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DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al cohort study in the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective

This information is current as of January 2 2014

httpwwwneurologyorgcontent823206fullhtmllocated on the World Wide Web at

The online version of this article along with updated information and services is

Neurology All rights reserved Print ISSN 0028-3878 Online ISSN 1526-632Xsince 1951 it is now a weekly with 48 issues per year Copyright copy 2014 American Academy of

reg is the official journal of the American Academy of Neurology Published continuouslyNeurology

Judith Breuer MDMaud Pacou BScAline Gauthier BScMartin M Brown MD

Correspondence toDr Breuerjbreueruclacuk

Supplemental data atwwwneurologyorg

Herpes zoster as a risk factor for strokeand TIAA retrospective cohort study in the UK

ABSTRACT

Objectives Stroke and TIA are recognized complications of acute herpes zoster (HZ) In this studywe evaluated HZ as a risk factor for cerebrovascular disease (stroke and TIA) and myocardialinfarction (MI) in a UK population cohort

Methods A retrospective cohort of 106601 HZ cases and 213202 controls matched forage sex and general practice was identified from the THIN (The Health Improvement Network)general practice database Cox proportional hazard models were used to examine the risks ofstroke TIA and MI in cases and controls adjusted for vascular risk factors including body massindex 30 kgm2 smoking cholesterol 62 mmolL hypertension diabetes ischemic heartdisease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heartdisease up to 24 years (median 63 years) after HZ occurrence

Results Risk factors for vascular disease were significantly increased in cases of HZ compared withcontrols Adjusted hazard ratios (AHRs) for TIA and MI but not stroke were increased in all patientswith HZ (AHR [95confidence interval] 115 [109ndash121] and 110 [105ndash116] respectively) How-ever stroke TIA and MI were increased in cases whose HZ occurred when they were younger than40 years (AHR [95 confidence interval] 174 [113ndash266] 242 [134ndash436] 149 [104ndash215]respectively) Subjects younger than 40 years were significantly less likely to be asked about vascularrisk factors than were older patients (p 0001)

Conclusion HZ is an independent risk factor for vascular disease in the UK population particu-larly for stroke TIA and MI in subjects affected before the age of 40 years In older subjects bet-ter ascertainment of vascular risk factors and earlier intervention may explain the reduction in riskof stroke after the occurrence of HZ Neurologyreg 201482206ndash212

GLOSSARYAHR 5 adjusted hazard ratio BMI 5 body mass index GP 5 general practitioner HR 5 hazard ratio HZ 5 herpes zosterHZO 5 herpes zoster ophthalmicus ICD 5 International Classification of Diseases MI 5 myocardial infarction THIN 5 TheHealth Improvement Network VZV 5 varicella-zoster virus

Herpes zoster (HZ) is caused by varicella-zoster virus (VZV) a ubiquitous pathogen that after pri-mary chickenpox in children persists asymptomatically (latently) in the sensory ganglia includingthe trigeminal ganglion Reactivation of VZV from latency and translocation via sensory nerveendings to the skin where it replicates is associated with the characteristic HZ rash1 Both ischemicand hemorrhagic strokes have been described after HZ affecting the ophthalmic branch of thetrigeminal nerve2 In these patients virus spreads transaxonally to cerebral arteries via trigeminaland other ganglionic afferents2 At autopsy viral inclusions DNA and antigen present in cerebralarteries confirms that VZV vasculopathy in these patients is associated with stroke and TIA2

Similar pathology has also been found in strokes and TIA that follow HZ occurring at non-ophthalmic sites and even in the absence of rash raising the possibility that VZV is more widelyimplicated in the pathogenesis of cerebrovascular disease23 This possibility is supported by findingsfrom a Taiwanese population study showing a 30 increase in the incidence of stroke for up to ayear after acute HZ and a 45-fold increase after HZ ophthalmicus (HZO)45 We analyzed the risk

From the Division of Infection and Immunity (JB) and Institute of Neurology (MMB) University College London and Amaris (MP AG)

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 30 License whichpermits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or used commercially

206 copy 2014 American Academy of Neurology

4

of stroke and TIA after HZ in a large retrospec-tive UK population-based matched cohort studyfollowed for up to 24 years (median 63 years)To examine the hypothesis that HZ is a riskfactor for vascular disease in general we alsomeasured the risk of myocardial infarction (MI)

METHODS Database sources and study population TheTHIN (The Health Improvement Network) database is a primary

care database that contains anonymous demographic medical and

prescription information covering more than 3 million active pa-

tients in the UK General practitioner (GP) episodes are coded

using READ codes a standardized hierarchical coding methodol-

ogy similar to the ICD codes which are used by primary care

physicians (GPs) in the UK to classify medical conditions6 Patients

in the THIN database are representative of the UK population by

age sex medical conditions and death rates7 Data were extracted

from patients routinely attending 464 general practices between

2002 and 2010 General practice is the term used in the UK to

denote a group of primary care physicians (GPs)

A retrospective matched cohort study was conducted Cases

were selected as patients who had experienced HZ Their index

date was defined as the date of onset of HZ as recorded in the

notes Patients with recurrent HZ were excluded because this is

a rare form of the disease that is often confused with herpes sim-

plex virus infection89 Patients with HZO identified using the

relevant code were included as part of the case cohort

Controls were identified as patients who had no record of HZ

To increase the power of the statistical analysis and reduce bias

2 controls per case were matched according to their age at index

date (6 2 years) sex and general (primary care) practice The index

date for controls was defined as the index date of the matched case

Patients and controls younger than 18 years or who had expe-

rienced a cardiovascular event (stroke MI or TIA) before the

index date were excluded All patients and controls had a minimum

follow-up time of 1 year after the index date The number of pa-

tients in the THIN database matching the selection criteria resulted

in a power of at least 96 for the statistical analysis

The THIN codes corresponding to recorded episodes of stroke

TIA and MI were identified This set of codes was used to search

patient and control records for incident stroke TIA and MI after

the index date

Standard protocol approvals registrations and patientconsents This study was reviewed and approved through the

National Research Ethics Service Scientific Research Committee

reference number 10-013

Statistical analysis and adjustment for potential sourcesof bias Demographic variables including age and sex and risk fac-

tors for vascular disease including obesity (body mass index [BMI]

30 kgm2) smoking status history of cholesterol 62 mmolL

hypertension diabetes ischemic heart disease atrial fibrillation

intermittent arterial claudication carotid stenosis and valvular heart

disease were compared in cases and controls at the index date using

Pearson x2 tests The proportion of cases and controls for which

BMI cholesterol level and smoking status were recorded was also

calculated Survival analysis was conducted to investigate whether

HZ influenced the time to stroke and independently to TIA and

MI Kaplan-Meier survival curves were generated and the log-rank

test was used to examine differences between the 2 cohorts Cox

proportional hazard regression models were used to calculate the

hazard ratio (HR) with 95 confidence interval of each of these

outcomes after HZ The survival models were adjusted for matching

variables risk factors and potential confounders for stroke and

MI1011 including obesity (BMI 30 kgm2) smoking status

history of cholesterol 62 mmolL hypertension diabetes

ischemic heart disease atrial fibrillation intermittent arterial

claudication carotid stenosis and valvular heart disease Subgroup

analyses were conducted by age at index date (10-year classes) and

by sex All statistical analyses were conducted using SAS software

version 92 (SAS Institute Cary NC)

RESULTS A total of 113411 cases of HZ were iden-tified in 36 million active patients collected over 237years (median 63 years) We excluded 6696 cases(590) of recurrent zoster because of the possibilitythat they represented misclassified cases of recurrentherpes simplex89 In addition 106601 HZ casestogether with 213202 controls 2 for each casematched for age sex and general practice werefurther evaluated (figure e-1 on the Neurologyreg Website at wwwneurologyorg) The total person-yearsfollow-up for cases of HZ was 781740

The characteristics of cases and controls are shownin table 1 The median age of HZ onset was 5943years Risk factors for vascular disease were significantlymore common in cases than in controls (table 2)

