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1.  Distribution, Severity and Radiologic Features of Intracranial Stenosis in Asymptomatic Pakistanis 
Intracranial atherosclerotic disease (ICAD) is the most common ischemic stroke subtype globally. It accounts for 30–50% of all ischemic strokes in Asians.
The aim of the study is to report the frequency of asymptomatic ICAD and its associated Magnetic Resonance Imaging (MRI) findings.
200 adult participants were recruited from the Radiology Departments of two major diagnostic centers in Karachi. Eligible participants were confirmed for the absence of stroke symptoms via the Questionnaire for Verifying Stroke Free Status (QVSFS). QVSFS negative subjects underwent MRI on a 1.5 Tesla scanner. Images were centrally reviewed on Di com Viewer 3.0 with electronic calipers to calculate the degree of ICAD.
Mean age of subjects was 37.1 years (S.D 15.1) with 50.5% men (n=101) and 49.5% women (n=99). Asymptomatic ICAD was found in 34.5% (n=69) subjects. Of the 3800 intracranial arteries studied, 2.2% (n=88) had biological disease. 20.5% (n=18) of these vessels had atherosclerotic irregularities, 43.2% (n=38) had mild stenos is, 11.4% (n=10) had moderate stenos is, 5.7% (n=5) had severe stenos is while 19.3% (n=17) were completely occluded. The posterior cerebral artery (42% of stenosed arteries, n=37) was most affected. 23.5% (n=47) of subjects had peri-ventricular lucencies, 10.5% (n=21) had brain atrophy while 3.5% (n=7) had silent brain infarcts. There was a significant association between asymptomatic ICAD and peri ventricular lucencies (PR 1.59; 95% CI 1.35–1.99).
Asymptomatic ICAD is common in young Pakistanis, with no gender predilection; it preferentially affects the posterior circulation. Silent infarcts are rare compared to peri ventricular lucencies and atrophy.
PMCID: PMC4324652
Stroke; Intracranial Stenosis; Developing Countries; Asymptomatic; Radiology; Prevention; Epidemiology
2.  CCR2+Ly6Chi Inflammatory Monocyte Recruitment Exacerbates Acute Disability Following Intracerebral Hemorrhage 
The Journal of Neuroscience  2014;34(11):3901-3909.
Intracerebral hemorrhage (ICH) is a devastating type of stroke that lacks a specific treatment. An intense immune response develops after ICH, which contributes to neuronal injury, disability, and death. However, the specific mediators of inflammation-induced injury remain unclear. The objective of the present study was to determine whether blood-derived CCR2+Ly6Chi inflammatory monocytes contribute to disability. ICH was induced in mice and the resulting inflammatory response was quantified using flow cytometry, confocal microscopy, and neurobehavioral testing. Importantly, blood-derived monocytes were distinguished from resident microglia by differential CD45 staining and by using bone marrow chimeras with fluorescent leukocytes. After ICH, blood-derived CCR2+Ly6Chi inflammatory monocytes trafficked into the brain, outnumbered other leukocytes, and produced tumor necrosis factor. Ccr2−/− mice, which have few circulating inflammatory monocytes, exhibited better motor function following ICH than control mice. Chimeric mice with wild-type CNS cells and Ccr2−/− hematopoietic cells also exhibited early improvement in motor function, as did wild-type mice after inflammatory monocyte depletion. These findings suggest that blood-derived inflammatory monocytes contribute to acute neurological disability. To determine the translational relevance of our experimental findings, we examined CCL2, the principle ligand for the CCR2 receptor, in ICH patients. Serum samples from 85 patients were collected prospectively at two hospitals. In patients, higher CCL2 levels at 24 h were independently associated with poor functional outcome at day 7 after adjusting for potential confounding variables. Together, these findings suggest that inflammatory monocytes worsen early disability after murine ICH and may represent a therapeutic target for patients.
PMCID: PMC3951693  PMID: 24623768
bone marrow chimeras; CCL2; CCR2; intracerebral hemorrhage; monocytes; neuroinflammation
3.  Review, Historical Context, and Clarifications of the NINDS rt-PA Stroke Trials Exclusion Criteria: Part 1: Rapidly Improving Stroke Symptoms (RISS) 
Background and Purpose
Since FDA approval of IV t-PA for treatment of acute ischemic stroke in 1996, it has become clear that several criteria used for exclusion from therapy were not based on actual data nor operationally defined for use in clinical practice. All eligibility criteria from the NINDS rt-PA Stroke Study were adopted within the alteplase package insert as contraindications/warnings. Many clinicians have expressed the need for clarification and better definition of these treatment criteria.
