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Does a cryptogenic stroke in a cancer patient spell doom?

Prachi Mehndiratta, MD

Navi BB, Singer S, Merkler AE, Cheng NT, Stone JB, Kamel HK, et al. Cryptogenic Subtype Predicts Reduced Survival Among Cancer Patients With Ischemic Stroke. Stroke. 2014


It is traumatic to experience a stroke and probably even more to not know what caused it. In about one-third of patients with acute ischemic stroke no clear etiology is found. It is hard to predict the recurrence risk of stroke in such patients particularly as the inciting factor or cause is not known. About 7% of patients with cancer experience a clinically significant stroke. These strokes can break their treatment cycles and often lead to significant disability. The authors in this article attempt to elucidate the frequency of cryptogenic stroke in patients with underlying malignancy as well as their outcomes after a cryptogenic stroke.



The authors identified 263 patients with acute ischemic stroke in a retrospective cohort of cancer patients admitted to their center between 2005 and 2009, by utilizing ICD 9 codes for stroke or transient ischemic attack. Patients that underwent only a CT scan and those seen exclusively in the outpatient setting were excluded due to concern for insufficient work up. Patients were followed till the primary outcome of death was reached or till July 31st 2012. Demographic, outcome and imaging data was rigorously collected and strokes were classified by using the TOAST classification. Stroke type was classified as cryptogenic if no clear cause was identified or if there were possibly two competing mechanisms. Multivariate cox proportional hazards analysis was used to determine an independent relationship between etiology of stroke and death and Kaplan-Meier survival curves were constructed.

Their results indicate that adenocarcinomas of solid organs such as lung, GI or GU tract were most often associated with ischemic stroke and stroke typically occurred about 10 months after cancer diagnosis. 69% of patients had disseminated disease at the time of stroke occurrence and stroke work up was equally comprehensive for the cryptogenic and non-cryptogenic stroke types. 133 of 263 patients were identified to have cryptogenic stroke and 76 of these had a cardioembolic appearing imaging pattern. Median survival among those with cryptogenic stroke was significantly lower (47 days vs. 141 days) as compared to those with known stroke mechanism and even lower in those that appeared cardioembolic (31 days). After adjusting for age, functional status, adenocarcinoma histology and known metastases, cryptogenic stroke type remained and independent predictor of death. (HR 1.64 95% CI (1.25-2.14)).

This study raised several important questions – does a cryptogenic stroke in a cancer patient spell doom? And if it does then what can we do to ascertain the cause better? One possible suggestion is that all patients undergo transesophageal echocardiogram and that the search for marantic endocarditis is more rigorous and a more comprehensive classification system such as the Causative Classification of Stroke (CCS) is employed to determine stroke etiology. I would have also liked to know a little more about differences in stroke severity between the two groups and if the patients underwent any repeat evaluations during follow up.  Practically speaking, should the patients that have a cryptogenic stroke and a cardioembolic appearing stroke be empirically treated with anticoagulation?


Change is not good: BP variability and ICH outcomes

Several studies have recently shown that even in the setting of better BP control, blood pressure variability may still have a negative effect on outcomes.  In this article, authors Tanaka et al utilized a prospective, multicenter, observational study to reinforce some of the previous findings.




205 patients were included, with inclusion criteria being age 20; initial SBP > 180, total GCS 5, supratentorial IPH and initial volume measurement < 60ml.  BP was measured every 15min for the first 2 hours after starting anti-HTN therapy, then every hour after that for the next 22 hours. Outcome measures included hematoma expansion, neurologic deterioration, and unfavorable outcomes of an MRS of 4-6 at 3 months.  On multivariate regression analyses, authors found standard deviation (SD) and successive variation (SV) of SBP to be associated with neurologic deterioration, and SV of SBP to be associated with unfavorable MRS outcomes at 3 months.  Neither SD or SV of SBP appeared to have significant associations with hematoma expansion.  There did not seem to be a significant link between SV/SD of DBP and any of the outcomes.

This study raises interesting questions about what the true causative agent is of the worse outcomes—is it a direct effect of variations in SBP, or are the negative effects somehow due to whatever caused that variation?  The authors touch on this, noting that “autonomic dysfunction, including sympathetic overactivity and diminished baroreflex sensitivity may be one of the mechanisms,” the thought being that these may contribute to altered perfusion, edema and secondary injury.   

