Diabetes, admission glucose, and outcomes after stroke thrombolysis. A registry and systematic review

Diogo C. Haussen, MD

Desilles JP, Meseguer E, Labreuche J, Lapergue B, Sirimarco G, Gonzalez-Valcarcel J. Diabetes Mellitus, Admission Glucose, and Outcomes After StrokeThrombolysis: A Registry and Systematic Review. Stroke. 2013

Desilles J-P, Meseguer E, Labreuche J, Lapergue B, Sirimarco G, Gonzalez-Valcarcel J, et al. Diabetes, admission glucose, and outcomes after stroke thrombolysis. A registry and systematic review.

The association between diabetes or post-stroke hyperglycemia and poor clinical outcomes after thrombolysis has not been clearly defined. Desilles et al. present data derived from their local prospective registry and a metaanalysis evaluating this relevant issue.

The systematic review indicated that a history of diabetes and higher admission glucose level predicted worse functional outcomes and increased rates of symptomatic intracerebral hemorrhages. Interestingly, the data from their registry revealed that diabetes and initial glycemia did not influence endovascular recanalization rates.

The authors discuss the potential inhibitory effect of hyperglycemia in the fibrinolytic system and the deleterious consequences of high glucose levels on the blood-brain barrier. However, they acknowledge that stress-hyperglycemia induced by the stroke may simply constitute a marker of a more severe disease given its reported correlation with higher NIH stroke scale and larger infarct core volumes. This would hypothetically explain why intensive glycemic control was not found to lead to improved outcomes in hyperacute ischemic strokes, and makes us wonder about the causal relationship between hyperglycemia and poor prognosis.

Alcohol and Stroke Severity

Tareq Kass-Hout, MD

Ducroquet A, Leys D, Al Saabi A, Richard F, Cordonnier C, Girot M, et al. Influence of Chronic Ethanol Consumption on the Neurological Severity in Patients With Acute Cerebral Ischemia. Stroke. 2013

Ducroquet and colleagues conducted a study, recently published online in Stroke, to test if excessive chronic ethanol consumption is associated with higher severity of the neurological deficit in acute ischemic stroke. Even though this phenomenon has been seen in animal studies, such effect has not been evaluated in humans.

In this prospective observational cohort of a 436 patients with a median age of 70 years old, being classified as a heavy drinker was independently associated with more severe strokes (OR 2.26; 95%CI 1.06-4.82; p=0.034). There is not necessarily a causal relationship between ethanol consumption and stroke severity, but just a statistical association, which could be related to confounders that were not included in the analysis.

In short, the link between chronic heavy alcohol consumption and neurological severity in patients with acute cerebral ischemia is yet to be understood. This study, however, showed that excessive chronic ethanol consumption is associated with higher baseline stroke severity. As an interventional study would not be feasible, this question can be answered only through experimental approaches in animals.

Protamine and CAS

Aaron Tansy, MD

McDonald JS, 

Kallmes DF, 

Lanzino G, 

and Cloft HJ. 

Protamine Does Not Increase Risk of Stroke in Patients With Elective Carotid Stenting. Stroke. 2013

Still in its relative infancy, the neuroendovascular field has adopted many of its procedural methods from those within interventional cardiology and vascular surgery on the assumption that they have already been tested and deemed safe within these preceding domains. As a result, whether the safety and efficacy of many of these practices actually generalizes to the neuroendovascular field is still unproven. 

In a paper published in Stroke, Jennifer McDonald and colleagues address the safety and efficacy of protamine to promote hemostasis and reduce femoral access site bleeding after elective carotid angioplasty and stenting. The group performed a retrospective analysis of patient data culled from a national, multi-center database comparing outcomes for carotid stenting patients who received protamine matched against those who did not. For both primary (ischemic stroke or TIA) and multiple secondary outcomes including mortality, ICH, and peripheral vascular complications, post-procedure protamine administration was not associated with significantly worse outcomes. Only blood transfusion incidence was significantly higher for those who received protamine compared to those who did not.

