POTENTIAL VACCINE FOR HERPES ZOSTER AND POSTHERPETIC NEURALGIA

An experimental varicella-zoster vaccine markedly reduced morbidity from herpes zoster and post-herpetic neuralgia in older patients, according to Michael N. Oxman, MD, and colleagues. The vaccine reduced the risk of herpes zoster by almost half and also lessened the severity of the virus. Details of the study were published in the June 2 New England Journal of Medicine.

A total of 38,546 patients 60 or older were enrolled in the study and received either a subcutaneous injection of varicella-zoster vaccine or placebo. Herpes zoster was diagnosed according to clinical and laboratory criteria, and pain and discomfort associated with herpes zoster were measured repeatedly for six months. More than 95% of the participants completed the study.

During a median follow-up period of 3.12 years, there were a total of 957 confirmed cases of herpes zoster (315 among patients who received the vaccine and 642 among patients who received placebo) and 107 cases of postherpetic neuralgia (27 among patients who received the vaccine and 80 among patients who received placebo). As a result of using the vaccine, the burden of illness due to herpes zoster fell by 61.1%; the incidence of postherpetic neuralgia and of herpes zoster declined by 66.5% and 51.3%, respectively. The incidence of herpes zoster was significantly reduced, from 11.12 per 1,000 person-years in the placebo group to 5.42 per 1,000 person-years in the vaccine group.

The researchers noted that adverse reactions at the injection site were more frequent among participants who received the vaccine but were generally mild. The most frequent adverse events at the injection site included erythema, pain or tenderness, swelling, and pruritus. The number of patients who had one or more hospitalizations was similar between the two groups, and no hospitalization among patients in either group was related to the vaccine.

“The greater number of early cases of herpes zoster in the placebo group, as compared with the vaccine group, and the fact that no vaccine virus DNA was detected, indicate that the vaccine did not cause or induce herpes zoster,” said the researchers.

Because the vaccine was tested only in individuals older than 60, the researchers said it is unclear whether the vaccine will be as effective in a younger population. They also stated that there is no data suggesting that the vaccine would be efficacious in protecting older adults from herpes zoster or postherpetic neuralgia. “The results of our study show that vaccination of immunocompetent persons 60 years of age and older with live attenuated zoster vaccine markedly decreases the morbidity associated with herpes zoster and the incidence of postherpetic neuralgia,” they said.

Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-2284.

LATINOS MAY DEVELOP ALZHEIMER’S DISEASE SYMPTOMS EARLIER THAN WHITE, NON-LATINOS

Latino individuals seem to have an earlier age at onset of Alzheimer’s disease symptoms than do white, non-Latino individuals with similar education levels. According to details of a report published in the May Archives of Neurology, these findings have “a potential impact on both the burden of dementia care carried by this population group and the dementia-related diagnostic and educational efforts directed toward the Latino population.”

Christopher M. Clark, MD, and colleagues conducted a two-phase study to compare the age at onset of Alzheimer’s disease symptoms in 366 Latino individuals with that of 2,823 white, non-Latino individuals. In the first phase, the researchers retrospectively compared the age at onset of Alzheimer’s disease symptoms for all Latino and white, non-Latino patients evaluated at five Alzheimer’s disease centers. They found that the mean age at onset of Alzheimer’s disease symptoms was 68.8 among Latino patients and 73.5 among white, non-Latino patients. The 4.7-year difference in age at onset did not differ between patients evaluated at either East or West Coast centers.

In the second phase of the study, 119 Latino patients and 55 white, non-Latino patients with probable Alzheimer’s disease were evaluated using a number of standardized assessment tests for severity of dementia and psychiatric symptoms. According to the researchers, there were no differences between Latino and white, non-Latino patients in sex distribution, the proportion with a diagnosis of probable versus possible Alzheimer’s disease, or the severity of cognitive impairment as measured by Mini-Mental State Examination score at baseline. After adjustment for sex and level of education, the mean age at onset of the first dementia symptom was 6.8 years earlier in Latino patients than in white, non-Latino patients. As in the first phase of the study, this difference did not differ between patients on the East Coast versus those on the West Coast.