A group of investigators who also practice as stroke physicians convened a collaborative endeavor to work toward developing more clinically meaningful and consensus-driven exclusion criteria for IV t-PA. The first of these exclusion criteria chosen was “rapidly improving stroke symptoms” (RISS). We reviewed and clarified the historical context and intention with the original investigators, held e-mail discussions, convened an in-person “RISS Summit”, and obtained the understanding of experienced stroke physicians broadly.
Historically, the intent of this exclusion criterion within the NINDS rt-PA Stroke Trial was to avoid treatment of transient ischemic attacks (TIAs) – who would have recovered completely without treatment. There was unanimous consensus that, in the absence of other contraindications, patients who experience improvement of any degree, but have a persisting neurological deficit that is potentially disabling, should be treated with IV t-PA. This statement is supported from the methods established for the original NINDS trial, based on detailed discussions and interviews with the former NINDS trialists. It was agreed that improvement should only be monitored for the extent of time needed to prepare and administer the IV t-PA bolus/infusion. An explicit operational definition of RISS was developed by consensus to guide future decision-making in acute stroke. There was unanimous agreement that all neurological deficits present at the time of the treatment decision should be considered in the context of individual risk and benefit as well as the patient’s baseline functional status.
A structured framework and quantitative approach towards defining RISS emerged through expert opinion and consensus. The term, RISS, should be reserved for those who improve to a mild deficit, specifically one which is perceived to be nondisabling. This is recommended to guide decision-making regarding IV t-PA eligibility going forward, including the design of future studies. An additional study of patients with rapid improvement to non-mild deficits is not justified as these patients should be treated.
PMCID: PMC3789593  PMID: 23847249
thrombolysis; patient selection; cerebrovascular diseases; tissue plasminogen activator; clinical trials; exclusion criteria; TIA
4.  Clinical, lifestyle, socioeconomic determinants and rate of asymptomatic intracranial atherosclerosis in stroke free Pakistanis 
BMC Neurology  2014;14:155.
Intracranial Atherosclerotic Disease (ICAD) is the most frequent etiology of stroke with high prevalence among Asians. Despite this, early determinants of ICAD have not been described from this region.
The study is an analytical prospective cross-sectional study of 200 adults from Radiology Departments of two diagnostic centers in Karachi. Eligible participants confirmed the absence of stroke symptoms via the Questionnaire for Verifying Stroke Free Status (QVSFS) and underwent an interview covering medical, socio demographic, lifestyle and anthropometric evaluation using locally validated and standardized definitions. Magnetic Resonance Images (MRI) were centrally reviewed to detect ICAD using the criterion used in the Warfarin–Aspirin Symptomatic Intracranial Disease study. The risk factors associated with asymptomatic ICAD are reported along with prevalence ratios.
Of the 200 participants, ICAD was found in 34.5% (n = 69) of the participants. Mean age was 37.1 (S.D 15.1) years with 62% younger than 45 years. Self-reported hypertension was found in 26.5% subjects, diabetes in 9%, dyslipidemia in 5% and depression in 60%. Smokeless tobacco (Adjusted PR 3.27 (1.07-6.05)), Western diet, high socioeconomic status (Adjusted PR 2.26 (1.99-5.62)) and dyslipidemia (Adjusted PR 1.88 (1.25-2.21)) had significant associations with ICAD after multivariable analysis. Age, gender, diabetes, hypertension, depression and physical activity did not have a significant association.
ICAD was found on MRI in one in three asymptomatic Pakistanis and was associated with modifiable risks. Initiatives targeting primary prevention may be able to decrease the burden of disease caused by stroke due to ICAD.
Study Registration Number
NCT02072876 2/25/2014
PMCID: PMC4236665  PMID: 25124284
Intracranial atherosclerosis; Stroke; Asymptomatic; Developing countries; Prevention; Sociodemographic risk factors; Epidemiology
5.  Disparities in Evaluation at Certified Primary Stroke Centers: REasons for Geographic And Racial Differences in Stroke 
Background and Purpose
Evaluation at Primary Stroke Centers (PSCs) has the potential to improve outcomes for patients with stroke. We looked for differences in evaluation at Joint Commission certified PSCs by race, education, income, and geography (urban vs. non-urban; southeastern stroke belt vs. non-belt).