Study outcomes Kaplan-Meier curves of the time tostroke for cases and controls up to a maximum of237 years (8672 days) after acute HZ are shown infigure 1 Although the incidence of stroke was higherin cases than controls Cox proportional HRs adjustedfor vascular risk factors showed the difference not tobe significant (table 3) The type of stroke (hemorrhageor infarction) was poorly recorded and there were nodifferences between cases and controls in incidence bystroke pathology (table e-1) Stroke occurring in asso-ciation with HZO is well described in the literature2

HZO normally accounts for approximately 16 of casesof HZ12 but was recorded in only 1600 (15) of casesin the THIN database Even when cases recorded infree text and HZ of the head and neck were includedthe number only increased to 2324 (218) The inci-dence of stroke although higher after HZO did notdiffer significantly from that of controls (table 3)However the risk of stroke was significantly increasedfor subjects whose HZ occurred when they were youn-ger than 40 years (table 3 figure 2)

The prevalence of TIA and MI in this population isshown in table 1 After adjustment for confoundingvascular disease risk factors the time to TIA and MIwas reduced in cases followed for a median of 63 years(2301 days) (range 10ndash237 years) (figure 1) Cox pro-portional HRs adjusted for vascular risk factors showeda 15 increased risk of TIA and to a lesser extent MIassociated with HZ (table 3) TIA itself was a risk factorfor stroke increasing the incidence 7-fold comparedwith age-matched controls (1432 vs 207)

As with stroke TIA and MI were significantlyincreased (24- and 15-fold respectively) in those

Neurology 82 January 21 2014 207

4

whose HZ occurred at ages 18 to 40 years even whenadjusted for vascular risk factors (figure 2) Most riskfactors for vascular disease were also more common insubjects whose HZ occurred at age 18 to 40 years ascompared with matched controls (table e-2) Analysisof BMI cholesterol level and smoking status showedthese to be recorded significantly more frequently incases of HZ than in controls (table e-3) but less fre-quently in subjects aged 18 to 40 years than in oldersubjects (table e-4)

DISCUSSION This retrospective cohort study is thelargest to examine HZ as a risk factor for strokeTIA and MI The study identifies HZ as an indepen-dent risk factor for TIA and MI occurring up to 24years after the acute episode in UK adults older than18 years and for stroke in those aged 18 to 40 yearsThe data also confirm that irrespective of age condi-tions that predispose to vascular disease includinglifestyle factors such as smoking and obesity which

have not previously been examined are significantlymore common in subjects with HZ (table 2)although some of this could be attributable to betterrecording of risk factors in patients who present withHZ (table e-3)

Our study has a number of potential limitationsAlthough representative of UK general practices theTHIN database depends on accurate coding byGPs7 Dermatomal HZ is easily diagnosed and codinghas been shown to be accurate in other database stud-ies13 To reduce miscoding we excluded recurrentHZ which can be confused with herpes simplex89

The THIN database does not require GPs to specifylocation of the HZ which may explain the 10-foldlower than expected percentage of HZO cases in thisstudy compared with previous UK studies (table 1)12

Low levels of HZO recording have also been observedfor another database the UK General PracticeResearch Database13 The low numbers in this studylimited robust evaluation of HZO as a risk factor forstroke or other vascular disease

Recording by GPs of transient neurologic symp-toms mimicking TIA for example benign positionalvertigo which do not predispose to stroke may haveled to overestimates of the incidence of TIA after HZoccurrence14 However patients with TIA in thisstudy had a 7-fold higher prevalence of stroke com-pared with patients who did not experience TIA(1432 vs 207) This suggests that records ofTIA in the THIN database in the main reflectedtypical disease a finding in line with previousobservations14

Although the overall prevalence of TIA and MIwas in agreement with published data14 the preva-lence of stroke in this population (25) was higherthan for recently reported studies based on other UKpopulation databases15 (table 1) This could be attrib-utable to the comparatively longer time span over

Table 2 Comparison of vascular disease risk factors in cases and controls

Risk factor

Cases Controls

p Value of thex2 testNo No

Obesity 19161 180 35597 167 00001

Smoking 37637 353 71763 337 00001

Cholesterol gt62 mmolL 14962 140 26921 126 00001

Hypertension 26396 238 46928 220 00001

Diabetes 5893 55 10372 49 00001

Ischemic heart disease 6536 61 10274 48 00001

Atrial fibrillation 2775 26 4683 22 00001

Intermittent arterial claudication 1042 10 1754 08 00001

Carotid stenosis 74 01 99 01 00084

Valvular heart disease 1190 11 1977 09 00001

Table 1 Comparison of patients with HZ and matched controls

CharacteristicPatients with HZ(n 5 106601)

Matched controls(n 5 213202) Total (N 5 319803)

Mean age at index date y (SD) 579 (177) 577 (177)

Sex female 63183 (593) 124620 (592)

HZO 1710 (16)

HZ in the head (including HZO) 2324 (21)

Other form of HZnot specified 104277 (978)

Stroke 5252 (246) 2727 (256) 7979 (249)

Myocardial infarction 4835 (227) 2762 (259) 7597 (238)

TIA 3904 (183) 2275 (213) 6179 (193)

Stroke in patients with HZO (n 5 1710) 130 (380) 68 (398) 198 (386)

Abbreviations HZ 5 herpes zoster HZO 5 HZ ophthalmicusData are numbers (percentage) unless otherwise marked

208 Neurology 82 January 21 2014

4

which this analysis was conducted 24 vs 8 years forother studies15 during which time the prevalence ofstroke decreased15

In the UK the incidence of stroke has decreasedby more than 30 in the past 10 years15 This hasbeen attributed in part to government initiativesencouraging GPs to screen opportunistically for and

treat vascular risk factors in subjects older than 45years1516 By contrast in those aged 45 years or youn-ger in whom these policies have not been imple-mented the incidence of stroke has remainedunchanged over the same time period15 The possi-bility that better ascertainment and treatment of vas-cular risk factors in older subjects may underlie thesedifferences is supported by our finding that BMIsmoking status and cholesterol levels were recordedless frequently in the notes of those younger than 40years (tables e-3 and e-4) Better control of vascularrisk factors in older patients presenting with TIAwhich itself increases the risk of stroke would alsoexplain why after HZ the incidence of TIA but notstroke was increased in the THIN patient populationas a whole Together with published data linkingstroke in children with a recent history of chicken-pox17ndash19 these results support a significant role forVZV independently of other vascular risk factorsin the pathogenesis of stroke and cerebrovascular dis-ease in the UK population particularly at youngerages The results are corroborated by populationcohort studies conducted in Taiwan4 and Denmark20

both of which identified HZ as a risk factor forstroke4 or stroke plus TIA20 The Danish study alsoidentified the risk of stroke and TIA to be highest inthose whose HZ occurred when they were youngerthan 40 years20 While the risks identified were higherfor the Danish and Taiwanese studies this may reflectdifferences in the study populations and designs Nei-ther the Danish nor Taiwanese study controlled forsmoking and BMI which may have biased resultswhile the former reported risks for stroke and TIAcombined The Danish study was designed to capturecerebrovascular events associated with acute HZwhereas this and the Taiwanese study excluded sub-jects without a yearrsquos follow-up data The incidence ofstroke was higher in the Taiwanese study (141 at ayear vs 03 in this study) but vascular risk factorswere 3 to 5 times more common in the UK Thiscould either reflect differences between the popula-tions or after current government recommenda-tions more complete ascertainment and treatmentof risk factors in the UK

How then might the findings of long-term in-creases in cerebrovascular and MI after HZ be ex-plained In the case of HZO with which strokesare unequivocally and temporally associated cranialartery pathology arises from direct VZV infectionvia afferent branches of the ophthalmic branch ofthe trigeminal nerve22122 In such cases transmuralspread of virus from the adventitia leads to disruptionof the internal elastic lamina intimal hypertrophyand proinflammatory conditions that increase the riskof stroke21 However these mechanisms cannot easilyexplain the pathogenesis of stroke or TIA after HZ

Figure 1 Kaplan-Meier curves for the risk of stroke TIA and MI over the studyfollow-up period

The time to stroke (A) after the index date does not differ significantly for cases of herpeszoster and matched controls but is significantly shorter for TIA (B) and myocardial infarction(MI) (C) in cases compared with controls

