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Collateral Circulation Status as Assessed by MR-Perfusion Modulates Relationship Between Time and Development of FLAIR Signal


The exact time of symptom onset cannot be determined for up to a fourth of acute stroke patients. In such cases, clinicians often use magnetic resonance imaging (MRI), in particular a difference of signal intensities between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences to approximate the age of a lesion.  Cytotoxic edema appears minutes after stroke onset and can be visualized using DWI.  Comparing this to FLAIR, which can demonstrate the vasogenic edema that appears hours after stroke onset, the so-called DWI/FLAIR mismatch has been proposed as a predictor with regards to the 4.5h window for intravenous thrombolysis. However, the sensitivity of DWI/FLAIR mismatch between studies. These variations are in part explained by imaging techniques, but it is likely that pathophysiological variables such as collateral circulation significantly contribute as well. Wouters et al. sought to investigate the association between timing of DWI/FLAIR mismatch and collateral circulation using hypoperfusion intensity ratio (HIR), a measurement of perfusion weighted imaging (PWI) severity that has been shown to be a good predictor for poor collaterals.

The authors utilized clinical and neuroimaging data from the AXIS 2 trial, a multicenter Phase IIb placebo-controlled, randomized and double blinded trial investigating recombinant Granulocyte Colony Stimulating Factor in acute stroke. A total of 141 patients were included for analysis, excluding patients with incomplete imaging sequences, severe FLAIR lesions overlapping the acute lesion or in the contralateral hemisphere (as the contralateral hemisphere was used for FLAIR intensity measurement), or reperfused core. Quantitative relative FLAIR maps (rFLAIR) were calculated in a voxel-based manner using in house software. Collateral status assessed by HIR was dichotomized into “good” (n= 87, 61.7%) and “poor” (n= 54, 38.3%). Patients with poor collaterals had more severe stroke symptoms at baseline (NIHSS 14 vs NIHSS 11, p= 0.01), larger DWI lesion volumes (47.2 mL vs 14.6 mL, p= <0.01), and larger TMax > 6s perfusion volumes (91.5 mL vs 45.8 mL, p=0.01). 


The predictive value of time for rFLAIR intensity was moderate in patients with poor collateral circulation (R2 = 0.28), but poor in patients with good collateral circulation (R2 = 0.03). The relationship between time from onset to rFLAIR signal intensity was stronger in patients with poor collaterals compared to those with good collaterals (p for interaction = 0.04). In addition, a strong interaction between increased Tmax in the region of perfusion deficit (a measurement of hypoperfusion severity) on the association between time and rFLAIR intensity was identified (p=0.001).

This study reinforces the concept that the development of DWI/FLAIR mismatch as a marker for ischemia is dependent on the severity of hypoperfusion. The authors’ omission of digital subtraction angiography (DSA) in the study precludes a definitive association with collateral status, but as the authors note, the HIR technique that was utilized has shown to have good correlation with DSA-assessed collateral circulation. These findings also provide valuable insight into the relationship between collateral status and the timing of DWI/FLAIR mismatch which will prove useful for clinical trials using this assessment as a substitute for last known well in cases where this is unable to be determined from history. Based on these results, patients with good collateral circulation may be misidentified as having lesions <4.5h old. Whether these patients would receive the same benefit from intravenous thrombolysis as compared to patients with poor collaterals and younger lesions presents an interesting avenue for future research, as DWI/FLAIR mismatch may emerge as a viable alternative to time of last known well in determining progression of ischemia in the context of thrombolysis eligibility. 