Community-dwelling, black and white participants from the national REasons for Geographic and Racial Differences in Stroke (REGARDS) prospective population-based cohort were enrolled between 1/2003 and 10/2007. Participants were contacted at 6 month intervals for suspected stroke events. For suspected stroke events it was determined if the evaluating hospital was a certified PSC.
Of 1000 suspected strokes, 204 (20.4%) were evaluated at a PSC. A smaller proportion of women than men (17.8% vs. 23.0%, p=0.04), those with a previous stroke (15.1% vs. 21.6%, p=0.04), those living in the stroke belt (14.7% vs. 27.3%, p<0.001) and in a non-urban area (9.1% vs. 23.1%, p<0.001) were evaluated at a PSC. There were no differences by race, education, or income. In multivariable analysis, subjects were less likely to be evaluated at a PSC if they lived in a non-urban area (OR=0.39, 95% CI 0.22–0.67), lived in the stroke belt (OR=0.54, 95% CI 0.38–0.77) or had a prior stroke (OR=0.46, 95% CI 0.27–0.78).
Disparities in evaluation by PSCs are predominately related to geographic factors but not to race, education, or low income. Despite an increased burden of cerebrovascular disease in the stroke belt, subjects there were less likely to be evaluated at certified hospitals.
PMCID: PMC3747032  PMID: 23640827
stroke centers; disparities; access to care; stroke
6.  A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing 
The New England journal of medicine  2013;369(24):2283-2293.
The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.
We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.
At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.
Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG number, NCT00839657.)
PMCID: PMC3942158  PMID: 24251361
7.  Risk factors and outcome of patients with symptomatic intracranial stenosis presenting with lacunar stroke 
Background and Purpose
We hypothesized that patients with intracranial stenosis with lacunar stroke presentations would face lower risks of recurrent stroke than those with index non-lacunar strokes, and that their recurrent strokes would predominantly be lacunar.
We analyzed subjects enrolled with an index stroke into the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. The index stroke was classified as lacunar or non-lacunar. The primary endpoint was recurrent ischemic stroke. Cox proportional hazard models were generated with stratification for severity of stenosis.
347 subjects were enrolled after an index stroke, 38 were lacunar and 309 were non-lacunar. Over a mean follow-up of 1.8 years there was no significant difference in stroke recurrence between patients whose index stroke was lacunar (7/38; 18%) vs. non-lacunar (69/309; 22%) (HR 0.79, 95%CI:0.36–1.71). Further, no significant differences were found when groups were stratified by 50–69% stenosis (HR 0.50, 95%CI:0.12–2.1) and ≥70% stenosis (HR 0.87, 95%CI:0.34–2.2). Of the 7 recurrent strokes in patients whose index stroke was lacunar, all 7 were non-lacunar and 3 were in the territory of the stenotic artery.
In patients with symptomatic intracranial stenosis, the risk of recurrent stroke was similar in patients who presented with lacunar and non-lacunar strokes, and recurrent strokes in patients presenting with lacunar stroke were typically non-lacunar. These findings suggest that the pathophysiology of these strokes is related to the stenosis rather than small vessel disease. Patients presenting with lacunar strokes should be included in trials investigating secondary prevention for symptomatic intracranial stenosis.
PMCID: PMC3336041  PMID: 22363054
8.  Headache as a risk factor for neurovascular events in pediatric brain tumor patients 
Neurology  2013;80(16):1452-1456.
To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors.
This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0–21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA.
Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7–9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8–15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7–5.5 years).
Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.
PMCID: PMC3662360  PMID: 23486881
9.  Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke–Enhanced Regimen Stroke Trial 
Background and Purpose
In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke–Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial.
CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression.
Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01–1.40; P=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70–4.31; P=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51–3.76; P=0.52).
The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen.
