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Monthly Archives: March 2015

Peri-Hematomal Edema – It is Not The Leaky Blood Brain Barrier But What is it Then?

Prachi Mehndiratta, MBBS

Intracerebral hemorrhage like other structural brain lesions is known to cause disruption of the blood brain barrier (BBB) and extravasation of fluid into the surrounding tissue. Stroke neurologists refer to this seepage of fluid from the intravascular to the extravascular space as vasogenic edema. The permeability of the BBB can be determined by determining the extent of contrast extravasation during CT perfusion (CTP) scans. The authors of this study proposed that the rate of iodinated contrast extravasation a.k.a. Permeability Surface area product (PS) that serves as an estimate of BBB permeability is increased in the peri-hematomal region and is predictive of hematoma growth.

The authors studied patients previously enrolled in the ICH ADAPT study (a prospective, randomized clinical trial evaluating the effect of BP reduction on cerebral blood flow (clinicaltrials.govNCT00963976)). All patients underwent non-contrast CT scans at baseline, 2±1h and 24±3h post-randomization and CTP imaging was performed at 2h. Post processing of images was performed to identify regions of interest and calculate hematoma volume; perihematoma edema volume and PS maps were generated. Out of 75 patients enrolled in ICH ADAPT, 53 had satisfactory imaging and were included in the present analysis. At baseline, median hematoma volume for all patients was 15.6 (19.7) ml and edema volume was 1.65 (3.4) ml. There were no differences between the <150mmHg (n=26) and the <180mmHg (n=27) treatment groups with respect to clinical characteristics, baseline volumes, and time to randomization.

Mean perihematoma PS (5.1±2.4 ml/100ml/min) was elevated relative to contralateral regions (3.6±1.6 ml/100ml/min, P<0.001) as was mean PS in the ipsilateral hemisphere. There was no relationship identified between baseline hematoma volume and hematoma PS or baseline BP and hematomal/peri-hematomal PS. Mean PS was similar in the two BP groups at 2 hours post randomization. Acute hematoma volume predicted absolute peri hematoma edema volume at baseline and the change in absolute edema volume over24h was also predicted by acute hematoma volume. Modest focal increases in BBB permeability were found which did not impact edema growth. 

What are the major take home points from this study? Does it change our clinical practice? The sample size is too small to conclude one way or the other. However, it is interesting to note that the permeability surface area product or BBB permeability does not seem to be affected by baseline BP or change in BP, nor does it seem to impact hematoma growth. The authors acknowledge that the imaging acquisition was at <24 hours and no conclusions can be drawn about hematoma growth past that time. Additionally, they postulate that the cause of peri-hematomal edema may not vasogenic as only modest focal changes in hematomal and peri-hematomal PS were observed that did increase edema volume. Although this is a novel approach to study permeability of BBB I think it needs further validation in a larger cohort.

Increased motor cortex functional connectivity after subcortical stroke: An anatomic correlate to stroke recovery

Prachi Mehndiratta, MD

Motor recovery after stroke has been correlated with rewiring and connection of ancillary pathways in the brain. This has been demonstrated in a sophisticated and complex manner by utilization of novel MRI techniques. Resting state functional connectivity (rFSC) is one such technique that measures the resting state MRI signals between any pair of brain regions. In patients with subcortical infarcts the bilateral motor cortex rFSC has been shown to undergo a dynamic evolution albeit over a varied time period ranging from 24 hours to a few weeks. The authors of this study chose to study subjects with chronic subcortical stroke > 6 months and excellent motor outcome as by that time structural and functional recovery is nearly stable. They aimed to identify a correlation between the rFSC of bilateral motor cortices (M1-M1) and fractional anisotropy  (FA) of the corticospinal tract (CST) as a measure of motor recovery. 


