CAN EARLY TREATMENT SLOW MS PROGRESSION?

Interferon beta-1a treatment during the earliest detectable phase of multiple sclerosis can delay the development of new lesions, according to results from the Early Treatment of Multiple Sclerosis (ETOMS) Study Group published in the May 19 Lancet. Treatment with a low dose of interferon beta-1a lowered the proportion of patients who converted to clinically definite multiple sclerosis and reduced the frequency of relapses overall, the researchers said. However, the observed effects were “quite small,” and the authors were quick to point out that the argument to begin treatment early is still debatable.

Patients with a recent first neurologic episode and a magnetic resonance imaging (MRI) scan suggestive of multiple sclerosis were randomly assigned to interferon beta-1a (22 mg) or placebo subcutaneously once weekly for two years. Conversion to clinically definite multiple sclerosis was defined by the occurrence of a second exacerbation—the appearance of a new symptom or worsening of a preexisting symptom, accompanied by a corresponding new neurologic sign or focal neurologic dysfunction lasting at least 24 hours, in the absence of fever, and preceded by stability or improvement for at least 30 days.

A total of 278 patients from 57 centers in 14 European countries completed the study. Fewer patients developed clinically definite multiple sclerosis in the interferon group (34%) than in the placebo group (45%) during the two-year study. The odds ratio for conversion was 0.61 after adjusting for country, onset type, baseline T2 lesion count, and time from first attack to randomization.

The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group. The annual relapse rates were 0.33 in the treated group and 0.43 in the placebo group. The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with interferon beta-1a treatment.

Interferon beta-1a did not stop disease activity in the majority of treated patients, the researchers pointed out. By the end of the study, only 16% of the patients in the interferon group and 6% of those in the placebo group were free of temporal dissemination of MRI lesions. One fifth of the placebo group and 15% of the interferon group had worsened by one point on the expanded disability status scale. Longer follow-up is needed, the researchers noted, to see whether early treatment can improve disability scores.

Adverse events were reported more frequently in the interferon group than in the placebo group. These events included injection site inflammation, fever, myalgia, and chills. Serious adverse events were reported in five patients in the placebo group and six patients in the interferon group.

Consistent with the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS), the ETOMS study demonstrated that type 1 interferons can prolong the time to a second clinical lesion. “However, have the findings any implications for everyday clinical practice?” questioned George C. Ebers, MD, FRCPC, in an accompanying commentary. “Both studies were stopped far too soon to enable definitive answers to the question of treatment value,” he said.

“The financial implications are enormous,” Dr. Ebers added. “Six years of treatment would be required to suppress a single relapse, given a one-third reduction of relapses and an average attack rate of 0.5 per year,” he said.

“Despite lack of evidence, the notion that early treatment is important has been widely promoted,” Dr. Ebers said. “Unfortunately, uncertainty on the key question of long-term effectiveness seems destined to persist for an uncomfortably long time.”

Suggested Reading
1. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582.
2. Ebers GC. Preventing multiple sclerosis? Lancet. 2001;357:1547.

HDL CHOLESTEROL—AN IMPORTANT MODIFIABLE RISK FACTOR FOR THE ELDERLY, MINORITIES

Increased high-density lipoprotein cholesterol (HDL-C) levels were associated with reduced risk of ischemic stroke in an elderly, multiethnic population of men and women. These data, from the Northern Manhattan Stroke Study published in the June 6 JAMA, add to the evidence relating lipids to stroke and support HDL-C as an important modifiable stroke risk factor.

To evaluate the association between HDL-C and ischemic stroke in a racially and ethnically diverse elderly population in New York City, researchers from Columbia University conducted a population-based, incident case-control study in a northern Manhattan community from July 1993 through June 1997.

The 539 cases of first ischemic stroke were enrolled and matched by age, sex, and race or ethnicity to 905 stroke-free community residents. Among the cases, 67% were age 65 or older; 55% were women; 53%, Hispanic; 28%, black; and 19%, white. Fasting blood samples were drawn within several days of study enrollment, usually within 72 hours of admission.

A protective effect was observed for HDL-C levels of at least 35 mg/dL, after adjusting for risk factors. A dose-response relationship was observed for HDL-C levels of 35 to 49 mg/dL, even when HDL-C levels were adjusted for total cholesterol or LDL-C and triglyceride levels, suggesting that this protective effect is not mediated by relationships between HDL-C and other measured lipids. It was greater for patients with HDL-C levels of 50 mg/dL or higher than patients with HDL-C levels between 35 and 49 mg/dL. An interesting finding, according to the authors, was that HDL-C level showed more protection for atherosclerotic stroke than for nonatherosclerotic infarction but was significantly protective against both subtypes. A similar dose-response relationship was observed in all three racial or ethnic groups studied.

