STUDY SUGGESTS NEW VIRAL LINK IN MULTIPLE SCLEROSIS

Although the cause of multiple sclerosis remains a mystery, speculation regarding an infectious, and probably viral, etiology continues. In the past decade, Chlamydia pneumoniae, human herpesvirus 6, and, most recently, Epstein-Barr virus have been implicated. In an effort to determine a more exact, possibly causal relationship between Epstein-Barr virus infection and multiple sclerosis, researchers at Harvard University School of Public Health undertook a prospective, nested case-control study of 62,439 women participating in the Nurses’ Health Study and Nurses’ Health Study II.

Alberto Ascherio, MD, DrPH, and colleagues collected blood samples taken from the cohort in 1989-1990 and 1996-1999, respectively. A total of 144 women with definite or probable multiple sclerosis were age-matched with 288 healthy controls. Analyses were conducted to determine elevations in serum antibody titers to Epstein-Barr viral capsid antigen, Epstein-Barr nuclear antigens (EBNA, EBNA-1, and EBNA-2), and diffuse and restricted early antigen (EA-D and EA-R), as well as to cytomegalovirus.

Of the 144 multiple sclerosis cases, 18 were documented through blood samples collected prior to disease onset. Compared with samples from controls, blood taken from multiple sclerosis patients had higher serum geometric mean titers of antibodies to Epstein-Barr virus but not to cytomegalovirus. Elevations were significant for antibodies to EBNA-1, EBNA-2, and EA-D. The strongest association between Epstein-Barr virus antibody titer levels and multiple sclerosis was for EBNA-2 (relative risk, 3.9). The authors concluded that their results “offer evidence that Epstein-Barr virus infection may increase the risk of multiple sclerosis,” but allow that “because few individuals infected with EBV develop multiple sclerosis, other cofactors are required.”

In an accompanying editorial, Donald H. Gilden, MD, offered his support for the theory that multiple sclerosis is likely a disease of viral origins. However, Dr. Gilden, a member of the Departments of Neurology and Microbiology at the University of Colorado Health Sciences Center, was hesitant to fully endorse the study’s conclusions. “While the findings would suggest a role of Epstein-Barr virus in the etiology of multiple sclerosis,” he said, “cerebrospinal fluid data would be helpful, since the immunoglobulin G in multiple sclerosis patients’ brain tissue and cerebrospinal fluid is synthesized intrathecally and may more accurately reflect the immune response at the site of disease.... If Epstein-Barr virus or any other virus causes multiple sclerosis, it should be possible to demonstrate that multiple sclerosis oligoclonal bands contain antibody directed against the suspected agent.” That objection aside, Dr. Gilden applauded the researchers’ efforts. “Although the cause of multiple sclerosis is not likely to be found under the Epstein-Barr virus lamppost, the search for a viral cause of multiple sclerosis must continue,” he concluded.

Suggested Reading

Ascherio A, Munger KL, Lennette ET, et al. Epstein-Barr virus antibodies and risk of multiple sclerosis. JAMA. 2001;286:3083-3088.

Gilden DH. Viruses and multiple sclerosis. JAMA. 2001;286:3127-3129.

EARLY ISCHEMIC CHANGES ON CT SCAN LACK CLINICAL SIGNIFICANCE

Stroke patients who were treated with recombinant tissue plasminogen activator (t-PA) fared better whether or not they had early ischemic changes in their brains, according to a study in the December 12 JAMA. This finding suggests that the early ischemic changes seen on the computed tomography (CT) scan are not critical to the decision of whether to treat a t-PA candidate within three hours of stroke onset.

Lead author Suresh C. Patel, MD, of the Henry Ford Hospital, and colleagues reported that early ischemic changes are not independently associated with an increased risk of adverse outcome after t-PA treatment, even though they are prevalent within three hours of stroke.