Sixteen controls and 20 chronic subcortical first-ever ischemic strokes with good motor recover and a Fugl Meyer score > 90/100, were selected for multimodal MRI imaging. FA of CST, M1-M1 anatomical connections and rFSC between M1-M1 cortices were measured.  Diffusion tensor imaging was obtained based on an elaborate but standard protocol and tractography was performed. Motor cortices or Brodman areas 4 were identified a region of interest based rFSC analysis was performed. For each individual dataset, the Pearson correlation coefficient between the mean time series of the left and right ROIs were computed and converted to z value using Fisher’s r-to-z transformation to improve the normality. Then, the general linear model (GLM) was applied to quantitatively compare group differences in the rsFC between stroke patients and healthy controls. In this process, age and sex were treated as covariates of no interest. Differences between two groups were considered significant if P < 0.05. Correlation analysis was performed to assess the relationship between the FA values of the affected CST and the M1-M1 rFSC.

Patients with stroke and healthy controls did not differ demographically. Stroke lesions were in the basal ganglia, thalamus, internal capsule and corona radiata, 9 on the right and 11 in the left hemisphere. Median Fugl Meyer score was  94/100 consistent with excellent motor recovery. Stroke patients with good outcomes demonstrated an increased rFSC M1-M1 connectivity and this was negatively correlated with the FA of the affected CST.

How does one understand these results? In simple terms, a subcortical stroke in the whereabouts of the corticospinal tract results in decreased fractional anisotropy of the tract itself. Increased rFSC represents an attempt by the brain to bypass the affected CST and improve motor cortex connectivity. The rFSC hence is a compensatory mechanism towards motor recovery.  This is a rather complex study, with small number of patients but it re-enforces that neural plasticity is of key importance in stroke recovery. Overall, it is very reassuring to know that the brain is connecting via alternate pathways!

Prognostic significance of perihematomal edema in acute intracerebral hemorrhage: pooled analysis from the INTERACT studies

Rajbeer Singh Sangha, MD

Yang J, Arima H, Wu G, Heeley E, Delcourt C, Zhou J, et al. for the INTERACT Investigators. Prognostic Significance of Perihematomal Edema in Acute Intracerebral Hemorrhage: Pooled Analysis From the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Studies. Stroke. 2015


The effects of the inflammatory response to intracranial hemorrhage (ICH) include toxicity of blood breakdown products, free radicals and perihematomal edema (PHE). Initial volume and subsequent growth of the hematoma is pivotal to determining outcome in ICH, but perihematomal edema (PHE) also contributes to the risk of death and disability from raised intracranial pressure and possibly hydrocephalus. In past studies, volumetric measurements have been performed to explore whether PHE is an independent predictor of outcome and have shown no statistically significant associations which have been attributed to limited power. The authors of this study investigated the prognostic significance of PHE by analyzing over 1000 patients with acute ICH combining data from INTERACT1 with those of the main phase INTERACT2. 

INTERACT1 and INTERACT2 were international, multicenter, prospective, open, blinded endpoint, randomized controlled trials that enrolled 404 and 2839 patients respectively. The patients enrolled were those with spontaneous ICH within 6 hours of onset and elevated systolic blood pressure (SBP, 150-220 mmHg) who were allocated to receive intensive (target SBP <140 mmHg within 1 hour) or guideline-recommended (target SBP <180 mmHg) BP lowering treatment. Patients were included in this analysis if they had 2 CTs available for edema analysis and outcome information. Of the 1138 (87%) patients analyzed, time from ICH onset to baseline CT, baseline hematoma volume, 24-hr hematoma growth, and intraventricular extension were independent predictors of 24-hr PHE growth. Absolute growth in PHE volume was significantly associated with death or dependency (adjusted OR 1.17, 95%CI 1.02-1.33 per 5 mL increase from baseline; p=0.025) at 90 days after adjustment for demographic, clinical and hematoma parameter prognostic factors.

