Progress Report 2008: Nervous System Injuries
The 2008 Progress Report on Brain Research


February, 2008

Nervous system injuries comprise a diverse group of disorders affecting the brain and spinal cord, including stroke, spinal cord injury, and brain tumors. In 2007, researchers reiterated the importance of acting quickly after stroke, tried new approaches to treating brain tumors, and worked to improve clinical trials in spinal cord injury.
 

Act Quickly After Stroke

Getting to a hospital in time and getting the right care once there continue to dominate the news in clinical research of stroke, and new data from Europe extend the urgency to the follow-up care of people with transient neurological symptoms as well.

In May, the American Heart Association and the American Stroke Association updated their acute-care guidelines for stroke, reaffirming top billing for tissue plasminogen activator (tPA), the anti-clotting agent that should be given within three hours of stroke onset in order to minimize brain damage after ischemic stroke.1 (Ischemic stroke is caused by a lack of oxygen to the brain, typically due to a blockage in arteries that feed blood to the brain.) The guidelines also urged better preparedness for rapid response by hospital emergency rooms and first responders; new data from the Centers for Disease Control and Prevention show that fewer than half of stroke patients reach hospitals within two hours of the onset of acute neurological symptoms.2

While a major stroke is often marked by overt symptoms, such as blurred vision, slurred speech, or numbness or paralysis in one side of the body, some brain effects of ischemia are temporary and leave no clinically detectable signs. These are referred to as transient ischemic attacks. Brain imaging studies of patients who have had temporary neurological symptoms show evidence suggestive of such transient attacks. Once a transient ischemic attack occurs, the underlying cause likely persists and may eventually cause a major stroke, unless treated appropriately. Transient ischemic attacks, therefore, are important risk factors for major stroke.

Interventions following a transient ischemic attack are aimed at preventing additional strokes in the weeks and months afterward. A large base of evidence now suggests that reducing stroke risk factors, such as high blood pressure and elevated cholesterol, can prevent strokes. Two papers published in October point to the importance of initiating such therapies immediately in people who have suffered a transient attack.

The first, by neurologist Peter Rothwell and colleagues at the University of Oxford, England, and published in Lancet, found that patients who were treated with existing preventative therapies within 24 hours of a transient ischemic attack had a dramatically reduced risk of developing a serious stroke in the next three months, compared with patients who did not receive immediate follow-up care.3 Specifically, the risk of a recurrent stroke was cut from 10 percent to 2 percent, an 80 percent reduction, which the authors said could translate to the prevention of 10,000 strokes a year in the United Kingdom alone. The study examined about 600 people, drawn from a larger Oxford study that is tracking the incidence of stroke and transient ischemic attack in nearly 100,000 people.

A second study, published in Lancet Neurology and led by stroke neurologist Pierre Amarenco of Bichat-Claude Bernard University Hospital in Paris, also affirmed the benefit of early intervention to prevent strokes.4 The researchers evaluated 1,085 patients with a suspected transient ischemic attack who were admitted to a 24-hour hospital clinic. Urgent assessment included imaging of the brain, blood vessels, and heart. Patients with confirmed or possible transient ischemic attacks were immediately put on a preventative therapeutic regimen, which typically involved drugs to reduce blood pressure and/or cholesterol and aspirin to reduce blood clotting.

About 5 percent of patients underwent procedures to open the carotid artery, the main artery in the neck that feeds blood to the brain. These patients underwent either open surgery (carotid endarterectomy) or trans-arterial placement of a stent to expand the carotid artery (endovascular therapy). Another 5 percent who had atrial fibrillation, a disturbance of the rhythm of the heartbeat, were given anticoagulant drugs to reduce the risk of blood clots forming in the heart due to this condition. Such clots can travel from the heart to the brain and cause a stroke.

Among patients who were treated early, the rate of stroke in the 90-day period after the transient ischemic attack was just over 1 percent, compared to an expected rate of nearly 6 percent based on previous observational studies. Taken together with the Lancet report, the findings prompted experts worldwide to urge a new standard of care for patients suffering transient ischemic attacks, emphasizing urgent assessment and treatment to prevent stroke.