This study, much like post-hoc analysis of INTERACT2, seems to imply that minimizing blood pressure variability in addition to aggressively lowering SBP may diminish rates of neurologic deterioration and improve long-term outcomes.  It will be interesting to see how this continues to play out in further studies, and if deterioration is found to be a direct effect of that variability or rather is just the effect of another, more damaging process.  If it is simply directly due to variability and we utilize effective methods to minimize that, what will we find “acceptable” levels of variability to be?

Brachial-ankle pulse wave velocity: A novel prognostic marker of recovery after stroke

Vivek Rai, MD

Kim J, Song TJ, Kim EH, Lee KJ, Lee HS, Nam CM, et al. Brachial-Ankle Pulse Wave Velocity for Predicting Functional Outcome in Acute Stroke. Stroke. 2014

The elastic component of arteries decreases with age and the consequent loss of elasticity results in hemodynamic changes, which are thought to be involved in pathogenesis of vascular diseases. Brachial-ankle pulse wave velocity (baPWV) is a recently developed automated tool for measurement of arterial elasticity used as an alternative to carotid-femoral pulse wave velocity (current gold standard). Carotid-femoral pulse wave velocity (cfPWV) and baPWV have been validated to produce reliable results and a high cfPWV is related to worse functional outcomes after stroke. The authors investigated whether baPWV can also be used as prognostic marker of recovery after stroke.



Kim et al analyzed data from1091 consecutive patients with first-ever acute cerebral infarction who underwent baPWV measurements. Poor functional outcomes were defined as modified Rankin Scale score of >2 at 3 months after stroke onset. The authors report that 181 (16.59%) patients had a poor functional outcome and the patients in the highest tertile of baPWV (>22.25 m/sec) were at an increased risk for poor functional outcome (adjusted OR, 1.88) compared to those in the lowest tertile (<17.55 m/sec). No significant interaction between baPWV and stroke subtype was noted.

The authors have shown that baPWV can be used as a simple, non-invasive marker for identification of patients at risk for poor recovery after stroke, regardless of stroke subtype according to TOAST criteria. In previous studies, increased baPWV and cfPWV were found to be independent predictors of new vascular events and cardiovascular mortality. It remains to be shown whether there is any causal effect to this association. Therapeutic interventions aimed at reducing progression of arterial stiffness may reduce stroke incidence and may even help in recovery after stroke. Further studies are necessary to prove these hypothesized benefits. Till then, in my view, the clinical application of this novel tool remains limited.

Can taped glasses and optokinetic training effectively treat neglect?

Matthew Edwardson, MD

Machner B, Könemund I, Sprenger A, von der Gablentz J, and Helmchen C. Randomized Controlled Trial on Hemifield Eye Patching and Optokinetic Stimulation in Acute Spatial Neglect. Stroke. 2014

Hemisensory neglect has a major detrimental impact on stroke recovery, impairing multiple activities of daily living. For this reason, many rehab experts feel that large right MCA strokes are worse than large left MCA strokes from a recovery stand point. Two strategies that demonstrate limited success in treating hemisensory neglect include hemifield eye patching (HEP) and optokinetic stimulation (OKS). HEP is somewhat akin to constraint-induced movement therapy of the limbs – the patient wears glasses that are taped with opaque tape over ½ of both lenses corresponding to the intact visual hemifield. OKS entails using an optokinetic strip to induce smooth pursuit eye movements, thereby correcting the shifted visuospatial midline experienced by these patients. In this article, Machner and colleagues compared a combined approach using HEP + OKS early after stroke to standard rehab in those with large right hemispheric strokes. They found that both groups achieved considerable improvement with no added benefit in the group receiving HEP + OKS.



The authors randomized 21 patients with right hemispheric stroke to one week of HEP + OKS within 14 days of stroke (n=11) vs. standard care (n=10). Study endpoints included a mean score from various tests for neglect, such as the Bell’s cancellation and line bisection tasks. Both the treatment and the control group demonstrated significant improvement on measures of neglect, both immediately after therapy and at one month. There was no significant difference between groups and notably no trends to suggest the study was underpowered.