Interestingly, the results show less growth of PHE in the intensive group, suggesting an effect of early intensive BP lowering on PHE. Furthermore the use of mannitol was one of the factors that also independently predicted growth of PHE. The authors recognize that this study is limited in its scope to the first 24 hours as PHE is recognized to expand beyond this time point, reaching a peak in growth after at least several days, and sometimes a few weeks. The results from this study and previous studies should spark further investigation into the factors that can mitigate and promote PHE growth in a patient. The role of MMP-9 has been implicated as a significant factor and correlation between location and PHE growth should also be investigated further. While the use of the INTERACT1 and 2 registry is useful in drawing some limited associations, focus should be placed on dedicated studies that investigate this topic in detail.

By |March 10th, 2015|treatment|0 Comments

The MoCA 5-minute Protocol for Cognitive Impairment Screening in Stroke/TIA Patients

Rizwan Kalani, MD

Wong A, Nyenhuis D, Black SE, Law LSN, Lo ESK, Kwan PWL, et al. Montreal Cognitive Assessment 5-Minute Protocol Is a Brief, Valid, Reliable, and Feasible Cognitive Screen for Telephone Administration. Stroke. 2015

Vascular cognitive impairment (VCI) is being increasingly recognized, particularly in patients with stroke and TIA. The Montreal Cognitive Assessment (MoCA) is a validated and reliable screening tool for VCI, but requires a significant amount of time and the physical presence of the patient being examined. Wong et al constructed a 5-minute protocol, based on 4 subtests of the MoCA, and tested the validity and reliability of its administration by 

Patients were recruited from the longitudinal Stroke Registry Investigating Cognitive Decline (STRIDE) study. This enrolled patients with stroke or TIA from a major hospital in Hong Kong between 2009 and 2010. Those with pre-stroke dementia or moderate/severe dementia (defined by clinical dementia rating scale (CDR) ≥2) were excluded. At annual clinical assessment, patients in this study were assessed with the full MoCA, mini-mental state exam (MMSE), and cognitive dementia rating (CDR) scale. The MoCA 5-min protocol consisted of four tests evaluating five cognitive domains – attention, orientation, language, verbal learning and memory, and executive function – with a score range of 0-30. This was administered to patients by telephone one month after the clinic visit.

104 patients participated in this study, with assessment being an average of (±SD) 39.4 (±7.6) months after discharge for stroke/TIA. 49% of them had cognitive impairment. The MoCA 5-min protocol actually took ~5 minutes to complete by telephone whereas the full MoCA took ~12 minutes in clinic. The total scores between the two assessments were highly correlated (r=0.87, p<0.001). The score on the MoCA 5-min protocol was about 1.8 points higher on average than the MoCA. The cognitively impaired (CDR≥0.5) did more poorly on the MoCA and MoCA 5-min protocol (and all of its items scores) (p<0.001) compared to those with normal cognition. Importantly, those with executive domain impairment had significantly lower scores on the 5-min protocol compared to those without (15.6 vs 23.6, p=0.001). Thirty of the patients completed a repeat MoCA 5-min protocol about one month afterwards, with excellent reliability between the two assessments (intraclass coefficient 0.89).

This study demonstrates that a 5 minute telephone version of a cognitive screening tool can be useful, feasible, and reliable in stroke/TIA patients. Such testing could be very impactful for both research and clinical purposes. Future studies will have to evaluate this screening method in other populations and compare it to other brief cognitive evaluations that can be administered remotely by telephone and other methods.

Can ambulatory cardiac telemetry tell us more than we know?

Chirantan Banerjee, MD

Gladstone DJ, Dorian P, Spring M, Panzov V, Mamdani M, Healey JS, et al. Atrial Premature Beats Predict Atrial Fibrillation in Cryptogenic Stroke: Results From the EMBRACE Trial. Stroke. 2015

Cryptogenic stroke patients have received a lot of research interest in the last couple of years. CRYSTAL AF and EMBRACE trials were published in June last year and made a strong case for longer duration of cardiac telemetry, especially in patients above age 55. Since these trials came out, several studies have found associations between EKG abnormalities such as QTc, as well as cardiac echo abnormalities such as left atrial enlargement with future detection of paroxysmal atrial fibrillation (PAF). For stroke providers, tools that help stratify a patient’s pretest probability assume special relevance as they may help tailor how long should a patient be monitored for PAF.

