Varicella Zoster Virus May Be An Underdiagnosed Cause of Stroke

The varicella virus is the cause of chickenpox. It is well established as a cause of strokes in children, in whom strokes are very rare, and also in adults with chickenpox, who are much more likely to have that and other serious complications. The virus causes a chronic infection, which reactivates in immunosuppressed persons and in the elderly, causing herpes zoster. Reactivation occurs earlier in those who had chickenpox especially early in life (<5 years old). Herpes zoster ophthalmicus (in the eye) is particularly associated with stroke.

Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: diagnosis and management approaches. DC Hilt, D Buchholz, A Krumholz, H Weiss, JS Wolinsky. Ann Neurol 1983 Nov;14(5):543-553. Four patients.

Hilt - Ann Neurol 1983 abstract / PubMed

Herpes zoster ophthalmicus and granulomatous angiitis. An ill-appreciated cause of stroke. A Verghese, AM Sugar. J Am Geriatr Soc 1986 Apr;34(4):309-312. "Forty-five cases have been reported to date, and the authors' experience with two additional cases seen in a one-year period is described."

Verghese - J Am Geriatr Soc 1986 abstract / PubMed

[Herpes zoster ophthalmicus with subsequent oculomotor paralysis and homolateral media infarct]. B Pfeifer, K Kempkes, G Kramer. Klin Monatsbl Augenheilkd 1989 Mar;194(3):184-186. "Since the first paper on HZO and cerebral ischemia was published, in 1919, about 70 cases have been described." One case.

Pfeifer - Klin Monatsbl Augenheilkd 1989 abstract / PubMed

Neurotropic herpesviruses, neural mechanisms and arteritis. JR Martin, WJ Mitchell, DB Henken. Brain Pathol 1990 Sep;1(1):6-10. Review.

Martin - Brain Pathol 1990 abstract / PubMed

Cervical (C2) herpes zoster infection followed by pontine infarction. JT Patrick, B Russell, J Meyer, J Biller, JL Saver. J Neuroimaging 1995 Jul;5(3):192-193. One case.

Patrick - J Neuroimaging 1995 abstract / PubMed

The patterns of varicella zoster virus encephalitis. BK Kleinschmidt-DeMasters, C Amlie-Lefond, DH Gilden. Hum Pathol 1996 Sep;27(9):927-938. All cases of VZV encephalitis at University of Colorado Health Sciences Center since 1984.

Kleinschmidt-DeMasters - Hum Pathol 1996 abstract / PubMed

Cerebral infarction associated with vasculitis due to varicella zoster virus in patients infected with the human immunodeficiency virus. O Picard, L Brunereau, B Pelosse, D Kerob, J Carbane, JC Imbert. Biomed Pharmacother 1997;51(10):449-454. Two patients.

Picard - Biomed Pharmacother 1997 abstract / PubMed

Mechanisms of ischaemic stroke after chickenpox. V Ganesan, FJ Kirkham. Arch Dis Child 1997 Jun;76(6):522-525. Seven cases of ischemic stroke in children after recent chickenpox.

Ganesan / Arch Dis Child 1997 full article
Ganesan - Arch Dis Child 1997 full article / PubMed Central

Early and late manifestations of cerebral vasculitis related to varicella zoster. MG Häusler, VT Ramakers, J Reul, R Meilicke, G Heimann. Neuropediatrics 1998 Aug;29(4):202-207. Four children with varicella-zoster associated cerebral vasculitis (VZCV) and stroke.

Häusler - Neuropediatrics 1998 abstract / PubMed

Middle cerebral arteritis and stroke after varicella in a young adult. MC Hosseinipour, NH Smith, EP Simpson, SB Greenberg, RM Armstrong, AC White. South Med J 1998 Nov;91(11):1070-1072. "In Hispanic immigrants, primary varicella often appears in adolescents and young adults. We describe the case of a 20-year-old Hispanic man with vasculitis and stroke after primary varicella infection."