The researchers stated that the basis for the younger age at onset of Alzheimer’s disease symptoms remains obscure. They noted that “from the individual patient and family standpoint as well as a public health perspective, it is important to identify modifiable factors that contribute to the symptomatic expression of Alzheimer’s disease in this significant minority group.”

Clark CM, DeCarli C, Mungas D, et al. Earlier onset of Alzheimer disease symptoms in Latino individuals compared with Anglo individuals. Arch Neurol. 2005;62:774-778.

ARE STROKE PATIENTS RECEIVING OPTIMAL CARE?

Only a minority of acute stroke patients are receiving care consistent with established guidelines, according to a study in the June Stroke. Shalini Arora, MPH, and colleagues said that quality improvement interventions, aimed primarily at the health care systems level, are needed to improve acute stroke care in the United States.

A total of 6,867 patients from 98 hospitals located in Massachusetts, Michigan, Georgia, and Ohio were included in the analysis. Most patients had an ischemic stroke; the remainder had a transient ischemic attack or an intracerebral hemorrhage. Nineteen percent to 26% of patients were younger than 60 and 52% to 58% were female.

The researchers found less than 10% of patients arrived at the emergency department within one hour of stroke onset, and only 20% to 25% of patients arrived at the emergency department within three hours. Furthermore, “only between one-third and one-half of acute stroke admissions had a specific stroke onset time documented, whereas onset information was not available for 20% to 40%,” said the researchers. “If we don’t know when a stroke occurred, then we are unable to give the patient the acute stroke therapies that are available,” related Mathew J. Reeves, PhD, a coauthor of the study.

The researchers also found that only 3.0% to 8.5% of ischemic stroke patients received treatment with recombinant tissue plasminogen activator (rt-PA). Of 118 patients who received intravenous rt-PA, less than 20% received it within 60 minutes of arrival to the emergency department. “These rt-PA treatment rates are consistent with those reported in the other community-based or multi-hospital reports, in which rt-PA treatment rates among all ischemic stroke admissions have varied from 1.6% to 9%,” said the researchers.

Compliance with secondary prevention practices was poorest for smoking cessation counseling and best for antithrombotics. Dr. Reeves commented that “for a stroke survivor who smokes, smoking cessation is the single best thing that can be done to reduce the risk of subsequent stroke.” The researchers added that in-hospital dysphagia screening and lipid testing were greatly underused as well.

“These findings point to the need for continued mass public education to increase awareness and recognition of early warning signs, and the importance of seeking emergency medical care,” said the researchers. They cited their results as an important step toward measuring and improving the quality of stroke care in the US. “Ongoing endeavors to define performance measures and incorporate them into common national standards for stroke-related quality insurance programs … will result in a national registry that will be able to identify, enable, and monitor improvements in hospital-based acute stroke care with tangible benefits to stroke patients and their families.”

Arora S, Broderick JP, Frankel M, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36:1232-1240.

SEX DIFFERENCES IN ALZHEIMER’S DISEASE PATHOLOGY

The association between Alzheimer’s disease pathology and clinical Alzheimer’s disease is substantially stronger in women than it is in men, according to Lisa L. Barnes, PhD, and colleagues. Their findings suggest that Alzheimer’s disease pathology is more likely to be expressed clinically as dementia in women than it is in men. “Understanding why the association between Alzheimer’s disease pathology and dementia differs in men and women could yield important clues about the pathophysiology of Alzheimer’s disease or eventually lead to sex-specific preventive or therapeutic strategies,” commented the researchers in a report published in the June Archives of General Psychiatry.

Dr. Barnes’ group analyzed data from the Religious Orders Study, which includes information on 141 elderly Catholic nuns, priests, and brothers who have undergone detailed annual clinical evaluations and brain autopsy at death. Researchers counted the number of neuritic plaques, diffuse plaques, and neurofibrillary tangles in a 1-mm² area sampled from the midfrontal, superior temporal, entorhinal, and inferior parietal cortices, derived a global measure of Alzheimer’s disease pathology and specific measures of each pathology, performed apolipo-protein genotyping, and quantified Lewy bodies. A set of 19 cognitive function tests was selected to assess the following functions: episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Patients with clinical conditions other than Alzheimer’s disease, such as Parkinson’s disease, delirium, or stroke, were excluded from the analyses.

