TREAT UP TO SIX HOURS AFTER ONSET OF STROKE?

Intra-arterial recombinant prourokinase (IA r-proUK) administered within six hours of the onset of acute ischemic stroke caused by middle cerebral artery (MCA) occlusion improves neurologic outcome at 90 days over heparin alone, according to the results of the PROACT II trial.

The Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial was designed to determine the clinical efficacy and safety of IA r-proUK as an alternative to intravenous tissue-type plasminogen activator (IV t-PA), which has been shown to benefit a subset of patients if administered within three hours of symptom onset. The researchers noted that many patients present more than three hours after onset.

Between February 1996 and August 1998, 54 centers in the United States and Canada were involved in PROACT II, a randomized, controlled, multicenter, open-label, clinical trial with a blinded follow-up. Although 12,323 patients with acute stroke were screened, only 180 patients were randomized. In a ratio of 2:1, they received either 9 mg IA r-proUK over two hours plus intravenous (IV) heparin (n = 121) or IV heparin alone (n = 59).

Clinical efficacy was assessed after initial treatment and at seven to 10 days, 30 days, and 90 days. The modified Rankin scale, the National Institutes of Health Stroke Scale (NIHSS) score, and the Barthel index were used to assess therapeutic efficacy. The primary efficacy outcome was the percentage of patients achieving a modified Rankin score of two or less (ie, negligible or no disability) at 90 days after initial therapy. The secondary outcomes were the percentage of patients reaching a NIHSS score of one or less at 90 days and the rate of angiographic recanalization.

The medical histories of the patient groups were generally well matched; but because of small sample size, there were some differences in baseline variables by chance. Two of these, computed tomography (CT) hypodensity and diabetes, have been correlated with stroke outcome.

Forty percent of the r-proUK patients and 25% of control patients had a modified Rankin score of two or less at 90 days after stroke onset. Also, the r-proUK treatment group achieved independence in activities of daily living earlier than the control group.

Treatment with r-proUK increased patients' chances of having no or only slight neurologic symptoms at 90 days after initial therapy, compared with the low-dose heparin group. According to the report in the December 1 JAMA, the 15% absolute increase in favorable outcome means that one in every seven patients treated with IA r-proUK will benefit.

The researchers noted that they restricted patient selection to MCA occlusion because of its poor natural history and because the MCA is the most frequent site of arterial occlusion in patients with severe stroke of less than six hours' duration.

Treatment with IA r-proUK was beneficial despite an increased risk of early intracranial hemorrhage. The hemorrhage rates were consistent with those previously reported for embolic stroke, and most of the hemorrhages were clinically irrelevant and detected only by the mandatory CT scans.

The researchers concluded that the therapeutic window for a significant number of patients with major stroke associated with MCA occlusion may extend to at least six hours. They added that through interpretation of PROACT II trials, patient selection may be refined, delivery techniques may be optimized to reduce the risk of hemorrhage, and treatment strategies may be modified.

Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. JAMA. 1999;282:2003-2011.

SECRETIN NO BETTER THAN PLACEBO FOR AUTISTIC DISORDERS

A single dose of synthetic human secretin is no more effective than placebo as a therapy for autism or pervasive developmental disorder, according to a report in the December 9 New England Journal of Medicine. The study was conducted following extensive media coverage of a child whose autism reportedly improved after a single dose of secretin.

The researchers, led by Adrian D. Sandler, MD, reported that the media escalated stories of the child's response to secretin into suggestions that secretin might be a "cure" for autism. They noted that 2,500 children with autism are estimated to have received secretin injections after the publicity and that the production of sham products, price gouging, and other forms of profiteering may have followed. Only one other study of the safety and efficacy of secretin for autistic patients has been published—an open-label study of three boys.

Dr. Sandler and his colleagues recruited 60 children for the study. Either they had been referred by the Treatment and Evaluation of Autism and Communication Handicaps program of the Department of Psychiatry at the University of North Carolina, or their parents had become aware of the study through advertisements in an autism support group's newsletter.

Two thirds of the 60 children who met inclusion criteria were autistic, and the other third had a diagnosis of pervasive developmental disorder. Fifty-six children completed the study.

