Science Rabbit Newsletter

Almost every individual in the world is infected with the varicella zoster virus (VZV). We typically get it as children which manifests as chickenpox initially, after which the virus goes dormant, or latent, in neurons in our peripheral nervous system. As we get older or during periods where our immune system is weakened (i.e., immunosuppressive treatments or times of high stress) the virus can reactivate from our neurons and travel down the nerves to the skin causing the incredibly painful rash called shingles (zoster).

Depending on which neurons the virus reactivates from will dictate where the rash will occur. For example, if the virus reactivates from neurons in your right side fifth cranial nerve ganglia, which supplies sensory information to your face, the rash will occur only on that side of the face. Similarly, if the virus reactivates from neurons in your left thoracic ganglia, you will develop a rash on your left torso. This characteristic rash distribution is used by physicians for diagnoses, which, can be problematic because VZV can also reactivate without the rash presentation. This is called ‘zoster sine herpete‘, or, ‘zoster without rash’ and is mathematically predicted to be the more common presentation. Specifically, a peer-reviewed study predicted that for every 1 reactivation event with shingles rash, there are 6-7 reactivation events without rash and may be completely asymptomatic.¹ This is potentially troubling because those individuals are likely going untreated with antivirals given the clinically difficult diagnosis.

The most common and well-known complication of shingles is the development of post-herpetic neuralgia (PHN), which is the prolonged duration of the pain associated with reactivation even after the rash has cleared. The debilitating pain can last for months, years, or in some cases can be life-long. The largest risk factor of developing PHN following shingles is age, with individuals over the age of 65 being at the highest risk. However, a lesser known complication of shingles is the elevated risk of cerebrovascular events such as stroke and transient ischemic attacks (TIAs). This may surprise people because shingles is largely considered a skin disease and VZV in general is thought to be a skin disease-causing pathogen.

Stroke risk – what do the numbers tell us?

There have been multiple epidemiological studies evaluating the risks of both stroke and TIAs following shingles. These studies used different clinical databases and population demographics and while there was robust variability in the degree of elevated risk for reasons I will discuss shortly, the conclusions were largely consistent – there is a significant increased risk of stroke and TIA following shingles. Importantly, almost all the studies found that this elevated risk remains for up to a year following the clearance of rash.

The data show that when lumped together there is a ~80% increased risk of stroke following shingles within the first month, ~40% increase within 3 months, and ~20% increase within the first year.² When you break the cases down by specific location of rash and by age, a different and more severe picture emerges. Specifically, if you have the shingles rash on your face, called herpes zoster ophthalmicus (HZO), the risk goes up to ~200% and seems to persist at this level for up to a year. Furthermore, if you are under the age of 40, this risk is the highest at an ~300% increased risk of stroke within the first year following shingles anywhere on the body.² For this cohort, three independent studies found the risk remains elevated at an ~40% increase a decade later.^2-5

It is important to note there is variability in these percentages due to the differences in study designs. For example, some studies did not account for any variables outside of age and sex so, for example, other independent risk factors such as smoking, weight etc. were not necessarily accounted for. Other studies applied the use of antivirals as a proxy to identify shingles patients which would not include individuals with shingles that were not treated with antivirals. This would artificially downplay the corresponding stroke risk if antivirals were protective against stroke risk (more on that below). Nonetheless, the results are compelling and point to a long-lasting, significant increase in stroke risk following shingles that appears to be dependent on age and location of shingles rash.

How does VZV cause a stroke?

A stroke, specifically ischemic stroke, is when blood supply is cutoff to the brain through the narrowing of arteries or blocked by a blood clot. While the precise mechanisms in which VZV causes a stroke are still being elucidated, multiple, non-mutually exclusive mechanisms have been proposed each with strong supporting data. It has been proposed that the virus directly infects the arterial wall of the brain vasculature causing a robust inflammatory response, including infiltration of immune cells and proliferation of vascular cells in a small focal area ultimately leading to the narrowing of the artery. This narrowing restricts blood flow to the brain. This is logical because the neurons in which VZV reactivates from innervate, or connect to, these brain arteries. A nice peer-reviewed study showed an artery biopsy from an individual who suffered a stroke during shingles with virus present in the arterial wall.⁶ Around the infected area there was significant inflammation and cellular proliferation with clear arterial narrowing. This is strong evidence for a direct arterial infection as the mechanism mediating VZV-induced stroke. However, some features of VZV pathogenesis suggest this is not the full picture. Specifically, it is well known that VZV can induce a chronic inflammatory response at sites very far from the active infection site and that stroke can still occur months to years after the initial infection has cleared.

Exosomes are vesicles that are released from essentially every cell type. They carry cargo such as proteins and nucleic acids to other cells types throughout the body and are critical to maintain normal biological functions. Exosomes can also be detrimental to human health during diseases and infections and are actually being targeted for new therapies for a variety of different diseases. My laboratory recently published a study investigating the contents of blood exosomes from patients with shingles compared to matched control blood samples.⁷ We found a number of proteins that were significantly elevated in the exosomes of shingles patients compared to healthy blood donors that have known blood clotting capacities. We next put these exosomes onto healthy donor blood platelets, the cells that aggregate together to form clots, and found something remarkable. Compared to exosomes from healthy donors, the exosomes from shingles patients made the platelets aggregate into a clot. Importantly, the blood exosomes from shingles patients were taken immediately at the time of rash and before antivirals were administered to the individuals. However, a subset of patients donated blood at a 3-month follow-up appointment, after taking antivirals and all symptoms have cleared, and the same experiment was repeated. Strikingly, the ability of their exosomes to induce a clot was still elevated which could explain why we still record strokes months after the initial shingles rash. Of note, this study had a small sample size and needs to be repeated to definitively prove this mechanism.