Adherence to DASH Diet Associated With Lower Stroke Risk

Neal S. Parikh, MD

The Dietary Approaches to Stop Hypertension (DASH) diet is known reduce blood pressure in hypertensive and normotensive individuals. The authors assessed whether DASH diet adherence is associated with incident stroke.
The authors performed their analyses in two large, prospective Swedish cohorts of middle-aged to older men and women free of incident stroke.  The participants answered a 350-item questionnaire on diet and vascular risk factors in the late 1990s and were followed by linkage with the National Patient Register and the Cause of Death Register.
The exposure variable was a modified DASH diet score, assessed based on a validated food-frequency questionnaire. Covariates included standard demographics and vascular risk factors (hypertension, hyperlipidemia, diabetes, atrial fibrillation, smoking history, aspirin use, family history of myocardial infarction at early age, and body mass index).  Total caloric intake was included as a covariate, but dietary sodium was not. The outcome measure was incident stroke (ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage).  Participants were classified into quartiles based on their DASH diet score. Multivariate analyses were performed to test the association between DASH adherence and incident stroke.
Participants with high adherence to the DASH diet were fairly similar to participants with low adherence. The mean age was 60 years. Approximately 50% were overweight. Approximately 20% had hypertension, 10% had hyperlipidemia, and 6% had diabetes.  Over 882,727 person-years of follow-up, there were 3,896 ischemic strokes, 560 intracerebral hemorrhages, and 176 subarachnoid hemorrhages. High adherence to the DASH diet was associated with a lower risk of ischemic stroke and a trend towards lower risk of intracerebral hemorrhage. Participants in the highest quartile had a 14% lower risk of ischemic stroke than those in the lowest quartile.
This study adds to two prior studies that suggested that adherence to a DASH diet is associated with lower risk of stroke. The two prior studies and this study are likely underpowered for intracerebral hemorrhage and subarachnoid hemorrhage. The authors note that a similar association between the Mediterranean diet and stroke risk has been identified. Features shared by the DASH and Mediterranean diets may be responsible for lower stroke risk.  
The main limitations of this study are the observational design and the outdated cohort, which likely did not benefit from contemporary vascular risk factor management. However, in the context of prior studies, this study provides compelling evidence in support of a healthy diet for the prevention of stroke.
By |April 11th, 2016|prevention|1 Comment

IV-tPA Treatment Prior to Mechanical Thrombectomy Did Not Improve Outcome in a Retrospective Matched Analysis

Jay Shah, MD

Broeg-Morvay A, Mordasini P, Bernasconi C, Bühlmann M, Pult F, Arnold M, et al. Direct Mechanical Intervention Versus Combined Intravenous and Mechanical Intervention in Large Artery Anterior Circulation Stroke: A Matched-Pairs Analysis. Stroke. 2016

Recently, 5 trials have consistently shown that mechanical thromectomy (MT) improves outcomes in acute ischemia due to proximal occlusion within the anterior circulation. In these trials, rates of intravenous tissue-type plasminogen activator (IV-tPA) were similar among treatment and medical arms thus raising the question whether pre-treatment with IV-tPA is necessary. In this study, the investigators compared clinical outcomes and safety of direct MT alone versus bridging IV-tPA.

This retrospective study is based on a stroke registry that registered stroke patients across a 5 year span. In total, 156 patients were treated with bridging tPA and 239 with direct MT. 40 patients within the latter group had no contraindications to IV-tPA but were opted for direct MT therapy. These patients were matched with patients receiving bridging therapy. Clinical outcomes at three months did not differ between groups; however, there was a trend toward better improvement in the direct MT group. While the rate of symptomatic hemorrhage did not differ, there was higher rates of asymptomatic hemorrhage in the bridging group. Lastly, recanalization and reperfusion rates were similar in both groups.

This study raises an interesting clinical question. Certainly, IV-tPA has been the standard of care for acute ischemic stroke patients. However, in the current new era of endovascular intervention, its role has been questioned in patients who qualify for MT. The majority of patients within the 5 randomized trials did receive IV-tPA per standard practice. Thus, guidelines have recommended to treat with IV-tPA if patients are eligible. tPA can usually be administered quicker and may aid in recanalization. However, recanalization rates of large vessel occlusions are poor and these patients will require MT. IV-tPA treatment in this group, as this study points out, does not improve clinical outcome and may increase rate of hemorrhage. This study was a retrospective study and the number of patients are relatively small. The reason for excluding IV-tPA to the 40 eligible patients is not clear and thus subject to selection bias. tPA may recanalize small vessels particularly within the penumbra and this may be important until recanalization of the proximal occluded artery can be achieved. From a practical standpoint, most hospitals are not endovascular-capable and thus need to transported to a comprehensive stroke center leading to an extensive time difference between tPA administration and MT. Therefore, IV-tPA use should follow current established guidelines. However, future prospective trials should address bridging IV-tPA in combination with MT.