Limited by its methodology including selection bias, urban-based hospital focus, unknown context for and non-standardized administration of protamine, this study does not provides any definite or readily generalizable conclusions. However, it does suggest that protamine’s use imparts no more danger than not using it after carotid stenting: in of itself, hardly a compelling reason for its use. Still, this finding provides a little fodder to evaluate further whether protamine’s post-procedural use may not only be no less safe, but also possibly safer.

Famridine for Stroke

Shruti Sonni, MD

Iaci JF, 

Parry TJ, 

Huang Z, 

Finklestein SP, 

Ren JM, 

Barrile DK. 

Dalfampridine Improves Sensorimotor Function in Rats With ChronicDeficits After Middle Cerebral Artery Occlusion. Stroke. 2013

In this study funded by two biotechnology companies, Laci et al. studied the effects of dalfampridine on persistent sensorimotor deficits after stroke. Dalfampridine, commonly marketed under the trade name ‘Ampyra’, is a potassium channel blocker that has been used extensively in demyelinating neurological condition such as spinal cord injury and multiple sclerosis. In ischemic stroke, it is thought to enhance function in areas of myelin damage or by enabling activation of undamaged pathways.

Rats underwent proximal MCA occlusions, and were administered Dalfampridine at 4 or 8 weeks after the ictus. Dalfampridine improved fore and hindlimb placing to stimuli, indicating recovery in sensorimotor systems and body swing symmetry indicating recovery in striatal function, both of which are affected by hemispheral infarcts.

A subsequent proof-of-concept study was conducted in 83 human post-stroke patients by Acorda Therapeutics Inc., and preliminary results appear promising in improving walking. The next step is a clinic development program, to be discussed with the FDA. This is an exciting new pharmacological opportunity in this largely affected population.

Silent Information Regulator 1 (SIRT1) and neuroprotection

Nandakumar Nagaraja, MD

Hernández-Jiménez M, Hurtado O, Cuartero MI, Ballesteros I, Moraga A, Pradillo JM. Silent Information Regulator 1 Protects the Brain Against Cerebral Ischemic Damage. Stroke. 2013

Silent Information Regulator 1 (SIRT1), also known as Sirtuin 1 is a NAD+ dependent protein deacetylase implicated in aging, neurodegeneration and ischemic preconditioning in the heart and brain.

In a recent article published in the journal Stroke, Hernandez-Jimenez and colleagues evaluated the role of SIRT1 in the mouse model of permanent MCA occlusion. The study showed that SIRT1 was found in the cytoplasm of neurons. Activation of SIRT1 resulted in decrease in infarct volume. Inhibition or genetic deletion of SIRT1 resulted in increase in infarct volume. They also found that SIRT1 played a role in inhibition of p53 and NFkB induced inflammatory and apoptotic pathways. Therapeutic agents that target SIRT1 and increase its activity could be potentially used for treatment of stroke to reduce the infarct volume.

Several neuroprotective agents that were shown to be effective in the laboratory have failed to show significant benefit in phase III clinical trials. In an effort to effectively translate preclinical studies into clinical trials the STAIR (Stroke Therapy Academic Industry Roundtable) committee has provided recommendations for the preclinical studies in the laboratory. Some of the recommendations include establishing efficacy in two or more laboratories, replication in a second species, studies involving females, aged animals and animals with co-morbid conditions such as hypertension, diabetes and hypercholesterolemia etc. In the next few years it would be interesting to watch out for such preclinical studies targeting SIRT1 modulation as a mechanism for neuroprotection in cerebral ischemia and also delineating the molecular cascade of events that result in neuroprotection.

Low DHEAS associated with increased risk of ischemic stroke in women

Waimei Tai, MD

Jiménez MC, 

Sun Q, 

Schürk M, 

Chiuve S,

 Hu FB, 

Manson JE. 

and Kathryn M. Rexrode. 