The negative results of this study are frustrating but it may be premature to give up on HEP and OKS as therapeutic strategies for hemisensory neglect. The authors chose to test these interventions in the early phase after stroke. The rapid recovery that stroke patients achieve naturally during this phase may have washed out any difference between groups. In addition, testing endpoints beyond 30 days, which was not performed, may have shown separation between groups. The authors did an admirable job getting subjects to wear the taped glasses for all waking hours, yet I wonder if taped glasses are truly comparable to constraint-induced therapy of the limbs. For the glasses to be fully effective, the subject must look straight forward at all times. If the subject cheats by looking to the left or right, much of the effect would be lost. Perhaps a better intervention would entail contact lenses darkened on one side to maintain hemifield coverage regardless of the direction of gaze. Despite these minor concerns, this was a well-designed study of HEP + OKS to treat hemisensory neglect. The results suggest that more work is needed to identify an effective therapy for this debilitating condition.

Incidence of Symptomatic Hemorrhage in Patients with Lobar Microbleeds

Sebina Bulic, MD

van Etten ES, Auriel E, Haley KE, Ayres AM, Vashkevich AV, Schwab KM, et al. Incidence of Symptomatic Hemorrhage in Patients With Lobar Microbleeds. Stroke. 2014

Cerebral amyloid angiopathy (CAA) represents amyloid β-peptide deposition in small and medium-sized blood vessels in the brain, leading to hemorrhagic and ischemic injury. Lobar microbleeds on MRI have also been identified as a marker of CAA severity. There is estimation that prevalence of CAA in the elderly population is 11 to 24%. This number is expected to increase as the life expectancy increases. Need for use of anticoagulation also is expected to increase because of 2 reasons. A-Fib is condition more prevalent in elderly. We also achieved significant improvement in detecting paroxysmal A-Fib. 


In this timely and well-conducted prospective study, 379 patients were enrolled between January 1993 and January 2012. Patients were grouped into two categories: those presenting with two or more lobar microbleeds in the absence of lobar ICH and those presenting with a lobar ICH with at least one lobar microbleed. In the second group, patients who survived the first 90 days after ICH were studied.

In addition to evaluation of fatality, ICH and white matter hyperintensity, Apolipoprotein E (APOE) genotype (ε2 and ε4 alleles) was determined in a large subset of patients.

Baseline demographics (age, gender), vascular risk factors, and APOE genotype did not differ significantly between microbleed-only and ICH groups. The lobar microbleed count was significantly higher in microbleed-only patients which was explained by referral of those patients.

In follow up, microbleed group had higher white matter hyperintensity (again explained by referral) and overall mortality. ICH group had higher rate of repeat ICH, but this did not reach statistical significance. Warfarin use and older age were independently associated with time to incident ICH. Use of ASA was not associated with increased ICH risk.

This study is highlighting that even patients with microbleeds in addition to those with CAA and ICH are at substantial risk future ICH. Also, it is raising very important question; whether this risk of future ICH is sufficient to tip the risk vs. benefit calculation away from anticoagulant treatment this significant subset of patients. This can only be answered in large, prospective trial. Till that time, caution with anticoagulation in patients with CAA.

In PURSUIT of faster door-to-needle times, is telemedicine the answer?

Jennifer Dearborn, MD

Wu TC, Nguyen C, Androm C, Yang J, Persse D, Vahidy F, et al. Prehospital Utility of Rapid Stroke Evaluation Using In-Ambulance Telemedicine: A Pilot Feasibility Study. Stroke. 2014

“Time is brain” and current research efforts, such as utilization of the mobile stroke unit, have sought to decrease the door-to-needle time to deliver thrombolysis therapy (r-tPA) quickly and efficiently. Tzu-Ching Wu et al. explore how telemedicine can facilitate shorter door-to-needle times by performing the stroke assessment while en route to a nearby stroke facility. In this pilot study, EMS providers are trained to interact with a telemedicine program that communicates with a remote vascular neurologist to perform the NIH stroke scale. This pilot study was a feasibility and reliability assessment of the technology, which used trained actors in different settings to complete remote and real-time assessments of the same scenarios. The authors found that the telemedicine approach was feasible in the majority (85%) of scenarios, and that common reasons for malfunction was due to cell phone connections through the network. There was also moderate to excellent reliability with the NIHSS compared to real-time raters.