Neurology 82 January 21 2014 209

4

located outside the head and neck or even of MI afterHZ Vascular events occurring within days of HZcould be due to the associated inflammatory responseas has been described for stroke and MI after acuterespiratory or urinary tract infections23 However thiscannot explain the increased risk persisting formonths and years after acute HZ The discovery inrecent years that VZV DNA can be detected in oralfluid and blood both in subjects whose rash is outsidethe head and neck and even in the absence of rashprovides a possible explanation24227 In theoryasymptomatic reactivation of VZV from cranialnerves detectable as virus in saliva could also leadto infection of cranial arteries stroke and TIAincluding in the absence of HZ rash and when therash occurs in noncranial dermatomes26 Thishypothesis is supported by findings from simian var-icella virus infection of macaques a model for VZV28

In this model asymptomatic reactivation of simianvaricella virus from trigeminal ganglia with the poten-tial to spread to cranial arteries has been detected inmacaques with thoracic zoster29 In humans VZVantigen has been demonstrated in arterial adventitialtissue together with intimal hypertrophy within skiplesions present in the cerebral arteries of diabeticswithout a history of HZ30 Notwithstanding the lackof history in these cases diabetics are known to be atincreased risk of HZ31 Furthermore asymptomaticshedding of virus in saliva is significantly more com-mon in those with a history of HZ26 Taken togetherthe possibility remains that certain individuals whoare predisposed to HZ are also more likely to shedvirus asymptomatically and that both represent a riskfor cerebrovascular disease At the same time asymp-tomatic reactivation of VZV from latency in thoracicsympathetic ganglia32 with transaxonal spread viaadrenergic nerves to systemic arteries could explain

the ongoing risk of MI long after an episode of HZAlthough accounting for 15 to 20 of all cases33

the incidence of HZ is comparatively low for thoseyounger than 40 years12 This together with the factthat those whose HZ occurs at ages 18 to 40 years areless likely to have predisposing immunosuppressiveconditions33 suggest a predisposition in this groupto VZV reactivation and a lifetime increased risk ofvascular disease VZV DNA has also been detected inblood for months after the resolution of HZ34 and inasymptomatic children receiving intensive care27 Ifcirculating virus is able to infect arterial tissue partic-ularly when damaged by preexisting risk factors thistoo could contribute to prolonged inflammation withincreased vascular insult In this scenario control ofrisk factors that predispose to arterial damage mightmitigate the risk from HZ which in turn mightexplain our findings that strokes are not more com-mon in UK citizens older than 40 years Takentogether the finding that virus reacts asymptomati-cally from cranial nerves resulting in prolonged oralshedding242534 particularly in subjects with a historyof HZ26 and circulation in the blood2734 provides aset of testable hypotheses to explain the increased riskof TIA MI and in some cases stoke persisting foryears after an episode of HZ particularly in the pres-ence of risk factors for vascular disease The possibilitythat VZV directly exacerbates preexisting arterialdamage would also explain why effective managementof risk factors has reduced the incidence of stroke afterHZ occurrence in the older UK subjects

Overall these data add to the growing body of evi-dence linking VZV a ubiquitous pathogen that es-tablishes persistent infection in more than 95 ofindividuals to vascular disease Immunization withthe licensed zoster vaccine has been shown to signif-icantly reduce the incidence of HZ as well as

Table 3 Hazard ratios (95 CI) for stroke TIA and MI after herpes zoster occurrence

Vascular eventa Cases (n 5 106601) n () Controls (n 5 213202) n ()

Hazard ratio (95 CI)

Unadjusted Adjustedb

Stroke 2727 (249) 5252 (246) 104 (099ndash109) 102 (098ndash107)

MI 2762 (259) 4835 (238) 115 (109ndash120) 110 (105ndash116)c

TIA 2275 (213) 3901 (183) 117 (111ndash123) 115 (109ndash121)c

Stroke in patients with HZO (n 5 2324) 68 (398) 130 (390) 106 (079ndash142) 103 (077ndash139)

Stroke in subjects 18ndash40 y (n 5 19301) 40 (021) 45 (012) 179 (117ndash273) 174 (113ndash266)c

MI in subjects 18ndash40 y (n 5 19301) 51 (026) 67 (017) 153 (106ndash220) 149 (104ndash215)c

TIA in subjects 18ndash40 y (n 5 19301) 25 (013) 20 (005) 251 (139ndash452) 242 (134ndash436)c

Abbreviations CI 5 confidence interval HZO 5 herpes zoster ophthalmicus MI 5 myocardial infarctiona Period of follow-up 1 to 237 yearsbHazard ratios were adjusted for sex age obesity (body mass index 30 kgm2) smoking status history of cholesterol 62 mmolL hypertensiondiabetes ischemic heart disease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heart diseasecp 005

210 Neurology 82 January 21 2014

4

significantly decrease the severity of neuropathic com-plications35 Population studies are now needed toevaluate whether immunization to prevent HZ couldalso reduce the incidence of vascular events includingstroke TIA and MI More research is needed to

understand the pathogenesis of increased HZ in pa-tients with risk factors for vascular disease and todetermine the impact of treatment on risk Impor-tantly the role if any of asymptomatic VZV reacti-vation in the pathogenesis of vascular disease and howthis might be affected by zoster immunization needsfurther clarification In the meantime the vaccinecould now be offered to adults with risk factors forvascular disease irrespective of age to reduce the asso-ciated risk of HZ431 At the same time screening forvascular risk factors in patients presenting with HZespecially younger patients in whom interventionmay have the most impact should now be encour-aged Ultimately high-coverage childhood varicellavaccination to reduce latency with wild-type virus isaltogether desirable

AUTHOR CONTRIBUTIONSJudith Breuer conceived and designed the study and wrote the manu-

script Maud Pacou and Aline Gauthier undertook analysis of the THIN

database and contributed to the study design and writing of the manu-

script Martin M Brown contributed to the study design and writing

of the manuscript

STUDY FUNDINGFunded by an unrestricted investigator grant from Sanofi Pasteur MSD to

Judith Breuer JB receives funding from the NIHR UCLUCLH Compre-

hensive Biomedical Research Centre MMBrsquos Chair in Stroke Medicine at

UCL is supported by the Reta Lila Weston Trust for Medical Research

DISCLOSUREJ Breuer has received funding from SPMSD for the VZV Identification

Programme which undertakes genotyping of VZV from vaccine adverse

events JB also heads the VZV reference laboratory which has geno-

typed VZV for GlaxoSmithKline M Pacou A Gauthier and MM

Brown report no disclosures Go to Neurologyorg for full disclosures

Received June 6 2013 Accepted in final form October 8 2013

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Schoub BD Griffiths PD Mortimer P editors Principles

and Practice of Clinical Virology 6th ed Chichester John

Wiley amp Sons 2009133ndash160

2 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella

zoster virus vasculopathies diverse clinical manifestations

laboratory features pathogenesis and treatment Lancet

Neurol 20098731ndash740

3 Gilden DH Lipton HL Wolf JS et al Two patients

with unusual forms of varicella-zoster virus vasculopathy

N Engl J Med 20023471500ndash1503

4 Kang JH Ho JD Chen YH Lin HC Increased risk

of stroke after a herpes zoster attack a population-based

follow-up study Stroke 2009403443ndash3448

5 Lin HC Chien CW Ho JD Herpes zoster ophthalmicus

and the risk of stroke a population-based follow-up study

Neurology 201074792ndash797

6 Booth N What are the Read Codes Health Libr Rev

199411177ndash182

7 Cegedim Strategic Data Available at httpcsdmruk

cegedimcomour-dataour-datashtml Accessed July 9 2013

8 Heskel NS Hanifin JM ldquoRecurrent herpes zosterrdquo an

unproved entity J Am Acad Dermatol 198410486ndash490

Figure 2 Adjusted risk (hazard ratio and 95 confidence interval) of strokeTIA and MI by age group at index date

Risk of (A) stroke (B) TIA and (C) myocardial infarction (MI) by decade (D) Time to stroke incases and controls younger than 40 years Hazard ratios adjusted for vascular risk factorsfor stroke TIA and MI are significantly higher for cases of herpes zoster occurring before40 years of age compared with matched controls

