Stroke Risk Highest in the 4 Weeks After Acute Zoster

Lara C. Pullen, PhD

May 26, 2014

Patients with a first-ever diagnosis of zoster have an increased risk for stroke within the first 6 months of diagnosis, with the highest risk shortly after acute zoster. These results suggest zoster vaccination programs may be able to reduce the risk for stroke. The data also suggest that antiviral therapy may reduce stroke risk after zoster.

Sinead M. Langan, MD, PhD, from the London School of Hygiene and Tropical Medicine in the United Kingdom, and colleagues published the results of their self-controlled case-series in the June issue of Clinical Infectious Diseases. The investigators used data from the United Kingdom Clinical Practice Research Datalink, which captures data from routine clinical care.

"[W]e used the self-controlled case series method to make within-person comparisons of the risk of stroke following zoster to the risk of stroke at other time periods, among individuals who had experienced both zoster and a stroke, " explained coauthor Sara Thomas, PhD, also from the London School of Tropical Medicine. "We then carried out stratified analyses to investigate whether the effect of zoster on stroke risk was different among those who received antiviral treatment for zoster compared to those who did not receive antiviral treatment."

The case-series design controlled for fixed confounders because analyses were performed within-person. This approach also allowed the investigators to control for the time-varying effect of age.

They found that the risk was highest in the first 4 weeks after zoster infection (age-adjusted incidence ratio [aIR], 1.63; 95% confidence interval [CI], 1.32 - 2.02). The risk declined somewhat in weeks 5 to 12 (aIR, 1.42; 95% CI, 1.21 - 1.68) and in weeks 13 to 26 (IR, 1.23; 95% CI, 1.07 - 1.42). They found no evidence of elevated risk beyond 26 weeks.

"Most patients in our study (60%) had no information documenting stroke type; despite the large sample size, this reduced the power of our study to assess the effect of zoster on stroke type, although the majority of strokes in adults are likely to be ischemic in nature," the authors write.

The investigators acknowledge there was likely some misclassification of herpes zoster ophthalmicus. Nonetheless, they found that the risk for incident stroke after zoster was higher for patients with herpes zoster ophthalmicus or zoster in the distribution of the trigeminal nerve. The investigators suggest that the systemic infection may lead to inflammation, which is associated with endothelial dysfunction and disruption of atheromatous plaques and hypercoagulability.

The findings of this study are similar to the results of 2 previous Taiwanese studies, which found a 30% increase in stroke risk in the year after zoster.

Antivirals May Reduce Stroke Risk

"Antiviral therapy may be critically important as our study suggests that stroke risk after zoster is lower in those treated with antiviral therapy than in untreated individuals, although this did not reach statistical significance in the smaller subset of ophthalmic zoster patients," the authors write.

Antiviral therapy reduces acute pain and zoster severity. It has also been shown to accelerate healing and possibly reduce postherpetic neuralgia. The authors suggest the antiviral drugs may also reduce inflammation, thereby reducing postzoster vascular events.

"A major advantage of the self-controlled case series method is that the within-person comparisons avoid between-person confounding. However, our assessment of the effect of antiviral treatment does involve between-person comparisons, because we compared the effect of zoster in the group receiving antivirals with the effect in the group with no antivirals," Dr. Thomas told Medscape Medical News. "So, we need some caution here. Could there be an alternative explanation for the lower stroke risk after zoster in the treated group that was not due to their receipt of antivirals? One such alternative explanation is that individuals who received antivirals may have had milder zoster compared to those who didn't receive antivirals, and milder zoster could potentially have a less marked effect on stroke risk."

The effect of antivirals on stroke risk is intriguing and deserves more follow-up, note Maria Nagel, MD, and Don Gilden, MD, from the University of Colorado School of Medicine in Aurora, in an accompanying editorial.

"[A]mong the 55% of zoster patients who received oral antiviral therapy, the risk of stroke was reduced compared with untreated patients with zoster. Overall, results of the novel self-controlled case series method confirmed studies from Taiwan, Denmark, and the earlier UK study that revealed an increased risk of stroke after zoster, particularly in patients with ophthalmic-distribution zoster.

Furthermore, the current study is the first to show that the increased risk of stroke after zoster can be reduced with antiviral treatment," they write.

This work was supported by the Stroke Association, the National Institute for Health Research, and the Wellcome Trust. The editorialists were supported by the National Institutes of Health. The authors, Dr. Nagel, and Dr. Gilden report no conflicts of interest.

Clin Infect Dis. 2014;58:1497-1506. Article full text, Editorial full text

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