PMCID: PMC3970761  PMID: 23887841
clinical trial; eptifibatide; ischemic stroke; tissue plasminogen activator
10.  Informed Consent: The Rate-Limiting Step in Acute Stroke Trials 
Successful implementation of a randomized clinical trial (RCT) for neuro-vascular emergencies such as cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage is extraordinarily challenging. Besides establishing an accurate, hyper-expedited diagnosis among many mimics in a person with acute neurological deficits, informed consent must be obtained from this vulnerable group of patients who may be unable to convey their own wishes, grasp the gravity of their situation, or give a complete history or examination. We review the influences, barriers, and factors investigators encounter when providing established and putative stroke therapies, and focus on informed consent, the most important research protector of human subjects, as the rate-limiting step for enrollment into acute stroke RCTs. The informed consent process has received relatively little attention in the stroke literature, but is especially important for stroke victims with acute cognitive, aural, lingual, motor, or visual impairments. Consent by a surrogate may not accurately reflect the patient’s wishes. Further, confusion about trial methodology, negative opinions of placebo-controlled studies, and therapeutic misconception by patients or surrogates may impede trial enrollment and requires further study. Exception from informed consent offers an opportunity that is rarely if ever utilized for stroke RCTs. Ultimately, advancing the knowledge base and treatment paradigms for acute stroke is essential but autonomy, beneficence (non-malfeasance), and justice must also be carefully interwoven into any well-designed RCT.
PMCID: PMC3195267  PMID: 22022320
informed consent; acute stroke; cerebral infarction; clinical trial
11.  Cranial Irradiation Increases Risk of Stroke in Pediatric Brain Tumor Survivors 
Background and Purpose
To determine the incidence of neurovascular events as late complications in pediatric brain tumor patients and to evaluate radiation as a risk factor.
Patients were ascertained using the tumor database of a pediatric tertiary care center. Included patients had a primary brain tumor, age birth to 21 years, initial treatment 1/1/93-12/31/02, and at least two visits with Neuro-Oncology. Radiation exposure included: whole brain, whole brain plus a focal boost, or focal brain. The primary outcome was stroke or transient ischemic attack (TIA).
Of 431 subjects, 14 had 19 events of stroke or TIA over a median follow-up of 6.3 years. The incidence rate was 548/100,000 person-years. Overall, 61.5% of subjects received radiation, including 13/14 subjects with events. Median time from first radiation to first event was 4.9 years. The stroke/TIA hazard ratio for any brain irradiation was 8.0 (95% CI:1.05-62, p=0.045); for Circle of Willis (COW) radiation was 9.0 (95% CI:1.2-70, p=0.035); and for focal non-COW radiation was 3.4 (95% CI:0.21-55, p=0.38).
The incidence of neurovascular events in this population is 100-fold higher than in the general pediatric population and cranial irradiation is an important risk factor. By defining the incidence of this late effect, physicians are better able to counsel parents regarding treatment, monitor patients at risk, and target a population for primary stroke prevention in future studies.
PMCID: PMC3492057  PMID: 22968468
childhood brain tumors; stroke; treatment-related stroke
12.  Predicting Early Awakening from Coma after Intracerebral Hemorrhage 
Introduction: Given the high morbidity and mortality associated with intracerebral hemorrhage (ICH), family members, and healthcare providers base early supportive management decisions, at least in part, on expected prognosis. In the comatose patient with ICH, this short-term prognosis is most overtly characterized by regaining of consciousness.
Design: A retrospective consecutive cohort of 51 patients admitted to a neuroICU with ICH and admission Glasgow Coma Scale score ≤8 was identified. Logistic regression was performed to assess the association of baseline characteristics and treatment parameters associated with awakening.
Results: Awakening from coma was observed in 53% of ICH patients: 83% with an initial GCS score of 7–8, 43% with an initial score of 5–6, and 20% with an initial score of 3–4. Awakening from coma in the cohort of 27 patients who regained consciousness occurred in 59% of patients by day 2, 89% by day 7, and 96% by day 9. In multivariable analysis, only higher admission GCS score was associated with a greater likelihood of awakening from coma [OR 4.9 (95% CI 1.9–13) per two-point category, p = 0.001]. DNR status during the first 24 h was not associated with awakening but was at later time points.
Conclusion: GCS score is the predominant initial predictor of early awakening in patients who present in coma after ICH. Patients who regained consciousness typically did so within the first 9 days of hospital admission.
