American Heart Association

Monthly Archives: April 2016

Is Anticoagulation Safe in ENT/CNS Infection Associated Central Venous Thrombosis?

Alexander E. Merkler, MD

Head and Neck Infections are not uncommonly associated with central venous thrombosis (CVT). Previous studies claimed that in as many as 60% of cases of CVT, there is an associated ENT or CNS infection, although more recent publications state that the rates of associated infections are much less, likely due to improved antibiotic treatment. Despite the presence of intracerebral hemorrhage, CVT is typically treated with anticoagulation. On the other hand, there is insufficient evidence to support treatment with anticoagulation for CVT due to or associated with a concurrent head or neck infection.

In the current study, Dr. Zuurbier et al. assess the differences between CVT patients with and without concurrent head or neck infection. In addition, the authors assess the use and effect of anticoagulation in patients with CVT and concurrent infection. This study data was collected as part of the prospectively gathered International Study on Cerebral Venous and Dural Venous Thrombosis (ISCVT) which included 624 adults with CVT.

Out of the 624 patients with CVT, 77 patients had an infection. Twenty had an infection outside of the head or neck and were excluded. Thus, out of the 600 patients that remained, 57 patients had a head or neck infection, out of which an ENT infection (mastoiditis) was the most common. Thirteen (22.8%) had a CNS infection. As compared to patients without an infection, cavernous sinus thrombosis was more common in patients with an infection (7.7 versus 0.7%). In addition, an ICH at baseline was less common in patients with an infection (21.1 versus 41.6%). The proportion of patients who received therapeutic anticoagulation was the same in patients with or without an infection (82.% versus 83.7%). Of the patients with an infection, there were no significant baseline differences between those who received anticoagulation and those who did not.

Neurological outcomes (as defined by mRS upon last follow-up) were similar between patients with or without infections; 15.8 versus 13.7% of patients were dead or dependent (mRS>2) at last follow-up. In addition, mortality was similar between patients with and without infection (5.3% versus 3.3%). A new ICH was more common in patients with an infection than without an associated infection (12.3 versus 5.3%) and although not statistically significant due to low numbers of patients, clinical worsening was more frequent in patients with an infection who were treated with anticoagulation (31.9 versus 10%). On the other hand, despite clinical worsening, clinical outcomes at last follow-up and mortality were very similar in patients with an infection treated or not treated with anticoagulation.

One of the most surprising findings of this study was the fact that clinicians were not deterred in prescribing full dose anticoagulation in patients with active ENT/CNS infection. Although overall mortality and neurological outcomes were similar in patients with CVT and concurrent infections treated or not treated with anticoagulation, only 10 patients with CVT and concurrent infection were not treated with anticoagulation and therefore it is hard to attest to the efficacy/safety of anticoagulation in this particularly challenging subgroup of patients.

What Makes a Lacune?

Peggy Nguyen, MD

The lacune, often used interchangeably with the definition of a stroke of small vessel atherosclerotic etiology, is traditionally based on a size definition of no greater than 15 mm. It is a classic feature of cerebral small vessel disease. However, despite its prolific use in the stroke literature, the exact characteristics and morphological features of a lacune are not well defined. Here, the authors analyzed the shape of incident lacunes in CADASIL, a genetically inherited small vessel arteriopathy, to better define the lacune’s morphological features.

Fifty-seven CADASIL patients with incident lacunes were included in the study, encompassing 88 incident lacunes, only 18 of which were associated with symptoms. The most common locations for lacunes were in the centrum semiovale (n=30) and the basal ganglia (n=27). In spectral shape analysis, elongation and planarity were found to be the primary determinants of lacune shape and tended to align along perforating arteries. Although 15 mm is traditionally used as the upper size limit of a lacune, about 10% of lacunes, particularly when evaluated in planes other than axial, exceeded this size, whereas only 1 lacune was larger than 15 mm in the axial plane.