The researchers sought to determine the frequency and significance of early ischemic changes on baseline head CT scans in the National Institute of Neurological Disorders and Stroke (NINDS) t-PA Stroke Trial. The original study, reported in 1995, involved taking CT images within three hours of stroke symptom onset and prior to the initiation of t-PA or placebo. In the current study, detailed reevaluation was undertaken of all baseline head CT scans with clinical data available pretreatment. Of 624 study participants (312 randomized to t-PA treatment and 312 to placebo), baseline CT scans were reviewed for 616 (99%).

The investigators identified 31% of patients who had baseline CT scans with subtle evidence of an evolving ischemic stroke. They noted that early ischemic changes were significantly associated with baseline National Institutes of Health Stroke Scale (NIHSS) score and time from stroke onset to baseline CT scan. After adjusting for baseline variables, they found no interaction between early ischemic changes and treatment detected for any clinical outcome, including deterioration at 24 hours, four clinical scales, lesion volume, and death at 90 days, which suggests that early ischemic changes are unlikely to affect response to t-PA. No early ischemic changes association with symptomatic intracranial hemorrhage at 36 hours was detected in the group treated with t-PA, after adjusting for NIHSS score.

“Although early subtle CT scan changes of evolving cerebral ischemia within three hours of stroke onset are more frequent than previously realized, these findings do not appear to be critical in the decision to treat an otherwise eligible patient with t-PA within three hours of stroke onset, provided the strict eligibility criteria ... of the NINDS t-PA Stroke Trial are followed,” the researchers concluded.

Suggested Reading

Patel SC, Levine SR, Tilley BC, et al. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke. JAMA. 2001;286:2830-2838.

HYPOTENSION AND COGNITIVE IMPAIRMENT—A SELECTIVE ASSOCIATION

The recent association of heart failure with an increased prevalence of cognitive impairment, particularly among older populations, has prompted vigorous research into the nature of the relationship between the two conditions. Because the extent of cognitive impairment correlates with the degree of left ventricular dysfunction, Giuseppe Zuccalà, MD, and colleagues undertook to analyze the link between blood pressure levels and cognitive impairment. They found that “systolic hypotension is selectively associated with cognitive impairment in older patients with heart failure.”

The study, published in the December Neurology, examined 13,635 patients enrolled in a pharmacoepidemiologic study at 81 clinical academic centers across Italy in 1995 and 1997. Blood pressure was taken at admission and upon discharge. A Hodkinson Abbreviated Mental Test was administered to patients in order to assess cognitive performance. The results of this test were examined against a discharge diagnosis of congestive heart failure.

Analysis revealed that 1,583 patients (mean age 80) were diagnosed with heart failure. Cognitive impairment was detected at hospital discharge in 26% of patients with heart failure, as compared with 19% of control (non-heart failure) subjects. Among patients with heart failure, a systolic blood pressure lower than a threshold of 130 mm Hg was found in 46% of patients demonstrating cognitive impairment and in 27% of patients with normal cognitive performance. No systolic blood pressure level was found to be predictive of cognitive impairment among control subjects.

“The pathophysiology of cognitive impairment among patients with heart failure is uncertain,” the authors noted, and “whether systolic hypotension is the cause or consequence of brain alterations in patients with cognitive impairment is debated.” Nonetheless, the researchers conclude that their data “indicate the need for trials aiming at reducing the burden of disability in older patients with heart failure based upon systematic neuropsychological assessment of subjects with systolic hypotension for prompt recognition of cognitive dysfunction and correction of low-output states.”

Patrick M. Pullicino, MD, PhD, and John Hart, MD, observed in an accompanying editorial that Dr. Zuccalà and colleagues’ “interesting findings support a hypoperfusion etiology for cognitive impairment in elderly patients with cardiac failure.” The editorialists maintain doubts that hypotension is the “main cause of reduced cerebral blood flow because blood pressure is usually well-maintained in patients with left ventricular systolic dysfunction.” However, they allow that hypotension “may play a role … because cerebrovascular reactivity is impaired in patients with cardiac failure [and in those] who have impaired autoregulation owing to old age, recent stroke, or severe carotid occlusive disease.” Such patients “may be particularly at risk for hypoperfusion-related cerebral ischemia,” which is known to impair cognition.

