Stroke Doc

Low Cholesterol May Increase Risk of Hemorrhagic Stroke

A large study finds that low cholesterol levels are associated with an increased risk of hemorrhagic stroke.

Summary:

Tobias Kurth presented data from the Women's Health Study at the International Stroke Conference (2/06) analyzing cholesterol levels and risk of hemorrhagic stroke.  The Women's Health Study is a large study of female health professionals.  Of the 39,876 participants, 28,345 women provided baseline blood samples.  Dr. Tobias et al. analyzed these baseline cholesterol levels as well as the number of hemorrhagic strokes occurring in these women an average of 10 years later.  A total of 65 women experienced a hemorrhagic stroke in this time.  Various cholesterol measures were analyzed, including total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and total cholesterol/HDL ratio.  (For an explanation of cholesterol types, click here).  Results were complex, but it was overall found that low LDL, triglycerides, and total cholesterol/HDL ratio were associated with a higher risk of hemorrhagic stroke.  A high HDL cholesterol level was also associated with high hemorrhagic stroke risk, although the relationship was complex (taking on a 'U'-shape with both very high and very low levels being bad, intermediate levels being beneficial).

Commentary:

Nearly everything you read regarding stroke and heart attack risk these days indicates that low total cholesterol reduces your chances of having an ischemic stroke or heart attack.  This study does nothing to challenge this notion, but it begins to explore the other side of the coin.  Is there a lower limit of cholesterol, below which one shouldn't go?  The ischemic stroke literature supports bringing LDL (so called 'bad' cholesterol) down below 100mg/dL in any patient who has suffered an ischemic stroke.  The cardiac literature supports pushing patients with coronary heart disease below 70mg/dL.  But no one knows just how low you can go to continue to achieve an overall benefit.  Clearly the lowest levels of LDL and total cholesterol in this study were associated with more hemorrhagic strokes, but if the overall risk of an ischemic stroke remains higher than that of a hemorrhagic stroke, the benefits of low cholesterol might still outweigh the risk. 

Perhaps the researchers involved in the Women's Health Study have the answers at their fingertips.  If they simply review the number of deaths (both overall, and due to vascular disease) stratified according to cholesterol level, they would be able to determine if people with the lowest cholesterol levels had a higher or lower chance of death overall and death due to vascular causes.  This would begin to give us insight into how seriously to take the risk of hemorrhagic strokes due to low cholesterol levels.

Intracerebral Hemorrhage Management (Review for Experts 1/06)

By David Alway, MD

Spontaneous intracerebral hemorrhage (ICH) accounts for only about 10 percent of all strokes, but it carries about a 50 percent risk of mortality. Even in the best treatment facilities the management guidelines are plagued with uncertainty, largely due to the paucity of randomized controlled trials. As a result, many physicians find themselves relying on less scientific data when planning a treatment strategy.

Fortunately, some recent discoveries may go a long way towards helping us make the best decisions for our patients. In this review I’ll look at some of the latest research on ICH that could carry over to clinical practice.

Picturing the Problem

Brain imaging is the only reliable way to diagnose ICH, since the presenting symptoms are often very similar to an ischemic stroke. The most commonly used method is CT due to its speed, widespread availability and reliability in detecting a hematoma.  MRI may also be used to detect ICH, but is generally unnecessary for this purpose acutely.

There are many ways an ICH can cause brain damage. Most often, the hematoma causes an immediate damage to surrounding tissues. Interestingly, even though the hemotoma’s compression of adjacent brain tissue may lead to reduced blood flow, recent PET and MRI data find no evidence of significant perihematomal ischemia in small or moderate sized hematomas.^2,3  Whether this observation applies to individuals with large hematomas remains unknown, hence concern remains over the best blood pressure management of these patients.  While blood pressure reduction is considered appropriate, the optimal amount of blood pressure reduction remains a matter of contention, even among experts.

Some recent studies suggest that there is also hematoma induced neurotoxicity which may lead to cerebral edema.⁴ Within a week this tissue edema may result in a volume twice as large as the hematoma itself.¹ The mass effect of the hematoma alone, or later with associated edema and further bleeding, may lead to increased ICP, with the possibility of global ischemia due to decreased brain perfusion pressure. Concomitant hydrocephalus may also develop, further increasing ICP.