Not all lacunes are created the same, but there are certainly similarities, and this may have to do with the mechanisms by which they develop. The findings in this study confirm some generalizations of lacunes, such as the common locations, but also refutes some others, for instance, the size of lacunes, particularly when viewed in non-axial planes. These findings are also suggestive of a mechanism in which lacunes of chronic small vessel diseases develop secondary to factors related to vascular anatomy, rather than tract degeneration.

Get With the Guidelines (GWTG) Participation is Associated with Improved Clinical Outcomes in Medicare Ischemic Stroke Patients

Jay Shah, MD

Quality improvement programs are essential in that they provide vital information on process of care but its impact on clinical outcomes is less known. One such program, Get With the Guidelines-Stroke (GTWG-Stroke), began in 2003 and was developed by the American Heart Association to improve stroke care infrastructure. Hospitals that enter this program have access to wide range of resources and staff support. Prior studies have shown that hospital participation was associated with increased frequency of thrombolysis and interventions to prevent complications. However, the impact on program participation has not been established. Therefore, in this study, the authors queried if clinical outcomes at GWTG-Stroke hospitals differed compared to matched patients at non-GWTG-Stroke hospitals.

This study was conducted in Medicare patients admitted within a 5-year span from 2003 to 2008. Three hundred sixty-six GWTG-Stroke hospitals were identified that had 88,000 ischemic stroke admissions compared to 366 non-GWTG-Stroke hospitals that cared for 85,000 ischemic stroke patients. Within 6 months of program participation, GWTG-Stroke hospitals had greater discharges to home and reduced mortality at 30 days and 1 year. The reduction of mortality at 1 year was sustained at 18 months after program participation.

This study found that hospital implementation in GWTG-Stroke program was associated with improved functional outcomes. It is important to note that improvement in outcomes did occur over time at non-GWTG-Stroke hospitals reflecting the overall increase in awareness, knowledge, and care of ischemic stroke patients. Stroke is a leading cause of morbidity but data on post-stroke modified Rankin scale was not available. While improvement in mortality is certainly noteworthy, improvement in morbidity remains a pertinent clinical question. It is possible that a hospital decision to participate in the program was due to hospital personnel, specifically availability of stroke-trained neurologist and nurses. Therefore, the improvement in outcomes could potentially be due to greater stroke expertise at the specific hospital rather than GWTG participation. Nonetheless, ischemic stroke is a complex disease with multiple variables and outcomes have important implications on quality of life and any method that can potentially improve outcomes should be undertaken.
By |April 27th, 2016|clinical|1 Comment

Early Appearance of Spot Sign on CT Perfusion Associated with Hematoma Expansion and Poor Outcome in Small Retrospective Study

Intracerebral hemorrhage (ICH) causes a significant amount of stroke-related morbidity and mortality. Of the various prognostic factors in ICH, hematoma expansion (HE) 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. The “spot sign,” a radiographic sign representing the leakage of contrast with a hematoma on CT scan has recently become a topic of extensive study with respect to its ability to predict hematoma expansion. As described previously, a recently published meta-analysis suggested that the sensitivity and positive predictive value of the spot sign was related to the time from ictus to scan acquisition and may not adequately predict HE when it is detected. Additionally, other studies have shown that using CT perfusion (CTP) improves the detection rate of the spot sign. Wang et al. sought to explore the relationship between spot sign characteristics on CTP (including number, timing, and maximum density) to evaluate the relationship between these characteristics and the risk of HE as well as clinical outcome.
The authors’ retrospectively reviewed a total of 83 patients from a prospectively collected database of consecutive patients with supratentorial SICH. Patients receiving surgical evacuation of their hematoma were excluded from the outcome analysis, and additionally were excluded from HE analysis if the intervention took place prior to the 24 h follow-up CT scan. Patients who died prior to the 24 h follow-up CT scan were excluded from the HE analysis.  Patients with secondary causes of ICH were also excluded. A total of eleven patients (6 with positive spot sign) were excluded from the HE analysis, and twelve patients (7 with positive spot sign) were excluded from outcome analysis due to receiving surgical evaluation. Excluded patients had higher SBP and DBP, over a three-fold greater median hematoma volume (52.30 mL vs 15.80 mL, P=0.029) and a nearly two-fold higher median NIHSS (21 vs 11, P=0.004). 

