Alessandro Adami

Relationship between severity of MR perfusion deficit and DWI lesion evolution

Objective: To assess whether a quantitative analysis of the severity of the early perfusion deficit on MRI in acute ischemic stroke predicts the evolution of the perfusion/diffusion mismatch and to determine thresholds of hypoperfusion that can distinguish between critical and noncritical hypoperfusion. Methods: Patients with acute ischemic stroke were studied in whom perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI MRI) were performed within 7 hours of symptom onset and again after 4 to 7 days. Patients with early important decreases in points on the NIH Stroke Scale were excluded. Maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were created. These hemodynamic parameters were correlated with the degree of recruitment of the baseline PWI lesion by the DWI lesion. Results: Twelve patients had an initial PWI > DWI mismatch of >20%. A linear relationship was observed between the initial MTT and the degree of recruitment of the baseline PWI lesion by the DWI lesion at follow-up (R2 = 0.9, p < 0.001). Higher CBV values were associated with higher degrees of recruitment (ρ = 0.732, p < 0.007). The volume of MTT of >4 (R2 = 0.86, p < 0.001) or >6 seconds (R2 = 0.85, p < 0.001) predicted final infarct size. Conclusion: Among patients who have had an acute stroke with PWI > DWI, who do not have dramatic early clinical improvement, the degree of expansion of the initial DWI lesion correlates with the severity of the initial perfusion deficit as measured by the mean transit time and the cerebral blood volume.

Relationship Between Apparent Diffusion Coefficient and Subsequent Hemorrhagic Transformation Following Acute Ischemic Stroke

Background and Purpose A method for identifying patients at increased risk for developing secondary hemorrhagic transformation (HT) after acute ischemic stroke could be of significant value, particularly in patients being considered for thrombolytic therapy. We hypothesized that diffusion-weighted MRI might aid in the identification of such patients. Methods We retrospectively analyzed 17 patients with ischemic stroke who received diffusion-weighted MRI within 8 hours of symptom onset and who also received follow-up neuroimaging within 1 week of initial scan. The apparent diffusion coefficient (ADC) for each pixel in the whole ischemic area was calculated, generating a histogram of values. Areas subsequently experiencing HT were then compared with areas not experiencing HT to determine the relationship between ADC and subsequent HT. Results A significantly greater percentage of pixels possessed lower ADCs (≤550×10−6 mm2/s) in HT lesions compared with non-HT lesions (47% versus 19%;P <0.001). Moreover, >40% of the pixels possessed values ≤550×10−6 mm2/s in all lesions experiencing secondary HT, compared with <31% of the pixels in the non-HT-destined lesions. Conclusions HT-destined stroke regions possess a significantly great percentage of low ADC values than non-HT-destined regions. Early measurement of ADC values may be a useful tool for assessing secondary HT risk.

Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third international stroke trial (IST-3): Secondary analysis of a randomised controlled trial

Summary Background Brain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase. Methods IST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0–2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518. Findings 3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55–0·81), large lesion (0·51, 0·38–0·68), swelling (0·59, 0·46–0·75), hyperattenuated artery (0·59, 0·47–0·75), atrophy (0·74, 0·59–0·94), and leukoaraiosis (0·72, 0·59–0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18–2·51), tissue hypoattenuation (1·54, 1·04–2·27), and hyperattenuated artery (1·54, 1·03–2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9–20·7; both signs absent, excess 3·2%, 1·4–5·1). However, no imaging findings—individually or combined—modified the effect of alteplase on independence or symptomatic intracranial haemorrhage. Interpretation Some early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke. Funding UK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental and philanthropic national funders.

Right-to-left shunt does not increase white matter lesion load in migraine with aura patients

Background: White matter lesions (WMLs) are commonly found on brain MRI of migraine patients. Migraine with aura (MA+) is associated with an increased frequency of right-to-left shunt (RLS) mostly due to patent foramen ovale. The relationship between WML load and RLS in MA+ is currently unknown. Methods: MA+ patients were consecutively enrolled as part of the Shunt Associated Migraine (SAM) study. Patients underwent a standardized headache and vascular risk factors questionnaire, contrast-enhanced transcranial Doppler, blood coagulation tests, and brain MRI. RLS was categorized into four grades: no shunt, <10 microbubbles (mb), >10 mb single spikes pattern, and >10 mb shower/curtain pattern. Standard and fluid-attenuated inversion recovery T2-weighted MRI sequences were inspected for WMLs by three independent raters blinded to RLS grade. WML load was scored in the periventricular areas (PV-WMLs) with the Fazekas scale and in the deep white matter (D-WMLs) with the Scheltens scale. Interobserver agreement was good to excellent (κ = 0.64 to 0.96, p < 0.0001). WML load was then correlated between patients with and without RLS. Results: One hundred eighty-five patients (77% women) were included. PV-WML load was similar between patients with and without RLS. D-WML load decreased in patients with RLS (p = 0.045). On logistic regression analysis, only age was associated with WMLs (p < 0.001). Conclusions: The presence of right-to-left shunt does not increase white matter lesion load in patients who have migraine with aura.