Neurology 82 January 21 2014 211

4

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

varicella-zoster virus viraemia in patients with herpes zos-

ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

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References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

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ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

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httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

Reprints

httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Page 2: Neurology 2014 Breuer 206 12

Judith Breuer MDMaud Pacou BScAline Gauthier BScMartin M Brown MD

Correspondence toDr Breuerjbreueruclacuk

Supplemental data atwwwneurologyorg

Herpes zoster as a risk factor for strokeand TIAA retrospective cohort study in the UK

ABSTRACT

Objectives Stroke and TIA are recognized complications of acute herpes zoster (HZ) In this studywe evaluated HZ as a risk factor for cerebrovascular disease (stroke and TIA) and myocardialinfarction (MI) in a UK population cohort

Methods A retrospective cohort of 106601 HZ cases and 213202 controls matched forage sex and general practice was identified from the THIN (The Health Improvement Network)general practice database Cox proportional hazard models were used to examine the risks ofstroke TIA and MI in cases and controls adjusted for vascular risk factors including body massindex 30 kgm2 smoking cholesterol 62 mmolL hypertension diabetes ischemic heartdisease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heartdisease up to 24 years (median 63 years) after HZ occurrence

Results Risk factors for vascular disease were significantly increased in cases of HZ compared withcontrols Adjusted hazard ratios (AHRs) for TIA and MI but not stroke were increased in all patientswith HZ (AHR [95confidence interval] 115 [109ndash121] and 110 [105ndash116] respectively) How-ever stroke TIA and MI were increased in cases whose HZ occurred when they were younger than40 years (AHR [95 confidence interval] 174 [113ndash266] 242 [134ndash436] 149 [104ndash215]respectively) Subjects younger than 40 years were significantly less likely to be asked about vascularrisk factors than were older patients (p 0001)

Conclusion HZ is an independent risk factor for vascular disease in the UK population particu-larly for stroke TIA and MI in subjects affected before the age of 40 years In older subjects bet-ter ascertainment of vascular risk factors and earlier intervention may explain the reduction in riskof stroke after the occurrence of HZ Neurologyreg 201482206ndash212

GLOSSARYAHR 5 adjusted hazard ratio BMI 5 body mass index GP 5 general practitioner HR 5 hazard ratio HZ 5 herpes zosterHZO 5 herpes zoster ophthalmicus ICD 5 International Classification of Diseases MI 5 myocardial infarction THIN 5 TheHealth Improvement Network VZV 5 varicella-zoster virus

Herpes zoster (HZ) is caused by varicella-zoster virus (VZV) a ubiquitous pathogen that after pri-mary chickenpox in children persists asymptomatically (latently) in the sensory ganglia includingthe trigeminal ganglion Reactivation of VZV from latency and translocation via sensory nerveendings to the skin where it replicates is associated with the characteristic HZ rash1 Both ischemicand hemorrhagic strokes have been described after HZ affecting the ophthalmic branch of thetrigeminal nerve2 In these patients virus spreads transaxonally to cerebral arteries via trigeminaland other ganglionic afferents2 At autopsy viral inclusions DNA and antigen present in cerebralarteries confirms that VZV vasculopathy in these patients is associated with stroke and TIA2

Similar pathology has also been found in strokes and TIA that follow HZ occurring at non-ophthalmic sites and even in the absence of rash raising the possibility that VZV is more widelyimplicated in the pathogenesis of cerebrovascular disease23 This possibility is supported by findingsfrom a Taiwanese population study showing a 30 increase in the incidence of stroke for up to ayear after acute HZ and a 45-fold increase after HZ ophthalmicus (HZO)45 We analyzed the risk

From the Division of Infection and Immunity (JB) and Institute of Neurology (MMB) University College London and Amaris (MP AG)

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 30 License whichpermits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or used commercially

206 copy 2014 American Academy of Neurology

4

of stroke and TIA after HZ in a large retrospec-tive UK population-based matched cohort studyfollowed for up to 24 years (median 63 years)To examine the hypothesis that HZ is a riskfactor for vascular disease in general we alsomeasured the risk of myocardial infarction (MI)

METHODS Database sources and study population TheTHIN (The Health Improvement Network) database is a primary

care database that contains anonymous demographic medical and

prescription information covering more than 3 million active pa-

tients in the UK General practitioner (GP) episodes are coded

using READ codes a standardized hierarchical coding methodol-

ogy similar to the ICD codes which are used by primary care

physicians (GPs) in the UK to classify medical conditions6 Patients

in the THIN database are representative of the UK population by

age sex medical conditions and death rates7 Data were extracted

from patients routinely attending 464 general practices between

2002 and 2010 General practice is the term used in the UK to

denote a group of primary care physicians (GPs)

A retrospective matched cohort study was conducted Cases

were selected as patients who had experienced HZ Their index

date was defined as the date of onset of HZ as recorded in the

notes Patients with recurrent HZ were excluded because this is

a rare form of the disease that is often confused with herpes sim-

plex virus infection89 Patients with HZO identified using the

relevant code were included as part of the case cohort

Controls were identified as patients who had no record of HZ

To increase the power of the statistical analysis and reduce bias

2 controls per case were matched according to their age at index

date (6 2 years) sex and general (primary care) practice The index

date for controls was defined as the index date of the matched case

Patients and controls younger than 18 years or who had expe-

rienced a cardiovascular event (stroke MI or TIA) before the

index date were excluded All patients and controls had a minimum

follow-up time of 1 year after the index date The number of pa-

tients in the THIN database matching the selection criteria resulted

in a power of at least 96 for the statistical analysis

The THIN codes corresponding to recorded episodes of stroke

TIA and MI were identified This set of codes was used to search

patient and control records for incident stroke TIA and MI after

the index date

Standard protocol approvals registrations and patientconsents This study was reviewed and approved through the

National Research Ethics Service Scientific Research Committee

reference number 10-013

Statistical analysis and adjustment for potential sourcesof bias Demographic variables including age and sex and risk fac-

tors for vascular disease including obesity (body mass index [BMI]

30 kgm2) smoking status history of cholesterol 62 mmolL

hypertension diabetes ischemic heart disease atrial fibrillation

intermittent arterial claudication carotid stenosis and valvular heart

disease were compared in cases and controls at the index date using

Pearson x2 tests The proportion of cases and controls for which

BMI cholesterol level and smoking status were recorded was also

calculated Survival analysis was conducted to investigate whether

HZ influenced the time to stroke and independently to TIA and

MI Kaplan-Meier survival curves were generated and the log-rank

test was used to examine differences between the 2 cohorts Cox

proportional hazard regression models were used to calculate the

hazard ratio (HR) with 95 confidence interval of each of these

outcomes after HZ The survival models were adjusted for matching

variables risk factors and potential confounders for stroke and

MI1011 including obesity (BMI 30 kgm2) smoking status

history of cholesterol 62 mmolL hypertension diabetes

ischemic heart disease atrial fibrillation intermittent arterial

claudication carotid stenosis and valvular heart disease Subgroup

analyses were conducted by age at index date (10-year classes) and

by sex All statistical analyses were conducted using SAS software

version 92 (SAS Institute Cary NC)

RESULTS A total of 113411 cases of HZ were iden-tified in 36 million active patients collected over 237years (median 63 years) We excluded 6696 cases(590) of recurrent zoster because of the possibilitythat they represented misclassified cases of recurrentherpes simplex89 In addition 106601 HZ casestogether with 213202 controls 2 for each casematched for age sex and general practice werefurther evaluated (figure e-1 on the Neurologyreg Website at wwwneurologyorg) The total person-yearsfollow-up for cases of HZ was 781740

The characteristics of cases and controls are shownin table 1 The median age of HZ onset was 5943years Risk factors for vascular disease were significantlymore common in cases than in controls (table 2)

Study outcomes Kaplan-Meier curves of the time tostroke for cases and controls up to a maximum of237 years (8672 days) after acute HZ are shown infigure 1 Although the incidence of stroke was higherin cases than controls Cox proportional HRs adjustedfor vascular risk factors showed the difference not tobe significant (table 3) The type of stroke (hemorrhageor infarction) was poorly recorded and there were nodifferences between cases and controls in incidence bystroke pathology (table e-1) Stroke occurring in asso-ciation with HZO is well described in the literature2

