HYPOTHERMIA AND ISCHEMIC STROKE—IS ACETAMINOPHEN THE ANSWER?

Evidence that there is “a twofold increase in mortality risk for every 1°C increase in body temperature” after acute ischemic stroke has sparked interest in hypothermic treatment as a means to improve patient outcome. A recent trial suggests that high-dose acetaminophen provides a “clinically worthwhile reduction of body temperature in patients with acute stroke, especially when they have no fever.”

In the July issue of Stroke, Dippel et al reported the results of a double-blind clinical trial in which 75 patients with acute ischemic anterior circulation stroke were randomized to receive either placebo, 500 mg of acetaminophen, or 1,000 mg of acetaminophen. The severity of the precipitating stroke was greater in the patients receiving active treatments. Patients treated with steroid or nonsteroid anti-inflammatory drugs within three days of stroke, those suffering severe or chronic illness, those with a history of alcohol abuse, and any allergic to acetaminophen or aspirin were excluded.

Body temperature for all patients ranged between 36°C and 39°C. Treatments were administered by suppository six times daily for five days following the onset of stroke. Measurements were taken via electronic rectal thermometer at the start of treatment and 24 hours later. Tympanic temperature was taken at two-hour intervals for the first day and every six hours for the next six days.

Because “the period in which hyperthermia is associated with poor outcome may be limited to the first 12 or 24 hours from stroke onset,” emphasis was placed on results in that interval. After adjustment for variables, statistical analysis showed no significant difference between placebo and the 500-mg acetaminophen treatment. The 1,000-mg treatment, however, resulted in a 0.4°C decrease in body temperature relative to placebo, and a mean reduction in body temperature 0.3°C greater than that in placebo-treated patients. After five days of treatment, no significant differences in temperature were apparent between any groups.

At one month, functional outcome did not differ significantly among the groups. The relative risk of poor outcome for patients on the 1,000-mg treatment as compared to placebo was 1.1. The authors attributed this to the slight skewing in baseline distribution of stroke severity. The frequency of adverse events was similar among the groups.

The researchers also note that “the concern that treatment with an antipyretic drug may mask emerging infections and thus lead to treatment delay, sepsis, and poor outcome, was not substantiated in this study.” They suggest the low cost and relative safety of acetaminophen would make the drug a particularly welcome therapy if further research continues to demonstrate its efficacy.

Suggested Reading
Dippel DWJ, van Breda EJ, van Gemert HMA, et al. Effect of paracetamol (acetaminophen) on body temperature in acute ischemic stroke: a double-blind, randomized phase II clinical trial. Stroke. 2001;32:1607-1612.

NEW GUIDELINES FOR DIAGNOSING MULTIPLE SCLEROSIS

Because “no single clinical feature or diagnostic test is sufficient for the diagnosis of multiple sclerosis,” established diagnostic parameters include both clinical and paraclinical studies. In July 2000, the International Panel on the Diagnosis of Multiple Sclerosis convened in London to “reassess existing diagnostic criteria and to recommend, if necessary, appropriate changes.” The guidelines were published in the July 2001 issue of Annals of Neurology.

The panel proposed to assemble diagnostic criteria for practicing physicians that were also adaptable for clinical trials, to implement magnetic resonance imaging into the diagnostic template, and to clarify and simplify diagnostic classification and descriptions “to reflect improved understanding of the disease and new technologies.”

The panel began by emending the descriptive categories appropriate to the disease, eliminating such terms as “clinically definite” and “probable multiple sclerosis.” Diagnostic evaluation will now result in an outcome of either “multiple sclerosis” or “possible multiple sclerosis” for patients considered at risk but having equivocal diagnoses, or “not multiple sclerosis.” The panel defined a multiple sclerosis attack as a neurologic disturbance whose causative lesions are clinicopathologically established as “inflammatory and demyelinating in nature.” For the purposes of definition, attacks should last at least 24 hours; separate attacks must occur 30 days apart. Multiple paroxysmal episodes occurring over not less than 24 hours constitute a relapse.

From a diagnostic perspective, “objective evidence of dissemination in time and space of lesions typical of multiple sclerosis” is essential for a secure diagnosis. A history of symptoms “may lead to a suspicion of the disease, but cannot be sufficient on their own for a diagnosis of multiple sclerosis.” In fact, the new guidelines state that anything less than two or more attacks in conjunction with clinical evidence of two or more lesions requires corroborating, paraclinical data as supporting evidence prior to diagnosis.