Predictors of Migraine Subtypes in Young Adults With Ischemic Stroke: The Italian Project on Stroke in Young Adults

Background and Purpose— The mechanisms underlying the relationship between migraine and ischemic stroke remain uncertain. The aim of the present study was to investigate the predictive value of major cardiovascular risk factors, cardiac interatrial abnormalities, and additional biological markers on migraine subtypes in young adults with ischemic stroke. Methods— Ischemic stroke patients aged 45 years or younger were consecutively enrolled as part of the Italian Project on Stroke in Young Adults. A comprehensive evaluation was performed including assessment of self-reported migraine and cardiovascular risk factors, interatrial right-to-left shunt, and genotyping to detect factor V Leiden and the G20210A mutation in the prothrombin gene. Results— Nine hundred eighty-one patients (mean age, 36.0±7.6 years; 50.7% women) were included. The risk of migraine with aura increased with decreasing number of cardiovascular risk factors (OR, 0.50; 95% CI, 0.24–0.99 for 2 factors or more), increasing number of thrombophilic variants (OR, 2.21; 95% CI, 1.05–4.68 for carriers of at least 1 of the 2), and the presence of right-to-left shunt (OR, 2.41; 95% CI, 1.37–3.45), as compared to patients without migraine. None of these factors had influence on the risk of migraine without aura. Conclusions— In young adults with ischemic stroke, low cardiovascular risk profile, right-to-left shunt, and an underlying procoagulant state are predictors of migraine with aura. The biological effects of these factors should be considered in future studies aimed at investigating the mechanisms linking migraine to brain ischemia.

Predictors of Long-Term Recurrent Vascular Events After Ischemic Stroke at Young Age The Italian Project on Stroke in Young Adults

Background— Data on long-term risk and predictors of recurrent thrombotic events after ischemic stroke at a young age are limited. Methods and Results— We followed 1867 patients with first-ever ischemic stroke who were 18 to 45 years of age (mean age, 36.8±7.1 years; women, 49.0%), as part of the Italian Project on Stroke in Young Adults (IPSYS). Median follow-up was 40 months (25th to 75th percentile, 53). The primary end point was a composite of ischemic stroke, transient ischemic attack, myocardial infarction, or other arterial events. One hundred sixty-three patients had recurrent thrombotic events (average rate, 2.26 per 100 person-years at risk). At 10 years, cumulative risk was 14.7% (95% confidence interval, 12.2%–17.9%) for primary end point, 14.0% (95% confidence interval, 11.4%–17.1%) for brain ischemia, and 0.7% (95% confidence interval, 0.4%–1.3%) for myocardial infarction or other arterial events. Familial history of stroke, migraine with aura, circulating antiphospholipid antibodies, discontinuation of antiplatelet and antihypertensive medications, and any increase of 1 traditional vascular risk factor were independent predictors of the composite end point in multivariable Cox proportional hazards analysis. A point-scoring system for each variable was generated by their &bgr;-coefficients, and a predictive score (IPSYS score) was calculated as the sum of the weighted scores. The area under the receiver operating characteristic curve of the 0- to 5-year score was 0.66 (95% confidence interval, 0.61–0.71; mean, 10-fold internally cross-validated area under the receiver operating characteristic curve, 0.65). Conclusions— Among patients with ischemic stroke aged 18 to 45 years, the long-term risk of recurrent thrombotic events is associated with modifiable, age-specific risk factors. The IPSYS score may serve as a simple tool for risk estimation.

Is migraine associated with right-to-left shunt a separate disease? Results of the SAM study

Migraine with aura (MA) is associated with the persistence of patent foramen ovale (PFO) in about 50% of cases, and migraineurs tend to have larger shunts than controls, suggesting that right-to-left shunt (RILES) determined by PFO could play a role in triggering migraine attacks. Moreover, some preliminary reports have suggested that PFO closure may give relief to both migraine and aura attacks. The aim of this study was to clarify if shunt-associated migraine (SAM) has clinical features that allow a distinction from shunt-unrelated migraine (SUM), in a prospective, multicentre, observational study (SAM study). We enrolled consecutive MA patients, who underwent a structured, standardized questionnaire for family and personal history and for detailed migraine features. All were systematically screened for RILES with transcranial Doppler, and for coagulation disorders. Overall, 460 patients were included; the SUM and SAM classes comprised 58% and 42% of patients, respectively. SAM patients were significantly younger (34.1 ± 10 vs. 37.1 ± 11 years), had a more frequent family history of migraine (76% vs. 66%) and a higher frequency of sensory symptoms of aura (51% vs. 41%); by contrast, there was a lesser association of SAM with other cardiac abnormalities and with coagulation disorders. The SAM study suggests that the effect of RILES on migraine features is not relevant. The higher family history of migraine in SAM suggests a possible genetic linkage between migraine and RILES.

