American Heart Association

Monthly Archives: March 2013

Changing Demographics at a Comprehensive Stroke Center

Jose Gutierrez, MD, MPH

  • Albright KC
  • Boehme AM
  • Mullen MT
  • Seals S
  • Grotta JC, 
  • and Savitz SI.
  • Changing Demographics at a Comprehensive Stroke Center Amidst the Rise in Primary Stroke Centers. Stroke. 2013

    Rapid access to care after an acute stroke is one of the most important aspects to improve the outcomes of this devastating disease. Primary and comprehensive stroke centers have a shared objective, to give IV-TPA as soon as possible if the situation warrants it. Comprehensive stroke centers are usually involved in carrying on clinical trials and have access to a multidisciplinary team that includes neurointensivist, neurosurgeons, and neuroradiologist, among others. We usually think of cases from a comprehensive stroke center, usually, tertiary care centers, to have a referral bias due to the complexity of their disease.

    In this issues of stroke, Albright et al. present data from the Houston metropolitan area that shows a shifting referring bias. While early in 2005 the majority of their stroke patients were brought directly to their hospital, 6 years after almost half of their patients were transfers from outside hospitals. This increased rates of transfers did not affect the overall rates of IV-TPA. The majority of the transfers were either intracerebral hemorrhages or minor strokes while the proportion of large artery occlusion strokes fell.The overall impact of the observed change was lower odds of enrollment in time-sensitive acute stroke clinical trials. The authors attributed this change to the increase in the number of primary care centers in the area.
    Although it is encouraging that the rates of IV TPA were not affected, it is worrisome that the enrollment in clinical trials has dropped. After all, without clinical trials like the NINDS, IV-TPA would not be in our landscape. Favoring recruitment of eligible patients in stroke trails seems a priority in planning the delivery of acute stroke care. But, some question arise: What would the role of primary care centers if all stroke were to be transferred to a comprehensive stroke center? Could we imagine a triage scheme that allows EMS to bypass primary care centers to comprehensive stroke centers for patients with more severe strokes without compromising the time to administer IV-TPA? What would be the financial incentives for smaller hospital to gear up and set up stroke care if more stroke cases are to be transferred to larger, comprehensive stroke center? The realities of stroke care vary widely in the US, so a one fit for all seem elusive, but the results from the UT Houston group open the conversation.

    Atrial Fibrillation is Associated With Reduced Brain Volume and Cognitive Function Independent of Cerebral Infarcts

    Shruti Sonni, MD

    Stefansdottir H, Arnar DO, Aspelund T, Sigurdsson S, Jonsdottir MK, Hjaltason H,et al. Atrial Fibrillation is Associated With Reduced Brain Volume and Cognitive Function Independent of Cerebral Infarcts. Stroke. 2013

    This large study by Arnar et al. aimed to assess the association between atrial fibrillation (AF)and brain structure and cognition in an elderly population. Measurements obtained included brain volume, presence of infarcts on MRI and cognitive battery tests including memory, speed of processing and executive function. The results showed that patients with AF had lower total brain volume, total gray and white matter, and higher volume of white matter hyperintensities. This association was stronger with persistent or permanent AF and there was a trend with increased time since diagnosis, suggesting a cumulative negative effect of AF on the brain.
    These findings may be explained by multiple microembolisms in AF causing microinfarcts and resulting atrophy, especially in the hippocampus. Another factor contributing is beat by beat variation in stroke volume, with previous studies suggesting cerebral perfusion is more affected in patients with persistent AF than paroxysmal AF. One of the drawbacks of this study was that the authors were unable to record the frequency and length of AF at enrollment, and hence were unable to fully assess the actual burden of AF. Future prospective studies need to determine the importance of maintaining sinus rhythm to prevent brain atrophy and cognitive decline, and these parameters should be considered as endpoints in future trials looking at outcomes in AF.

    Parkinsonism is a Late, Not Rare, Feature of CADASIL

    Nandakumar Nagaraja, MD

    Ragno M, Berbellini A, Cacchiò G, AMancaA, Di Marzio F, Pianese L, et al. Parkinsonism is a Late, Not Rare, Feature of CADASIL: A Study on Italian Patients Carrying theR1006C Mutation. Stroke. 2013.

