Update: Stroke Research

Highlights from the World Stroke Conference

by Ed Susman

VANCOUVER, British Columbia--More than 2,000 specialists dealing with the second leading cause of death met at the 5th World Stroke Congress here to discuss new findings that overwhelmingly affect older people.

"Stroke is the second most common cause of death and major disability worldwide," said Vladimir Hachinski, MD, professor of neurology at the University of Western Ontario, London, Canada, and chairman of the international conference. "Advances in medical and surgical management are accelerating at a rapid pace, and many of these new developments are relevant to people who live in long-term care facilities and the clinicians who work with them."

In a key presentation at the meeting, researchers headed by Stephan Mayer, MD, associate professor of clinical neurology and neurosurgery at Columbia University College of Physicians and Surgeons and director of the neurological intensive care unit at Columbia University Hospital, New York, said that if patients who suffer intracerebral hemorrhage--the deadliest and most devastating form of stroke--are treated with activated recombinant Factor VII (rFVIIa NovoSeven Novo Nordisk) the amount of bleeding within the brain can be reduced by as much as 50%.

Early Administration Required

The treatment has to occur within four hours of onset of the stroke for NovoSeven to make a difference. The Phase II study was designed only to see if NovoSeven could stem bleeding. The mortality reduction of 10% seen in the trial did not reach statistical significance.

The study was conducted at 73 centers worldwide. Dr. Mayer and colleagues enrolled 400 patients into the study and randomly assigned them to received one of three doses of NovoSeven or a placebo.

Intracerebral hemorrhage occurs in about 15% to 20% of strokes, and mortality can be as high as 40%. Numerous other patients who suffer from this form of stroke and survive the initial insult can be severely and permanently impaired.

In the study patients had intracerebral hemorrhage confirmed by computer-assisted tomography within three hours of onset and treatment was administered within one hour of the baseline scan.

Dr. Mayer said that one advantage to intracerebral bleeding is that symptoms usually occur almost immediately and are unmistakably recognized as an emergency, so patients with this form of brain attack are taken to the emergency department more quickly than those suffering ischemic strokes that may evolve more slowly.

A Few Drops of Blood

"We attained a 50 percent relative reduction in bleeding after baseline," said Dr. Mayer. At 24 hours, the hematoma volume increased by 29% in the placebo arm and 16%, 14%, and 11%, respectively, in the 40, 80, and 160 micro/kg treatment arms of NovoSeven. He said further studies would likely use the 80 micro/kg dose.

"The relative risk reduction in mortality was 35 percent, with a 10 percent absolute reduction in mortality, but this was not significant," he said, noting that the number needed to treat to avoid death or severe disability was "five to seven patients."

The overall event rate was 5.6%, which included seven cerebral infarcts and seven myocardial infarctions. But Dr. Mayer said that only two of these events were fatal. "I learned a difference a few drops of blood can make," he said. "We learned you can cut bleeding a little and get a huge difference in outcome. One teaspoon of blood meant we avoided death or severe disability in one out of five patients."

Response to the study has been cautiously positive. "I would classify this as a proof-of-concept study," said Dr. Hachinski. "I don't believe that there have been enough studies about this treatment to warrant its widespread use. Nevertheless, this report was one of the highlights of the conference. The results are encouraging that we may have a treatment for this type of stroke."

Sleep Problems

In another study presented at the meeting, researchers reported that stroke survivors are more likely to have sleep problems than people who haven't had a stroke.

"Thus far, it has not been determined if sleep disorders and stroke arise from common predisposing factors, or a causal relationship," said Pennie Seibert, PhD, director of research for the Idaho Neurological Institute at Saint Alphonsus Regional Medical Center, Boise, Idaho. "Sleep disorders often go undiagnosed in stroke survivors. That's because risk factors, such as smoking and high blood pressure, are found among stroke survivors and individuals with sleep disorders."

Dr. Hachinski said that sleep disruptions among these patients could be caused by actual damage in the brain to areas controlling sleep, or may be caused by the fact that stroke-caused physical deficits make it difficult to change position while asleep.

Dr. Seibert and colleagues studied 317 patients, including 15 stroke survivors, who were referred for possible sleep disorders. Her team used a database that included 305 measures in a11 categories to examine sleep habits, sleep problems, medical history, sleep study information, and gender differences in the patients.

"All 15 of the people with stroke were subsequently diagnosed with some form of sleep disorder," said Dr. Seibert, a professor and chair of the Psychology Department at Boise State University, Idaho. Stroke survivors more often reported frequent stress and were more likely to experience seizures and obstructive sleep apnea, she reported.

Monday Strokes

When the Mamas and Papas sang their hit song "Monday, Monday" it might have been great for music, but Mondays are not good for strokes. And winter months are not good times for strokes in the elderly.

Those findings were based on data gleaned from a registry of 12,529 first-occurrence stroke patients over age 40 in Japan's Tottori Prefecture between 1985 and 2001. "The purpose of this study is to clarify the occurrence and distribution of stroke onset in this region of Japan.

Dr. Hachinski said the data found in the Japanese study correlates with other studies about heart attacks, which tend to cluster in the mornings. "Changes in activity and stress appear to be associated with heart attacks and strokes," he said. "In winter when one is wearing a lot heavier clothes and working through snow, it can cause increases in blood pressure and trigger strokes."

Dr. Hachinski said that long-term care staff or people tending to elderly individuals should be more alert to signs of stroke in the winter.

In the Japanese epidemiological study, "these results seem to show that the seasonal variation in stroke onset is affected by the natural environment and daily events," said Keiko Kurashiki, RN, from the department of adult and elderly nursing in the School of Health Science, Faculty of Medicine, Tottori University, Japan.