Thus, the findings of Dr. Zuccalà’s research team “suggest a potentially reversible element [in the treatment of cognitive impairment], as improvement in cognition has been noted following cardiac transplantation.” Continued assessments of cognition as it relates to cardiac dysfunction “will help shed further light on this area,” they conclude.

Suggested Reading

Pullicino PM and Hart J. Cognitive impairment in congestive heart failure? Embolism vs hypoperfusion. Neurology. 2001;57:1945-1946.

Zuccalà G,Onder G, Pedone C, et al. Hypotension and cognitive impairment. Selective association in patients with heart failure. Neurology. 2001;57:1986-1992.

IS THERE A LINK BETWEEN PSYCHOLOGICAL DISTRESS AND STROKE?

While psychological distress is common in the wake of stroke, its etiological relationship to stroke had previously been little examined. Recently, however, phase II of the Caerphilly study in South Wales demonstrated a significant relationship between depression and anxiety and the risk of ischemic stroke. The results were detailed in the January Stroke.

The study, conducted by Margaret May, MSc, and colleagues, examined 2,201 men ages 45 to 59 during the period from 1979 to 1988. At baseline, subjects completed the 30-item General Health Questionnaire (GHQ), a measurement of psychiatric distress. Detailed medical histories, as well as echocardiograms, were collected. More than 20% of the cohort had GHQ test scores indicative of mood disorders. After a follow-up period of 14 years in which data were collected on incidence of stroke, statistical analysis was conducted to determine the relative risk of stroke as related to psychological stress.

One hundred thirty incident strokes occurred (17 of which were fatal). Men who had strokes were older, heavier, had higher blood pressure, and were more likely to be current smokers and have at least one other chronic disease than men who did not. They also showed a tendency “to report more symptoms of anxiety and depression.” History of general psychological distress, as recorded by the GHQ, was indicative of a 3.36 relative risk for fatal stroke, a 1.25 relative risk for nonfatal stroke, and a 0.63 relative risk of transient ischemic attack (TIA). These results mark psychological distress as a significant predictor of fatal stroke, but not of nonfatal stroke or TIA. The significance remained unaltered by adjustment for other risk factors. Controlling for previously diagnosed ischemic heart disease, diabetes, respiratory disease, and retirement due to ill health “attenuated the relative risks, but not markedly.”

In an accompanying editorial, Robert M. Carney, PhD, and Kenneth E. Freedland, PhD, from Washington University, St. Louis, acknowledged the work of the Caerphilly study group as “a unique contribution” to research into the role of psychological stress as related to stroke. They found that the major drawback in the Caerphilly study was a failure to monitor possible changes in psychological state over the follow-up period. “All we know about the psychological state of the subjects is that they were distressed at enrollment,” the editorialists remarked. “Additional studies are needed in which standardized psychiatric interviews, along with questionnaires that assess depression and anxiety with higher specificity than the GHQ-30, are administered repeatedly over time.”

The editorialists also pondered the etiological implications of the findings, particularly as significant results were documented only for fatal stroke. “Psychological distress may not promote the development of cerebrovascular disease, but it may instead heighten the risk of fatal stroke in patients with existing cerebrovascular disease,” postulated Drs. Carney and Freedland. “Another explanation for the relationship between depression and stroke is that both may be caused by cerebrovascular disease,” they added. “The Caerphilly study is an excellent beginning, but the relationship between psychological distress and cerebrovascular disease, stroke, and stroke mortality deserve further investigation,” particularly in terms of whether treating depression can reduce the risk of fatal stroke, the commentators concluded.

NR