The participants were randomized after a two-week baseline period to receive either a placebo saline solution or a single dose of secretin, which was adjusted according to individual body weight. The children's behavior was assessed by their parents, their teachers, and by the study clinicians. The assessments were collected at the end of the first and second baseline weeks, on the first and second days after infusion, and at the end of the first, second, and fourth weeks after infusion. The Autism Behavior Checklist was used to measure severity of autistic symptoms; The Clinical Global Impression Scale was used to assess eight selected features often associated with autism; and the Treatment Emergent Symptoms Scale was used to record possible side effects of medication. The researchers also measured communication skills with the communication subscale of The Vineland Adaptive Behavior Scales.

Neither patient group improved significantly during the four weeks of follow-up. This lack of effect was seen overall and on an individual basis. Although there appeared to be minor improvements among the patients treated with secretin, the differences were not considered to have any clinical significance.

Dr. Sandler and his colleagues acknowledged several weaknesses of the current study. First, it was short-term, and significant brain-based behavioral changes would not likely be perceived within days or weeks. Second, they suggested that a multidose study might have more dramatic results. Third, as other diagnostic schedules have been used in recent studies, other subtypes of autism may have a different potential for response to treatment with secretin. Fourth, they used a synthetic secretin, although the anecdotal reports of secretin's benefit involved the biologic (porcine) product. Despite the findings, the authors noted the children's parents' continued interest in secretin's potential in the treatment of autistic disorders.

In an accompanying editorial, Fred R. Volkmar, MD, of the Yale University School of Medicine in New Haven, Connecticut, reiterated the study's limitations as well as continued parental hopes for secretin's potential. He emphasized that physicians must help families make informed decisions about treatments for autism. Pursuing unproven treatment jeopardizes the financial and psychosocial resources of families, he wrote, in addition to the physical health of the patient. Dr. Volkmar cautioned that an unexpected finding is more dramatic and thus is often considered more newsworthy than findings reached through methodological work. "What makes an interesting television program may not, of course, be the same as what makes good science," Dr. Volkmar concluded.

Sandler AD, Sutton KA, DeWeese J, et al. Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J Med. 1999;341:1801-1806.

Volkmar FR. Lessons from secretin. N Engl J Med. 1999;341:1842-1844.

CAN DEPRESSION BE THE FIRST SIGN OF ALZHEIMER'S DISEASE?

Motivation-related depression is a symptom of the preclinical phase of Alzheimer's disease, according to a report in the December 10 Neurology. Researchers from Karolinska Institute and Uppsala University, Stockholm, Sweden, examined three related questions: Do individuals who will develop Alzheimer's disease present with an elevation in depressive signs and symptoms compared with control subjects three years before diagnosis? If elevated depressive symptoms could be demonstrated, is there a predominance of either mood- or motivation-related symptoms? Are these symptoms related to perceived decline in cognitive functioning, or are they independent of subjectively experienced cognitive problems?

Study participants, who were at least age 75 and lived in the Kungsholmen parish of Stockholm, Sweden, completed a questionnaire that included the Mini-Mental State Examination and were clinically evaluated for depression. Those who were not found to be demented were scheduled for reevaluation in three years.

Over that period, some participants dropped out or were eliminated from the study. (They had either died or moved or had been diagnosed with non-Alzheimer's disease dementia, a psychiatric disease, Parkinson's disease, or stroke.) There were 222 people remaining in the follow-up group; 34 had developed Alzheimer's disease and 188 had no symptoms of dementia by the end of follow-up.

At follow-up, both groups completed the Comprehensive Psychopathological Rating Scale, a psychiatric test designed to identify symptoms of depression as either mood- or motivation-related. Symptoms of mood-related disturbance included dysphoria, appetite disturbance, feelings of guilt, and thoughts of death/suicide ideation; symptoms of motivation-related disturbance included lack of interest, psychomotor change, loss of energy, and concentration difficulties. Sleep disturbance was not considered either mood- or motivation-related for the purposes of this study, but it was included in the final analysis since it is a DSM-III-R symptom of depression.

The investigators reported that the incident Alzheimer's disease group had more depressive symptoms—and that a higher percentage of these were motivation—related-at baseline than did the nondemented group. Both of the groups, however, showed similar rates of mood disturbance, which was unrelated to the rate of subjective reports of memory loss. According to the researchers, this dissociation between mood and memory loss suggests that the increased depression is not a reaction to self-perceived cognitive difficulties.