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small-vessel disease caused by mutations in the NOTCH3 gene. Ragno and colleagues report 5 CADASIL patients with R1006C mutation in the exon 19 of the NOTCH3 gene who develop parkinsonism during the late stage of the disease. 

    These patients are characterized by slow onset of parkinsonism symptoms after the diagnosis of CADASIL with early shuffling of gait, akathesia, rigidity, and postural instability but with rare presence of tremor. Symptoms are bilateral and non responsive to treatment with levodopa unlike idiopathic Parkinson’s Disease. MRI shows increased signal in periventricular white matter, internal and external capsules, basal ganglia and thalamus.

    Parkinsonism was seen in only 5 (11%) of the total 45 CADASIL patients with R1006C mutation followed by the authors. Based on previous literature basal ganglia symptoms were present in 48% of patients older than 60 years. Parkinsonism is probably a late feature of many CADASIL patients irrespective of type of mutation in the NOTCH3 gene because of the involvement of basal ganglia and its connections. The significance of different types of NOTCH3 mutation in these patients causing phenotypic variability in the presentation of parkinsonism symptoms remains to be determined.

    Strictly Lobar Microbleeds Are Associated With Executive Impairment in Patients With Ischemic Stroke or Transient Ischemic Attack

    Jiaying (Jayne) Zhang, MD



    Cerebral microbleeds (CMBs) are small perivascular hemorrhages seen on MR susceptibility sequences. They are markers of microangiopathic disease mainly classified into two general patterns: deep CMBs signifying hypertensive arteriopathy; and strictly lobar CMBs signifying Cerebral Amyloid Angiopathy (CAA). CMBs are increasingly recognized as a hallmark of small vessel pathology. The rationale for studying CMBs and its correlation to cognitive dysfunction stems from the putative relationships between cerebral small vessel disease, vascular cognitive impairment (VCI), and Alzheimer’s disease (AD). Studies have shown the synergistic effect of cerebrovascular disease and neurodegenerative pathology in producing more severe cognitive dysfunction.

    Although the association between CMB and cognitive function has been explored in the past with large population studies, the nature of this link in the stroke population is obscure. As such, in a study by Werring et al, the authors investigated this relationship in a cohort of patients with known ischemic strokes or TIA who had undergone MRI (including GRE T2*-weighted and FLAIR sequences), and complete neuropsychological testing in multiple cognitive domains. The study also looked at what location of CMB is most associated with cognitive dysfunction. Of the 320 patients included, at least one CMB was identified in 72 patients (22.5%). Thirty patients (42%) had strictly lobar CMBs. Impairment in executive functions, but not other cognitive domains, was more prevalent in patients with CMBs regardless of the location. Moreover, the presence and number of strictly lobar CMBs (≥1 or ≥5) was independently associated with increased likelihood executive impairment.

    The results of this study bring several points to mind. First, whether there is a direct cause and effect between CMBs and cognitive impairment remains unclear. Second, this study gives added evidence that strictly lobar CMBs may reflect cognitive impairment associated with CAA. Finally, while Gradient-echo is widely used as a standard sequence for detecting hemosiderin on MRI, newer MRI techniques such as T2*-weighted angiography (SWAN) and Susceptibility-weighted imaging (SWI) will be even more sensitive at uncovering the presence of CMBs. As the authors suggested, ascertaining the exact nature of the co-existence and interaction between neurodegenerative and cerebrovascular processes may have important implications for the treatment and prevention of cognitive impairment in stroke patients.

    The Natural History of Depression up to 15 Years After Stroke

    Tareq Kass-Hout, MD

    Ayerbe L, Ayis S, Crichton S, WolfeCDA, Rudd AG. The Natural History of Depression up to 15 Years After Stroke: The South London Stroke Register. Stroke. 2013.

    In a study recently published online in Stroke, Ayerbe and colleagues are studying the incidence, prevalence, duration, and recurrence rate of depression up to 15 years after stroke. Evidence on the natural history and prognosis of depression after stroke is still lacking which complicate treatment strategies. Interventions for depression after stroke has limited effect because it is not started at the right time or not given for an adequate length of time to obtain maximal sustained response.