By |April 8th, 2016|treatment|0 Comments

Streamlined Hyperacute MRI Identifies tPA Eligible Stroke Patients Among Stroke Mimics

Peggy Nguyen, MD

Goyal MS, Hoff BG, Williams J, Khoury N, Wiesehan R, Heitsch L, et al. Streamlined Hyperacute Magnetic Resonance Imaging Protocol Identifies Tissue-Type Plasminogen Activator–Eligible Stroke Patients When Clinical Impression Is Stroke Mimic. Stroke. 2016

Despite advances in imaging, the radiologic component of the tPA decision-making is predicated on a non-contrast CT head, guided by the clinical history and exam. Sometimes, however, the clinical exam or history can be confusing and the CT scan does not provide much additional diagnostic data; stroke mimics make up anywhere between 1-16% of the patients presenting with stroke-like symptoms at large institutions. The use of a hyperacute MRI (hMRI) can help differentiate strokes from stroke mimics, and potentially minimize tPA given to mimics and, perhaps more importantly, ensure that tPA is not withheld from patients who are suspected to be mimics, but are actually strokes.

Here, the authors report an institution-specific streamlined hMRI protocol in the setting of acute stroke. The hMRI protocol described here provides DWI/ADC, FLAIR, and T2*GRE sequences in just under 6 minutes. In order to avoid overutilization, physicians were instructed to order the hMRI only when the initial diagnostic impression was likely stroke mimic, but ischemic stroke could not be entirely ruled out and, if MRI was not available at their institution, the physician would not give the patient tPA. 57 patients, identified as stroke mimics, underwent the hMRI protocol, with 11 having the final diagnosis of stroke, 4 with the final diagnosis of TIA, and the remaining diagnoses being conversion disorder, seizure, complicated migraine, and other. Seven of the 11 stroke patients received IV tPA. There were no differences in door-to-needle, onset-to-needle, or door-to-arrival times for all IV tPA treated patients pre- and post-hMRI; however, the door-to-needle time for tPA treated patients screened with CT alone were significantly shorter than the 7 tPA patients screened with hMRI (37 minutes vs 112 minutes).

Although the overall metrics (door to needle, onset to needle, etc) did not change much with the institution of hMRI protocol, likely due to the minority of patients who went on to receive tPA under the protocol, using the hMRI protocol did lead to substantially longer door-to-needle times for patients who received tPA. However, longer door-to-needle times are preferable than withholding tPA, and it is probable that these patients, having been initially identified as stroke mimics, would not have received tPA otherwise. The use of a hMRI does have its limitations, given it is not widely available and many institutions may not have the resources to staff it emergently, but in institutions where the resources are available, it could potentially increase tPA usage to patients with strokes and decrease tPA usage to patients without strokes.

Small Vessel Disease is Associated With a Worse Outcome After Intracranial Hemorrhage

Neal S. Parikh, MD


Question & Rationale
Small vessel disease (SVD), as reflected by white matter lesions (WML), brain atrophy and lacunar strokes, is associated with hypertension and possibly abnormal autoregulation. The INTERACT 2 investigators therefore hypothesized that SVD is associated with a poor outcome after intracranial hemorrhage (ICH) and investigated whether this association is mediated by intensive blood pressure lowering in ICH treatment.
Cohort
The INTERACT2 cohort was used for this study. In this international, multicenter, open, blinded endpoint, randomized trial, patients with spontaneous ICH were randomized within 6 hours to SBP<140 versus SBP<180. The cohort did not include patients with pre-existing advanced dementia or disability.

Exposures, Outcomes, and Covariates

There were three measures of SVD on baseline CT: WML, atrophy, and lacunar strokes. On baseline CT, WML were graded by the van Swieten scale.  Atrophy was measured by linear measurements (frontal ratio, third ventricle Sylvian fissure distance) and visual inspection. Lacunar stroke was defined as a round/ovoid cavity of 3-15 millimeters in diameter. The outcome was defined as 90 days death or major disability. Interaction term analysis was used to determine effect of intensive BP lowering on outcome. 