The researchers also noted that in clinical Alzheimer's disease, mood-related symptoms are thought to dominate in mild to moderate stages, while motivation-related symptoms dominate in mild to severe stages of the disease. However, this study indicates that although mood-related symptoms of depression may dominate in early clinical Alzheimer's disease, motivation-related symptoms dominate in preclinical and severe stages of the disease. The researchers proposed that the preclinical cognitive deficits in Alzheimer's disease are not severe enough to trigger noticeable mood-related disturbance. They also noted that a certain level of cognitive ability is necessary to sense or express mood-related symptoms of depression.

Lars Bäckman, PhD, Director of the Stockholm Gerontology Research Center, stressed that the preclinical symptoms of Alzheimer's disease were mostly motivation-related in this study. "Because these symptoms—lack of interest, loss of energy, and difficulty concentrating—are fairly common in the normal older population, these symptoms may be easily overlooked as early signs of an emerging disease," he said.

Berger A-K, Fratiglioni L, Forsell Y, et al. The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study. Neurology. 1999;53:1998-2002.

HOW EFFECTIVE IS VITAMIN E FOR NEUROPROTECTION?

Pharmacologic doses of vitamin E may be effective in the treatment of certain disorders of the central nervous system in the aged, reported Govind T. Vatassery, PhD, Timothy Bauer, PA-C, MPH, and Maurice Dysken, MD, in the November issue of the American Journal of Clinical Nutrition.

The researchers, from the Research Service and Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Minneapolis, and the Department of Psychiatry, University of Minnesota, Minneapolis, analyzed the results of previously published studies of vitamin E's therapeutic efficacy in disorders of the nervous system in elderly subjects. Although vitamin E in pharmacologic doses was not apparently effective in Parkinson's disease, the data suggested, it did show evidence of benefit in Alzheimer's disease and tardive dyskinesia. The researchers were unable to assess its preventive role in nervous system disorders or its long-term safety and efficacy because studies have not been definitive.

The DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) trial was unable to demonstrate any benefit of vitamin E in Parkinson's disease. This double-blind, placebo-controlled study evaluated the effect of 2,000 IU/day of vitamin E and 10 mg/day of deprenyl (selegiline) in 800 North American participants with untreated Parkinson's disease. The end point was the time before required levodopa treatment. The authors noted that, as Parkinson's disease had already been diagnosed in the DATATOP subjects, an estimated 80% or more of the neurons in their substantia nigra had already degenerated. The trial, therefore, did not examine vitamin E's prophylactic role in Parkinson's disease. Other studies of vitamin E's preventive effects in Parkinson's disease have had conflicting results, reported Dr. Vatassery and colleagues. Although studies by De Rijk et al and Golbe et al suggested that a high intake of vitamin E may reduce the risk of Parkinson's disease, Logroscino et al found no evidence of an association between antioxidant intake and later development of Parkinson's disease.

As in Parkinson's disease, oxidative stress has been linked to Alzheimer's disease. A two-year, double-blind, placebo-controlled, randomized, multicenter trial was designed to evaluate the effect of vitamin E (2,000 IU/day), selegiline (10 mg/day), or a combination of these two dosages in 341 patients with moderate Alzheimer's disease. Efficacy was measured by the time to death, institutionalization, loss of ability to perform two of three designated activities of daily living, and severe dementia.

The authors of this two-year study concluded that vitamin E or selegiline slows the progression of Alzheimer's disease. However, the study has been criticized for measuring symptomatic effects rather than disease progression, and for using an end point—death—that could be caused by factors unrelated to disease progression. The study also did not measure the prophylactic effect of vitamin E or determine its optimum course, Dr. Vatassery and colleagues pointed out.

Vitamin E has been shown by several studies to reduce the incidence of cardiovascular disease, they reported. The epidemiologic studies, for example, indicated that the relative risk for a cardiovascular end point (fatal or nonfatal) was reduced by 31% to 65% after intake of supplemental vitamin E. These studies also showed that vitamin E is more beneficial than beta carotene or vitamin C. The researchers noted that, while several studies have evaluated the preventive effect of vitamin E, few, if any, have evaluated its therapeutic effect on existing cerebrovascular disease. Data are expected, however, from at least six prospective clinical trials of vitamin E in dosages greater than 300 IU/day.