In the current edition of Stroke, Gladstone et al. used data from the EMBRACE trial to investigate the association between Holter-detected atrial premature beats (APB), in addition to age and left atrial enlargement, on the subsequent detection of AF by 30-day ECG monitoring, and during clinical follow-up over 90 days and 2 years. This was a pre-planned subanalysis of patients in the intervention arm of the trial, who received the AF auto-detect ECG loop recorder for up to 30 days. In 237 participants, they found that those who subsequently had AF detected had 629 APBs/24h vs. 45 in those without AF. APB count was a significant predictor of AF detection in a multivariable logistic regression analysis at all the time-points chosen (30 days, 90 days , and 2 years). The authors were also able to demonstrate a dose response relationship between APBs detected and AF detection rate.

The authors thus establish APBs as another biomarker that may help stratify a cryptogenic stroke patient’s risk of undetected PAF. The authors propose that those with with >1000APBs /24 hours may warrant longer than 30 day monitoring, and those with <500APBs/24 hours may need just 2 weeks. We are heading towards an era of individualized medicine, and novel biomarkers like this one are leading the way!

Walking the Walk: Gait Measures as Predictors of Post-Stroke Cognitive Function

Vikas Pandey, MD

Assayag E, Shenhar-Tsarfaty S, Korczyn A, Kliper E, Hallevi H, Shopin L, et al. Gait Measures as Predictors of Poststroke Cognitive Function: Evidence From the TABASCO Study. Stroke. 2015

Cognitive impairment related to stroke is a hot topic for discussion given the fact that cognition, obviously, is something that is very important to patient themselves as well as their long-term functionality, however is something that is not as easily predictable given the poor true localization of cognitive pathways. Cognitive impairment is not something that is immediately addressed when dealing with stroke patients. An example of this would be how carotid stenosis may be asymptomatic given the usual definitions of the term that are lack of speech, motor, sensory or visual deficits related to the carotid stenosis, however may be truly “symptomatic” from the cognitive standpoint (i.e. slower processing ability, poor short term memory, impaired concentration, etc). There have been established links previously between motor and cognitive domains in stroke patients however the reason for these connections has not been illuminated. Rightfully, the group from Israel decided to address the issue of post-stroke cognitive decline and test whether the assessment of balance and gait has any impact on prediction of long-term cognitive outcome in stroke survivors.

The group took 298 patients with first-time mild to moderate stroke or TIA from the TABASCO cohort which followed patients for at least 2 years with neurologic, neuropsychological, and mobility examinations. They found that 15.4% of the patients suffered cognitive decline over the 2 years of follow-up, but that these patients did not differ in neurological deficits or infarct volume/location compared to the group that did not decline. A specific test (Timed Up and Go) assessing patient mobility showed that there was a difference in the cognitive decline group (performed the test slower) compared to the cognitively intact group (p < 0.001). Other measures that were different were that the cognitive decline patients had lower Berg Balance scores (non-vestibular balance test), slower gait (p<0.001) and fewer correct answers during dual-task walking (p = 0.006). They found that patients with a Timed Up and Go time of 12 seconds at 6 months post-stroke/TIA was a significant independent risk marker of cognitive decline 24 months post-stroke (OR= 6.07, 95% CI: 1.36-27.15).

The authors found a link between balance and gait measures and development of cognitive impairment. These are tests that are routine and are rather simple to perform and thus there is high utility in performing these tests to predict those who are at higher risk of developing cognitive impairment. Perhaps it is these patients who would benefit from early intervention such as with cholinesterase inhibitors to prevent the progression of their decline. The understanding of why this link is present would also be important to explore and so the authors should be applauded for opening the door to new possibilities of discovery in an area that is currently underdeveloped.