Covariates were age, gender, location, history of ischemic stroke, hypertension, diabetes, use of anti-thrombotic and lipid lowering agents, onset to randomization time, systolic BP, NIHSS, volume/location of hematoma, and intraventricular extension.

Findings
In crude and adjusted regression analyses, measures of WML and atrophy were associated with death or major disability. Lacunar stroke was not associated with the outcome in crude or multivariate models. High intensity BP lowering did not result in excess poor outcomes in patients with evidence of SVD.

Limitations
There was only fair-moderate intra-class correlation for WML, brain atrophy, and especially lacunes. Additionally, the study was not pre-specified and therefore subject to type I error. Last, pre-ICH cognitive and physical disability were not rigorously assessed; however, this is compatible with clinical practice – it is often not possible to thoroughly assess a patient’s pre-ICH function at the time of ICH.

Conclusions
Pre-existing SVD burden may be associated with poor outcome after ICH, and this relationship is not mediated by intensity of blood pressure control. Therefore, these data allay fears regarding intensive BP management after ICH in patients with sequela of chronic hypertension such as SVD. 

Meta-Analysis Concludes Utility of CTA Spot Sign is Dependent Upon Timing and is Not Sufficient to Predict Hematoma Expansion in Acute ICH

Danny R. Rose, Jr., MD

Dowlatshahi D, Brouwers HB, Demchuk AM, Hill MD, Aviv RI, Ufholz L-A, et al. Predicting Intracerebral Hemorrhage Growth With the Spot Sign: The Effect of Onset-to-Scan Time. Stroke. 2016

Intracerebral hemorrhage (ICH) causes a significant amount of stroke-related morbidity and mortality. Of the various prognostic factors in ICH, hematoma expansion is one of the few potentially modifiable ones and as such has been a topic of increasing research. Unfortunately, large-scale randomized controlled trials aimed at preventing hematoma expansion have not shown robust results, possibly owing to the limited ability of clinicians to predict which patients are at greatest risk. One of the more promising diagnostic features in identifying such patients is the “spot sign” of contrast extravasation in the hematoma bed of ICH patients undergoing CT angiography (CTA). However, the predictive value of the spot sign has differed widely across studies, which may reflect variability in delay between ictus and CTA acquisition. Dowlatshahi et al. sought to examine the predictive value of the spot sign in relationship to onset-to-CTA times in patients with acute ICH by conducting a systematic review and patient-level meta-analysis.

The authors found eight studies in which patient-level data was able to be obtained regarding spot sign status, baseline and follow-up hematoma volumes and time from onset to presentation and CTA. Onset-to-CTA time was categorized a priori into five strata: <120 minutes, 120-239 minutes, 240-359 minutes, 360-479 minutes, and >480 minutes.  Hematoma size was measured by computer-assisted planimetry in three studies and the ABC/2 in five studies. A total of 1343 patients were evaluated across the eight studies, with 1176 having baseline hematoma volumes, spot sign status and time-to-CTA, 1039 of whom had follow-up hematoma volume measurements. 
There was significant heterogeneity of spot sign frequency among the studies (I2 = 20.67, p=0.004), due to heterogeneity in the 0-2h (I2 = 15.5, p=0.016) and the 2-4h stratas (I2 = 16.5, p=0.011). There was no heterogeneity for the later time strata. The frequency of the spot sign was 26% for the group as a whole with a significant relationship with onset-to-CTA time strata (p<0.001), decreasing from 39% within two hours of onset to 13% after eight hours. There was no heterogeneity in hematoma expansion between studies (F=0.45, p=0.87) or time strata (F=0.75, p=0.56). Across all time intervals, the median volume of hematoma expansion was greater for spot positive as compared to spot negative patients, and there was no change in median hematoma expansion by time-strata in spot positive patients (F=1.28, p=0.14). Spot positivity and significant hematoma expansion (defined as 6mL or ≥33%) as onset-to-CTA time strata increased. Sensitivity and PPV of the spot sign for hematoma expansion was greatest in the earlier time strata, whereas the specificity and negative predictive value (NPV) of spot sign increased with time. 