Baseline clinical variables included patient demographics, medical history, medications, onset to imaging time (OIT), baseline National Institute of Health Stroke Scale (NIHSS), and laboratory results. The clinical outcomes assessed were NIHSS at 24 h, in-hospital mortality, and modified Rankin Scale (mRS) including death at 3 months follow-up. Spot sign was assessed with CTP and the timing of occurrence (time from the start of scan to first detection of spot sign), total number of spots, maximum spot attenuation, and axial dimensions were recorded. The median time of onset to CP was 180 (120 to 240) minutes. Hematoma expansion was defined as an absolute ICH growth ≥ 6 mL or relative growth ≥ 33% as recorded on 24 h follow-up CT scan. 

The rate of spot sign was higher in patients with HE than those without (62.5% vs 12.5%, P<0.001). The presence of spot sign was independently associated with HE after correcting for APTT, glucose, NIHSS, baseline hematoma volume, and antiplatelet use. There was a trend for an association between the presence of spot sign and 3-month mortality (32% vs 8%, OR=5.649; 95% CI 0.913-34.954; P=0.063) after multivariate analysis. Spot sign was detected much earlier in patients with HE than those without (18.75 s vs 26.87 s, P=0.007). The timing of spot sign was significantly correlated with both absolute and relative ICH volume growth, and there was no association between the other spot sign characteristics and HE. The authors defined a subset of spot sign patients as having an “early occurring spot sign (EOSS),” defined as detection of the spot sign before 23.13 seconds. EOSS was found to have 0.67 sensitivity and 0.90 specificity for HE. On multivariate analysis, EOSS was an independent predictor of HE (OR=28.835; 95% CI, 6.960-119.458; P<0.001) and 3-month mortality (OR=22.377, 95% CI, 1.773-282.334; P=0.016). EOSS maintained a higher specificity for HE compared to spot sign (91% vs 74%).

In this single-center cohort of SICH patients, spot sign as assessed by CTP was associated with HE. The authors also found that early detection of the spot sign was the most important characteristic with respect to predicting HE and significantly correlated with ICH growth. The primary limitations of the study were related to the retrospective nature of the study, the relatively small sample size, and the use of a single center for recruitment and determining imaging parameters. External validation with a larger sample size and standardized imaging parameters will be necessary. In addition, the high rate of excluded surgical evacuation patients with positive spot sign may have led to an underestimation of the spot sign’s PPV with respect to mortality. It is also important to note that the predictive value and associations with spot sign on CTP in this study should not be applied patients evaluated with single-phase CT angiography. However, replicating this study with multi-phase CTA could be feasible and represents a potential future avenue of research.

Exendin-4: A Novel Candidate to Reduce Infarct Volume in Acute Ischemic Stroke with Hyperglycemia

Alexander E. Merkler, MD

Kuroki T, Tanaka R, Shimada Y, Yamashiro K, Ueno Y, Shimura H, et al. Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice. Stroke. 2016

Hyperglycemia exacerbates acute brain injury and leads to worse outcomes in patients with ischemic stroke. In animal models of acute ischemic stroke, hyperglycemia is associated with increased infarct volume, increased blood-brain–barrier permeability, and hemorrhagic transformation. In order to avoid hyperlgycemia-induced brain injury, normoglycemia is recommended, and typically attained via use of insulin. Unfortunately, up to now, insulin has failed to show improvement in short-term outcomes in human studies and hypoglycemia, a not uncommon consequence of exogenous insulin is associated with further brain injury.[1] Exendin-4 is an agonist of Glucagon-like peptide-1 (a hormone secreted by the small intestines) that mitigates hyperglycemia in diabetes and has a low risk of hypoglycemia. In addition, exendin-4 has shown been shown to reduce oxidative stress and inflammation.