Posted by Vikas Pandey (@DrVikasNeuro)

Results of Phase I Acute Stroke Treatment Trial: Tenecteplase for Minor Stroke & Intracranial Occlusion

Mark N Rubin, MD

Coutts SB, Dubuc V, Mandzia J, Kenney C, Demchuk AM, Smith EE, et al. Tenecteplase–Tissue-Type Plasminogen Activator Evaluation for Minor Ischemic Stroke With Proven Occlusion. Stroke. 2015

As we recently discussed, there is a fair amount of heterogeneity in the evaluation and treatment of “minor strokes,” which actually represents the most common reason to not provide IV tPA. This is based on the assumption that the natural history of minor stroke is benign and the deficits amenable to rehabilitation. Even those of us firmly committed to syndromic neurology, however, have to admit that minor strokes can fool us with early and/or severe recrudescence. This is particularly the case in the presence of a cervical or intracranial arterial occlusion, which is probably an under-recognized phenomenon due to the fact that many stroke providers do not perform angiography of any kind in the setting of acute but minor stroke.

This study was a multicenter Phase I dose-escalation trial of tenecteplase for minor stroke (NIHSS < or = 5) within 12 hours of symptom onset. Fifty patients were enrolled, the first 25 getting 0.1mg/kg and the subsequent 25 received 0.25mg/kg (half the approved dose for coronary occlusion, as a frame of reference). The primary endpoint was safety, namely symptomatic ICH (defined idiosyncratically alongside SITS-MOST, ECASS, NINDS, etc.), extracranial hemorrhage or allergic reaction. Secondary endpoints included vessel recanalization (repeat CTA 8-12h after bolus) and 90 day mRS. Patients were followed in-person in a standardized format. The details are in the manuscript, but the basic idea is that 66% of the patients achieved an excellent outcome (mRS 0-1) and 90% good outcome (mRS 0-2) in this cohort, and the only adverse event was a single temporal hematoma in the distribution of a symptomatic occlusion and this was in the larger dose group.

The nebulous clinical phenomenon of “minor stroke” is difficult for patients and providers, and this is highlighted by the upwards of 34% of patients deemed to have a minor stroke that end up disabled or dead within 90 days of their supposedly minor stroke. Since the majority of these patients seem to have a relatively benign course, the level of risk tolerance in this setting is appropriately low, which is probably why tPA is so infrequently given in this population, possibly to their detriment and also to those with a wolf in sheep’s clothing: an intracranial occlusion with minor symptomatology. That being the case, these data are exciting but, as the authors suggest, a carefully designed Phase II trial is warranted to see if we might be able to provide safe and effective therapy for this not-so-uncommon cohort of minor stroke with intracranial occlusion.

By |March 4th, 2015|treatment|0 Comments

Determining Rates of Dementia in Stroke/TIA Patients – The Impact of Selection Bias

Rizwan Kalani, MD

Pendlebury ST, Chen PJ, Bull L, Silver L, Mehta Z, and Rothwell PM, for the Oxford Vascular Study. Methodological Factors in Determining Rates of Dementia in Transient Ischemic Attack and Stroke: (I) Impact of Baseline Selection Bias. Stroke. 2015

Rates of dementia in the first year after stroke have varied in prior studies. In this report, Pendlebury et al evaluated the methods used for measuring TIA/stroke-related dementia rates to better understand potential sources of bias. They looked at the impact of various study entry criteria on the pre- and post-event rate of dementia from a large population-based study.

Patients with TIA or stroke (as defined by the WHO criteria) from 2002-2007 were assessed from the Oxford Vascular Study, a prospective cohort study from Oxfordshire, UK. Cognitive testing was done using the MMSE, MoCA (or telephone MoCA), and telephone interview for cognitive status (TICS) assessment at 1, 3, and 6 months as well as 1, 5, and 10 year follow-up. Pre-cerebrovascular event dementia was recorded when it was a listed diagnosis at the time of the index TIA/stroke (from documentation by primary care provider) or determined by physician review of prior patient records. Post-event dementia was diagnosed when MMSE<24 or MOCA<20, telephone MOCA<9, or TICS<22 during follow-up assessment (those with pre-event dementia were excluded). For those who could not complete testing (due to aphasia, visual field loss, etc.), primary care physician records and collateral history from patient informant/family was used to determine cognition using the DSM-IV criteria.

