Mazya MV, Ahmed N, Ford GA, Hobohm C, Mikulik R, Nunes AP, and Wahlgren N. Remote or Extraischemic Intracerebral Hemorrhage—An Uncommon Complication of Stroke Thrombolysis: Results From the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register. Stroke. 2014
Intraparenchymal hemorrhage remote (PHr) from the area of focal ischemia is an uncommon complication of IV-TPA treatment. Rates of PHr were difficult to extract in prior stroke trials because they were often grouped together with rates of intraparenchymal hematoma (PH) – hemorrhage within the existing ischemic stroke bed. Herein Mazya and colleagues describe the first comprehensive study of PHr using data from a huge stroke registry. They show previously unknown risk factors for PHr and an intermediate prognosis for recovery.
The authors performed a retrospective analysis of prospectively collected data from the SITS-International Stroke Thrombolysis Register (SITS-ISTR), which contains demographic and neuroimaging data from 43,494 patients treated with IV-TPA. They found rates of PHr, PH, and PHr + PH of 2.2%, 5.5%, and 1% respectively. A comparison of risk factors for PHr vs. PH showed that PHr patients were more likely to have remote prior infarct (OR 1.3), female gender (OR 1.23), and older age (OR 1.09). Mortality rates at 3 mo. were lower for those with PHr (33.9%) than for those with PH (39.2%) and PHr + PH (62.1%), but higher than for those with no intracranial bleeding (12.1%).
This is by far the most comprehensive study of PHr to date. Although PHr is relatively uncommon (3.2% if one includes both PHr and PH + PHr), this underappreciated complication of IV-TPA increases morbidity and mortality and therefore warrants further study. The authors made huge strides in this regard, uncovering risk factors specific to PHr including remote prior infarct and female gender. Despite these associations, the authors note relatively low odds ratios for each risk factor and suggest that another variable not collected in SITS-ISTR may be more important in predisposing patients to PHr. They suggest cerebral amyloid angiopathy (CAA) as a possibility given the association between CAA and female gender. I would offer another – prior head trauma. Even patients with mild concussion often show evidence of blood-brain-barrier disruption on acute MRI. Such disruption could make patients more susceptible to hemorrhagic conversion in the setting of future IV-TPA administration. Whatever the cause, this study definitely raises awareness of the importance of PHr and will prompt future investigations.
Why don't you cover what is being done about the major problems in stroke? And tie each of your blog posts to a problem being solved.
1. There is no fast, easy and objective way to diagnose a stroke. Maybe when the Qualcomm Tricorder X Prize is available. A number of friends have waited hours in ERs until stroke symptoms have visibly manifested themselves.
http://oc1dean.blogspot.com/2013/11/34-teams-are-building-medical.html
2. Only 10% get to almost full recovery.
http://www.ninds.nih.gov/disorders/stroke/stroke_rehabilitation.htm
3. 12% tPA efficacy
http://wrkf.org/post/more-stroke-patients-now-get-clot-busting-drug
4. Nothing being done to stop the neuronal cascade of death during the first week.
http://newswire.rockefeller.edu/2009/01/15/discovery-could-help-scientists-stop-the-death-cascade-after-a-stroke/
5. No one knows how to cure spasticity.
6. No one know how to cure fatigue.
Hi Dean – I would like to address your comments. As you may or may not be aware, all of the bloggers on this site are assigned articles from the most recent edition of the AHA journal stroke. We are asked to comment on what we find interesting and how the article may impact the stroke community. The idea is to cast a spotlight on the article and hopefully entice people into wanting to read more in the original article. We are encouraged to also submit blog posts when we attend major conferences. That might be one way in which we disseminate major breakthroughs in the field. Here is more information on the stroke blog.
http://stroke.ahajournals.org/content/43/12/3157.extract
Regarding your other questions:
1. This is a more difficult problem than you might think. Unlike heart attack, were the very specific enzyme troponin is immediately spilled into the blood, there is no such enzyme specific enough for stroke to make a quick diagnosis. The NIH is working on this. I would direct you to the work of Frank Sharp at UC Davis, who is devising a test of genetic changes in the peripheral blood for stroke diagnosis.
2. Yes – this is something that I personally plan to work on during my career. We currently have very few effective therapies in the recovery phase of stroke. You'll be happy to know that the recovery phase will receive much more attention and research funding with the launch of the stroke trials network.
http://www.nihstrokenet.org/
3. It looks like you are referring to the fact that only 12% of patients recover with little to no disability even after TPA. Newer thrombolytics are being tested that may improve efficacy, but the reality is that most of the damage is often done before patients even get to the hospital. While we can save some neurons by restoring blood flow we currently have no way to reverse much of the ischemia incurred before they arrive.
4. Somewhere around 100 different neuroprotective agents shown to reverse this cascade of death in rats and mice were developed and eventually tested on humans over the last few decades. Not one of them was effective. The result was the STAIR criteria to try and improve our translational efforts.
http://www.thestair.org/
5. This is true. The mechanisms behind post-stroke spasticity are poorly understood. Unfortunately there are only a handful of people researching this.
6. Also true. At the moment I think there's a lot more research going on in treating fatigue from Multiple Sclerosis as opposed to stroke. One would hope any breakthroughs would also work for stroke.
Hi Matthew,
Thanks for a very nicely written blog piece, really appreciate your reflections on our paper!
I completely agree with your suggestion on the possibility of minor head trauma being a risk factor for thrombolysis-related SICH. I am sure you have seen the analysis of the GUSTO-1 trial by Kandzari et al from 2004 (Am J Cardiol 2004;93:458–461). This was a huge myocardial infarction thrombolysis trial enrolling >41 000 patients, with 268 (0,7%) suffering an intracranial hemorrhage following treatment. Here, facial/head trauma within 2 weeks was the heaviest independent risk factor for ICH, adjusted OR 13 (95% CI 3 – 86). They defined trauma as "resulting in bruising, bleeding, or loss of consciousness". Unfortunately, we lack data on this topic in the SITS-ISTR ( https://sitsinternational.org/ ), and I assume the GWTG-Stroke does as well (would be great if they had it). Are you aware of any other clinical or preclinical results on the topic?
On a personal clinical practice note, time and aphasia permitting, I usually ask patients/family about recent head trauma, weighing it in together with everything else useful in IV tPA decision-making. Another question which may at least help sharpen monitoring in the acute phase, is whether the patient "bleeds easily", i e frequent nose bleeds, gum bleeds while brushing teeth etc. I would not withhold therapy if given positive answers, but they could prepare our stroke unit nurses for such eventualities. This would be a decent topic for a prospective project – one or two short questions should not prolong the door to needle time.
Once again, thanks for highlighting our results in a great way!
With kind regards,
Michael Mazya, MD
Department of Neurology
Karolinska University Hospital
Stockholm, Sweden