This study suggests that the utility of spot sign assessment may be dichotomized depending on onset-to-CTA time. The earlier time strata had the highest sensitivity and PPV which both decreased with time, and the later time strata suggested a high specificity and NPV. Identifying patients at risk for hematoma expansion as well as patients who likely have stable hematomas are both of value to clinicians, and understanding this information in the context of CTA timing suggests clinically relevant information can be gleaned regardless of the time of onset-to-CTA. Even in the acute setting, however, the best sensitivity to detect hematoma expansion was only 60%. This suggests that the spot sign alone is insufficient to identify at-risk patients and should be incorporated into future studies designed to identify other potential predictive factors. As the authors were unable to include any studies published after 2013 due to the time needed to acquire regulatory approvals for patient-level data, analysis of more recent studies would be helpful to validate these results.

Intra-Arterial Therapy, Post-Treatment Infarct Volumes, and Functional Outcomes in the ESCAPE Trial

Peggy Nguyen, MD

Al-Ajlan FS, Goyal M, Demchuk AM, Minhas P, Sabiq F, Assis Z, et al. Intra-Arterial Therapy and Post-Treatment Infarct Volumes: Insights From the ESCAPE Randomized Controlled Trial. Stroke. 2016

Outcome measurements in stroke trials commonly use measurements such as the mRS, NIHSS, or Barthel index as surrogates of functional improvement; the primary outcome measurement in the ESCAPE trial was the commonly used 3-month mRS. However, the relationship between outcomes at the functional level versus outcomes at a radiologic or anatomical level are not always delineated. Here, the authors perform a post-hoc analysis of the ESCAPE trial data, to evaluate the effect of IAT on saving brain tissue, and secondarily analyzed (1) clinical and imaging variables at baseline associated with post treatment infarct volume as well (2) the relationship between post treatment infarct volume and the 3-month mRS.

In the ESCAPE trial, the median post treatment infarct volume in the IAT group was significantly
lower than the control group (15.5 mL vs 33.5 mL, p < 0.01). Similarly, regardless of the intervention, successful recanalization in both groups was associated with smaller infarct volumes (14.5 mL vs 35 mL, p < 0.01). Baseline variables that were independently associated with smaller post treatment infarct volume were baseline NIHSS, site of occlusion, baseline ASPECTS and recanalization status, while age, sex, treatment type, IV tPA and time from onset to randomization were not. Post treatment infarct volume was found to strongly predict the 3-month mRS, particularly when including the change from baseline NIHSS.

Some interesting points came out of this study. The results reinforce the finding that recanalization, regardless of intervention, is a significant predictor of smaller infarct volumes. Interestingly, age had no interaction with the infarct volumes; one of the current debates in the stroke world these days is the benefit of IAT in older populations and this finding seems to suggest that age might not be a criteria for intervention if other variables are equal. Thirdly, the association of post treatment infarct volume with 3-month mRS was strongest when modeled with the change in baseline NIHSS, which makes sense, given large strokes in silent areas do not necessarily lead to better (or worse) outcomes, and small strokes in eloquent areas may have small post-treatment infarct volumes, but poor functional outcomes. This last finding, in a roundabout way, reinforces the utility of functional measures, such as mRS or Barthel index as outcome measures for clinical trials, rather than anatomical or radiological markers. 
By |April 4th, 2016|treatment|0 Comments

Silent Brain Infarctions Are Associated With an Increased Risk of Future Stroke

Neal S. Parikh, MD



Citing the potential utility of silent brain infarcts (SBI) as both a possible stroke risk factor and a surrogate outcome in stroke trials, Dr. Gupta and colleagues performed a systematic review and meta-analysis to evaluate the precise association between SBI and subsequent stroke.

The authors selected studies of adults who had baseline MRI-ascertained SBI and at least 12 months of follow-up for clinical stroke. Studies were vetted and abstracted in a rigorous, pre-specified manner. Meta-analyses were performed with random effects modelling, which controls for occult heterogeneity between individual study samples. The risks of selection bias and publication bias were assessed and found to be low.