Low Dehydroepiandrosterone Sulfate is Associated With Increased Risk of Ischemic Stroke Among Women. Stroke. 2013

A large observational nested case-control study by Jimenez et. al. using collected data from the Nurses Health Study demonstrated decreased dehydroepiadrosterone sulfate (DHEAS) in women who have an ischemic stroke during the >10 year follow up period. 

DHEAS is the major precursor for 50% of androgens in men, 75% of estrogens in premenopausal women, and almost 100% of estogrens in postmenopausal women. Low DHEAS level has been previously associated with increased incidence of ischemic heart disease.  

In this study, the lowest quartile of DHEAS was associated with being older, less educated, higher prevalence of hypertension, high cholesterol, history of heart disease, and higher proportion of hormone therapy use. However, after adjusting for matching risk factors, women in the lowest quartile of DHEAS versus the highest quartile of DHEAS had a non-significant increased risk for ischemic stroke.

The authors propose that a novel association with a stable hormonal biomarker with increased ischemic stroke risk. Whether this is merely an association and a risk marker of underlying vascular disease, or a causative factor in ischemic stroke, be it directly or through its downstream androgenic/estrogenic activity, is unclear.

I think this is an interesting study, as it potentially proposes new markers of disease that may not have been previously studied. As the authors’ point out, this initial study may suggest other new research questions. Much work in the neuro-hormonal arena has been focused on how hormones act as neuro-transmitters, or interact in the brain’s chemical milieu. Now potentially new directions of research can look at how hormones act on cerebral vessels, or neuronal activity and recovery.

HgbA1c Predicts Symptomatic Hemorrhage after Thrombolysis in Ischemic Stroke

Waimei Tai, MD

Rocco A, Heuschmann PU, Schellinger PD, Köhrmann M, Diedler J, Sykora M. Glycosylated Hemoglobin A1 Predicts Risk for Symptomatic Hemorrhage After Thrombolysis for Acute Stroke. Stroke. 2013

Rocco, et al. published an interesting article recently looking at the relationship between glycosylated hemoglobin A1c and the risk of bleeding after an acute ischemic stroke. This was a registry study at a single, large stroke center of acute ischemic stroke patients treated with iv-tpa. Patients were evaluated for symptomatic intracranial hemorrhage (sICH) and other clinical factors including HgbA1c. Without surprise, higher NIHSS, history of diabetes, entry serum glucose and higher HgbA1c were associated with a higher sICH rate. In fact, the c-statistic for HgbAc was 0.8 to predict sICH which is quite high for a clinical parameter.

In addition, after multivariate anaylsis, age, NIHSS and HgbA1c were independent predictors of dependent status (mRS 3-5). Similarly age, history of diabetes sICH, and HgbA1c predicted risk of death at 90 days.

Previous studies have suggested that diabetes and hyperglycemia at stroke presentation increases sICH and subsequent poor outcomes for ischemic stroke patients. This has been the premise for such randomized controlled trials such as SHINE (Stroke Hyperglycemia Insulin Network Effort Trial, NCT01369069) which is evaluating strict glycemic control with intravenous insulin versus more traditional subcutaneous insulin regimens in the first 72 hours after ischemic stroke.

This study bolsters current clinical knowledge about the relationship between diabetes and outcomes from acute ischemic stroke. HgbA1c, a quantifiable measure, is a better independent predictor for sICH and functional status after stroke, than merely the history of diabetes alone.

I don’t think this would really change current clinical practice. We already routinely check HgbA1c as a marker for diabetes in our acute ischemic stroke patients. We also routinely get repeat imaging 1-2 days after acute iv thrombolysis treatment and monitor patients carefully to evaluate for sICH. This may perhaps persuade me to be more cautious or delay in starting antithrombotic therapy if poorly controlled diabetic patients had any hint of micro hemorrhages on imaging. How do you see this affecting your clinical practice?