Shingles prevention and treatment effect.

The Food and Drug Administration-approved vaccine to prevent shingles, Shingrix, is available for individuals over the age of 50 and immunocompromised adults over the age of 18. However, as discussed above, the highest risk of stroke following shingles is in individuals under the age of 40 and are ineligible for the vaccine. Although this age group is statistically at a lower risk of getting shingles compared to individuals over the age of 50, we are starting to see an uptick in shingles cases in this younger group potentially warranting a broader conversation about eligibility recommendations.

The big question is whether the vaccine or antiviral treatment lowers the subsequent stroke risk. It is very difficult to know whether the vaccine prevents the stroke risk because the vaccine is very effective at preventing shingles (~95% effective). Therefore, the sample size of ‘breakthrough cases’ is too low to gather conclusive information. However, it is likely that by preventing shingles you are likely reducing your overall risk. Prompt antiviral therapy has been shown to reduce the risk but not eliminate. Specifically, one study showed that the increased risk is half as high as those who do not take antivirals for shingles.⁸ Other studies, however, did not find a protective effect of antiviral therapy and subsequent stroke risk following shingles.^9-10 Therefore, this question remains inconclusive at the moment but perhaps studies where longer durations of antiviral treatment following shingles would show greater protective effects.

The takeaway.

VZV is much more than a virus that causes a rash and discomfort; it has significant potential to affect our vascular system and elevate stroke risk well beyond the resolution of the shingles rash. Studies clearly indicate that individuals, including those under 40 who develop shingles, face a heightened risk of stroke that can persist for at least a year—and possibly longer. Importantly, shingles can present without a rash (zoster sine herpete), meaning people can potentially experience harmful VZV reactivation and its vascular complications without classic skin lesions, making diagnosis and timely treatment more challenging.

Although current data suggest that prompt antiviral therapy may reduce—but not eliminate—stroke risk, there is a compelling need for more research. Extending antiviral treatment and expanding vaccination guidelines to younger, at-risk populations might help reduce the broader burden of VZV-related complications. Until then, healthcare providers and patients should remain vigilant about possible symptoms, especially neurological signs, in the weeks and months following shingles. As our understanding of VZV’s far-reaching effects grows, so does the importance of taking this virus seriously—not just as a cause of chickenpox and shingles, but as a potential driver of long-term health risks.

References.

1. Cohrs, R. J., Koelle, D. M., Schuette, M. C., Mehta, S., Pierson, D., Gilden, D. H., & Hill, J. M. (2009). Asymptomatic alphaherpesvirus reactivation. Herpesviridae: Viral Structure, Life Cycle and Infections, 133, 168.
2. Marra, F., Ruckenstein, J., & Richardson, K. (2017). A meta-analysis of stroke risk following herpes zoster infection. BMC Infectious Diseases, 17, 1-11.
3. Breuer, J., Pacou, M., Gauthier, A., & Brown, M. M. (2014). Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology, 82(3), 206-212.
4. Sreenivasan, N., Basit, S., Wohlfahrt, J., Pasternak, B., Munch, T. N., Nielsen, L. P., & Melbye, M. (2013). The short-and long-term risk of stroke after herpes zoster-a nationwide population-based cohort study. PloS one, 8(7), e69156.
5. Kwon, S. U., Yun, S. C., Kim, M. C., Kim, B. J., Lee, S. H., Lee, S. O., … & Kim, S. H. (2016). Risk of stroke and transient ischaemic attack after herpes zoster. Clinical Microbiology and Infection, 22(6), 542-548.
6. Nagel, M. A., Traktinskiy, I., Azarkh, Y., Kleinschmidt-DeMasters, B., Hedley-Whyte, T., Russman, A., … & Gilden, D. (2011). Varicella zoster virus vasculopathy: analysis of virus-infected arteries. Neurology, 77(4), 364-370.
7. Bubak, A. N., Coughlan, C., Posey, J., Saviola, A. J., Niemeyer, C. S., Lewis, S. W., … & Nagel, M. A. (2023). Zoster-associated prothrombotic plasma exosomes and increased stroke risk. The Journal of Infectious Diseases, 227(8), 993-1001.
8. Langan, S. M., Minassian, C., Smeeth, L., & Thomas, S. L. (2014). Risk of stroke following herpes zoster: a self-controlled case-series study. Clinical infectious diseases, 58(11), 1497-1503.
9. Lin, H. C., Chien, C. W., & Ho, J. D. (2010). Herpes zoster ophthalmicus and the risk of stroke: a population-based follow-up study. Neurology, 74(10), 792-797.
10. Yang, Q., George, M. G., Chang, A., Tong, X., Merritt, R., & Hong, Y. (2020). Effect of herpes zoster vaccine and antiviral treatment on risk of ischemic stroke. Neurology, 95(6), e708-e717.