HZO normally accounts for approximately 16 of casesof HZ12 but was recorded in only 1600 (15) of casesin the THIN database Even when cases recorded infree text and HZ of the head and neck were includedthe number only increased to 2324 (218) The inci-dence of stroke although higher after HZO did notdiffer significantly from that of controls (table 3)However the risk of stroke was significantly increasedfor subjects whose HZ occurred when they were youn-ger than 40 years (table 3 figure 2)

The prevalence of TIA and MI in this population isshown in table 1 After adjustment for confoundingvascular disease risk factors the time to TIA and MIwas reduced in cases followed for a median of 63 years(2301 days) (range 10ndash237 years) (figure 1) Cox pro-portional HRs adjusted for vascular risk factors showeda 15 increased risk of TIA and to a lesser extent MIassociated with HZ (table 3) TIA itself was a risk factorfor stroke increasing the incidence 7-fold comparedwith age-matched controls (1432 vs 207)

As with stroke TIA and MI were significantlyincreased (24- and 15-fold respectively) in those

Neurology 82 January 21 2014 207

4

whose HZ occurred at ages 18 to 40 years even whenadjusted for vascular risk factors (figure 2) Most riskfactors for vascular disease were also more common insubjects whose HZ occurred at age 18 to 40 years ascompared with matched controls (table e-2) Analysisof BMI cholesterol level and smoking status showedthese to be recorded significantly more frequently incases of HZ than in controls (table e-3) but less fre-quently in subjects aged 18 to 40 years than in oldersubjects (table e-4)

DISCUSSION This retrospective cohort study is thelargest to examine HZ as a risk factor for strokeTIA and MI The study identifies HZ as an indepen-dent risk factor for TIA and MI occurring up to 24years after the acute episode in UK adults older than18 years and for stroke in those aged 18 to 40 yearsThe data also confirm that irrespective of age condi-tions that predispose to vascular disease includinglifestyle factors such as smoking and obesity which

have not previously been examined are significantlymore common in subjects with HZ (table 2)although some of this could be attributable to betterrecording of risk factors in patients who present withHZ (table e-3)

Our study has a number of potential limitationsAlthough representative of UK general practices theTHIN database depends on accurate coding byGPs7 Dermatomal HZ is easily diagnosed and codinghas been shown to be accurate in other database stud-ies13 To reduce miscoding we excluded recurrentHZ which can be confused with herpes simplex89

The THIN database does not require GPs to specifylocation of the HZ which may explain the 10-foldlower than expected percentage of HZO cases in thisstudy compared with previous UK studies (table 1)12

Low levels of HZO recording have also been observedfor another database the UK General PracticeResearch Database13 The low numbers in this studylimited robust evaluation of HZO as a risk factor forstroke or other vascular disease

Recording by GPs of transient neurologic symp-toms mimicking TIA for example benign positionalvertigo which do not predispose to stroke may haveled to overestimates of the incidence of TIA after HZoccurrence14 However patients with TIA in thisstudy had a 7-fold higher prevalence of stroke com-pared with patients who did not experience TIA(1432 vs 207) This suggests that records ofTIA in the THIN database in the main reflectedtypical disease a finding in line with previousobservations14

Although the overall prevalence of TIA and MIwas in agreement with published data14 the preva-lence of stroke in this population (25) was higherthan for recently reported studies based on other UKpopulation databases15 (table 1) This could be attrib-utable to the comparatively longer time span over

Table 2 Comparison of vascular disease risk factors in cases and controls

Risk factor

Cases Controls

p Value of thex2 testNo No

Obesity 19161 180 35597 167 00001

Smoking 37637 353 71763 337 00001

Cholesterol gt62 mmolL 14962 140 26921 126 00001

Hypertension 26396 238 46928 220 00001

Diabetes 5893 55 10372 49 00001

Ischemic heart disease 6536 61 10274 48 00001

Atrial fibrillation 2775 26 4683 22 00001

Intermittent arterial claudication 1042 10 1754 08 00001

Carotid stenosis 74 01 99 01 00084

Valvular heart disease 1190 11 1977 09 00001

Table 1 Comparison of patients with HZ and matched controls

CharacteristicPatients with HZ(n 5 106601)

Matched controls(n 5 213202) Total (N 5 319803)

Mean age at index date y (SD) 579 (177) 577 (177)

Sex female 63183 (593) 124620 (592)

HZO 1710 (16)

HZ in the head (including HZO) 2324 (21)

Other form of HZnot specified 104277 (978)

Stroke 5252 (246) 2727 (256) 7979 (249)

Myocardial infarction 4835 (227) 2762 (259) 7597 (238)

TIA 3904 (183) 2275 (213) 6179 (193)

Stroke in patients with HZO (n 5 1710) 130 (380) 68 (398) 198 (386)

Abbreviations HZ 5 herpes zoster HZO 5 HZ ophthalmicusData are numbers (percentage) unless otherwise marked

208 Neurology 82 January 21 2014

4

which this analysis was conducted 24 vs 8 years forother studies15 during which time the prevalence ofstroke decreased15

In the UK the incidence of stroke has decreasedby more than 30 in the past 10 years15 This hasbeen attributed in part to government initiativesencouraging GPs to screen opportunistically for and

treat vascular risk factors in subjects older than 45years1516 By contrast in those aged 45 years or youn-ger in whom these policies have not been imple-mented the incidence of stroke has remainedunchanged over the same time period15 The possi-bility that better ascertainment and treatment of vas-cular risk factors in older subjects may underlie thesedifferences is supported by our finding that BMIsmoking status and cholesterol levels were recordedless frequently in the notes of those younger than 40years (tables e-3 and e-4) Better control of vascularrisk factors in older patients presenting with TIAwhich itself increases the risk of stroke would alsoexplain why after HZ the incidence of TIA but notstroke was increased in the THIN patient populationas a whole Together with published data linkingstroke in children with a recent history of chicken-pox17ndash19 these results support a significant role forVZV independently of other vascular risk factorsin the pathogenesis of stroke and cerebrovascular dis-ease in the UK population particularly at youngerages The results are corroborated by populationcohort studies conducted in Taiwan4 and Denmark20

both of which identified HZ as a risk factor forstroke4 or stroke plus TIA20 The Danish study alsoidentified the risk of stroke and TIA to be highest inthose whose HZ occurred when they were youngerthan 40 years20 While the risks identified were higherfor the Danish and Taiwanese studies this may reflectdifferences in the study populations and designs Nei-ther the Danish nor Taiwanese study controlled forsmoking and BMI which may have biased resultswhile the former reported risks for stroke and TIAcombined The Danish study was designed to capturecerebrovascular events associated with acute HZwhereas this and the Taiwanese study excluded sub-jects without a yearrsquos follow-up data The incidence ofstroke was higher in the Taiwanese study (141 at ayear vs 03 in this study) but vascular risk factorswere 3 to 5 times more common in the UK Thiscould either reflect differences between the popula-tions or after current government recommenda-tions more complete ascertainment and treatmentof risk factors in the UK

How then might the findings of long-term in-creases in cerebrovascular and MI after HZ be ex-plained In the case of HZO with which strokesare unequivocally and temporally associated cranialartery pathology arises from direct VZV infectionvia afferent branches of the ophthalmic branch ofthe trigeminal nerve22122 In such cases transmuralspread of virus from the adventitia leads to disruptionof the internal elastic lamina intimal hypertrophyand proinflammatory conditions that increase the riskof stroke21 However these mechanisms cannot easilyexplain the pathogenesis of stroke or TIA after HZ

Figure 1 Kaplan-Meier curves for the risk of stroke TIA and MI over the studyfollow-up period

The time to stroke (A) after the index date does not differ significantly for cases of herpeszoster and matched controls but is significantly shorter for TIA (B) and myocardial infarction(MI) (C) in cases compared with controls