Targeting Brain Tumors with Molecular Precision

While brain tumors continue to evade effective treatment approaches, much of the current anticipation relates to the development of molecularly targeted therapies to attack tumors, as is true in cancer research overall. There is also a growing appreciation that no one therapy may be enough to eradicate the most lethal brain cancers, leading to increasing investigation of combination approaches that add newer therapies to standard treatments such as radiation and chemotherapy.

Many researchers are convinced that such multimodal therapies offer the best hope for people facing a diagnosis of malignant glioma, a family of brain tumors that, though relatively rare, have high death rates within a short period following diagnosis. Glioblastoma multiforme, one of the most aggressive members of this family, has been particularly difficult to treat.

Clinical research in this area is being driven by new understanding about the pathogenesis of tumor development at the molecular level as scientists unravel the specific signaling factors and pathways that tumors use to grow and spread. Differences among tumors are negating a “one-size-fits-all” approach to treatment. Still, there appear to be commonalities in some elements of the pathways tumors use, and researchers are focusing many of their efforts on these common features.

One promising avenue is to starve tumors of their blood supply, an approach that is being investigated for many types of cancer. In January 2007, Rakesh Jain and colleagues from the Massachusetts General Hospital Cancer Center reported preliminary results in Cancer Cell of an investigational drug that suppresses the growth of blood vessels that feed tumors.5 This drug, AZD2171, blocks the three primary receptors for VEGF, a powerful blood vessel growth promoter known to be present on vessels that feed glioblastoma tumors. (Mature blood vessels in normal tissue do not rely on VEGF for survival.

Potential effects of angiogenesis - Spotlight

An experimental drug, AZD2171, that suppresses the growth of blood vessels that feed brain tumors shows promise in brain scans of the most responsive test patient. The numbers at the top correspond to days before or after starting treatment. The top row shows the tumor shrinking over time. Other rows show drops in tumor blood-vessel size, the permeability of the blood-brain barrier, and swelling in regions around the tumor. The last row shows white matter visibility as swelling subsides. (Rakesh Jain/Dr. A. Gregory Sorenson) 

 

 

Results from a Phase 2 clinical trial in 16 patients with recurrent glioblastoma who were treated with AZD2171 found that tumors shrank by 50 percent or more in half of the patients, and by at least 25 percent in three-quarters of the study participants. Brain imaging showed a rapid effect on the normalization of blood vessels, beginning after just one dose of the medication in some patients, and a decrease in brain swelling, a common problem in brain cancer. The trial is continuing, and the researchers hope to also investigate the drug in combination with traditional cancer therapies in people newly diagnosed with glioblastoma.

 

Researchers at Duke University have combined another blood vessel inhibitor, bevacizumab (Avastin), with the chemotherapeutic drug irinotecan in a Phase 2 trial of 32 patients with advanced glioma. Preliminary results, published in Clinical Cancer Research in February 2007 by James Vredenburgh and colleagues, suggest that the combination is active against this lethal form of tumor and has “acceptable” toxicity.6 In nearly two-thirds of the patients, tumors shrank by at least 50 percent, and at six months, tumors had not started to regrow in 38 percent of the patients. In contrast, chemotherapy alone typically slows glioma growth for just six weeks to three months.

 

Vredenburgh and other brain tumor experts say the key to improving treatment for malignant gliomas lies in better determining which patients are most likely to respond to specific therapies and in improving combinatory approaches to treatment. They also point to the need for improving clinical trial designs to obtain the maximum amount of information in the shortest period of time.

Spinal Cord Injury:
Paving the Way for Clinical Trials

Better clinical trial design also has been a focus in spinal cord research, as work in this area advances toward the translation of basic science findings into therapeutic approaches. In March 2007, an international multidisciplinary panel of researchers published the first guidelines for clinical trials in spinal cord injury in a series of four papers in Spinal Cord.7–10

 

The effort, by the International Campaign for Cures of Spinal Cord Paralysis, is an attempt to delineate criteria for robust, realistic, and useful clinical trials for anticipated therapeutic options that are currently being tested in preclinical investigations. The panel called for rigorous and standardized attention to outcome measures, inclusion and exclusion criteria, and ethics in designing and conducting human research trials.