This pilot study is important because it shows that an easy to introduce technology that is commonly used in other hospital emergency rooms is feasible in the ambulance and emergency setting. This approach has the potential to rapidly triage patients upon arrival in the emergency room to thrombolysis, with the final decision pending only a CT scan evaluating for hemorrhage. As the majority of thrombolysis cases are staffed by a vascular neurologist upon hospital arrival, this approach does not add many costly resources, and instead could save time and brain. I am excited to see if use of this technology is incorporated into EMS care. If it is proven to be effective in one system, other regions will incorporate it into the ambulance-based care of stroke patients.

Expression of Inflammatory Genes: A Prelude to Intracranial Aneurysmal Rupture.

Hassanain Toma, MD

Nakaoka H, Tajima A, Yoneyama T, Hosomichi K, Kasuya H, et al. Gene Expression Profiling Reveals Distinct Molecular Signatures Associated With the Rupture of Intracranial Aneurysm. Stroke. 2014

Nakaoka et al. sought to investigate genes associated with rupture of saccular intracranial aneurysms. They employed gene clustering methods to compare gene expression between ruptured (RIAs) and unruptured (UIAs) aneurysms.



Their analysis revealed that RIAs segregated into two distinct subgroups, with an average age of 46.6 and 80.7. Furthermore, RIAs from younger patients had 430 up-regulated, and 617 down-regulated genes, as compared to UIAs. The up-regulated genes were associated with phagocytosis, inflammatory and immune responses, while the down-regulated genes suggest mechanical weakness of aneurysm walls.

The results of this study suggest that the pathophysiology of aneurysmal rupture in young and old patients is different. Aneurysms of younger patients rupture because of elevated immune responses, while aneurysms of older patients rupture due to longstanding “wear and tear”.

The findings of Nakaoka et al. raise the question of whether statins should be given to young patients with intracranial aneurysms. Previously, the JUPITER trial demonstrated that statins are associated with a 48% relative risk reduction of total strokes in patients with normal LDL levels and elevated CRP. This is presumed to be due to the statins’ anti-inflammatory properties. Thus, the hypothesis of medically managing intracranial aneurysms with statins is not far fetched, especially since some data suggest that statin therapy is associated with a decreased expansion rate in patients with small abdominal aortic aneurysms.

IV-tPA + MCA occlusion: which patients benefit?

Deepa Bhupali, MD

Rohan V, Baxa J, Tupy R, Cerna L, Sevcik P, Friesl M, et al. Length of Occlusion Predicts Recanalization and Outcome After Intravenous Thrombolysis in Middle Cerebral Artery Stroke. Stroke. 2014

In a recent article, Rohan et al explore predictors of successful IV-tPA recanalization and outcome in patients with proximal MCA occlusion as measured by 4D CTA imaging. They looked at 80 patients with M1-M2 occlusion (the majority had isolated M1 occlusions), calculated the length of the occlusion, recorded the NIHSS at presentation and at 24 hours after tPA and assessed clinical outcome at three months using the mRS (favorable outcome=mRS 0-2). Successful recanalization was defined as a TIMI grade 2 or 3. With univariate analysis, they found that a lower baseline NIHSS, length of occlusion and ASPECTS score were significant predictive factors of favorable outcome. In multivariate analysis, only baseline NIHSS and length of occlusion in the M1 segment were significant independent predictors of favorable outcome.



I really enjoyed this article. It speaks to our desire to improve our practice and deliver better care. We’ve been administering IV-tPA to treat acute stroke for years but we’re still learning about how it performs in different situations. We are facing a newer, similar challenge in the endovascular world: trying to identify the patients who will benefit most from the interventional reperfusion. Overall, the results of this study are not surprising: patients with better NIHSS, smaller lengths of occlusion and less area of ischemia benefit more from IV-tPA than their counterparts.