In the current article by Dr. Kuroki et al, the authors assess the protective effect of exendin-4 in a murine model of transient hyperglycemia in acute ischemic stroke using middle cerebral artery occlusion (MCAO). All mice underwent a 60 minute MCAO and were randomly assigned to four groups: 1) Transient hyperglycemia, 2) Transient hyperglycemia treated with insulin, 3) Transient hyperglycemia treated with exendin-4, or 4) control (no hyperglycemia). Histopathological evaluation was performed at 24 hours and 7 days after ischemic stroke.

Consistent with prior data, mice with induced hyperglycemia had significantly increased infarct volume, brain edema, and hemorrhagic transformation as compared with the control. In addition, hyperglycemia was associated with an increase in blood-brain-barrier disruption, more activation of matrix metalloproteinase-9, and a higher degree of neutrophilic infiltration in infracted tissue. Mice treated with Exendin-4, but not insulin, had attenuated levels of matrix metalloproteinase-9, decreased levels of TNF-α, and decreased neutrophilic infiltration. Furthermore, mice treated with Exendin-4 had significantly less total infarct volume at 24h and at 7 days after ischemic injury as compared to not only the control group, but also the insulin treated group. Finally, hyperglycemia decreased 7-day survival and the mice treated with Exendin-4, but not insulin had an improved survival rate.
Hyperglycemia is common in patients with ischemic stroke and leads to increased blood-brain-barrier disruption, increased inflammation, increased stroke volume, increased hemorrhagic transformation, and overall worse outcomes. Treatment of hyperglycemia in acute stroke is paramount, but by how much and by what mechanism is yet to be determined. Exendin-4 shows promise as a neuroprotective agent that can lower glucose levels and improve outcomes in acute ischemic stroke. 

Recent and Regular Use of Cocaine Significantly Increases Odds of IS in a Case-Control Study of Young Adults

Benjamin R. Kummer, MD

Cheng Y-C, Ryan KA, Qadwai SA, Shah J, Sparks MJ, Wozniak MA, et al. Cocaine Use and Risk of Ischemic Stroke in Young Adults. Stroke. 2016

Case series have reported biologically plausible associations between cocaine use and stroke in young patients, but few studies have rigorously investigated this relationship or the effects of drug ingestion timing or route of ingestion in large populations. Using a case-control design, Cheng and colleagues attempted to confirm the existence of the link between cocaine use and stroke in young patients, and delineate the relationship between timing and route of cocaine on the risk of ischemic stroke (IS). In this study, the authors drew their population from an existing, prospectively collected, case-control registry of 1,100 cases between the ages of 15 and 49 with first-ever IS, and approximately 1,100 controls. Cocaine use and timing/route were recorded on the basis of individual patient recollections (a small subset of patients had urine drug screening), as was confounding clinical and demographic data.
After adjusting for age, gender, ethnicity, smoking, hypertension, and alcohol use, patients that used cocaine in the 24 hours prior (OR 5.7, 95%CI 1.7-19.7) had significantly increased odds of IS compared to controls. However, the odds ratio for IS lost its statistically significance (OR 3.5, 95%CI 0.9-12.6) after removing higher-odds study periods. Patients that had smoked cocaine in the previous 24 hours had even higher adjusted odds of IS (OR 7.9, 95% 1.8-35.0), although no adjustment was made for smoking, hypertension, or alcohol use. Patients that reported smoking cocaine at any point also had slightly increased but not statistically significant adjusted odds of IS (OR 1.2, 95%CI 0.9-1.6). Patients that reported use of at least once in the past 1-30 days had a slightly increased, non-significant adjusted odds of IS (OR 1.1; 95% CI 0.7-1.9).

