Intracerebral hemorrhage: the least treatable form of stroke.

Stroke is the third leading cause of death in the United States. There are important regional disparities with patients in the South having the highest stroke hospitalization rates. (1) Intracerebral hemorrhage (ICH) is one of the least treatable and most debilitating forms of stroke. In addition, profound morbidity and mortality occurs in these patients when blood from an intracerebral hemorrhage extends into the ventricular system. This is not an uncommon problem; intraventricular hemorrhage (IVH) occurs in more than 30,000 adult patients with ICH each year in the United States. (2) When blood enters the ventricular system, cerebrospinal fluid drainage is blocked, leading to hydrocephalus and increased intracerebral (IC) pressure. Conventional treatment for IVH involves placing an external ventricular catheter to drain the spinal fluid and reduce IC pressure. This is a highly unsatisfactory approach to the problem because 1) the catheters typically become occluded and 2) drainage of spinal fluid does not speed resolution of the clot itself. With the advent of thrombolytic agents such as urokinase and recombinant tissue plasminogen activator (tPA), a series of promising experimental and clinical studies began to demonstrate the therapeutic benefit of intraventricular administration of fibrinolytic agents for the treatment of IVH. Indeed, the off label clinical use of both urokinase and tPA for the indication of intraventricular thrombolysis has increased considerably over the past 10 years. While this therapy has the potential to improve clot resolution, it is also clear that administration of a thrombolytic agent in a patient with a fresh IC hemorrhage can lead to increased IC bleeding. Indeed, the risks of intraventricular thrombolysis are delineated in the current study in the Southern Medical Journal, where four of 21 (19%) patients treated with intraventricular tPA for IVH experienced a new IC hemorrhage; two of these patients died. Thus, while intraventricular thrombolysis in this setting may speed resolution of the clot and clear the ventricles of blood, there are considerable risks. Studies to address this problem have been difficult to conduct. Indeed, there has been a paucity of well-controlled, prospective, randomized clinical trials to assess the safety and efficacy of this approach. A recent phase II randomized, double blind, multicenter study by Naff et al demonstrated both the safety and efficacy of intraventricular urokinase for treatment of IVH. (2) Results from this study are promising and clearly point to the need for well-designed clinical studies with larger populations to validate the clinical efficacy and safety of intraventricular thrombolysis. Many fundamental questions, such as which thrombolytic agent is best remain. Dose escalation studies are needed to define the optimal therapeutic window. Perhaps the most important question will be to determine if thrombolytic therapy to hasten clot resolution actually leads to clinical benefit of important variables such as incidence of infection, hydrocephalus, duration of catheter placement, and especially, neurologic morbidity and mortality.

New, novel approaches to treatment of intracerebral hemorrhage are on the horizon. A recent study in the New England Journal of Medicine demonstrated that administration of recombinant activated factor VII in patients with acute intracerebral hemorrhage reduced the growth of the hematoma, and improved functional outcomes. (3) Yet, while hemostatic therapies such as recombinant activated factor VII hold promise to limit clot expansion, the ideal treatment will be to prevent the development of intracerebral hemorrhage. It is clear that until we are more successful in identifying and controlling risk factors for the development of ICH, it will remain the least treatable form of stroke.

References

1. Fang J, Alderman MH. Trend of stroke hospitalization, United States, 1988-1997. Stroke 2001;32:2221-2226.

2. Naff NJ, Hanley DF, Keyl PM, et al. Intraventricular thrombolysis speeds blood clot resolution: results of a pilot, prospective, randomized, double-blind, controlled trial. Neurosurgery 2004;54:577-584.

3. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-785.

Reid C. Thompson, MD

Vanderbilt University Medical Center, T4224 Medical Center North, Nashville, Tennessee 37232-2380

Reprint requests to Reid C. Thompson, MD, Vanderbilt University Medical Center, T4224 Medical Center North, Nashville, TN 37232. Email: [e-mail]

Accepted May 12, 2005.