PMCID: PMC3797437  PMID: 24137155
intracerebral hemorrhage; intracranial hemorrhage; ICH; prognosis; coma
13.  Neutrophil Depletion Diminishes Monocyte Infiltration and Improves Functional Outcome After Experimental Intracerebral Hemorrhage 
Inflammation contributes to secondary injury and neuronal loss after intracerebral hemorrhage, but the role of individual immune populations in these processes is unclear. In a mouse model, the injection of autologous blood into the striatum was associated with an intense inflammatory cell infiltrate composed of neutrophils, monocytes, and dendritic cells. Selective depletion of neutrophils resulted in decreased infiltration of monocytes and improved functional outcomes at day 3 post-hemorrhage. These findings indicate that neutrophil infiltration into the site of hemorrhage contributes to brain injury either by direct cellular damage or the recruitment of monocytes.
PMCID: PMC3702167  PMID: 21725751
Intracerebral hemorrhage; Inflammation; Neutrophils; Monocytes
14.  Toll-like Receptor 4 Contributes to Poor Outcome after Intracerebral Hemorrhage 
Annals of neurology  2011;70(4):646-656.
Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which perihematomal inflammation contributes to neuronal injury and functional disability. Histologically, the region becomes infiltrated with neutrophils and activated microglia followed by neuronal loss but little is known about the immune signals that coordinate these events. This study aimed to determine the role of Toll-like receptor 4 (TLR4) in the innate immune response after ICH and its impact on neurobehavioral outcome.
Transgenic mice incapable of TLR4 signaling and wild-type controls were subjected to striatal blood injection to model ICH. The perihematomal inflammatory response was then quantified by immunohistochemistry, whole brain flow cytometry, and PCR. The critical location of TLR4 signaling was determined by blood transfer experiments between genotypes. Functional outcomes were quantified in all cohorts using the cylinder and open field tests.
TLR4-deficient mice had markedly decreased perihematomal inflammation, associated with reduced recruitment of neutrophils and monocytes, fewer microglia, and improved functional outcome by day 3 after ICH. Moreover, blood transfer experiments revealed that TLR4 on leukocytes or platelets within the hemorrhage contributes to perihematomal leukocyte infiltration and the neurological deficit.
Together, these data identify a critical role for TLR4 signaling in perihematomal inflammation and injury and indicate this pathway may be a target for therapeutic intervention.
PMCID: PMC3671585  PMID: 22028224
15.  Vertebral artery dissection and cerebral infarction in a patient with recurrent ovarian cancer receiving bevacizumab☆ 
•Ovarian cancer patients receiving bevacizumab treatment can experience significant adverse events.•We report a case of vertebral artery dissection associated with bevacizumab treatment.
PMCID: PMC3862306  PMID: 24371692
Bevacizumab; Adverse events; Vertebral artery dissection; Cerebrovascular accident
16.  Echocardiography in Patients with Symptomatic Intracranial Stenosis 
Background and Purpose
Echocardiography is often performed in stroke patients, even when alterative stroke etiologies are identified. We evaluated the utility of echocardiography in patients with TIA or stroke due to stenosis of a major intracranial artery.
The Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial was an NIH-funded randomized, double-blinded, multicenter clinical trial in which 569 patients with TIA or ischemic stroke attributed to angiographically-proven 50–99% stenosis of a major intracranial artery were randomly assigned to warfarin or aspirin. Patients with unequivocal cardiac sources of embolism were excluded. The risk of ischemic stroke, myocardial infarction (MI), and vascular death was compared among patients who had or did not have echocardiography performed prior to enrollment, and Cox proportional hazards models were employed to determine whether echocardiographic abnormalities present in >5% of subjects were associated with these outcomes.
264 of 569 patients in WASID had echocardiograms; 37% were transesophageal. Of these 264 patients, 69 suffered subsequent ischemic stroke, MI, or vascular death. Patients who underwent echocardiography had similar event rates to those who did not (p=0.18). Common abnormalities identified on echocardiography were not associated with subsequent risk in this population.
Among patients with TIA or stroke due to intracranial arterial stenosis, echocardiography appears to offer limited diagnostic and prognostic value.
