STATINS MAY REDUCE STROKE RISK

Statin therapy could reduce the risk of ischemic stroke by up to one third among high-risk individuals, according to the results of a large-scale, prospective study carried out by the Heart Protection Study Collaborative Group at Oxford University in the United Kingdom. The results confirm the findings of previous smaller randomized trials that indicated that statin therapy to lower cholesterol levels reduced the risk of stroke, the researchers reported in the March 6 Lancet.

The study included 3,280 adults (ages 40 to 80) with cerebrovascular disease and 17,256 with other occlusive arterial disease or diabetes. Participants were randomized to 40 mg simvastatin daily or placebo. Follow-up was five years. Subgroup analyses included first “major vascular event” (ie, nonfatal myocardial infarction or coronary death, stroke of any type, or any revascularization procedure) in prior disease subcategories. The results were also analyzed by stroke type.

The investigators found that simvastatin conferred an average difference in LDL cholesterol of 1.0 mmol/L during the treatment period. Among the patients in the treatment group, there was a 25% reduction in the first event rate for stroke compared with the placebo group (4.3% versus 5.7%), “reflecting a definite 25% reduction in presumed ischemic strokes and no apparent difference in strokes attributed to hemorrhage,” the researchers wrote.

Additionally, simvastatin reduced the number of transient ischemic attacks alone (2.0% versus 2.4%) or requiring carotid endarterectomy or angioplasty (0.4% versus 0.8%). The reduction in stroke was not significant in the first year but became significant during the second year, the investigators noted. Also, among patients with preexisting cardiovascular disease, there was no apparent reduction in stroke rate, “but there was a highly significant 20% reduction in the rate of any major vascular event,” they said. In each of the other subcategories investigated (age younger or older than 70 at entry, presence of coronary disease or diabetes, blood pressure, and lipid levels), the proportional reductions in stroke risk were about 25%.

“The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events but also of ischemic strokes, with no apparent effect on cerebral hemorrhage, even among individuals who do not have high cholesterol concentrations,” the investigators said. “After making allowance for noncompliance in the trial, actual use of [40 mg simvastatin daily] would probably reduce the stroke rate by about a third,” they remarked. “Given that stroke is one of the major causes of mortality and major morbidity worldwide, these findings indicate that statin therapy should now be considered routinely for all patients at high risk of stroke, irrespective of their initial cholesterol concentrations or the presence of coronary disease.”

Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757-767.

NOVEL PATHOLOGY IN NEW MS LESIONS

Australian researchers revealed new insights into the pathologic onset of multiple sclerosis (MS) lesions and demonstrated that tissue destruction as the result of a T-cell–mediated cellular immune response directed against myelin may not be the earliest event in triggering a MS relapse. Rather, “the earliest change observed in the lesions examined in this study was widespread oligodendrocyte apoptosis in tissue in which T cells, macrophages, activated microglia, reactive astrocytes, and neurons appeared normal,” said study author John W. Prineas, MBBS, of the University of Sydney.

Dr. Prineas and his colleague, Michael H. Barnett, MBBS, developed their study based on findings in a 14-year-old female patient with relapsing-remitting MS who died within 24 hours of the onset of a new symptomatic brainstem lesion. An autopsy examination conducted 13 hours after death revealed that “there was relatively little loss of myelin throughout the lesion,” Dr. Prineas reported. “In broad areas within and extending from the lesion, myelin sheaths showed only a slight reduction in staining intensity, whereas all normal appearing oligodendrocytes were replaced by apoptotic oligodendrocytes.”

These findings led Drs. Prineas and Barnett to examine brain tissue in 11 other patients with relapsing-remitting MS who died during or shortly after the onset of a relapse. The six most acute cases, all demonstrating new lesions similar to the fatal lesion in Case 1, were compared. Patients ranged between ages 14 and 40; five were female. The results were published in the February 23 advanced online edition of Annals of Neurology.

Drs. Prineas and Barnett found that “the earliest structural change shared by all 10 lesions was extensive oligodendrocyte apoptosis in tissue exhibiting early microglial activation but few or no infiltrating lymphocytes or myelin phagocytes.” They determined that their findings were “likely to be related to, if not the cause of, the initial two- to three-day progressive phase of a typical relapse, namely, an abrupt loss of oligodendrocytes throughout a circumscribed and relatively small volume of tissue.”

