American Heart Association

Monthly Archives: May 2015

Do alcoholics benefit less from tPA?

Ali Saad, MD

Lemarchand E, Gauberti M, Martinez de Lizarrondo S, Villain H, Repessé Y, et al. Impact of Alcohol Consumption on the Outcome of Ischemic Stroke and Thrombolysis: Role of the Hepatic Clearance of Tissue-Type Plasminogen Activator. Stroke. 2015

The authors put 10% alcohol in mice’s drinking water and allowed them to drink as much as they’d like for 6 weeks. the volume of consumed liquid was similar to the control group who got regular water. They then injected the mice with thombin directly into their MCAs followed by tPA 20 minutes later. Both groups were randomized to either tPA or saline injections (placebo) resulting in 4 treatment groups. finally they got MRIs on them at 2h30min and 24 hours from thrombin administration.

Mice who had been drinking alcohol had 115% larger DWI volumes on MRI compared to control mice who just drank water (p<0.05) when scanned at 2h30min. However, there was no significant difference in DWI volumes at this early time point between the mice who got tPA and those who got saline.

At 24 hours, the DWI volume on MRI remained significantly larger in the alcohol drinking mice compared to control at +78%, p<0.05. Control mice who got tPA had -61.3% DWI volume reduction compared to those who got saline, but this difference disappeared in the alcohol exposed mice. Moreover, the alcohol exposed mice had a 7.6 fold increase in the DWI volume between the 2h30min and 24 hour scans.

The authors did control for perfusion differences between alcohol and normal water mice and found that alcohol did not alter perfusion to the brain. There were no differences in brain swelling/bleeding between the 2 groups. What did change was that alcohol exposed mice had higher factor VII levels and lower PT, factor V, and platelet counts. Low density lipoprotein receptor-related protein 1 (LRP1), which is involved in tPA metabolism, was also down in the alcohol exposed mice. They also found that tPA remained enzymatically active and in the bloodstream significantly longer in the alcohol exposed mice and the penetration into brain tissue was also greater than control by 6 fold. The authors suggest that the neurotoxic effects of tPA is increased in alcohol exposed mice due to BBB leakage thereby leading to worse strokes.

Limitations of this study include: it is a murine model, strokes were induced artificially, and the longer term effects of alcohol on the liver and the clotting cascade are not assessed with this model. The authors mention specific changes to the clotting cascade, but state that there were no differences in the endogenous/exogenous fibrinolytic activity of the 2 groups, which seems contradictory.

Implications of the study would be if this were duplicated in human models, a history of alcoholism or low LRP1 might preclude someone from receiving tPA.

How does this literature change my practice? I might be less optimistic about the beneficial effects of tPA in patients with alcohol abuse. However, i would not withhold treatment. the BBB leakage of tPA leading to direct neuro-toxicity reinforces my belief that the decision to give tPA for stroke mimics is usually OK unless the differential includes RPLS or status epilepticus where there is likely breakdown of the blood brain barrier and increased risk of neuro-toxicity, stroke, or ICH.

Brain MRI findings fail to suspect Fabry disease in young patients with an acute cerebrovascular event

Rajbeer Singh Sangha, MD

Fazekas F, Enzinger C, Schmidt R, Grittner U, Giese AK, Hennerici MG, et al. Brain Magnetic Resonance Imaging Findings Fail to Suspect Fabry Disease inYoung Patients With an Acute Cerebrovascular Event. Stroke. 2015

Fabry disease (FD) is a genetic X-linked lysosomal storage disorder in which the patients are deficient of α-galactosidase A. Due to the deficiency of this enzyme, it leads to accumulations of globotriaosylceramide (Gb-3) into the vascular endothelial, neural and renal cells. Systemic manifestations of the disease include effects on the kidneys, cardiac functioning and central nervous system complications all of which occur later in life. Previous abnormalities that have been reported with FD in the brain include extensive white matter changes, cerebral infarctions primarily in the territories supplied by the posterior circulation and dilation of the vertebrobasilar vessels. One of the pathognomonic signs of FD include high signal intensity of the pulvinar thalami on T1-weighted MRI and this can be found in only a quarter of the patients. The authors of this study focused on analyzing MRI data of young stroke patients who had definite or probable FD. 