PMCID: PMC2063439  PMID: 17845919
17.  Concurrent Validity and Reliability of Retrospective Scoring of the Pediatric NIH Stroke Scale 
Background and Purpose
The Pediatric National Institutes of Health Stroke Scale (PedNIHSS), an adaptation of the adult NIH Stroke Scale, is a quantitative measure of stroke severity shown to be reliable when scored prospectively. The ability to calculate the PedNIHSS score retrospectively would be invaluable in the conduct of observational pediatric stroke studies. The study objective was to assess the concurrent validity and reliability of estimating the PedNIHSS score retrospectively from medical records.
Neurological examinations from medical records of 75 children enrolled in a prospective PedNIHSS validation study were photocopied. Four neurologists of varying training levels blinded to the prospective PedNIHSS scores reviewed the records and retrospectively assigned PedNIHSS scores. Retrospective scores were compared among raters and to the prospective scores.
Total retrospective PedNIHSS scores correlated highly with total prospective scores (R2=0.76). Interrater reliability for the total scores was “excellent” (intraclass correlation coefficient of 0.95, 95% confidence interval 0.94–0.97). Interrater reliability for individual test items was “substantial” or “excellent” for 14 of 15 items.
The PedNIHSS score can be scored retrospectively from medical records with a high degree of concurrent validity and reliability. This tool can be used to improve the quality of retrospective pediatric stroke studies.
PMCID: PMC3265644  PMID: 22076000
arterial ischemic stroke; pediatric; NIH stroke scale
18.  Anti-Phosphatidylserine-Prothrombin Antibodies are Associated with Outcome in a TIA Cohort 
Background: Antiphospholipid antibodies (aPLs) have been associated with thrombosis in the antiphospholipid antibody syndrome (APS) and with atherosclerotic vascular events in patients without APS. We examined the significance of aPLs in transient ischemic attack (TIA). Patients/methods: Patients with TIA <48 h from symptom onset were prospectively enrolled. Traditional aPLs, including anticardiolipin and β2-glycoprotein-I (β2GPI), and newer aPLs, including anti-phosphatidylserine/prothrombin (aPS/PT), β2GPI Domain 4/5 and β2GPI Domain 1 were measured. Primary outcome was a composite of stroke or death within 90 days or identification of a high risk stroke mechanism. Secondary outcomes were stroke or death and the presence of clinical/sub-clinical atherosclerosis. Results: Over 4.5 years, 167 patients were enrolled. Forty one patients (25%) had the composite endpoint. Antibodies were measured in 158 subjects. aPS/PT IgG antibodies were significantly associated with stroke/death (OR 16.3, 95% CI 2.3–116.7, p = 0.005) and were non-significantly associated with the composite endpoint (OR 4.7, 95% CI 0.8–29.2, p = 0.10). In multivariate analysis adjusting for ABCD2 risk score, aPS/PT IgG remained associated with stroke/death (OR 15.7, 95% CI 2.0–125.6, p = 0.009). Other aPLs were not associated with clinical outcome and no association between APLs and atherosclerosis was identified. Conclusion: In contrast to other aPLs, aPS/PT IgG antibodies are independently associated with stroke or death in patients with TIA.
PMCID: PMC3460224  PMID: 23060855
anticardiolipin; antiphospholipid; biomarker; infarction; thrombosis; transient ischemic attack; aPS/PT antibodies
19.  The Safety and Efficacy of Thrombolysis for Strokes After Cardiac Catheterization 
The purpose of this study was to systematically compare clinical outcomes of patients treated with thrombolysis with those without treatment in a multi-year, multicenter cohort of strokes after cardiac catheterization.
Ischemic strokes after cardiac catheterization procedures, although uncommon, lead to the morbidity and mortality of thousands of patients each year. Despite the availability of Food and Drug Administration–approved thrombolytic therapy for acute ischemic stroke since 1996, thrombolysis remains unestablished in the setting of cardiac catheterization, owing to unique concerns regarding safety and efficacy.
Consecutive cases of ischemic stroke after cardiac catheterization were abstracted retrospectively and reviewed by clinicians at 7 major North American academic centers with acute stroke teams. Safety and efficacy outcome measures were pre-defined.