    This is a prospective population-based cohort of 1233 patients, in the South London Stroke Register between 1995 and 2009, showed that the incidence of depression post-stroke was 7-21% in the 15 years following stroke. Thirty three percent of post-stroke depression started in the first three month, half of them recovered after one year. Interestingly, proportion of recurrence ranged from 38% in year two to 100% in year 14.

    Post-stroke depression requires periodic clinical attention in the long term. This study shed  light on the high rate of recurrence of depression post-stroke. Assuming that a patient recovering from depression is a “closed case” could lead to a late diagnosis or an overlooking of a further episode.

    Reducing Delay of Carotid Endarterectomy in Acute Ischemic Stroke Patients

    Vasileios-Arsenios Lioutas, MD
    Carotid artery disease is a frequent cause of ischemic infarction and carotid endarterectomy (CEA) is a well established method in preventing recurrent stroke. In the past, unjustified fear of complications delayed operation for several weeks post-stroke, in effect negating its beneficial effect. Analysis of pooled data from large CEA trials clearly showed that the benefit from surgery is time-dependent and maximal if performed within the first two weeks after stroke, leading to a revision of guidelines and clinical practice.
    In this study, Witt et al. describe the effect of a multidisciplinary nationwide initiative aiming to reduce the time to CEA after acute ischemic stroke, using data from the Danish Stroke and Vascular Registries. Percentage of patients receiving CEA within 2 weeks and carotid ultrasound within 4 days from stroke is used as metrics.

    The results undeniably show an improvement in both outcomes following the implementation of new, stricter national guidelines. Many questions are raised, however: Was there a similar trend toward reduction in stroke recurrence? Was there in increase in CEA-related complications? Additionally, patients with TIAs were not included in this analysis and it would be interesting to know how this would affect the results.

    It is striking that a majority of patients (exceeding 50%) are still operated more than 2 weeks after the stroke and despite the nationwide initiative, the median time to surgery is 16 days. Notably, this occurs in the context of a well organized, essentially universal healthcare system, not lacking access to technological advances. First and foremost, the study shows very clearly that there is still significant potential for improvement.


    Perfusion Computed Tomography Adds Value

    Jose Gutierrez, MD, MPH
    Is perfusion imaging useful to predict stroke outcome at 90 days? As per Zhu et al. it might be. The investigators present data on 165 patients with acute stroke secondary to an ICA or m1 occlusion that underwent reperfusion therapy on an average of almost 9 hours from stroke onset, mostly in the form of IA TPA, although a minority received TPA as well. The author obtained, among other clinical variables, the core infarct and perfusion volumes as well as 90 day mRs as the outcome. In ordinal logistic regression, they found that the infract volume can be predicted by clinical and radiological data including CTA but not the perfusion volumes. Recanalization status (yes vs. no), age and baseline NIHSS were all independent predictors of outcome at 90 days. They also found that the perfusion volume was a predictor of good outcome, although it was recanalization status dependent. 

    The authors in their discussion suggest that learning perfusion status might help identify patients in whom interventions can be planned to rescue the “tissue at risk”. After the International Stroke Conferencepresentations in Honolulu and simultaneous publications of three large acute stroke trials, one of them focused on selecting patients for acute intervention based on “penumbra imaging”, we could say that penumbra imaging per se failed to identify those who might benefit from an intervention (i.e., embolectomy) other than IV TPA. So, how do we contextualize the results by Zhu et al. in the post MR-RESCUE era? Could it be the case that IA TPA and not embolectomy might be beneficial for patients with a penumbra pattern? In IMS-III and MR-Rescue, the time to intervention was significantly shorter than the one presented by Zhu et al., but the rates of good outcome were smaller. What factor can contribute to this observed discrepancy? Are biases from observational studies playing a role? The evolving field of acute stroke treatment has become even more exciting, but “time is brain” and “IV-TPA” appeared to be the only two unscarred concepts to lead the fight.

    The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial

    Shruti Sonni, MD

    Butcher KS, Jeerakathil T, Hill M, Demchuk AM, Dowlatshahi D, Coutts SB,et al. The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial. Stroke. 2013; 44: 620-626.