The SIFAP 1 study prospectively collected clinical, laboratory and radiologic data of 5023 patients (18-55 years) with an acute CVE. Biochemical findings and genetic testing served to diagnose FD in 45 (0.9%) patients and the MRI data was collected and interpreted centrally without knowing the diagnosis and compared between FD and non-FD patients. The authors found that the presence or extent of white matter hyperintensities, infarct localization, vertebrobasilar artery dilatation, T1-signal hyperintensity of the pulvinar thalami or any other MRI finding did not distinguish FD patients from non-FD CVE patients. Furthermore, the high signal intensity seen in the pulvinar thalami was not visualized in any patients with FD and in 6 non-FD patients. 

The authors conduct a well-designed study in which they analyze radiologic findings for patients with FD and subsequently find there are no significant predictors on MRI which could have be utilized to help direct diagnostic workup for patients. Due to the low power of the study, the authors are not able to make definitive conclusions regarding the ability of MRI to predict Fabry’s disease. They do acknowledge that a complete workup (genetic and laboratory testing) and consideration of clinical history is required in order to identify this difficult to diagnose condition. This holds true in the majority of stroke where the clinical exam, history and totality of findings help in arriving to the correct diagnosis, with radiologic imaging serving as an important tool giving surrogate markers of the disease process itself. With better imaging modalities and tools it is possible that these markers will improve in the near future.

Ischemia in Intracerebral Hemorrhage: The Blood Pressure Conundrum

Michelle Christina Johansen, MD

Gioia LC, Kate M, Choi V, Sivakumar L, Jeerakathil T, Kosior J, et al. Ischemia in Intracerebral Hemorrhage Is Associated With Leukoaraiosis and Hematoma Volume, Not Blood Pressure Reduction. Stroke. 2015

What corresponds to DWI lesions in intracerebral hemorrhage (ICH)? Is this reflective of true ischemic injury? The INTERACT trials refocused the neurointensivist on aggressive blood pressure control as this was shown to correlate with decreased hematoma growth and better functional outcomes. But is there a downside to controlling the blood pressure too aggressively? Does this result in ischemic insult or DWI changes on MRI? 

Dr. Gioia et al., sought to identify the frequency of ischemic lesions in primary ICH patients with the hypothesis that larger hematoma volumes and blood pressure reduction are associated with the presence DWI lesions. 

The Canadian based study retrospectively identified 117 ICH patients who underwent DWI within 14 days of symptom onset. Hematoma/perihematoma edema volumes were measured using planimetric techniques. Perihematoma and remote DWI lesion volumes were measured using apparent diffusion coefficient. The investigators established two thresholds to define the amount of ischemic damage; moderate (<730×10-6mm/s) and severe (<550×10-6mm/s). Acute blood pressure changes over the first 24 hours were calculated using the formula admission systolic blood pressure (SBP) minus nadir SBP. Mean age of the population was 65 and 52% were male. Hypertension was the most common cause indicated in the medical record for ICH (45.7%).

The authors, after controlling for age, baseline NIHSS and perihematoma edema volumes, found that perihematoma DWI lesions were independently associated with larger hematoma volumes. There was no association between changes in blood pressure (maximal systolic blood pressure drop) and the presence of DWI lesions. They did find remote DWI lesions in 17 patients. For the remote lesions, once again no relationship was found with blood pressure, but they did note these patients were more likely to use antiplatelet drugs, have a history of ICH and larger leukoaraiosis (hyperintensity on FLAIR) volumes.

How should the results of this study be applied? The mean time to MRI was 2 days which is a consideration when drawing conclusions between volumes and the presence of DWI lesions. That being said, there was excellent interreliability among the radiologists and they accounted for edema volume which should help mitigate over calculation of hematomal volumes. Blood pressure data was missing in 4 patients with perihematoma DWI lesions in a relatively small cohort of patients (38). Would a larger sample size have led to different results? How does the fact that the majority of patients had lobar ICH affect the data? Thus we are still unable to define the relationship between blood pressure control and patients with cerebral amyloid angiopathy.

Where does the vascular neurologist go from here when faced with perihematoma diffusion restriction after ICH? In ischemic injury, we allow for permissive hypertension to provide critical blood flow to the penumbra yet research supports aggressive blood pressure control for ICH. The authors of this study did not find a relationship between aggressive blood pressure control and ischemia but it cannot be ruled out. In their discussion, they suggest that larger hematomas be treated more conservatively with respect to blood pressure control but appropriately caveat this statement with the need for larger clinical trials. While the answer remains unclear, we must strive to clarify this issue so that our patients can receive the best medical care based on evidence.