A total of 66 cases of ischemic strokes after cardiac catheterization were identified over 3 to 4 years; 12 (18%) were treated with thrombolysis, consisting of 7 intravenous and 5 intra-arterial recombinant tissue plasminogen activator cases. Improvement in stroke symptoms, as measured by the primary efficacy measure of median change in National Institutes of Health Stroke Scale score from baseline to 24 h, was greater in treated versus nontreated cases (p < 0.001). Additional secondary measures of efficacy also showed better outcomes in the treated group. There were no significant differences in bleeding events, defined as symptomatic intracerebral hemorrhage, hemopericardium, or other systemic bleeding resulting in hemodynamic instability or blood tranfusions. Mortality rates were also similar.
Thrombolysis might improve early outcomes after post-catheterization strokes and seems safe in this context. Emergent cerebral revascularization should be a routine consideration.
PMCID: PMC3420805  PMID: 18308158
20.  Treatment of Acute Ischemic Stroke: Beyond Thrombolysis and Supportive Care 
Neurotherapeutics  2011;8(3):425-433.
The initial therapeutic approach to acute ischemic stroke consists of thrombolytic therapy and early initiation of supportive care, usually commenced prior to the determination of the underlying stroke etiology. Varying stroke mechanisms may call for specific, etiology-based treatment. The majority of strokes result from cardioembolism, large-vessel atherothromboembolism, and small-vessel occlusive disease. There are scant data to support the use of acute anticoagulation therapy over anti-platelet therapy in cardioembolic stroke and large-vessel atherosclerosis, although it may be reasonable in a certain subset of patients. However, augmentation of blood flow with early surgery, stenting, or induced hypertension, may play a role in patients with large artery stenosis. The less commonly identified stroke mechanisms may warrant special consideration in treatment. Controversy remains regarding the optimal anti-thrombotic treatment of arterial dissection. Reversible cerebral vasoconstriction syndrome may benefit from therapy with calcium channel blockers, high-dose steroids, or magnesium, although spontaneous recovery may occur. Inflammatory vasculopathies, such as isolated angiitis of the central nervous system and temporal arteritis, require prompt diagnosis as the mainstay of therapy is immunosuppression. Cerebral venous thrombosis is a rare cause of stroke, but one that needs early identification and treatment with anticoagulation. Rapid determination of stroke mechanism is essential for making these critical early treatment decisions.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0041-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3250267  PMID: 21556680
Nonthrombolytic stroke therapy; Cardioembolic stroke; Large-artery atherosclerosis; Arterial dissection; Inflammatory cerebral vasculopathy; Cerebral venous thrombosis
21.  Hemorrhagic Transformation of Childhood Arterial Ischemic Stroke 
Background and Purpose
To describe the occurrence of hemorrhagic transformation (HT) among children with arterial ischemic stroke (AIS) within 30 days after symptom onset and to describe clinical factors associated with HT.
Sixty-three children age 1 month to 18 years with AIS between January 2005 and November 2008 were identified from a single center prospective pediatric stroke registry. All neuroimaging studies within 30 days of stroke were reviewed by a study neuroradiologist. Hemorrhage was classified according to the European Cooperative Acute Stroke Study-1 definitions. Association of HT with clinical factors, systemic anticoagulation, stroke volume, and outcome was analyzed.
HT occurred in 19 of 63 children (30%; 95%CI 19–43%), only 2 (3%) of whom were symptomatic. Hemorrhage classification was HI1 in 14, HI2 in 2, PH1 in 2, and PH2 in 1. HT was less common in children with vasculopathy (RR 0.27; 95%CI 0.07–1.06; p=0.04) than in those with other stroke mechanisms. HT was not significantly associated with anticoagulation versus antiplatelet therapy (RR 0.6; 95%CI 0.2–1.5; p=0.26) but was associated with larger infarct volumes (p=0.0084). In multivariable analysis, worse PSOM scores were associated with infarct volume ≥5% of total supratentorial brain volume (OR 4.0; 95%CI 1.1–15; p=0.04), and a trend existed toward association of worse PSOM scores with HT (OR 4.0; 95%CI 0.9–18; p=0.07).
HT occurred in 30% of children with AIS within 30 days. Most hemorrhages were petechial and asymptomatic. Infarct volume was associated with HT and worse outcome.