Surgery vs. Medical Management

There are few firm data regarding surgical intervention for supratentorial hemorrhages.  Many surgeons avoid surgical evacuation of small, deep hematomas in patients without signs of increased ICP or clinical worsening, preferring to operate on patients who are clinically worsening or who have more superficial/accessible hematomas and significant neurological disability.

However, a recent large randomized study⁵ compared the best medical management techniques to early (within 24 hours of randomization) surgical evacuation for supratentorial hemorrhages. Surgeons were allowed to use whatever techniques they felt were indicated, including craniotomy or minimally invasive techniques for clot aspiration and lysis.  Of note, surgery was allowed in any patient who worsened, even if he/she was originally in the medical arm. Using an intention-to-treat analysis, there was no significant difference found in neurological outcomes after six months. In light of these results, we must consider surgery for supratentorial intracerebral hemorrhages of unproven benefit. However, surgical management will require continual reappraisal since newer surgical techniques are continually being developed and may prove beneficial.⁶

In contrast to supratentorial hemorrhages, surgery for cerebellar hemorrhages is often indicated.  The American Heart Association study group recommends that patients with cerebellar hematomas larger than 3 cm who are either neurologically worsening or who appear to be headed towards hydrocephalus or early brainstem compression, undergo emergent surgical evacuation.

Elevated ICP can cause a decreased level of consciousness, nausea, vomiting, and herniation. Physicians have varying opinions about how to manage elevated ICP, but measures such as IV mannitol infusion, hyperventilation, induction of barbituate coma and placement of a ventriculostomy in patients who develop hydrocephalus are all considered reasonable. Steroids have no proven benefit in the management of ICH and may damage patients due to a higher number of infections and elevated glucose.

An intracranial pressure monitor may help the physician balance the desire to avoid hypertension, which theoretically increases the tendency toward hematoma enlargement, with the need to maintain adequate cerebral perfusion. AHA guidelines recommend that the cerebral perfusion pressure (MAP–ICP) be kept at >70 mm Hg.⁷

Early Treatment Option

Hematoma growth is common within the first few hours of an ICH and uncommon after 24 hours. With this in mind, a recent clinical trial⁸ involved treating patients who were diagnosed with acute intracerebral hemorrhage with recombinant activated factor VII (NovoSeven). Within four hours of symptom onset, 399 patients received either placebo or one of three doses of rFVIIa (40mcg, 80mcg, or 160mcg per kg). After three months mortality was significantly lower in the treated groups compared with the placebo group (18-19 percent vs. 29 percent p<0.01). Neurological outcomes were also better in the treated groups, although there was no clear dose/response relationship. While there was a statistically significant increase in the percentage of thrombotic complications in the treated groups, the clinical effect of these tended to be mild.  Although this intervention appears promising, we should await further trials (now in progress) to determine the optimal dose and range of side effects of this treatment.

Prevention After Hospitalization

Follow-up is essential after patients are  discharged. Before they go back home or to their assisted care facility, they should be educated on the risk factors for recurrent ICH. 

Patients who suffered from a spontaneous ICH thought to be due to hypertension should have their blood pressure maintained in the normal range (120/80mmHg) or below and they should avoid both legal and illegal stimulants. Antiplatelet medications should be avoided for at least the first few months after an ICH and, in cases of cerebral amyloid angiopathy, lobar hemorrhage, residual tumor, or residual vascular malformation, they should never be restarted. In other cases, the risk of ischemic events must be weighed against the potential for further intracerebral hemorrhages, it being reasonable to restart antiplatelet medications in patients who also suffer from coronary artery disease.⁹

David Alway, MD, is a physician at The Neurology & Headache Center in Alexandria, VA (www.neurologychannel.com/neuro-headache/). He writes about stroke treatment and prevention at Stroke Doc (http://strokedoc.typepad.com/) and he has recently published a stroke prevention book targeted at those who have had a stroke or TIA called Stop Your Next Stroke.

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1. Kidwell, KS et al.Comparison of MRI and CT for Detection of Acute Intracerebral Hemorrhage. JAMA 2004;292:1823-1830.