Neurology 82 January 21 2014 209

4

located outside the head and neck or even of MI afterHZ Vascular events occurring within days of HZcould be due to the associated inflammatory responseas has been described for stroke and MI after acuterespiratory or urinary tract infections23 However thiscannot explain the increased risk persisting formonths and years after acute HZ The discovery inrecent years that VZV DNA can be detected in oralfluid and blood both in subjects whose rash is outsidethe head and neck and even in the absence of rashprovides a possible explanation24227 In theoryasymptomatic reactivation of VZV from cranialnerves detectable as virus in saliva could also leadto infection of cranial arteries stroke and TIAincluding in the absence of HZ rash and when therash occurs in noncranial dermatomes26 Thishypothesis is supported by findings from simian var-icella virus infection of macaques a model for VZV28

In this model asymptomatic reactivation of simianvaricella virus from trigeminal ganglia with the poten-tial to spread to cranial arteries has been detected inmacaques with thoracic zoster29 In humans VZVantigen has been demonstrated in arterial adventitialtissue together with intimal hypertrophy within skiplesions present in the cerebral arteries of diabeticswithout a history of HZ30 Notwithstanding the lackof history in these cases diabetics are known to be atincreased risk of HZ31 Furthermore asymptomaticshedding of virus in saliva is significantly more com-mon in those with a history of HZ26 Taken togetherthe possibility remains that certain individuals whoare predisposed to HZ are also more likely to shedvirus asymptomatically and that both represent a riskfor cerebrovascular disease At the same time asymp-tomatic reactivation of VZV from latency in thoracicsympathetic ganglia32 with transaxonal spread viaadrenergic nerves to systemic arteries could explain

the ongoing risk of MI long after an episode of HZAlthough accounting for 15 to 20 of all cases33

the incidence of HZ is comparatively low for thoseyounger than 40 years12 This together with the factthat those whose HZ occurs at ages 18 to 40 years areless likely to have predisposing immunosuppressiveconditions33 suggest a predisposition in this groupto VZV reactivation and a lifetime increased risk ofvascular disease VZV DNA has also been detected inblood for months after the resolution of HZ34 and inasymptomatic children receiving intensive care27 Ifcirculating virus is able to infect arterial tissue partic-ularly when damaged by preexisting risk factors thistoo could contribute to prolonged inflammation withincreased vascular insult In this scenario control ofrisk factors that predispose to arterial damage mightmitigate the risk from HZ which in turn mightexplain our findings that strokes are not more com-mon in UK citizens older than 40 years Takentogether the finding that virus reacts asymptomati-cally from cranial nerves resulting in prolonged oralshedding242534 particularly in subjects with a historyof HZ26 and circulation in the blood2734 provides aset of testable hypotheses to explain the increased riskof TIA MI and in some cases stoke persisting foryears after an episode of HZ particularly in the pres-ence of risk factors for vascular disease The possibilitythat VZV directly exacerbates preexisting arterialdamage would also explain why effective managementof risk factors has reduced the incidence of stroke afterHZ occurrence in the older UK subjects

Overall these data add to the growing body of evi-dence linking VZV a ubiquitous pathogen that es-tablishes persistent infection in more than 95 ofindividuals to vascular disease Immunization withthe licensed zoster vaccine has been shown to signif-icantly reduce the incidence of HZ as well as

Table 3 Hazard ratios (95 CI) for stroke TIA and MI after herpes zoster occurrence

Vascular eventa Cases (n 5 106601) n () Controls (n 5 213202) n ()

Hazard ratio (95 CI)

Unadjusted Adjustedb

Stroke 2727 (249) 5252 (246) 104 (099ndash109) 102 (098ndash107)

MI 2762 (259) 4835 (238) 115 (109ndash120) 110 (105ndash116)c

TIA 2275 (213) 3901 (183) 117 (111ndash123) 115 (109ndash121)c

Stroke in patients with HZO (n 5 2324) 68 (398) 130 (390) 106 (079ndash142) 103 (077ndash139)

Stroke in subjects 18ndash40 y (n 5 19301) 40 (021) 45 (012) 179 (117ndash273) 174 (113ndash266)c

MI in subjects 18ndash40 y (n 5 19301) 51 (026) 67 (017) 153 (106ndash220) 149 (104ndash215)c

TIA in subjects 18ndash40 y (n 5 19301) 25 (013) 20 (005) 251 (139ndash452) 242 (134ndash436)c

Abbreviations CI 5 confidence interval HZO 5 herpes zoster ophthalmicus MI 5 myocardial infarctiona Period of follow-up 1 to 237 yearsbHazard ratios were adjusted for sex age obesity (body mass index 30 kgm2) smoking status history of cholesterol 62 mmolL hypertensiondiabetes ischemic heart disease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heart diseasecp 005

210 Neurology 82 January 21 2014

4

significantly decrease the severity of neuropathic com-plications35 Population studies are now needed toevaluate whether immunization to prevent HZ couldalso reduce the incidence of vascular events includingstroke TIA and MI More research is needed to

understand the pathogenesis of increased HZ in pa-tients with risk factors for vascular disease and todetermine the impact of treatment on risk Impor-tantly the role if any of asymptomatic VZV reacti-vation in the pathogenesis of vascular disease and howthis might be affected by zoster immunization needsfurther clarification In the meantime the vaccinecould now be offered to adults with risk factors forvascular disease irrespective of age to reduce the asso-ciated risk of HZ431 At the same time screening forvascular risk factors in patients presenting with HZespecially younger patients in whom interventionmay have the most impact should now be encour-aged Ultimately high-coverage childhood varicellavaccination to reduce latency with wild-type virus isaltogether desirable

AUTHOR CONTRIBUTIONSJudith Breuer conceived and designed the study and wrote the manu-

script Maud Pacou and Aline Gauthier undertook analysis of the THIN

database and contributed to the study design and writing of the manu-

script Martin M Brown contributed to the study design and writing

of the manuscript

STUDY FUNDINGFunded by an unrestricted investigator grant from Sanofi Pasteur MSD to

Judith Breuer JB receives funding from the NIHR UCLUCLH Compre-

hensive Biomedical Research Centre MMBrsquos Chair in Stroke Medicine at

UCL is supported by the Reta Lila Weston Trust for Medical Research

DISCLOSUREJ Breuer has received funding from SPMSD for the VZV Identification

Programme which undertakes genotyping of VZV from vaccine adverse

events JB also heads the VZV reference laboratory which has geno-

typed VZV for GlaxoSmithKline M Pacou A Gauthier and MM

Brown report no disclosures Go to Neurologyorg for full disclosures

Received June 6 2013 Accepted in final form October 8 2013

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Schoub BD Griffiths PD Mortimer P editors Principles

and Practice of Clinical Virology 6th ed Chichester John

Wiley amp Sons 2009133ndash160

2 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella

zoster virus vasculopathies diverse clinical manifestations

laboratory features pathogenesis and treatment Lancet

Neurol 20098731ndash740

3 Gilden DH Lipton HL Wolf JS et al Two patients

with unusual forms of varicella-zoster virus vasculopathy

N Engl J Med 20023471500ndash1503

4 Kang JH Ho JD Chen YH Lin HC Increased risk

of stroke after a herpes zoster attack a population-based

follow-up study Stroke 2009403443ndash3448

5 Lin HC Chien CW Ho JD Herpes zoster ophthalmicus

and the risk of stroke a population-based follow-up study

Neurology 201074792ndash797

6 Booth N What are the Read Codes Health Libr Rev

199411177ndash182

7 Cegedim Strategic Data Available at httpcsdmruk

cegedimcomour-dataour-datashtml Accessed July 9 2013

8 Heskel NS Hanifin JM ldquoRecurrent herpes zosterrdquo an

unproved entity J Am Acad Dermatol 198410486ndash490

Figure 2 Adjusted risk (hazard ratio and 95 confidence interval) of strokeTIA and MI by age group at index date

Risk of (A) stroke (B) TIA and (C) myocardial infarction (MI) by decade (D) Time to stroke incases and controls younger than 40 years Hazard ratios adjusted for vascular risk factorsfor stroke TIA and MI are significantly higher for cases of herpes zoster occurring before40 years of age compared with matched controls

Neurology 82 January 21 2014 211

4

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

varicella-zoster virus viraemia in patients with herpes zos-

ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

httpwwwneurologyorgcgicollectioncohort_studiesCohort studies

ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

Reprints

httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Page 3: Neurology 2014 Breuer 206 12

of stroke and TIA after HZ in a large retrospec-tive UK population-based matched cohort studyfollowed for up to 24 years (median 63 years)To examine the hypothesis that HZ is a riskfactor for vascular disease in general we alsomeasured the risk of myocardial infarction (MI)