The study has important public health implications for minority groups and elderly persons, the researchers stress. Blacks and Hispanics have a greater mortality and incidence of stroke. This study has also shown a protective effect of high HDL-C levels for ischemic stroke among the “older-elderly,” a finding significant in that several researchers have questioned the need to diagnose or treat dyslipidemia in individuals older than 70; the data from the Northern Manhattan Stroke Study suggest that HDL-C is still strongly protective against ischemic stroke among those older than 75 years.

Suggested Reading
Sacco RL, Benson RT, Kargman DE, et al. High-density lipoprotein cholesterol and ischemic stroke in the elderly: the northern Manhattan stroke study. JAMA. 2001;285:2729-2735.

NEW AND MORE ACCURATE STROKE CLASSIFICATION SCHEME

Researchers have devised a third and, they say, more accurate classification scheme to estimate stroke risk in patients with atrial fibrillation—the CHADS₂ index, which combines two existing classification schemes. The authors of a June 13 JAMA study believe that application of the three classification schemes can quantify risk of stroke for patients who have atrial fibrillation and may also aid in the selection of antithrombotic therapy.

Data from peer review organizations representing seven states were used to assemble a National Registry of atrial fibrillation consisting of Medicare beneficiaries ages 65 to 95 years who had nonrheumatic atrial fibrillation and were not prescribed warfarin at hospital discharge.

The study had several strengths, the researchers noted. Their study utilized chart review to document the presence of atrial fibrillation and to identify the stroke risk factors. The chart review also identified patients who received aspirin and, due to the number of strokes, enabled the authors to calculate with precision the stroke rates. The CHADS₂ was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. CHADS₂ is an acronym for these risk factors.

Overall, the new stroke risk index had greater predictive accuracy than did either the Stroke Prevention in Atrial Fibrillation (SPAF) and Atrial Fibrillation Investigators (AFI) schemes, the researchers reported.

The 1,733 Medicare beneficiaries were followed up for a mean of 1.2 years. During 2,121 patient-years of follow up, 94 patients were readmitted for an ischemic event (rate, 4.4 per 100 patient years). Although the two existing classification schemes were able to predict stroke better than chance, the CHADS₂ index was the most accurate. The stroke rate per 100 patient-years without antithrombotic therapy increased by a factor of 1.5 for each one-point increase in the CHADS₂ score.

CHADS₂ was also found to be a more accurate predictor of stroke both in those who did and who did not receive aspirin. Their study results suggest that aspirin therapy should be prescribed for elderly patients with atrial fibrillation who are not suitable candidates for warfarin.

Suggested Reading
Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke. JAMA. 2001;285:2864-2870.

CHILDHOOD HEADACHE “GROWS INTO” OTHER DISORDERS IN ADULTHOOD

Children with frequent headache are at an increased risk of headache and multiple physical and psychiatric symptoms in adulthood, according to the first study using prospectively collected population-based data. “Children with headache do not simply ‘grow out’ of their somatic complaint and may also ‘grow into’ others,” the researchers suggested.

This study included 9,841 participants from the British national child development study, a population-based birth cohort study established in 1958. Headache, as well as physical and psychiatric symptoms, was assessed at ages 7, 11, 16, 23, and 33. Physical symptoms included backache, indigestion, upset stomach, heart racing, eye pain, rheumatism or fibrositis, worries about health, and twitching of the face, head, or shoulders. Psychologic health was assessed using the 15-item subscale of the malaise inventory.

Children with frequent headache had an increased risk of headaches in adulthood (odds ratio, 2.22). Those with headache were more likely to have a mother with a chronic physical illness or a family member with a mental illness.

By age 33, 9.3% of the participants had three or more physical complaints, 14.1% mentioned headaches, and 13.9% had evidence of psychiatric morbidity. For all three outcomes, there was a significant association with childhood headache, even after adjusting for sex, social class, and adult psychiatric morbidity.

“The pathway from psychosocial factors and somatic symptoms in childhood to somatic and psychiatric symptoms in adulthood remains unclear,” the researchers said. However, they suggest that teachers and physicians should consider the possible role of psychosocial factors underlying the child’s headache. “Strategies for coping with psychosocial adversity in childhood may improve the prognosis in adulthood,” they concluded.

NR