Hosseinipour - South Med J 1998 abstract / PubMed

Varicella as a risk factor for cerebral infarction in childhood: a case-control study. G Sebire, L Meyer, S Chabrier. Ann Neurol 1999 May;45(5):679-680. "The results of this case-control study show a significant statistical link between idiopathic arterial ischemic strokes in children and varicella-zoster virus infection."

Sebire - Ann Neurol 1999 abstract / PubMed

Central nervous system and renal vasculitis associated with primary varicella in a child. JM Caruso, GA Tung, WD Brown. Pediatrics 2001 Jan;107(1):e9. One case.

Caruso / Pediatrics 2001 full article

Chickenpox and stroke in childhood: a study of frequency and causation. R Askalan, S Laughlin, S Mayank, A Chan, D MacGregor, M Andrew, R Curtis, B Meaney, G deVeber. Stroke 2001 Jun;32(6):1257-1262. News re Askalan: Chicken pox risk factor in childhood stroke. Anne MacLennan. PSL Doctors Guide 2001 Jun 1. Chickenpox linked to about one third of ischemic strokes in children. Medscape - Reuters Health news 2001 Jul 3.

Askalan - Stroke 2001 abstract / PubMed
Askalan / PSL 2001 news

The expanding specturm of herpesvirus infections of the nervous system. BK Kleinschmidt-DeMasters, DH Gilden. Brain Pathol 2001 Oct;11(4):440-451.Review. "[S]troke due to VZV-mediated large vessel disease (herpes zoster ophthalmicus) occurs predominantly in immunocompetent hosts, while small vessel disease (leukoencephalitis) and ventriculitis develop almost exclusively in immunocompromised patients."

Kleinschmidt - Brain Pathol 2001 abstract / PubMed

Detection of herpesvirus genomes by polymerase chain reaction in cerebrospinal fluid and clinical findings. S Minjolle, C Arvieux, AL Gautier, I Jusselin, R Thomas, C Michelet, R Colimon. J Clin Virol 2002 Jul;25 Suppl 1:S59-70. 141 patients. "...CSF samples of immunocompetent patients contained mostly VZV (9%) and HSV-1 (7.3%)... For VZV, we report the possibility of mild, transient cerebral reactivation."

Minjolle - J Clin Virol 2002 abstract / PubMed

Varicella Zoster Virus and Central Nervous System Syndromes. D Gilden. Herpes 2004;11(suppl 2):89A-94A. Review; The International Herpes Management Forum treatment guidelines.

Gilden - Herpes 2004 / International Herpes Management Forum (pdf, 6pp)

The Course and Outcome of Unilateral Intracranial Arteriopathy in 79 Children With Ischaemic Stroke. KPJ Braun, MMM Bulder, S Chabrier, FJ Kirkham; CSP Uiterwaal, M Tardieu, G Sébire. Medscape Infectious Diseases 2009 May 29. "Stroke was preceded by chickenpox in 44% of TCA [transient cerebral arteriopathy] patients, and in none of the patients with progressive arteriopathies. Most infarcts were localized in the basal ganglia... Although the arterial inflammation probably causing TCA is 'transient', most children are left with permanent arterial abnormalities and residual neurological deficits."

Braun / Medscape Infectious Diseases 2009 full article

Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. D Gilden, RJ Cohrs, R Mahalingam, MA Nagel. Lancet Neurol 2009 Aug;8(8):731-740. Review.

Golden - Lancet Neurol 2009 author manuscript / PubMed Central

Increased Risk of Stroke After a Herpes Zoster Attack. A Population-Based Follow-Up Study. J-H Kang, J-D Ho, Y-H Chen, H-C Lin. Stroke 2009 Nov;40(11):3443-3448. 133 / 7760 stroke patients (1.71%) and 306 / 23,280 randomly selected subjects (1.31%) had herpes zoster. "The log rank test indicated that patients with herpes zoster had significantly lower 1-year stroke-free survival rates than the control (P<0.001). The adjusted hazard ratios of stroke after herpes zoster and herpes zoster ophthalmicus during the 1-year follow-up period were 1.31 and 4.28, respectively."

