Neurological and Systemic Complications of Varicella Zoster Virus Reactivation: A Comprehensive Review

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Summary of  Nature Reviews Disease Primers https://doi.org/10.1038/s41572-026-00735-5
Dr. Andrew N. Bubak et al.

Points

University of Colorado Anschutz researchers reviewed varicella zoster virus manifestations, emphasizing that latent infection persists in neuraxis ganglionic neurons in over ninety percent of global populations.
Reactivation occurs in at least one-third of carriers, presenting as shingles, post-herpetic neuralgia, or severe systemic complications like zoster sine herpete without cutaneous rash.
Paediatric clinical evaluations demonstrate that varicella zoster virus reactivation accounts for up to one-third of all pediatric arterial ischemic stroke cases worldwide.
Antiviral therapeutic protocols rely on oral valacyclovir, famciclovir, acyclovir, or amenamevir, while severe or disseminated disease requires intravenous acyclovir or secondary foscarnet administration.
Preventive strategies utilize live attenuated varicella and recombinant zoster vaccines to decrease viral reactivation, though substantial global diagnostic gaps persist regarding non-exanthematous cases.

Summary

This study evaluated the clinical manifestations, diagnostic hurdles, and therapeutic management of varicella zoster virus (VZV), an exclusively human alphaherpesvirus infecting greater than 90% of the global population. Led by Maria Nagel at the University of Colorado Anschutz School of Medicine and published in Nature Reviews Disease Primers, the review examined how primary VZV infection establishes lifelong latency within neuraxis ganglionic neurons. Given that at least 33% (1 in 3) of infected individuals experience viral reactivation due to age-related or iatrogenic immunosuppression, the investigation sought to characterize atypical systemic and neurological complications that manifest independently of dermatomal rash.

Viral reactivation frequently precipitates herpes zoster, which can progress to post-herpetic neuralgia or zoster sine herpete. Systemic complications include VZV vasculopathy, cranial neuropathies, myelopathy, and gastrointestinal pathology. In pediatric cohorts, VZV reactivation or primary infection accounts for up to 33% (one-third) of arterial ischemic strokes. Furthermore, VZV reactivation significantly escalates long-term risks for cardiovascular events, cerebrovascular accidents, and dementia. Because viral dissemination along internal vascular or visceral networks can occur without a cutaneous rash, clinical recognition relying solely on dermatomal lesions remains inadequate for detecting occult neurovascular involvement.

Therapeutic management of acute VZV infection centers on oral antiviral agents, with valacyclovir serving as the primary drug of choice alongside famciclovir, acyclovir, or amenamevir. Severe or disseminated presentations necessitate intravenous acyclovir or foscarnet rescue therapy. Prophylactic prevention relies on live attenuated varicella and recombinant zoster vaccines. The authors conclude that expanding clinician awareness of non-exanthematous VZV manifestations, improving serological and cerebrospinal fluid diagnostic testing, and elucidating VZV-driven vascular and neurodegenerative mechanisms represent critical priorities to optimize patient care.

Link to the article: https://www.nature.com/articles/s41572-026-00735-5

References

Bubak, A. N., Warren-Gash, C., Tommasi, C., Breuer, J., Mahalingam, R., Srikanth, P., & Nagel, M. A. (2026). Varicella zoster virus infection. Nature Reviews Disease Primers, 12(1), 58. https://doi.org/10.1038/s41572-026-00735-5