1,234 patients were evaluated – 33% with TIA, 37% with minor stroke (NIHSS≤3), 30% major stroke, and 5% ICH. 1189 patients were alive at ascertainment and 1097 patients completed baseline assessment. The authors found that pre-stroke dementia rates were >2 times higher in those who died early. This resulted in a true population-based pre-event dementia rate that was one-third higher than when measured in the 1097 surviving patients. When excluding patients who were age>80 years or functionally impaired (mRS≥3), the pre-event dementia rate was cut in half – from 8% to 3% (p<0.001). Excluding aphasic patients or those with significant co-morbidities reduced the pre-event dementia rate by about a quarter. Rates were ~2-fold higher in hospitalized compared to non-hospitalized patients in both pre-event (10% vs 6%, p=0.01) and post-event (24% vs 11%, p<0.0001) dementia. Newly diagnosed post-event dementia was three times more common in those >80 years old (27% vs 9%, p<0.0001) and those with prior functional impairment (39% vs 10%, p<0.0001); it was also significantly higher in aphasic patients (22% vs 15%, p=0.02).

This study demonstrates that various selection criteria can influence pre- and post-event dementia rates when applied to a large cohort. Prior studies have excluded patients who were older, aphasic, had baseline functional impairment, and those who could not be available for study assessment. As shown in this report, this can have a substantial effect on measured rates of dementia after stroke/TIA.

The authors used collateral information – from primary care provider records, patient informants/family, etc. – to determine cognition in those who could not be formally tested in this study. They also depended on cognitive assessment scores for determining dementia rather than a making a true clinical diagnosis. Despite the limitations of the manuscript, a valid point is made – future studies that assess pre- and post-stroke/TIA cognitive impairment should be as inclusive as possible to maximize validity.

Novel means of identifying & quanitfying occult antegrade flow with brain vessel occlusion, a predictor of early recanalization

Mark N. Rubin, MD

Hwan Ahn SH, d’Esterre CD, Qazi EM, Najm M, Rubiera M, et al. Occult Anterograde Flow Is an Under-Recognized But Crucial Predictor of Early Recanalization With Intravenous Tissue-Type Plasminogen Activator. Stroke. 2015

Clinical experience and the published evidence all suggest that tPA is most effective for intracranial vessel occlusive disease when the drug is able to hit and penetrate the thrombus, whether it gets there through typical IV/IA measures, supported by ultrasound or mechanical thrombectomy. The particular concern with large proximal clots is that the tPA is delivered to the arterial dead-end and unable to work on the extensive thrombus. We know from our diagnostics, particularly transcranial Doppler and conventional angiography, that in the presence of what looks like a complete dead end on non-invasive angiography actually allows for minimal flow around the thrombus. However, this finding remains descriptive and of unknown clinical significance.

An international collaboration of stroke neurologists studied the use of a CT perfusion algorithm focused on contrast delay to quantify this very phenomenon and correlate it to vessel recanalization. The details of the sequence – not currently a mainstream clinical parameter – are in the manuscript but, on a very basic level, the CT study is of the time delay of contrast moving across a CTA-identified thrombus. Lower delay time to the distal end of a thrombus, and indicator of occult antegrade flow, predicted early recanalization as compared to those with longer delay time. In multivariate analysis, patients with occult antegrade flow and a delay of < 2s were 12 times more likely to have early recanalization (within 4 hours in this study) than those with a delay of > 2s.

These data have implications for clinical practice. The first application that comes to mind is that the detection of occult antegrade flow with a proximal occlusion may be a biomarker of the rare bird who responds favorably to IV tPA alone. This finding may also assist in the selection of multimodal clot extraction tools. Studies for another day!