Thirteen studies were ultimately included. All studies defined SBI as T2 hyperintense lesions at least three millimeters in size, with various methods employed to distinguish SBI from leukoaraiosis and dilated perivascular spaces. Clinical ischemic stroke was typically defined as a neurological deficit lasting greater than 24 hours in the absence of hemorrhage. Not all studies distinguished between ischemic and hemorrhagic stroke.

A total of 14,764 subjects were included, and the mean follow-up for clinical stroke was 76 months. Most subjects were middle-aged or elderly. 3,007 (20%) had SBI on MRI. The crude relative risk of clinical stroke in patients with SBI was 2.94 (95% confidence interval (CI), 2.24-3.86). Eight of the 13 studies provided covariate-adjusted hazard ratios (HR); the aggregate adjusted HR was 2.08 (95% CI, 1.69-2.56).

Subgroup analyses found that the association between SBI and subsequent stroke was present in both stroke-free community-dwelling patients and in patients with prevalent stroke. In both groups, patients with SBI experienced a two-fold increased risk of subsequent stroke.

The major limitations of their study are: variable definitions of SBI as diagnosed on MRIs of variable magnetic field strength, variable inclusion of relevant covariates, inconsistent reporting of ischemic versus hemorrhagic stroke, non-tissue based definition of ischemic stroke, and outdated cohorts (e.g. not subject to contemporary maximum medical therapy of vascular risk factors). These limitations do not, on the whole, negate the study’s findings.

There appears to be a clear, positive association between SBI and subsequent stroke. In current clinical practice, incidental SBIs do not prompt thorough stroke mechanism evaluation or personalized secondary prevention. Our evolving understanding of this entity will surely impact our practice patterns.

Clear and Robust Benefit From Solitaire Stent Retriever in Acute Ischemic Stroke: Pooled Analysis From 4 Clinical Trials

Jay Shah, MD

Campbell BCV, Hill MD, Rubiera M, Menon BK, Demchuk A, Donnan GA, et al. Safety and Efficacy of Solitaire Stent Thrombectomy: Individual Patient Data Meta-Analysis of Randomized Trials. Stroke. 2016

The five positive endovascular trials in acute ischemic stroke have revolutionized the management of acute cerebral ischemia and established endovascular revascularization as standard of care in eligible patients. However, there were differences in device type and procedures in the trials. Thus, the authors of all trials agreed to pool patient data in order to potentially detect subgroup differences. In this study, data from 4 trials (SWIFT PRIME, ESCAPE, EXTEND-IA, and REVASCAT) were pooled to examine treatment effects in patients specifically treated with Solitaire stent retriever. The primary outcome was degree of disability at 90 days as evaluated by modified rankin scale (mRS). 

In total, 787 anterior circulation ischemic strokes were included and 401 were randomized to thrombectomy. The odds ratio for improvement in mRS was 2.7 with a number needed to treat of 2.5 patients to improve at least one level on the mRS. There was benefit in secondary outcomes as well such as early neurological recovery. These benefits were consistent across various patient characteristics such age, gender, stroke severity, site of occlusion, presence of tandem cervical carotid occlusion, ASPECT score, and time to randomization. 

There is clear benefit to endovascular intervention in patients with acute ischemic stroke. The benefit is likely a direct result of recanalization and reestablishing perfusion rather than a direct effect of the device itself. With increasing experience, the use of stent retrievers such as Solitaire will likely increase and patient selection will broaden. The subgroup analysis of this study suggests that patients >80 age showed benefit and age should not be sole exclusion criterion. Similarly, there was equal benefit in “low” stroke scale < 15 compared to >20 although decision to intervene on NIHSS < 6 should be made on an individual basis as the trials had very few patients within this category. Lastly, similar to IV-tPA, there is a declining probability of good outcome with time so once a treatment decision is made in an expedited but judicious manner, the focus should then tailor to minimizing delays. However, clinical utility in patients with low ASPECT scores and poor collaterals is unclear and should be addressed in future trials. 