The researchers found that 57 subjects met clinical criteria for probable Alzheimer’s disease, 31 met clinical criteria for mild cognitive impairment, and 53 had no cognitive impairment. Women had slightly more global pathology than men, which appeared to be due primarily to more neurofibrillary tangles. On a global measure of Alzheimer’s disease pathology that ranged from 0 to 3, each 1-U increase in Alzheimer’s disease pathology was associated with a nearly threefold increase in the odds of clinical Alzheimer’s disease in men and a 20-fold increase in the odds of clinical Alzheimer’s disease in women. These results were unchanged after using level of cognition as the outcome or controlling for potential confounders such as age, education, possession of an apolipoprotein E ε4 allele, the effect of Lewy bodies, and the presence of stroke pathology.

When analyses were adjusted for measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles, researchers found that each type of Alzheimer’s disease pathology was related to the odds of clinical Alzheimer’s disease proximate to death. Odds ratios of 4.90, 2.41, and 4.51 were observed for neuritic plaques, diffuse plaques, and neurofibrillary tangles, respectively. The researchers added that each 1-U increase in neuritic plaques was associated with a more than twofold increase in the odds of clinical Alzheimer’s disease in men compared with a more than 11-fold increase in women. Similarly, each 1-U increase in neurofibrillary tangles was associated with nearly a twofold increase in the odds of clinical Alzheimer’s disease in men and more than a 13-fold increase in women.

Because the cohort in their study consisted of a select group of patients who differ in many ways from the general population, the researchers recommended replicating these findings in more diverse groups.

Barnes LL, Wilson RS, Bienias JL, et al. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry. 2005;62:685-691.

PREDICTING RESPONSE TO WARFARIN THERAPY

Variations of the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may alter response to warfarin therapy, according to Mark J. Rieder, PhD, and colleagues. VKORC1 haplotypes could be used to determine which patients would benefit most from low, intermediate, or high doses of warfarin and may also be used to explain differences in dose requirements among patients of different ancestries. Details of their study were published in the June 2 New England Journal of Medicine.

The researchers conducted a retrospective study of 186 European-American patients receiving long-term warfarin maintenance therapy. They then replicated their results in a secondary population consisting of 368 European-American patients. In addition, the researchers analyzed DNA panels consisting of samples from African-American, European-American, and Asian-American patients to determine haplotype frequencies in these populations and assessed 53 human liver samples for levels of VKORC1 mRNA expression to explore the mechanism of the association between warfarin dose and VKORC1 polymorphisms.

Among the primary population, 10 common noncoding single-nucleotide polymorphisms were identified. Of the 10 common single-nucleotide polymorphisms, seven were significantly associated with warfarin dose. Of these seven, five were strongly correlated with one another. Five common haplotypes (H1, H2, H7, H8, and H9) were inferred, comprising two groups: Group A consisted of haplotypes H1 and H2 and was associated with a lower dose of warfarin, whereas group B consisted of haplotypes H7, H8, and H9 and was associated with a higher dose of warfarin. The researchers found that approximately 25% of the variance in warfarin dose could be explained by haplotype alone. When a haplotype group combination was assigned to each patient, the mean maintenance doses of warfarin were 2.7, 4.9, and 6.2 mg/day for those with the haplotype combinations A/A, A/B, B/B, respectively.

Similar results were found in the secondary patient population; 21% of the variance in warfarin dose could be explained by haplotype in this population. Also, the mean maintenance doses of warfarin were 3.2, 4.4, and 6.1 mg/day for those with the A/A, A/B, and B/B haplotype group combinations, respectively.

Also, the African-American and Asian-American populations showed significant differences in the frequencies of haplotype groups A and B compared with the European-Americans. Group A haplotypes were more common in Asian-Americans and were predictive of a lower warfarin dose; group B haplotypes were more common in African-Americans and were predictive of higher warfarin doses.

When liver samples were assessed, the team found a highly significant gene–dose effect. In patients with the B/B haplotype group combination, mRNA levels were about three times as high as those in the patients with the A/A haplotype group combination. “We hypothesize that the level of VKORC1 mRNA is directed by each haplotype and determines the level of protein synthesis of the vitamin K epoxide reductase complex, [accounting] for differences among these patients in their warfarin maintenance-dose requirements,” they said.

Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005;352:2285-2293.

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