METHODS Database sources and study population TheTHIN (The Health Improvement Network) database is a primary

care database that contains anonymous demographic medical and

prescription information covering more than 3 million active pa-

tients in the UK General practitioner (GP) episodes are coded

using READ codes a standardized hierarchical coding methodol-

ogy similar to the ICD codes which are used by primary care

physicians (GPs) in the UK to classify medical conditions6 Patients

in the THIN database are representative of the UK population by

age sex medical conditions and death rates7 Data were extracted

from patients routinely attending 464 general practices between

2002 and 2010 General practice is the term used in the UK to

denote a group of primary care physicians (GPs)

A retrospective matched cohort study was conducted Cases

were selected as patients who had experienced HZ Their index

date was defined as the date of onset of HZ as recorded in the

notes Patients with recurrent HZ were excluded because this is

a rare form of the disease that is often confused with herpes sim-

plex virus infection89 Patients with HZO identified using the

relevant code were included as part of the case cohort

Controls were identified as patients who had no record of HZ

To increase the power of the statistical analysis and reduce bias

2 controls per case were matched according to their age at index

date (6 2 years) sex and general (primary care) practice The index

date for controls was defined as the index date of the matched case

Patients and controls younger than 18 years or who had expe-

rienced a cardiovascular event (stroke MI or TIA) before the

index date were excluded All patients and controls had a minimum

follow-up time of 1 year after the index date The number of pa-

tients in the THIN database matching the selection criteria resulted

in a power of at least 96 for the statistical analysis

The THIN codes corresponding to recorded episodes of stroke

TIA and MI were identified This set of codes was used to search

patient and control records for incident stroke TIA and MI after

the index date

Standard protocol approvals registrations and patientconsents This study was reviewed and approved through the

National Research Ethics Service Scientific Research Committee

reference number 10-013

Statistical analysis and adjustment for potential sourcesof bias Demographic variables including age and sex and risk fac-

tors for vascular disease including obesity (body mass index [BMI]

30 kgm2) smoking status history of cholesterol 62 mmolL

hypertension diabetes ischemic heart disease atrial fibrillation

intermittent arterial claudication carotid stenosis and valvular heart

disease were compared in cases and controls at the index date using

Pearson x2 tests The proportion of cases and controls for which

BMI cholesterol level and smoking status were recorded was also

calculated Survival analysis was conducted to investigate whether

HZ influenced the time to stroke and independently to TIA and

MI Kaplan-Meier survival curves were generated and the log-rank

test was used to examine differences between the 2 cohorts Cox

proportional hazard regression models were used to calculate the

hazard ratio (HR) with 95 confidence interval of each of these

outcomes after HZ The survival models were adjusted for matching

variables risk factors and potential confounders for stroke and

MI1011 including obesity (BMI 30 kgm2) smoking status

history of cholesterol 62 mmolL hypertension diabetes

ischemic heart disease atrial fibrillation intermittent arterial

claudication carotid stenosis and valvular heart disease Subgroup

analyses were conducted by age at index date (10-year classes) and

by sex All statistical analyses were conducted using SAS software

version 92 (SAS Institute Cary NC)

RESULTS A total of 113411 cases of HZ were iden-tified in 36 million active patients collected over 237years (median 63 years) We excluded 6696 cases(590) of recurrent zoster because of the possibilitythat they represented misclassified cases of recurrentherpes simplex89 In addition 106601 HZ casestogether with 213202 controls 2 for each casematched for age sex and general practice werefurther evaluated (figure e-1 on the Neurologyreg Website at wwwneurologyorg) The total person-yearsfollow-up for cases of HZ was 781740

The characteristics of cases and controls are shownin table 1 The median age of HZ onset was 5943years Risk factors for vascular disease were significantlymore common in cases than in controls (table 2)

Study outcomes Kaplan-Meier curves of the time tostroke for cases and controls up to a maximum of237 years (8672 days) after acute HZ are shown infigure 1 Although the incidence of stroke was higherin cases than controls Cox proportional HRs adjustedfor vascular risk factors showed the difference not tobe significant (table 3) The type of stroke (hemorrhageor infarction) was poorly recorded and there were nodifferences between cases and controls in incidence bystroke pathology (table e-1) Stroke occurring in asso-ciation with HZO is well described in the literature2

HZO normally accounts for approximately 16 of casesof HZ12 but was recorded in only 1600 (15) of casesin the THIN database Even when cases recorded infree text and HZ of the head and neck were includedthe number only increased to 2324 (218) The inci-dence of stroke although higher after HZO did notdiffer significantly from that of controls (table 3)However the risk of stroke was significantly increasedfor subjects whose HZ occurred when they were youn-ger than 40 years (table 3 figure 2)

The prevalence of TIA and MI in this population isshown in table 1 After adjustment for confoundingvascular disease risk factors the time to TIA and MIwas reduced in cases followed for a median of 63 years(2301 days) (range 10ndash237 years) (figure 1) Cox pro-portional HRs adjusted for vascular risk factors showeda 15 increased risk of TIA and to a lesser extent MIassociated with HZ (table 3) TIA itself was a risk factorfor stroke increasing the incidence 7-fold comparedwith age-matched controls (1432 vs 207)

As with stroke TIA and MI were significantlyincreased (24- and 15-fold respectively) in those

Neurology 82 January 21 2014 207

4

whose HZ occurred at ages 18 to 40 years even whenadjusted for vascular risk factors (figure 2) Most riskfactors for vascular disease were also more common insubjects whose HZ occurred at age 18 to 40 years ascompared with matched controls (table e-2) Analysisof BMI cholesterol level and smoking status showedthese to be recorded significantly more frequently incases of HZ than in controls (table e-3) but less fre-quently in subjects aged 18 to 40 years than in oldersubjects (table e-4)

DISCUSSION This retrospective cohort study is thelargest to examine HZ as a risk factor for strokeTIA and MI The study identifies HZ as an indepen-dent risk factor for TIA and MI occurring up to 24years after the acute episode in UK adults older than18 years and for stroke in those aged 18 to 40 yearsThe data also confirm that irrespective of age condi-tions that predispose to vascular disease includinglifestyle factors such as smoking and obesity which

have not previously been examined are significantlymore common in subjects with HZ (table 2)although some of this could be attributable to betterrecording of risk factors in patients who present withHZ (table e-3)

Our study has a number of potential limitationsAlthough representative of UK general practices theTHIN database depends on accurate coding byGPs7 Dermatomal HZ is easily diagnosed and codinghas been shown to be accurate in other database stud-ies13 To reduce miscoding we excluded recurrentHZ which can be confused with herpes simplex89

The THIN database does not require GPs to specifylocation of the HZ which may explain the 10-foldlower than expected percentage of HZO cases in thisstudy compared with previous UK studies (table 1)12

Low levels of HZO recording have also been observedfor another database the UK General PracticeResearch Database13 The low numbers in this studylimited robust evaluation of HZO as a risk factor forstroke or other vascular disease

Recording by GPs of transient neurologic symp-toms mimicking TIA for example benign positionalvertigo which do not predispose to stroke may haveled to overestimates of the incidence of TIA after HZoccurrence14 However patients with TIA in thisstudy had a 7-fold higher prevalence of stroke com-pared with patients who did not experience TIA(1432 vs 207) This suggests that records ofTIA in the THIN database in the main reflectedtypical disease a finding in line with previousobservations14

Although the overall prevalence of TIA and MIwas in agreement with published data14 the preva-lence of stroke in this population (25) was higherthan for recently reported studies based on other UKpopulation databases15 (table 1) This could be attrib-utable to the comparatively longer time span over