PMCID: PMC3066279  PMID: 21350202
hemorrhagic transformation; arterial ischemic stroke; anticoagulation; pediatric
22.  Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) Study: Rationale and Design 
Over one third of ischemic strokes occur in the posterior circulation, a leading cause of which is atherosclerotic vertebrobasilar disease (VBD). Symptomatic VBD carries a high annual recurrent stroke risk, averaging 10–15% per year. Endovascular angioplasty and stenting are increasingly employed, but carry risks, and the benefit remains unproven. Determining stroke predictors in this population is critical to identifying high risk patients for future trials of intervention. Preliminary studies indicate that stroke risk in VBD is strongly related to hemodynamic compromise, which can be measured noninvasively using quantitative magnetic resonance angiography (QMRA).
Methods/Study Design
The VERiTAS Study, a prospective multi-center NIH funded observational study of symptomatic vertebrobasilar stenosis (≥ 50%) or occlusion, is designed to test the hypothesis that patients demonstrating compromised blood flow as assessed by QMRA are at higher stroke risk. The study will recruit 80 patients at 6 sites in North America over four years. Upon enrollment, subjects will undergo hemodynamic assessment with blinded QMRA to assess large vessel flow in the vertebrobasilar territory, and be prospectively designated as compromised or normal flow. Patients will be reimaged with QMRA at 6, 12 and 24 months, and followed for 12 to 24 months for the primary endpoint of stroke in the vertebrobasilar territory.
VERiTAS is the first prospective study of hemodynamics and stroke risk in the posterior circulation. The results may impact the selection criteria for interventional candidates and also define a low risk population in whom the risks of invasive interventions would be unnecessary.
PMCID: PMC3057649  PMID: 21050408
stroke; vertebrobasilar ischemia; magnetic resonance imaging; quantitative magnetic resonance angiography; blood flow
23.  Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study 
Background and Purpose
To describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study.
Single-center prospective consecutive cohort study of spontaneous ICH in children age 1-18 years from January 2006 to June 2008. Exclusion criteria were inciting trauma; intracranial tumor; isolated epidural, subdural, intraventricular, or subarachnoid hemorrhage; hemorrhagic transformation of ischemic stroke; and cerebral sinovenous thrombosis. Hospitalization records were abstracted. Follow-up assessments included outcome scores using the Pediatric Stroke Outcome Measure (PSOM) and King's Outcome Scale for Childhood Head Injury (KOSCHI). ICH volumes and total brain volumes (TBV) were measured by manual tracing.
Twenty-two patients, median age of 10.3 years (range 4.2-16.6 years), had presenting symptoms of headache in 77%, focal deficits 50%, altered mental status 50%, and seizures 41%. Vascular malformations caused hemorrhage in 91%. Surgical treatment (hematoma evacuation, lesion embolization or excision) was performed during acute hospitalization in 50%. One patient died acutely. At median follow-up of 3.5 months (range 0.3-7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on PSOM and KOSCHI scores was worse in patients with ICH volume >2% of TBV (p=0.023) and altered mental status at presentation (p = 0.005).
Spontaneous childhood ICH was due mostly to vascular malformations. Acute surgical intervention was commonly performed. Although death was rare, 71% of survivors had persisting neurological deficits. Larger ICH volume and altered mental status predicted clinically significant disability.
PMCID: PMC2821039  PMID: 20019325
intracerebral hemorrhage; outcome; childhood; vascular malformation
25.  Intracranial Vertebrobasilar Artery Dissection Associated with Postpartum Angiopathy 
Stroke Research and Treatment  2009;2010:320627.
Background. Cervicocephalic arterial dissection (CCAD) is rare in the postpartum period. To our knowledge this is the first reported case of postpartum angiopathy (PPA) presenting with ischemic stroke due to intracranial arterial dissection. Case. A 41-year-old woman presented with blurred vision, headache, and generalized seizures 5 days after delivering twins. She was treated with magnesium for eclampsia. MRI identified multiple posterior circulation infarcts. Angiography identified a complex dissection extending from both intradural vertebral arteries, through the basilar artery, and into both posterior cerebral arteries. Multiple segments of arterial dilatation and narrowing consistent with PPA were present. Xenon enhanced CT (Xe-CT) showed reduced regional cerebral blood flow that is improved with elevation in blood pressure. Conclusion. Intracranial vertebrobasilar dissection causing stroke is a rare complication of pregnancy. Eclampsia and PPA may play a role in its pathogenesis. Blood pressure management may be tailored using quantitative blood flow studies, such as Xe-CT.
PMCID: PMC2911601  PMID: 20700423

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