    Determining a balance between blood pressure that is neither too high leading to hematoma expansion, nor too low leading to hypoperfusion has always been a challenge in patients with acute intracranial hemorrhage. Butcher et al. randomized 75 spontaneous ICH patients within 24 hours to two groups, one with goal SBP<150 and the other with goal SBP<180. They obtained CT perfusion images to assess perihematoma relative CBF, which was defined as the difference between perihematoma and contralateral homologous region CBF. The result was that perihematoma relative CBF was not different in both groups, leading to the conclusion that acute BP reduction does not lead to cerebral ischemia.

    This study reproduced the safety of acute BP lowering shown in the INTERACT trial. A recent study has shown the development of ischemic DWI lesions on MRI in bilateral hemispheres associated with BP reduction in ICH patients. This raises the question that relative CBF may not the best parameter to determine risk of ischemia, and this may be better demonstrated in a prospective study utilizing MRI. The authors address this concern by pointing out that there was no significant difference found in relative CBF of the contralateral hemisphere in the two groups. Neverthless, this study addresses an important and commonly encountered question regarding the safety of aggressive BP lowering in the acute phase in ICH patients.

    Incidence and Associations of Poststroke Epilepsy

    Vasileios-Arsenios Lioutas, MD

    Post-stroke seizures, especially in the acute phase is a relatively well described and understood entity, but the incidence of post-stroke epilepsy, especially in the long term is far less thoroughly studied. In this interesting population-based study, Graham et al. investigate the epidemiology and associations of post-stroke epilepsy utilizing data collected over a 12-year period in the South London Stroke Register of first strokes.

    Salient findings are the increase of epilepsy incidence with time from stroke (up to 12.4% at 10 years), as well as independent association of large, anterior circulation strokes and presence of signs of cortical involvement (dysphasia and visual neglect). These findings are on a par with conventional wisdom; one would expect large lesions with cortical involvement to lead to epilepsy as opposed to smaller, subcortical strokes. However, there are also less expected results, the most outstanding being an inverse association between age and post-stroke epilepsy incidence. The explanation offered by the authors – that younger patients are more likely to experience large, cortical infarcts – is more hypothetical than factual at this point and merits further in-depth study.

    Despite several limitations, most importantly the fact that the diagnosis of epilepsy was self-reported and not confirmed by a physician, the study offers provides potentially useful information both for patients and physicians and more importantly underlines the need for prospective studies possibly including prophylactic antiepileptic treatment post-stroke.

    Temporal Pattern of Cytotoxic Edema in the Perihematomal Region After Intracerebral Hemorrhage

    Nandakumar Nagaraja, MD

    Whether the cytotoxic edema (CE) exists surrounding the hematoma in patients with intracerebral hemorrhage is still a controversy and the clinical significance of CE in the perihematomal region is unknown.  In a recent article by Li et al., 21 patients with primary ICH were prospectively evaluated with MRI at 24hrs, 3 days and 7 days for the presence and temporal pattern of CE.

    Areas of increased DWI with corresponding reduced ADC value by more than 10% compared to mirror ROI were interpreted as CE. CE was seen on day 1 in 45% of patients, persisted till day 3 and significantly reversed by day 7.  Presence of CE on day 1 was associated with higher NIHSS and larger perihematomal edema (PHE). Patients with CE had faster PHE growth within the first 24hours but had significantly attenuated PHE volume growth during the first week compared to those without CE. 

    The authors suggest that the presence of CE indicates secondary brain injury in patients with ICH and determines prognosis. Unfavorable outcome defined as mRS 4-6 at 90days was associated with larger PHE volume on day 3, and a trend was noticed in patients with CE on day 3 but not with baseline hematoma volume.  

    The authors state that the CE is a reversible step if the compensatory mechanisms such as ATP pump activity are still effective. The concept of reversal of CE is exciting. There are several reports of reversal of restricted diffusion after thrombolysis in acute ischemic stroke patients. However, whether it represents the same pathophysiological process in patients with ICH or if it is pseudonormalization of ADC remains to be determined.