The investigators believe their work raises the possibility of some novel process underlying lesion formation in MS. Although their work did not provide “direct evidence” of this prospective cause of oligodendrocyte apoptosis, Drs. Prineas and Barnett postulated that “one unexplained finding that may relate to the genesis of a new lesion was the occasional occurrence of perivascular cuffs of mononuclear cells adjacent to periventricular white matter, at the corticomedullary junction, and close to the pia, all areas where new MS lesions tend to form,” they noted.

Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004; e-pub ahead of print.

CAN TIAs REDUCE STROKE SEVERITY?

An investigation of whether transient ischemic attacks (TIAs) before stroke “can induce tolerance by raising the threshold of tissue vulnerability in the human brain” found that the hypothesis of “endogenous preconditioning” has merit, according to a report in the February Stroke.

Susanne Wegener, MD, of the Department of Neurology, University Hospital Charité, Berlin, and colleagues enrolled 65 patients with first-ever ischemic territorial stroke. Patients were recruited from the university hospitals of Düsseldorf, Hamburg, Heidelberg, and Berlin. The average age of participants was 59; 30.8% were female. Forty-nine of the patients had no prodromal TIA. The investigators assessed perfusion and tissue damage using perfusion- and diffusion-weighted MRI and compared the extent of the initial perfusion and diffusion deficit and final infarct volume, said Dr. Wegener. Time of the first MRI assessment was 4.5 hours in the no-TIA group and 4.9 hours in the TIA group. Stroke symptoms and functional disability were significantly less severe in patients with prodromal TIA at the acute stage as well as on discharge, she noted.

“Despite similar size and severity of perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2, 9.1 versus 36.5) in patients with a history of TIA,” the investigators reported. “The fact that the sizes of the perfusion lesion as well as cerebral blood flow and cerebral blood volume values were not different between patients with and without prodromal TIAs indicates that both patient groups were subjected to the same extent and severity of flow restriction and microvascular capacity disruption,” Dr. Wegener and colleagues wrote. “Nevertheless, infarcts in patients with prodromal TIA were smaller.”

According to the researchers, “this is the first study to suggest that protection by a prodromal TIA is not explained by changes in blood flow, as would be expected from collateral recruitment or enhanced vascularization, but rather by intrinsic neuroprotective mechanisms.” They suggested that “further delineation and exploration of naturally occurring ischemic tolerance may be a new perspective in future neuroprotection and acute stroke therapy.”

Wegener S, Gottschalk B, Jovanovic V, et al. Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke. 2004;35:616-621.

AN AED FOR MIGRAINE PREVENTION?

Topiramate showed significant efficacy in migraine prevention within the first month of treatment, an effect that was maintained for the duration of the double-blind phase of a study reported in the February 25 JAMA. Jan Lewis Brandes, MD, of the Nashville Neuroscience Group, and colleagues made their findings after conducting a 26-week, randomized, double-blind, placebo-controlled trial during outpatient treatment at 52 North American clinical centers. Patients ranged in age from 12 to 65 and had a six-month history of migraine. In addition, they had three to 12 migraines a month but no more than 15 headache days per month during a 28-day prospective baseline phase. After a washout period, patients meeting entry criteria were randomized to topiramate at doses of 50, 100, or 200 mg/day or placebo. Topiramate was titrated by 25 mg/ week for eight weeks to the assigned or maximum tolerated dose, whichever was less. Patients continued to receive that dose for 18 weeks.

A total of 483 patients were randomized, of whom 468 provided at least one postbaseline efficacy assessment and comprised the intent-to-treat population. Dr. Brandes and colleagues found that the mean monthly migraine frequency decreased significantly for patients who received topiramate at 100 mg/ day and topiramate at 200 mg/day versus placebo. Statistically significant reductions occurred within the first month with topiramate at 100 and 200 mg/day. The responder rate was significantly greater with topiramate at 50 mg/day, 100 mg/ day, and 200 mg/day compared with placebo. Reductions in migraine days were significant for the 100-mg/day topiramate group, and rescue medication use was reduced in the 100-mg/day and 200-mg/day topiramate groups. Adverse events resulting in discontinuation in the topiramate groups included paresthesia, fatigue, and nausea, according to the researchers.

“Topiramate showed statistically significant efficacy in migraine prevention within the first month of treatment, an effect maintained for the duration of the double-blind phase,” the investigators reported. “Topiramate appeared to be safe and had an acceptable tolerability profile, although pooled analyses of a larger number of patients and data on longer treatment duration should help complete the safety profile.”

NR

Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291:965-973.

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