This evidence will be chiefly supplied by radiologic and laboratory investigations. Magnetic resonance imaging, cerebrospinal fluid analysis, and visual evoked potentials should be implemented “when clinical presentation alone does not allow a diagnosis to be made,” and will all be forced to meet stringent criteria for sensitivity and specificity in defining “abnormal lesions,” but the panel noted that in all of these evaluations, “correct interpretation is essential.”

Even if all clinical evidence and paraclinical support is strongly indicative of multiple sclerosis, the panel insisted that “there must be no better explanation” for the abnormalities than multiple sclerosis in order for the secure diagnosis to be made.

Suggested Reading
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121-127.

SECONDARY PREVENTION NEEDS PRIMARY ATTENTION IN CARDIOVASCULAR EVENT SURVIVORS

Survivors of myocardial infarction or stroke are already at high risk for subsequent cardiovascular events. However, an “alarming” number of these survivors are increasing their risk even further by abandoning secondary prevention measures, according to Adnan I. Qureshi, MD. Dr. Qureshi and colleagues at the School of Medicine and Biomedical Sciences at the State University of New York, Buffalo, drew upon participants in the Third National Health and Nutrition Examination Survey (NHANES III) to determine the “adequacy of risk factor modification” for survivors of cardiovascular events.

Between 1988 and 1994, 17,752 adults were enrolled in NHANES III. The survey included a household interview, medical examination, and phlebotomy to determine hematologic factors. Based on recorded physician diagnoses, 1,252 participants were determined to be survivors of myocardial infarction, stroke, or both. This cohort was evaluated by a research team led by Dr. Qureshi for the frequency of the defined cardiovascular disease risk factors, including hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, and alcohol use. Additionally, the potentially related factors of age, sex, race/ethnicity, educational attainment, socioeconomic status, and medical insurance status were evaluated.

The results, published in the July 9 issue of Archives of Internal Medicine, were revealing. Hypertension was diagnosed in 738 participants; of these, hypertension was uncontrolled in 388 (53%). Likewise, hypertension was detected in 138 (11%) previously undiagnosed individuals.

Serum glucose control was inadequate in 141 (49%) of 289 diabetic persons, and hypercholesterolemia was poorly controlled in 185 of 405 persons (46%). The latter was also observed in 160 (13%) participants in whom it had been previously undetected.

Of the survivors, 225 (18%) were current smokers and 56 (4%) participants were “heavy alcohol users” (consuming more than nine drinks per day, seven times per year, or more than five drinks per day, 14 times per year). High-risk profiles were more frequent in persons ages 47 to 65 years, in women, and in African-Americans. The overall statistics are “highly lamentable,” and, as Dr. Qureshi noted, “call for major efforts directed toward secondary prevention in a subset of the population at highest risk for CVD events.”

Suggested Reading
Qureshi AI, Suri MFK, Guterman LR, Hopkins LN. Ineffective secondary prevention in survivors of cardiovascular events in the US population: report from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2001;161:1621-1628.

MIDLIFE VASCULAR RISK FACTORS AND LATE-LIFE ALZHEIMER’S DISEASE

Midlife vascular risk factors such as raised systolic blood pressure and high serum cholesterol concentration, and the combination of these two factors in particular, increase the risk of Alzheimer’s disease later in life, according to a study in the June 16 BMJ. Because both hypertension and hypercholesterolemia can be treated, more emphasis should be placed on identifying and treating these conditions, concluded lead author, Miia Kivipelto, MD, a research fellow at the Department of Neuroscience and Neurology, University of Kuopio, Finland. As the proportion of elderly people in the population increases, Alzheimer’s disease will become an enormous problem worldwide, and, therefore, any interventions that could delay the onset of the disease would have a major impact on public health. Identifying early risk factors for Alzheimer’s disease is important, because the neurodegenerative processes of the disease may begin in midlife.

Previous studies had determined that vascular risk factors may play an important role as risk factors for Alzheimer’s disease, but no population-based studies had prospectively evaluated the impact of both midlife blood pressure and cholesterol concentration on the subsequent development of Alzheimer’s disease. This latest research was a large, population-based, longitudinal study with a substantial response rate, which increases the credibility of these findings, according to the investigators. This study was based on individuals living in Kuopio and Joensuu in eastern Finland and derived from four separate independent samples from 1972, 1977, 1982, and 1987. After an average of 21 years’ follow-up, a total of 1,449 (73%) men and women ages 65 to 79 years took part in the reexamination in 1998. People with raised systolic blood pressure or high serum cholesterol concentration in midlife had a significantly higher risk of Alzheimer’s disease in later life, even after adjustment for age, body mass index, education, vascular events, smoking status, and alcohol consumption, than did those with normal systolic blood pressure or serum cholesterol. Participants with both these risk factors had a significantly higher risk of developing Alzheimer’s disease than those with either factor alone.

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