Overall, the number of patients exposed to cocaine use was very small relative to the sample size. Aside from the small number of observations, which caused effect estimates to be very wide, cases also had a greater proportion of patients with stroke risk factors (HTN, DM2, smoking, black race) than controls. The determination of drug use history could have been influenced by recall bias, and there may have also been a bias in under-reporting drug use by the study population (although this would have generated a conservative bias for the effect estimates). Also, while the logistic regression model was adjusted for some confounders, it was not adjusted for income level, education, employment, and insurance status, as well as important risk factors in young patients, such as hypercoagulable state, hyperlipidemia, family history of stroke, or obesity.
Despite its small number of observations, this study by Cheng and colleagues argues for a biologically plausible relationship between acute cocaine smoking and IS in young patients. It would have been interesting to see whether the association between acute cocaine smoking and IS disappeared with further adjustment for markers of health care access. These findings support urine toxicology screening for young patients with acute IS, although the implications for acute stroke management in such cases are unclear.

Sumoylation of NCX3 a Possible Mechanism of Neuroprotection in Ischemic Preconditioning

Peggy Nguyen, MD

Cuomo O, Pignataro G, Sirabella R, Molinaro P, Anzilotti S, Scorziello A, et al. Sumoylation of LYS590 of NCX3 f-Loop by SUMO1Participates in Brain Neuroprotection Induced byIschemic Preconditioning. Stroke. 2016

Small ubiquitin-like modifier (SUMO) conjugation, or sumoylation, is a post-translational modification of various proteins similar to ubiquination, and has been noted in stress conditions including anoxia, hypothermia, and hypoxia. Changes in sumolyation patterns have been reported after brain ischemia, where it is thought to be possibly protective. To this end, the authors here attempt to further elucidate a possible mechanism underlying the role of sumoylation of the transmembrane protein NCX3, which is thought to be an effector of neuroprotection in ischemic mouse models.

Using mouse models, the authors identified 3 significant findings:
  • First, that SUMO1 conjugation does increase at various times points following induced ischemia via transient middle cerebral artery occlusion (tMCAO) (at 5 and 24 hours), after preconditioning (at 3, 5, 24, and 72 hours) and when preconditioning was combined with tMCAO (at 5 hours).
  • Second, using immunohistochemical stains, the authors identified NCX and SUMO1 colocalization to the neuronal cell bodies in the primary cortical neurons, with a probable sumoylation site in the NCX f-loop of the antiporter. 
  • Third, in SUMO1 knockdown mouse models, NCX3 expression decreased 72 hours after tMCAO  and after preconditioning + tMCAO and displayed a significant increase in ischemic volume after tMCAO at 24 and 72 hours after tMCAO induction.

Identifying targets for neuroprotection seems to be the next frontier in the world of stroke research. This takes us one step closer to characterizing the mechanisms underlying the possible neuroprotectant effect of ischemic preconditioning, whereby targeting either sumoylation of NCX, or regulation of NCX itself, may lead to the development of better neuroprotectants.

Intracranial Aneurysm Growth and Rupture Have Risk Factors in Common in a Large Meta-Analysis

Benjamin R. Kummer, MD

Backes D, Rinkel GJE,  Laban KG, Algra A, and Vergouwen MDI. Patient- and Aneurysm-Specific Risk Factors for Intracranial Aneurysm Growth: A Systematic Review and Meta-Analysis. Stroke. 2016

Three percent of the general population harbors an unruptured intracranial aneurysm (UIA). Due to their unfavorable interventional risk-benefit profile, small, asymptomatic UIAs are often left untreated and followed with serial imaging for growth—a well-established risk factor for aneurysm rupture. Because many factors associated with aneurysm growth are also associated with rupture, patients needing increased frequency of monitoring or even intervention might be identifiable by characteristics associated with aneurysm growth. Building on their previous work on aneurysm growth published in 2015 in Stroke, Baackes and colleagues further the aim of identifying patients at increased risk for rupture in this systemic review and meta-analysis of the clinical and aneurysm-specific factors associated with the growth of UIAs.

