Advances in stroke in 2004 have been varied and many, from unraveling the genetics of intracerebral aneurysms to showing the high cost-effectiveness of even short-term care in stroke units.
After a slow beginning and a few false starts, the study of the genetics of stroke is picking up pace. Familial intracerebral aneurysms (IA) tend to be larger and more often multiple compared with sporadic ones. Familial IAs can show anticipation in certain kindred, manifesting in children some 20 years earlier than the mean age of subarachnoid hemorrhage in the parents. A locus near the elastin gene has been identified in one family, suggesting elastin abnormalities as a potential cause of strategically weakened vessels.
Polymorphism of the COX-2 gene has shown an association with ischemic events, a highly relevant finding in view of the recent reports regarding increased rates of stroke and myocardial infarction among consumers of two widely sold COX-2 inhibitors. COX-2 is expressed preferentially in some organs, such as the brain. It can be upregulated dramatically by inflammatory mediators and by cerebral ischemia in neurons, vascular cells, and inflammatory cells invading the brain. Contrariwise, inhibition of COX-2 in ischemic models of stroke attenuates the damage, even if given as late as 24 hours after injury, suggesting a new therapeutic target in the management of acute ischemic stroke.
Nitric oxide (NO) is a potent and major mediator of endothelium-dependent relaxation and thus a regulator of tone in large arteries and brain microvessels. It reacts extremely well with superoxide, resulting in loss of NO bioavailability and impaired vasodilatation. The fact that increased levels of superoxide occur in angiotensin II–dependent hypertension, hyperhomocysteinema, diabetes, inflammation, ischemia with reperfusion, and subarachnoid hemorrhage suggests that oxidative stress occurs in the cerebral circulation. Also, the observation that risk factors for stroke also seem to make individuals prone to Alzheimer disease points to oxidative stress as one possible common mechanism underlying both conditions.
Advances occur individually but are best understood collectively. A broad look at the evolving field of cerebral ischemia reveals a shift from focusing on a single step in the ischemia cascade to trying to understand and stop the multi-step dance of death of the components of the brain. Excitotoxicity, generation of free radicals, and apoptosis not only act but interact in ischemia. Some of the anti-ischemic strategies involve agents that have multiple effects, again a shift from one step, single drug action, to addressing multiple mechanisms with polyactive agents.
Males and females differ when it comes to cerebral ischemia. Females resist it better. Moreover, estradiol is protective in a long list of experimental models. However, much more needs to be done to reconcile the biological protective effect of estrogen experimentally with the apparent harmful clinical effect as seen with replacement therapy in postmenopausal women.
The white matter, for too long the gray matter of our understanding of ischemia, is gaining the attention that it deserves, thanks in part to improved imaging. It seems that white matter resists ischemia to a degree comparable to that of gray matter, and it is finally being recognized that histoprotective strategies, to be successful, need to act both on gray and white matter. Among cellular elements, neutrophils, microglia, and macrophages are beginning to be imaged in the living human brain, shedding light on the evolution of cerebral infarction.
Thrombolysis for acute ischemic stroke was approved in the United States in 1996 and subsequently in an increasing number of countries. Despite this, the proportions of stroke patients receiving tissue plasminogen activator (tPA) remains disappointingly small. Delay in recognition and transport of stroke patients, effective triaging of patients once they reach hospital, and physician’s uncertainties about administering tPA have been recognized as obstacles. Additional factors may be that stroke neurologists administer tPA in the majority of cases and there are not enough of them to do it at the required scale. Emergency physicians, the most obvious practitioners of urgent therapy, have been reluctant to play a role. The time has come to take a broad look at the problem, address practical issues of physicians availability, willingness, compensation and protection from lawsuits, and begin implementing widely the only proven therapy for acute stroke.
Basilar artery occlusion proves fatal 90% of the time. The fact that intravenous tPA administration can reduce this rate to as low as 40%, based on registry data, suggests that it is making a difference. It also appears that the intra-arterial route is more effective, but in the absence of a sophisticated interventional set-up, the intravenous may be the initial route of choice. The number of reported cases justifies the setting up a worldwide registry with a view of carrying out a clinical trial that may compare two approaches.
Some of the most encouraging advances have occurred in the treatment of intracerebral hemorrhage (ICH). The basic approaches of aneurysm care are being applied to ICH: stabilization of the bleeding site, removal of blood, and relief of obstruction. A phase IIb study has shown great promise in the use of a recombinant activated Factor VII decreasing the volume of the hematoma.
Two milestones marked interventional neuroradiology in 2004: the publication of the results of a study of angioplasty and stenting in high risk carotid stenosis patients and the approval of a clot retrieving device. Reactions have included admiration for technical prowess and reservations about scientific proof.
Animal and human studies buttress the growing conclusion that in stroke rehabilitation, early intense treatment is best, but that much can still be gained in the chronic phase.
Statins and the treatment of hyperhomosteinemia may yet be proven to be effective preventive measures against stroke. At the moment the indications derive from biological plausibility and from extrapolations from studies where stroke was not the primary end point.
Because aspirin and clopidogrel lower the risk of stroke by different mechanisms, combining them could be expected to boost the protective effect. One randomized study failed to show a benefit and instead demonstrated increased risk of complications. Questions remain about the timing of treatment, the nature of the population studied, and the high prevalence of diabetes in the study, known to blunt the effectiveness of antiplatelet agents.
Health policy and outcomes research continues to provide evidence that relatively low cost measures can have powerful effects. Caregiver training cuts costs, and stroke units providing even short term care are highly cost effective.
The advances in stroke summarized in this issue provide a comprehensive guide to understanding and action. May both occur widely.