 

For example, the authors said that outcome measures should include anatomical and neurologic assessment to demonstrate “reconnection” of the spinal cord, measures of patients’ ability to engage in activities of daily living, and quality-of-life measures. With respect to inclusion/exclusion criteria, the panel said that patients participating in studies should be at stages of injury where there are data from animal studies or previous human studies to support a potential benefit of intervention, and that the severity, level, type, and size of their injury should be considered in relation to the likelihood that an experimental treatment would benefit them. Study participants must provide informed consent based on a clear, adequate explanation of the risks, benefits, and scientific rationale of investigational therapies, the authors said.

 

Prospective, double-blind, randomized trials utilizing appropriate control participants are optimal, the group said, while recognizing that in some situations, other trial procedures may have to be considered.

 

The guidelines appear to be prompted in part by the frustration of Western scientists trying to evaluate the effectiveness of uncontrolled human research. In a field where no treatment is known to be effective, patients and their families have been desperate for a treatment for spinal cord injury. As a consequence, they and some researchers have been willing to try anything. This has become a particular problem in countries where regulations governing clinical research are lacking, including China, where scores of unproven stem cell transplants are being done in spinal cord–injured patients. The panel also seeks to avoid clinical trial design problems that have plagued the development of treatments for other complex neurological problems—notably the lack of sufficiently sensitive outcome measures in clinical trials investigating new neuroprotective therapies for stroke.

Notes

1. Adams HP Jr., del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch ED, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, and Wijdicks EF. Guidelines for the early management of adults with ischemic stroke: Guidelines from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007; 38(5):1655–1711. [Epub Apr 12, 2007]

2. Centers for Disease Control and Prevention. Prehospital and hospital delays after stroke onset: United States, 2005–2006. Morbidity and Mortality Weekly Report 2007 56(19):474–478.

3. Rothwell PM, Giles MF, Chandratheva A, Marquardt L, Geraghty O, Redgrave JN, Lovelock CE, Binney LE, Bull LM, Cuthbertson FC, Welch SJ, Bosch S, Carasco-Alexander F, Silver LE, Gutnikov SA, and Mehta Z. On behalf of the Early Use of Existing Preventive Strategies for Stroke (EXPRESS) Study. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): A prospective population-based sequential comparison. Lancet 2007 Oct 8. [Epub ahead of print].

4. Lavallee PC, Meseguer E, Abboud H, Cabrejo L, Olivot JM, Simon O, Mazighi M, Nifle C, Niclot P, Lapergue B, Klein IF, Brochet E, Steg PG, Leseche G, Labreuche J, Touboul PJ, and Amarenco P. A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): Feasibility and effects. Lancet Neurology 2007 Oct 8. [Epub ahead of print].

5. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, and Jain RK. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007 11(1):83–95.

6. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, and Friedman HS. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clinical Cancer Research 2007 13(4):1253–1259.

7. Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynksi MH, Lammertse D, Bartlett PF, Blight AR, Dietz V, Ditunno J, Dobkin BH, Havton LA, Ellaway PH, Fehlings MG, Rivat A, Grossman R, Guest JD, Kleitman N, Nakamura M, Gaviria M, and Short D. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: Spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 2007 45(3):190–205. [Epub Dec 19, 2006]

8. Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, Ellaway PH, Fehlings MG, Guest JD, Kleitman N, Bartlett PF, Blight AR, Dietz V, Dobkin BH, Grossman R, Short D, Nakamura M, Coleman WP, Gaviria M, and Privat A. International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: Clinical trial outcome measures. Spinal Cord 2007 45(3):206–221. [Epub Dec 19, 2006]

9. Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Rask C, Curt A, Ditunno JF, Fehlings MG, Guest JD, Ellaway PH, Kleitman N, Bartlett PF, Blight AR, Dietz V, Dobkin BH, Grossman R, and Privat A. International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: Clinical trial inclusion/exclusion criteria and ethics. Spinal Cord 2007 45(3):222–231. [Epub Dec 19, 2006]

10. Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, Ditunno JF, , Fehlings MG, Guest JD, Ellaway PH, Kleitman N, Blight AR, Dobkin BH, Grossman R, Katoh H, Privat A, and Kalichman M. International Campaign for Cures of Spinal Cord Injury Paralysis. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: Clinical trial design. Spinal Cord 2007 45(3):232–242. [Epub Dec 19, 2006]


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