Approximately 4,000 patients and 5,000 unruptured intracranial aneurysms were studied, drawn from 18 separate publications and 15 unique patient cohorts (5 separate studies overlapped on 2 independent cohorts), followed over a mean of 2.8 years. The analysis only pooled studies that had clear definitions and effect estimates of aneurysm growth; however, a significant amount of epidemiologic and methodologic heterogeneity was present. Prospective and retrospective designs, studies with different population sizes, growth definitions, imaging modalities (CTA, DSA, MRA), Newcastle-Ottawa publication bias scores (mean 6, SD 1.9), as well as the numbers of growing UIAs were all analyzed together. Sensitivity analyses were performed to account for some, but not all of this heterogeneity. 

As previously shown, many factors associated with aneurysm rupture, like female sex, smoking, hypertension, larger aneurysm size, posterior circulation location and aneurysm shape, were also associated with aneurysm growth. However, the degree of heterogeneity in the effect estimates was moderate to substantial. The presence of multiple UIAs, which has not been readily identified as a factor associated with aneurysmal rupture, was shown to be significantly associated with aneurysm growth, raising the possibility that patients with multiple aneurysms might have a possibly connective-tissue based predilection towards more rapid growth than patients with single aneurysms, although it is important to note that this signal was also confounded by quite heterogeneous effect estimates. In contrast to their well-established association with aneurysmal rupture, family history of SAH and previous SAH were not significant factors for aneurysmal growth. Interestingly, UIA cohorts from Japan (where rates of aneurysmal rupture are higher than in European and North American cohorts) were had a lower risk of aneurysmal growth than North American cohorts. After stratifying effect estimates by study design and quality, the overall relative risk of aneurysm growth was lower in higher quality and prospective study designs than in lower-quality and retrospective designs, again suggesting that bias may have also contributed to the overall results.  

Despite the degree of heterogeneity, which the authors attempted to incompletely adjust for with sensitivity analyses, this meta-analysis suggests that aneurysmal growth and rupture may share a common pathophysiology, and yields some interesting hypothesis-generating findings on UIA growth and rupture.

Vascular Cell Senescence Contributes To Blood-Brain Barrier Breakdown

Ilana Spokoyny, MD 

Accumulating senescent cells in tissues is known to contribute to age-related systemic organ dysfunction. The authors investigated whether a similar process happens in the cerebral vasculature, leading to compromised bloodbrain barrier and potentially contributing to neurodegenerative and cerebrovascular diseases. The bloodbrain barrier (BBB) is kept intact by endothelial cells (ECs) forming tight junctions, and these ECs are covered by pericytes, astrocyte end-feet, and the capillary basement membrane. BBB integrity is compromised by aging, but the exact process by which this occurs is still unknown. We know that senescent cells limit the regeneration potential of tissues and that there are more senescent vascular smooth muscle cells and endothelial cells found in aged peripheral vessels and atherosclerotic lesions, but the effects of increased senescent cells on the BBB have not been well studied. 

The authors used both an in vitro model made of endothelial cells, pericytes, and astrocytes; and an in vivo model in mice with accelerated aging phenotypes. In the in vitro model using senescent ECs and PCs, tight junction structure and barrier integrity were significantly impaired compared with the model using young ECs and PCs. The authors also determined that the reduced BBB integrity is due to altered TJ structure and distribution in the EC layer, rather than with decreased TJ protein expression.
The in vivo model also demonstrated this, with an exacerbation of senescence and compromised BBB integrity. Specifically, the coverage of cortical microvessels by tight junction proteins was impaired, but the coverage of microvessels by astrocytuc end-feet was not altered.

Limitations are noted, especially in the in vitro model, due to needing to keep the three cell types in different media (ECs in one, PCs and astrocytes in another); so  the possibility exists that if they were mixed we would see different effects. This is compensated by the in vivo model, however. Overall, this is an important study demonstrating a critical link and setting the foundation for future diagnostic and therapeutic advances in cerebrovascular and neurodegenerative disorders. 

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.