2. Rosand J, Eskey C, Chang Y, Gonzalez RG, Greenberg SM, Koroshetz WJ. Dynamic single-section CT demonstrates reduced cerebral blood flow in acute intracerebral hemorrhage. Cerebrovasc Dis. 2002;14(3-4):214-20

3. Zazulia AR, Diringer MN, Videen TO, Adams RE, Yundt K, Aiyagari V, Grubb RL Jr, Powers WJ. Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab. 2001 Jul;21(7):804-10

4. Lampl Y, Shmuilovich O, Lockman J, Sadeh M, Lorberboym M. Prognostic Significance of Blood Brain Barrier Permeability in Acute Hemorrhagic Stroke. Cerebrovasc Dis. 2005;20(6):433-7.

5. Mendelow AD, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005 Jan 29-Feb 4;365(9457):387-97.

6. Nishihara T et al. Newly developed endoscopic instruments for the removal of intracerebral hematoma. Neurocrit Care. 2005;2(1):67-74.

7. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage. A Statement for Healthcare Professionals From a Special Writing Group of the Stroke Council, American Heart Association. Broderick JP et. al. Stroke 1999;30:905-915

8. Mayer, SA et al. Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage. NEJM 352:8 Feb 24,2005.

9. Kissela BM et al. Subarachnoid hemorrhage: a preventable disease with a heritable component. Stroke 2002 May;33(5):1321-6.)

10. Report from the Priorities for Clinical Research in the Treatment of Acute, non-Traumatic Intracerebral hemorrhage Workshop, Nov 2003.

11. Carvi y Nievas, MN. Why, when, and how spontaneous intracerebral hematomas should be operated. Med Sci Monit. 2005 11(1):RA24-31.

12. Bernstein, RA. Recent advances in the management of acute intracerebral hemorrhage Curr Neurol Neurosci Rep. 2005;5(6):483-7.

Coiling Better Than Clipping For Brain Aneurysms

A large study (ISAT) finds that clotting brain aneurysms (from the inside) is superior to surgical treatment.

Review:

(As reported by Matthew Fink in the October 2005 issue of Neurology Alert)

Bleeding into the fluid that surrounds the brain (subarachnoid hemorrhage) is often devastating, in terms of neurological damage.  Typically the cause of such bleeding is rupture of a ballooned region of brain artery, called an aneurysm.  Physicians have devised two main methods of treating a ruptured brain aneurysm.  One is surgical clipping (see diagram), which involves opening the cranium, finding the aneurysm, and placing a tight metal clip across its base, cutting it off from the blood supply.  Another method of treatment is endovascular coiling (see diagram), during which a fine wire is threaded through the leg artery and up into the aneurysm.  A fine coil of wire is then packed into the aneurysm.  This coil is coated with a substance that makes blood clot rapidly and the aneurysm subsequently clots off.  In the International Subarachnoid Aneurysm Trial (ISAT), 2143 patients were studied, all of whom had suffered from a ruptured intracranial aneurysm and who were felt by treating physicians to be appropriate for either clipping or coiling.  Patients were randomized to either treatment and were followed for 1 year to monitor their outcomes.  After 1 year, 23.5% of patients undergoing coiling were either dead, or were in a dependent condition (unable to care for themselves).  This was statistically better than the outcomes of those undergoing surgical clipping (30.9% in the dead or dependent category).  After 4 years, similar results were obtained.

Commentary:

Coiling has clear advantages since there are no major surgical scars (and therefore chances for significant infections), brain damage from the procedure itself is highly unlikely, and seizures secondary to the procedure are unlikely. While the ISAT study lends support to the practice of coiling, the issue is not simple.  First of all, surgery itself is not a static practice.  There are constantly new techniques and tools being invented to make surgery outcomes better and better.  As a result, one can never think that the question of which intervention has been proved more beneficial has been settled once and for all. Surgical clipping also has the advantage of immediately and completely clotting off the aneurysm.  As pointed out by Dr. Fink, there may be as many as 66% of coiled aneurysms which are not completely clotted off.  If these aneurysms cause recurrent subarachnoid bleeds in the ISAT patients over the next 5 years, coiling may loose its apparent advantage.  Finally, the patients selected for this study were felt by treating physicians to be appropriate for both techniques.  Some patients (say, those with large and superficial aneurysms) may be more appropriate for surgical clipping and others (those with smaller aneurysms in the brainstem) may be better treated with coiling.

