized trials, and recent meta-analyses that compare surgical and medical treatments in adult patients with MMD, and to critically analyze the modern literature in the context of current practice standards. Data from the available literature is limited, but revascularization seems superior to conservative therapy in adult patients presenting with hemorrhage, and in preventing future hemorrhages. Conversely, evidence that surgery is superior to medical therapy is not convincing in adult patients presenting with cerebral ischemia, or for the prevention of future ischemic events. In contrast to East Asian populations, MMD in Europe and in the Americas is predominantly an ischemic disease that presents in adulthood. Adequate multinational trials are warranted.

A comprehensive analysis of the relationship between ACA velocities and ACA infarction following aneurysmal subarachnoid hemorrhage.

PURPOSE: To evaluate the relationship between anterior cerebral artery (ACA) velocities (and ancillary parameters) and ACA infarction following aneurysmal subarachnoid hemorrhage (aSAH), and to examine the factors that influence velocities. METHODS: Retrospective investigation of 500 consecutive aSAH patients. ACA mean velocities (Vm) were evaluated by daily transcranial ultrasound during the early (days 1-4) and late (days 5-20) periods posthemorrhage. Presence and timing of acute ACA infarctions were identified by serial retrospective review of cerebral computerized tomography (CT) scans. Predictors of ACA velocities were identified and compared to predictors of vasospasm and infarction from the literature. RESULTS: Decreased velocities on the day of infarction were observed in infarct-positive vessels when compared to infarct-negative vessels. ACA velocity increases, ipsilateral/contralateral ACA velocity ratios, and ACA velocity ranges, were inaccurate in anticipating infarction. Decreased ACA index velocities were moderately accurate in anticipating ACA infarction during the early [Vm<60cms/s], late [Vm<70cms/s] and overall [Vm<70cms/s] time periods. Decreased index velocities also independently predicted infarction during all time periods. ACA velocities were most consistently predicted by age, race, hemorrhage quantity on CT, and ACA/ACom (anterior communicating artery) aneurysm location. CONCLUSIONS: ACA velocity increases and ancillary parameters do not relate to the development of infarction, whereas velocity decreases are moderately accurate in anticipating infarction. Predictors of velocity increases generally coincide with those of vasospasm, whereas predictors of velocity decreases coincide more with those of infarction following aSAH.

Eclamptic subarachnoid haemorrhage without hypertension.

Subarachnoid haemorrhage in pregnancy is often the result of aneurysmal rupture or severe hypertension. A young woman with postpartum eclampsia and 'normal' blood pressure developed sudden-onset head pain, and was found to have minor biconvexity subarachnoid hemorrhages. Serial angiograms of the cervicocranial vessels revealed no evidence of aneurysm or arteriovenous malformation. A follow-up angiogram revealed diffuse vessel narrowing, consistent with postpartum angiopathy. Treatment consisted only of nimodipine for the prevention of vasospasm. The patient made an excellent recovery, without residual neurological deficits.

Analysis of the endothelial nitric oxide synthase gene as a modifier of the cerebral response to ischemia.

We studied the endothelial nitric oxide synthase (eNOS or NOS-3) gene as a potential modifier of the cerebral response to ischemia by investigating the association of two common polymorphisms with ischemic stroke volume. We genotyped an intronic variable number tandem repeat and a single nucleotide polymorphism, G894T, in 132 patients with nonlacunar ischemic strokes in whom clinical data and stroke lesion volume were recorded. Our results show that all genotypes are in Hardy-Weinberg equilibrium. After adjustment of covariates, neither of the NOS-3 polymorphisms showed significant differences comparing the genotypes and mean stroke volume (analysis of variance). Our results do not suggest a major gene effect of the NOS-3 gene as a modifier of the cerebral response to ischemia.

Silent Cerebral Small Vessel Disease in Restless Legs Syndrome.

STUDY OBJECTIVES: Growing literature suggests that patients with restless legs syndrome (RLS) may be at increased risk for hypertension, heart disease, and stroke. Cerebral small vessel disease (SVD) is a known risk factor for clinical stroke. This study evaluated silent cerebral SVD by MRI in patients with RLS, in the absence of a history of previous clinical stroke or known stroke risk factors and taking into account disease duration. METHODS: Fifty-three patients with RLS < 10 y were prospectively recruited along with 44 with RLS > 10 y and 74 normal controls. A magnetic resonance imaging study was obtained from all subjects and scans were analyzed for area and volume of SVD. RESULTS: There was a significant increase in SVD area in the entire group of RLS patients compared to controls (P = 0.036); this was almost entirely driven by the group with RLS > 10 y. SVD area and volume were significantly increased in patients with RLS > 10 y with respect to both controls (P < 0.0001 and P < 0.0014, respectively) and RLS < 10 y (P < 0.00022 and P < 0.003, respectively). Age, duration of RLS, and the interaction of age and duration of RLS were independent predictors of SVD disease. Duration of RLS was an independent predictor of the burden of cerebral SVD (area P < 0.00012 and volume P < 0.0025), whereas sex and insomnia were not. CONCLUSION: RLS duration should be taken into account when analyzing the association between RLS and cerebrovascular disease; our data support the hypothesis that a long-lasting RLS and its accompanying periodic limb movements in sleep are a risk factor for silent SVD and perhaps for the development of clinical stroke.

Combination antiplatelet agents in ischemic cerebrovascular disease.

Combination antiplatelet agents with multiple mechanisms of action are being used with increasing frequency for vascular disorders, including cerebrovascular disease. Limited data exist regarding the efficacy of combination antiplatelet therapy in the primary or secondary prevention of cerebral ischemia, and combination therapies are often used without adequate evidence of efficacy. However, over the last few years, several cerebrovascular and cardiovascular trials have provided some preliminary information on the effectiveness of various combination therapies in preventing cerebral ischemic disease. This article reviews recently completed cerebrovascular and cardiovascular trials that tested a combination antiplatelet regimen against aspirin alone, and that assessed cerebral ischemia as an outcome measure. Controversies pertaining to these trials and to the use of the various combination antiplatelet regimens are discussed. Based on cardiovascular studies, clopidogrel in combination with aspirin has not been proven superior to aspirin alone for the primary prevention of cerebral ischemia. No data exists regarding the combination of clopidogrel and aspirin for the secondary prevention of cerebrovascular disease. The combination of aspirin plus extended-release dipyridamole (xrDP) appears to be superior to aspirin alone in the secondary prevention of cerebral ischemia, but may compromise cardiovascular protection in patients with coexisting coronary artery disease. Combination therapy with aspirin and clopidogrel seems to increase the risk of major hemorrhages, whereas aspirin plus xrDP does not. Ongoing trials are expected to clarify the role of various combination antiplatelet regimens.