Cerebral distribution of white matter lesions in migraine with aura patients

Objective: The objective of the study was to compare the cerebral distribution of white matter lesions (WMLs) between migraine patients with different aura symptoms. Methods: Migraine with aura (MA) patients were consecutively enrolled as part of the Shunt-Associated Migraine (SAM) study. According to clinical symptoms, aura was classified as motor, aphasic, sensory, visual or vertebrobasilar. Standard and FLAIR (fluid attenuated inversion recovery) T2-weighted MRI sequences were inspected for WMLs by three independent raters blinded to clinical data. WMLs were assessed in the periventricular areas (PV-WMLs) with the Fazekas scale and in the deep white matter (D-WMLs) with the Scheltens scale. Interobserver agreement was good to excellent (k = 0.64 to 0.96, p < .0001). Results: One hundred and eighty-five patients (77% women) were included. Aura symptoms were classified as visual in 172 (99%) patients, sensory in 76 (42%), aphasic in 54 (30%), motor in 39 (21%) and vertebrobasilar in 17 (9%) patients. One hundred and four patients (57%) exhibited more than one type of aura. D-WMLs were mainly detected in the frontal lobes (86%). There was no association between type of aura and the presence of WMLs in any cerebral location. Conclusion: Aura symptoms do not influence the cerebral distribution of WMLs associated with migraine disease.

Use of diffusion weighted MRI to predict the occurrence and severity of hemorrhagic transformation in a rabbit model of embolic stroke

Severe hemorrhagic transformation (HT) is an important complication of thrombolytic therapy. A method to identify stroke victims destined to severe HT could improve the patient selection and thus the safety of such treatment. In this study, we investigated whether very early serial diffusion weighted magnetic resonance imaging (DWI) could predict the occurrence of HT in an embolic model of experimental stroke. We tested the hypothesis that the ischemic brains with very low initial apparent diffusion coefficients (ADC) are destined to severe early (<or=5.5 h) HT. We retrospectively analyzed DWI scans of 45 New Zealand white rabbits subjected to thromboembolic stroke and treated with thrombolysis. DWI was obtained 0.5, 2, 3 and 5 h after embolization. Various thrombolytics were administered 1 h post embolization. The percentage of pixels within the ischemic hemisphere with ADC values below 550 x 10(-6) mm(2)/s was calculated and then compared to the severity of HT observed on gross brain sections at 5.5 h. As early as 30 min after embolization, ischemic brains destined to severe HT exhibited a significantly greater percentage of pixels below the cut-off value compared to those without HT: severe HT: 25%, 18.75-37.25% vs. no HT: 12%, 5.00-16.00% (median, 25th-75th %, P<0.001). Petechial HT when percentages were in the intermediate range. Quantitative analysis of initial ADC value might identify individual stroke patients at risk of severe HT.

Glyceryl Trinitrate for Acute Intracerebral Hemorrhage: Results From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial, a Subgroup Analysis.

Background and Purpose— The Efficacy of Nitric Oxide in Stroke (ENOS) trial found that transdermal glyceryl trinitrate (GTN, a nitric oxide donor) lowered blood pressure but did not improve functional outcome in patients with acute stroke. However, GTN was associated with improved outcome if patients were randomized within 6 hours of stroke onset. Methods— In this prespecified subgroup analysis, the effect of GTN (5 mg/d for 7 days) versus no GTN was studied in 629 patients with intracerebral hemorrhage presenting within 48 hours and with systolic blood pressure ≥140 mm Hg. The primary outcome was the modified Rankin Scale at 90 days. Results— Mean blood pressure at baseline was 172/93 mm Hg and significantly lower (difference −7.5/−4.2 mm Hg; both P⩽0.05) on day 1 in 310 patients allocated to GTN when compared with 319 randomized to no GTN. No difference in the modified Rankin Scale was observed between those receiving GTN versus no GTN (adjusted odds ratio for worse outcome with GTN, 1.04; 95% confidence interval, 0.78–1.37; P=0.84). In the subgroup of 61 patients randomized within 6 hours, GTN improved functional outcome with a shift in the modified Rankin Scale (odds ratio, 0.22; 95% confidence interval, 0.07–0.69; P=0.001). There was no significant difference in the rates of serious adverse events between GTN and no GTN. Conclusions— In patients with intracerebral hemorrhage within 48 hours of onset, GTN lowered blood pressure was safe but did not improve functional outcome. Very early treatment might be beneficial but needs assessment in further studies. Clinical Trial Registration— URL: http://www.isrctn.com/ISRCTN99414122. Unique identifier: 99414122.