One of the limitations of the study is that it cannot be applied at the bedside at this point. The imaging modalities used to determine the length of the occlusion are not yet feasible or practical in the acute setting. Even if we know the length of the occlusion at the time we’re considering administering tPA , it would most likely not affect our decision as to whether or not to give the medication. But, just as meaningfully, knowing the relationship between occlusion length, IV-tPA and clinical outcome with more certainty would surely help us when speaking with patients and families about potential outcomes and expectations.

It’s important to constantly evaluate how we can deliver care more effectively and this article is an example of that pursuit. It brings up an interesting topic and although the results are not yet ready for prime-time clinical use, as more information is gathered, it may factor into our treatment decisions and it will certainly factor in to our discussions with patients and their families.

Warfarin-Associated Intracerebral Hemorrhage after Ischemic Stroke

Sebina Bulic, MD


Åsberg S, Eriksson M, Henriksson KM, and Terént A. Warfarin-Associated Intracerebral Hemorrhage After Ischemic Stroke. Stroke. 2014

Warfarin continues to be major player for anticoagulation. NOAC became equally acceptable alternative. In safety analyzes of subgroups of patients with previous stroke, the annual rate of ICH in patients allocated warfarin was 0.8%, 1.0% and 0.5% for dabigatran, apixaban, and rivaroxaban trials respectively. In this register-based observational study, comprised of patients with first-ever ischemic stroke, who were discharged on warfarin, results were somewhat different.



Data from the two Swedish national registers linked through the patient’s unique personal identification numbers were used; The Swedish Stroke Register and Cause of Death Register. Data were analyzed for 2 periods; period 1 from January 2001 to December 2004, and period 2 from January 2005 to December 2008. Mean time of follow-up was 2.6 years, with a minimum follow-up time of 1 year.During the two 4-year periods, all ischemic stroke survivors discharged on warfarin (n=12,790) were included in the study. The proportion of patients with AF increased from 63.9% (n=3857) in the first period to 72.1% (n=4870) in the second period. During 31,800 person-years, there were 1237 recurrent strokes, of which 127 were ICH. Annual rates of ICH ranged from 0.37% in the first period to 0.39% in the second period, showing that incidence of ICH did not significantly change despite increased use of warfarin. Reasons for discrepancy of ICH incidence between this register-based observational study and subgroup analysis of the randomized prospective trials was not offered, but these results are certainly reassuring. 

Did the Presence of Collaterals Undermined the SWIFT Study Results?

Hassanain Toma, MD

Liebeskind DS, Jahan R, Nogueira RG, Zaidat OO, and Saver JL. Impact of Collaterals on Successful Revascularization in Solitaire FR With the Intention for Thrombectomy. Stroke. 2014

The presence of collateral circulation has been shown to be associated with improved recanalization after thrombolysis and mechanical thrombectomy. However, with the advent of stent retrievers, it is hypothesized that improved recanalization can be achieved irrespective of collaterals. To test this, Liebeskind et al. retrospectively analyzed angiographic collateral grade prior to endovascular therapy in the SWIFT (SOLITAIRE™ FR With the Intention For Thrombectomy) study to ascertain the potential impact of collaterals on revascularization without symptomatic hemorrhage. They also sought to identify predictors of collateral grade in that study population.



They authors revealed a significant association between elevated blood glucose and systolic blood pressure at presentation and worse collaterals. In addition, the absence of prior HTN, a positive history for smoking, and high blood glucose were predictors of worse collaterals. Furthermore, low ASPECTS at baseline and at 24 hrs post-intervention were associated with worse collaterals.

The presence of collaterals was closely linked with improved reperfusion and revascularization without symptomatic hemorrhage, and overall better clinical outcome at defined by NIHSS at day 7 and mRS at day 90.

These data undermine the credibility of the SWIFT study results. You may recall that the SWIFT study compared the Solitaire device to the Merci retriever. The study concluded that the Solitaire device achieved substantially better angiographic, safety, and clinical outcomes than did the Merci Retrieval System. The current study by Liebeskind et al. reveals that collateral grade (partly driven by HTN, DM, and smoking) ultimately made a significant difference in outcome, irrespective of device used (although the authors did not discuss this point). The presence of collaterals was a confounding variable that was unadjusted for in the SWIFT trial. Perhaps the hype about the Solitaire device is unwarranted. It would be interesting to see the outcome of the SWIFT study after adjusting for the collateral grade.