Young patients were defined as between the ages of 40 and 59; older patients for the purpose of the study referred to people over age 60 (retirement age in Japan). Although stroke occurrence peaked on Monday in younger subjects, the strokes appeared to be milder, causing less disruption of mental or motor functions. "We believe that patients tend to visit the hospital when they have some symptoms of stroke on Monday even though it is not so severe," she said.

The registry included 2,116 subjects in the 40 to 59 age group, and 10,413 people over age 60.

Rhythmic Training

An experimental therapy improves arm function in chronically impaired stroke survivors long after the possibility of spontaneous recovery has been exhausted, researchers reported.

The study, the first on brain changes linked to a bilateral repetitive rhythmic training intervention (BATRAC), also found changes in brain regions that govern movement. Interestingly, researchers found the changes only in patients who responded to the therapy, said lead author Andreas Luft, MD, of the Department of General Neurology in the Hertie Institute for Clinical Brain Research at the University of Tubingen, Germany.

BATRAC is an experimental treatment studied since 1998. "Reorganization of the central motor networks in the brain occurs during the spontaneous recovery and rehabilitative therapy in the weeks following a stroke," said Dr. Luft.

He explained that reorganization includes lasting changes in the strength of nerve synapses (connections), formation of new dendrites and axons--two components of neurons (nerve cells), and even the formation of new neurons, resulting in the recovery of movements.

"Our hypothesis was that brain reorganization is the mechanism by which BATRAC improves function in chronic stroke patients," he said. The study compared eight impaired stroke survivors who received hour-long, thrice-weekly BATRAC therapy sessions for six weeks with 12 others who had standard physical therapy for the same amount of time.

"While this work is interesting," commented Dr. Hachinski, "I don't think it is ready for prime time yet. I don't think it would be necessary for facilities that deal with stroke patients to incorporate these findings into their routine rehabilitation efforts until further confirmatory studies have been under taken."

Vascular Dementia Drug

Donepezil (Aricept) used to treat Alzheimer's disease patients shows promise in treating dementia caused by stroke and blood vessel disease, researchers reported. Stroke is the second most common cause of dementia. In two studies doctors said the cholinesterase inhibitor donepezil modestly but significantly improved some vascular dementia patients' ability to perform daily functions.

Both studies analyzed data on the same 1,219 patients with vascular dementia who were identified in two earlier randomized, double-blind trials. The first analysis found that the drug modestly improved the ability to perform daily functions in patients with vascular dementia.

The second study found that the drug improved cognitive symptoms in patients regardless of whether the damage was in the cortical or subcortical regions of the brain. Vascular dementia--usually caused by an obvious or silent stroke or by atherosclerotic plaque build up that narrows the arteries--is the second most common cause of dementia after Alzheimer's.

Unlike Alzheimer's, in which memory problems are most obvious, vascular dementia affects the brain's executive functions (e.g., planning, organization, problem solving, and the abilities to multitask and sustain attention) said Sandra E. Black, MD, professor of medicine (neurology) at the University of Toronto.

Activities of Daily Living

Dr. Black's team focused on activities of daily living that depend on executive functions, such as the ability to manage one's finances, handle mail and e-mail, drive a car, plan and cook meals, and participate in hobbies and activities.

Although the improvements were modest, they were meaningful, said Dr. Black. Patients receiving either of the two test doses of donepezil showed benefits over placebo-treated patients. Placebo-treated patients showed slight deterioration in six months, while the treated groups maintained slight improvements.

The second analysis looked at the question of whether the location of blood vessel damage would affect treatment outcomes, said Philip Teal, MD, professor of neurology at the Vancouver Hospital and Health Sciences Centre. Of the 1,219 patients enrolled, 11% had predominantly cortical lesions while 51% had deeper predominantly subcortical lesions and white matter disease without cortical lesions. Abrupt onset of symptoms was reported in 90% of the cortical vascular dementia patients, while 57% of the subcortical had slowly progressive symptoms. "Despite their differences, donepezil was associated with small but significant benefits compared to placebo in both groups and at both doses," said Dr. Teal. "These results show that donepezil is effective for the cognitive symptoms of both cortical and subcortical vascular dementia."

Aspirin Resistance

Results of a small prospective study suggest that almost half of patients hospitalized for treatment of ischemic stroke or transient ischemic attack are "aspirin resistant" as defined by an abnormal finding on a PFA-100 test.

Mark Alberts, MD, professor of neurology at Northwestern University Medical School in Chicago, said 47% of the patients demonstrated aspirin resistance (defined as a clotting time of 171 seconds or less). In an earlier study, Dr. Alberts reported that 37% of patients were aspirin resistant. The study included 59 patients who had taken aspirin for at least three days prior to a stroke or TIA. The PFA-100 testing was done at the time of hospital diagnosis. Sixty-three percent of patients were taking 325 mg/day of aspirin: 37% were using baby aspirin. He said that aspirin resistance was most common in patients taking low-dose aspirin. Of those taking baby aspirin, 73% of the patients were resistant, while 32% of those taking high dose aspirin were resistant.

Dr. Hachinski cautioned that it is difficult to put the study findings into clinical relevance. "Studies show that aspirin can reduce the chance of a second stroke by about 25 percent," he said, noting that even if a person shows resistance to aspirin with the test it doesn't mean that the use of aspirin has not prevented a stroke or heart attack.

"I don't think I would change my patients' regimen of taking aspirin on the basis of these resistance studies at this point in time," he said.

Contributing Writer Ed Susman is based in Southern Florida.

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