By |March 31st, 2016|treatment|0 Comments

Cortical Venous Filling in Dynamic CTA Predicts Clinical Outcome in Proximal MCA Occlusion

Danny R. Rose, Jr., MD


As the scope and availability of endovascular treatment for large vessel occlusions in patients with ischemic stroke continues to increase, it is important for providers to have the ability to screen and predict which patients will benefit from these therapies. The most effective approach has been a topic of much debate and research, including utilizing ancillary testing to account for individual variations in collateral circulation and other factors that could potentially extend treatment indications and predict outcomes. Nearly all endovascular treatment trials use some combination of noncontrast head CT (NCCT), CT angiography (CTA) and/or CT perfusion (CTP) imaging to assist in clinical decision making due to the speed and availability of such scans. However, recent studies found that the currently utilized modalities may be insufficient to predict treatment effect or outcome. Wijngaard et al. sought to use cortical venous filling (CVF), a potential marker for collateral extent and perfusion, to assess whether the  extent or velocity of CVF as obtained through dynamic CTA predicts clinical outcome at 3 months in ischemic stroke patients with proximal middle cerebral artery occlusion.

All patients received a NCCT evaluated for early ischemic changes (ASPECTS); CTP/CTA was used for clot burden score, collateral status, cerebral-blood-flow (CBF), cerebral-blood-volume (CBV), mean-transit-time (MTT) and time-to-peak (TTP). Using the dynamic CTAHo, CVF was assessed visually—cortical venous contrast opacification and the number of cortical and anastomotic veins were evaluated in comparison with the contralateral hemisphere. The number of seconds to reach first CVF (appearance of any cortical vein draining into the superior sagittal sinus), optimal CVF (maximum contrast opacification of all cortical veins), and end of venous filling (complete absence of contrast) was measured. The velocity of CVF was calculated as the median differences between venous filling of the affected versus non-affected hemisphere. In addition, the extent of CVF was defined as either “good” or “poor,” based on comparing the extent of cortical vein filling at optimal CVF with the unaffected hemisphere using 50% as a cutoff.

A total of 88 patients were selected from two Dutch medical centers from previously published studies (DUST and MR-CLEAN). The mean age of participants was 67 years; median NIHSS was 15 and 50% of the participants were women. The median time from onset to imaging was 77 minutes. Most patients (59%) were treated with IV thrombolysis alone, with 25% of patients receiving intra-arterial therapy. At 3 months, 54 patients (61%) had a poor clinical outcome (mRS 3-6), and 22 of 88 patients (25%) had died. Venous predictors of poor outcome at 3 months were: poor extent of optimal CVF (RR 1.8; 95% CI 1.4-2.4) and slow velocity of optimal CVF (RR 1.6; 95% CI 1.1-2.2). Logistic regression models were utilized, using a layered approach in which successive models included more variables. Model 1 included age, NIHSS, treatment and ASPECT score, model 2 included CBF, model 3 included collateral status, and model 4 included extent and velocity of CVF. The addition of venous filling parameters resulted in a significant (p<0.02) improvement in prediction of clinical outcome. Although only 22 patients underwent mechanical thrombectomy, good CVF parameters (good extent and fast CVF) predicted good clinical outcomes in patients with mTICI 2b and 3 reperfusion (RR 3.3; 95% CI 1.1-10.6, p<0.05), compared with patient groups with poor CVF and/or poor perfusion status combined.

This study represents a novel use of venous filling parameters in predicting clinical outcome after ischemic stroke, resulting in a more accurate prediction when used in combination with previously studied measures. Based on these preliminary findings, one of the more promising applications may be its utility in predicting treatment effect of mechanical thrombectomy, but the small number of patients examined requires evaluation in a larger, prospective trial. If supported in additional research, CVF has the potential to become an important part in future trial design with respect to selecting patients for endovascular intervention. The authors’ choice to utilize dynamic CTA, however, limits its widespread application, as the more ubiquitous single-phase CTA cannot obtain time-resolved measurements. Parameters designed for use in single-phase CTA could be evaluated in a future study for its potential utility in facilities without dynamic CTA.