MRI Best Test for Detecting Artery Spasm After Brain Bleed

A special MRI technique demonstrates superiority in detecting vasospasm after a subarachnoid hemorrhage.

Review:

(As reported in the June 2005 issue of Clinical Neurology News)

Dr. Dileep Yavagal et. al evaluated 78 patients who had experienced a subarachnoid hemorrhage due to an aneurysm.  Patients who experienced neurological worsening after admission were evaluated for evidence of vasospasm with conventional techniques, including ultrasound of the large arteries of the brain and cerebral angiogram.  In addition, they also underwent a brain MRI using diffusion/perfusion techniques.  (These techniques allow for sensitive detection of regions of recent ischemic stroke as well as regions of poor blood flow.)  Eighteen of the 78 patients experienced neurological worsening during hospitalization.  Of these 18, conventional testing discovered arterial vasospasm in 10.  MRI with diffusion/perfusion also identified vasospasm in these 10, as well as 8 more patients who had smaller diffusion abnormalities.  Dr. Yavagal suggests that conventional techniques can discover large artery spasm, but often miss small vessel spasm.

Commentary:

A subarachnoid hemorrhage is bleeding into the fluid that surrounds the brain (within the subarachnoid space).  The usual cause is an outpouching of an artery in the brain (an aneurysm) and to prevent it from bleeding again, it is either surgically clipped or techniques are applied to cause it to clot off.  In either case, any further potential bleeding from the aneurysm is quickly eliminated or dramatically reduced.

Unfortunately, the blood that continues to surround the brain hangs around for a few weeks.  This blood acts as an irritant to the normal blood vessels that are near it, causing them to spasm and, therefore, narrow.  If the narrowing is severe enough, it will lead to an ischemic stroke.  Among the techniques for preventing an ischemic stroke in this setting, is simply to raise a patient's blood pressure - essentially forcing more blood through the narrow artery.  This is generally done if evidence of vasospasm exists on imaging (either ultrasound or cerebral angiogram).  Given the apparent superiority of MRI with perfusion/diffusion over conventional testing, many more cases of vasospasm will now likely be detected and appropriately treated.  As mentioned by Dr. Yavagal, this technique would also be useful in clinical trials of drugs used to prevent vasospasm.

New Treatment for Intracerebral Hemorrhage on the horizon

A new study indicates that patients who experience bleeding into the brain (Intracerebral Hemorrhage)may benefit from a pro-clotting medication.

Review

(As reported in the New England Journal of Medicine [Feb. 2005])

Dr. Stephen Mayer et al studied the effects of activated factor VII (administered intravenously) in 399 patients who presented to the hospital acutely with an intracerebral hemorrhagic stroke (ICH).  Patients were randomly assigned to receive placebo, or one of three doses of rFVIIa (40mcg/kg, 80mcg/kg, 160mcg/kg).  Twenty-four hours after enrollment in the study, those patients who received the highest dose of rFVIIa had the smallest brain hematomas (volume of blood in the brain).  After 90 days, mortality was 29% in patients who received placebo and 18% (combined total) in the three rFVIIa groups.  All results were statistically significant.  There was a trend towards increased rates of heart attack and brain ischemic stroke in the treated groups (7%) versus the placebo group (2%).

Commentary

An intracerebral hemorrhage (ICH) is bleeding directly into the substance of the brain.  The mortality associated with such a hemorrhage is about 50%.  Much of the mortality that occurs is due to the mass effect of the blood on surrounding brain tissue.  Until recently, it was thought that bleeding into the brain stopped relatively soon after starting (within a few minutes) due to the tamponade effect of surrounding brain.  Recently, through the use of serial CT brain scans in such patients, it has been found that the hematoma may continue to enlarge over the next few hours.

Mayer et al have found a ‘window of opportunity’, introducing a pro-clotting agent (rFVIIa) which has reduced the tendency for brain hematomas to enlarge.  Despite a small increase in ischemic events (heart attacks and ischemic strokes), treatment results in an impressive reduction in mortality.  Although rFVIIa (marketed as NovoSeven) is currently only FDA approved to treat bleeding epidodes in patients with hemophilia or certain other bleeding disorders, physicians likely will begin to use it off label to treat intracerebral hemorrhages.