Kang / Stroke 2009 full article

Herpes zoster ophthalmicus and the risk of stroke: a population-based follow-up study. HC Lin, CW Chien, JD Ho. Neurology 2010 Mar 9;74(10):792-797. 658 patients diagnosed with herpes zoster ophthalmicus, vs 1974 controls. "Stroke developed in 8.1% of patients with HZO and 1.7% of patients in the comparison cohort during the 1-year follow-up period. HZO patients had significantly lower 1-year stroke-free survival rates than patients in the comparison cohort. After adjusting for patients' demographic characteristics, selected comorbidities, and medication habits, HZO patients were found to have a 4.52-fold (95% confidence interval 2.45-8.33) higher risk of stroke than the matched comparison cohort. There was no significant difference in the rate of stroke development between patients who had received systemic antiviral treatment and those who had not."

Lin - Neurology 2010 abstract / PubMed

Virus vasculopathy and stroke: an under-recognized cause and treatment target. MA Nagel, R Mahalingam, RJ Cohrs, D Gilden. Infect Disord Drug Targets 2010 Apr 1;10(2):105-111. Review. 37% of VZV vasculopathy cases do not have the characteristic varicella or zoster rash, and stroke can occur months after the rash. "The diagnostic value of detecting anti-VZV immunoglobulin (Ig) G antibody in CSF is greater than that of detecting VZV DNA." "VZV is the only virus for which there is clear evidence of virus DNA and antigen in cerebral arteries corresponding to areas of ischemia or infarction."

Nagel - Infect Disord Drug Targets 2010 author manuscript / PubMed Central

Thrombophilia and varicella zoster in children. M Ferrara, F Bertocco, D Ferrara, L Capozzi. Hematology 2013 Mar;18(2):119-122. 25 children with acute varicella zoster virus infection (5 with deep venous thrombosis) and 30 controls. "Coagulation disorders and [free S protein] antibody were found in children with acute VZV (groups I and II). Significant differences were shown among the three groups (P < 0.05)."

Ferrara - Hematology 2013 abstract / PubMed

Herpes zoster as a risk factor for stroke and TIA: A retrospective cohort study in the UK. J Breuer, M Pacou, A Gauthier, MM Brown. Neurology 2014 Jan 21;82(3):206-212. 106,601 HZ cases and 213,202 controls. "Adjusted hazard ratios (AHRs) for TIA and MI but not stroke were increased in all patients with HZ (AHR [95% confidence interval]: 1.15 [1.09-1.21] and 1.10 [1.05-1.16], respectively). However, stroke, TIA, and MI were increased in cases whose HZ occurred when they were younger than 40 years (AHR [95% confidence interval]: 2.42 [1.34-4.36], 1.49 [1.04-2.15], and 1.74 [1.13-2.66], respectively)."

Breuer - Neurology 2014 full article / PubMed Central

Central nervous system complications of varicella-zoster virus. M Science, D MacGregor, SE Richardson, S Mahant, D Tran, A Bitnun. J Pediatr 2014 Oct;165(4):779-785. 84 children admitted with VZV-associated neurological symptoms. 10 had stroke. "The time between rash onset and stroke ranged from 2 weeks to 26 weeks (median 16.0 weeks)."

Science - J Pediatr 2014 abstract / PubMed

Herpes Zoster and the Risk for Stroke in Patients with Autoimmune Diseases. LH Calabrese, F Xie, H Yun, K Winthrop, JW Baddley, C Calabrese, JR Curtis. Arthritis Rheumatol 2016 Sep 2 [Epub ahead of print]. Number of patients not given in abstract. "After multivariable adjustment for multiple stroke-related factors, the incidence rate ratio (IRR) for stroke in the first 90 days after HZ was 1.36 (1.10-1.68) compared to stroke >1 year after HZ. The risk was greater for patients with zoster with cranial nerve complications (IRR 2.08, 95%CI 0.99-4.36). Prompt antiviral therapy was associated with lower incidence of subsequent stroke (IRR 0.83, 95% CI 0.70- 0.98)."

Calabrese - Arthritis Rheumatol 2016 abstract / PubMed

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cast 09-04-16