The etiology of tardive dyskinesia is still unclear. Its incidence, however, is estimated to be 19% after four years of treatment with neuroleptic drugs and 40% after eight years. Vitamin E has been shown to improve tardive dyskinesia in nine of 12 studies reviewed by Lohr and Caligiuri. Dr. Vatassery and colleagues noted that patients who had tardive dyskinesia for less than five years tended to do better with vitamin E treatment than did those who had tardive dyskinesia for a greater duration of time. According to the current review, all studies of the therapeutic effect of vitamin E on tardive dyskinesia have lasted for no more than a few months. No studies have yet been designed to assess the preventive effect of vitamin E on tardive dyskinesia.

Vitamin E is relatively inexpensive and safe, Dr. Vatassery and colleagues commented. In previous studies, vitamin E "did not alter results on any of the tests of hepatic or renal function, hematologic status, plasma lipid or lipoprotein concentrations, bleeding time, serum autoantibody concentrations, or the ability of neutrophils to kill Candida albicans." Dosages of vitamin E ranging from 100 to 3,200 IU/day continued for up to several months have not been associated with adverse effects. "The primary contraindication for vitamin E is the existence of changes in coagulation indexes induced by warfarin-type drugs," Dr. Vatassery and colleagues wrote. Adequate vitamin K, however, seems to prevent further complications.

Vatassery GT, Bauer T, Dysken M. High doses of vitamin E in the treatment of disorders of the central nervous system in the aged. Am J Clin Nutr. 1999; 70:793-801.

SLEEP AND BEHAVIOR PROBLEMS ARE COMMON IN CHILDHOOD EPILEPSY

Children with epilepsy had considerably more sleep and behavioral problems than did either their siblings or healthy controls, reported researchers from the University of Rome. Since altered sleep habits may reflect emotional maladjustment, the researchers suggested that the sleep patterns of children with epilepsy should be carefully assessed.

According to the report in the November Epilepsia, 89 children with epilepsy were recruited from the Epilepsy Center at the Department of Developmental Neurology and Psychiatry, University of Rome. Children who were eligible for inclusion in the study were between ages 6 and 14, had either partial or generalized idiopathic epilepsy, had been epileptic for at least one year, had normal cognitive skills with an IQ of at least 85, had normal neurologic and neuroradiologic examinations, and were undergoing antiepileptic drug (AED) monotherapy with sodium valproate.

Exclusion criteria included other chronic or current illness; history of psychiatric disorder, nonepileptic neurologic disorders, or sleep disorders; or use of any non-AED in the previous month. Two groups of controls were also recruited: 48 siblings of epileptic children and 321 healthy children randomly selected from local primary and middle public schools.

Parents of the participants assessed their sleep patterns using the Sleep Behavior Questionnaire. They evaluated quantity and quality of sleep, bedtime and waking time on school and nonschool nights, sleep latency, parental involvement at bedtime, night waking, co-sleeping, naps, nighttime events, daytime drowsiness, and unrefreshing sleep. Parents also assessed their children's behavior and social functioning using the Child Behavior Checklist. With this checklist, they evaluated their children's social involvement, somatic complaints, anxiety, depression, social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior. The emotional health of the primary caregiver was also evaluated (with the Rutter Malaise Inventory) because of parents' influence on the development and maintenance of their children's sleep patterns.

While the study found that epileptic children experienced more sleep problems than the two control groups, it did not uncover any sex differences in the rates of sleep disruption. Analyzed by age group (ages 6 to 10 and 10.1 to 13.6), the data demonstrated more sleep problems in the younger subjects. Behavioral problems were also somewhat more common in the epilepsy group—again, particularly among the younger children. Scores on the Malaise Inventory revealed high stress levels among primary caregivers, reported the authors.

Antiepileptic medication may have an influence on sleep patterns, the researchers suggested. The lower levels of behavioral problems in this study than in previous studies may be linked to the exclusion of children who were not in the normal IQ range and who did not have primary well-controlled epilepsy.

Cortesi F, Giannotti F, Ottaviano S. Sleep problems and daytime behavior in childhood idiopathic epilepsy. Epilepsia. 1999;40:1557-1565.

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