Table 2 Comparison of vascular disease risk factors in cases and controls

Risk factor

Cases Controls

p Value of thex2 testNo No

Obesity 19161 180 35597 167 00001

Smoking 37637 353 71763 337 00001

Cholesterol gt62 mmolL 14962 140 26921 126 00001

Hypertension 26396 238 46928 220 00001

Diabetes 5893 55 10372 49 00001

Ischemic heart disease 6536 61 10274 48 00001

Atrial fibrillation 2775 26 4683 22 00001

Intermittent arterial claudication 1042 10 1754 08 00001

Carotid stenosis 74 01 99 01 00084

Valvular heart disease 1190 11 1977 09 00001

Table 1 Comparison of patients with HZ and matched controls

CharacteristicPatients with HZ(n 5 106601)

Matched controls(n 5 213202) Total (N 5 319803)

Mean age at index date y (SD) 579 (177) 577 (177)

Sex female 63183 (593) 124620 (592)

HZO 1710 (16)

HZ in the head (including HZO) 2324 (21)

Other form of HZnot specified 104277 (978)

Stroke 5252 (246) 2727 (256) 7979 (249)

Myocardial infarction 4835 (227) 2762 (259) 7597 (238)

TIA 3904 (183) 2275 (213) 6179 (193)

Stroke in patients with HZO (n 5 1710) 130 (380) 68 (398) 198 (386)

Abbreviations HZ 5 herpes zoster HZO 5 HZ ophthalmicusData are numbers (percentage) unless otherwise marked

208 Neurology 82 January 21 2014

4

which this analysis was conducted 24 vs 8 years forother studies15 during which time the prevalence ofstroke decreased15

In the UK the incidence of stroke has decreasedby more than 30 in the past 10 years15 This hasbeen attributed in part to government initiativesencouraging GPs to screen opportunistically for and

treat vascular risk factors in subjects older than 45years1516 By contrast in those aged 45 years or youn-ger in whom these policies have not been imple-mented the incidence of stroke has remainedunchanged over the same time period15 The possi-bility that better ascertainment and treatment of vas-cular risk factors in older subjects may underlie thesedifferences is supported by our finding that BMIsmoking status and cholesterol levels were recordedless frequently in the notes of those younger than 40years (tables e-3 and e-4) Better control of vascularrisk factors in older patients presenting with TIAwhich itself increases the risk of stroke would alsoexplain why after HZ the incidence of TIA but notstroke was increased in the THIN patient populationas a whole Together with published data linkingstroke in children with a recent history of chicken-pox17ndash19 these results support a significant role forVZV independently of other vascular risk factorsin the pathogenesis of stroke and cerebrovascular dis-ease in the UK population particularly at youngerages The results are corroborated by populationcohort studies conducted in Taiwan4 and Denmark20

both of which identified HZ as a risk factor forstroke4 or stroke plus TIA20 The Danish study alsoidentified the risk of stroke and TIA to be highest inthose whose HZ occurred when they were youngerthan 40 years20 While the risks identified were higherfor the Danish and Taiwanese studies this may reflectdifferences in the study populations and designs Nei-ther the Danish nor Taiwanese study controlled forsmoking and BMI which may have biased resultswhile the former reported risks for stroke and TIAcombined The Danish study was designed to capturecerebrovascular events associated with acute HZwhereas this and the Taiwanese study excluded sub-jects without a yearrsquos follow-up data The incidence ofstroke was higher in the Taiwanese study (141 at ayear vs 03 in this study) but vascular risk factorswere 3 to 5 times more common in the UK Thiscould either reflect differences between the popula-tions or after current government recommenda-tions more complete ascertainment and treatmentof risk factors in the UK

How then might the findings of long-term in-creases in cerebrovascular and MI after HZ be ex-plained In the case of HZO with which strokesare unequivocally and temporally associated cranialartery pathology arises from direct VZV infectionvia afferent branches of the ophthalmic branch ofthe trigeminal nerve22122 In such cases transmuralspread of virus from the adventitia leads to disruptionof the internal elastic lamina intimal hypertrophyand proinflammatory conditions that increase the riskof stroke21 However these mechanisms cannot easilyexplain the pathogenesis of stroke or TIA after HZ

Figure 1 Kaplan-Meier curves for the risk of stroke TIA and MI over the studyfollow-up period

The time to stroke (A) after the index date does not differ significantly for cases of herpeszoster and matched controls but is significantly shorter for TIA (B) and myocardial infarction(MI) (C) in cases compared with controls

Neurology 82 January 21 2014 209

4

located outside the head and neck or even of MI afterHZ Vascular events occurring within days of HZcould be due to the associated inflammatory responseas has been described for stroke and MI after acuterespiratory or urinary tract infections23 However thiscannot explain the increased risk persisting formonths and years after acute HZ The discovery inrecent years that VZV DNA can be detected in oralfluid and blood both in subjects whose rash is outsidethe head and neck and even in the absence of rashprovides a possible explanation24227 In theoryasymptomatic reactivation of VZV from cranialnerves detectable as virus in saliva could also leadto infection of cranial arteries stroke and TIAincluding in the absence of HZ rash and when therash occurs in noncranial dermatomes26 Thishypothesis is supported by findings from simian var-icella virus infection of macaques a model for VZV28

In this model asymptomatic reactivation of simianvaricella virus from trigeminal ganglia with the poten-tial to spread to cranial arteries has been detected inmacaques with thoracic zoster29 In humans VZVantigen has been demonstrated in arterial adventitialtissue together with intimal hypertrophy within skiplesions present in the cerebral arteries of diabeticswithout a history of HZ30 Notwithstanding the lackof history in these cases diabetics are known to be atincreased risk of HZ31 Furthermore asymptomaticshedding of virus in saliva is significantly more com-mon in those with a history of HZ26 Taken togetherthe possibility remains that certain individuals whoare predisposed to HZ are also more likely to shedvirus asymptomatically and that both represent a riskfor cerebrovascular disease At the same time asymp-tomatic reactivation of VZV from latency in thoracicsympathetic ganglia32 with transaxonal spread viaadrenergic nerves to systemic arteries could explain

the ongoing risk of MI long after an episode of HZAlthough accounting for 15 to 20 of all cases33

the incidence of HZ is comparatively low for thoseyounger than 40 years12 This together with the factthat those whose HZ occurs at ages 18 to 40 years areless likely to have predisposing immunosuppressiveconditions33 suggest a predisposition in this groupto VZV reactivation and a lifetime increased risk ofvascular disease VZV DNA has also been detected inblood for months after the resolution of HZ34 and inasymptomatic children receiving intensive care27 Ifcirculating virus is able to infect arterial tissue partic-ularly when damaged by preexisting risk factors thistoo could contribute to prolonged inflammation withincreased vascular insult In this scenario control ofrisk factors that predispose to arterial damage mightmitigate the risk from HZ which in turn mightexplain our findings that strokes are not more com-mon in UK citizens older than 40 years Takentogether the finding that virus reacts asymptomati-cally from cranial nerves resulting in prolonged oralshedding242534 particularly in subjects with a historyof HZ26 and circulation in the blood2734 provides aset of testable hypotheses to explain the increased riskof TIA MI and in some cases stoke persisting foryears after an episode of HZ particularly in the pres-ence of risk factors for vascular disease The possibilitythat VZV directly exacerbates preexisting arterialdamage would also explain why effective managementof risk factors has reduced the incidence of stroke afterHZ occurrence in the older UK subjects

Overall these data add to the growing body of evi-dence linking VZV a ubiquitous pathogen that es-tablishes persistent infection in more than 95 ofindividuals to vascular disease Immunization withthe licensed zoster vaccine has been shown to signif-icantly reduce the incidence of HZ as well as

Table 3 Hazard ratios (95 CI) for stroke TIA and MI after herpes zoster occurrence

Vascular eventa Cases (n 5 106601) n () Controls (n 5 213202) n ()

Hazard ratio (95 CI)

Unadjusted Adjustedb

Stroke 2727 (249) 5252 (246) 104 (099ndash109) 102 (098ndash107)

MI 2762 (259) 4835 (238) 115 (109ndash120) 110 (105ndash116)c

TIA 2275 (213) 3901 (183) 117 (111ndash123) 115 (109ndash121)c

Stroke in patients with HZO (n 5 2324) 68 (398) 130 (390) 106 (079ndash142) 103 (077ndash139)

Stroke in subjects 18ndash40 y (n 5 19301) 40 (021) 45 (012) 179 (117ndash273) 174 (113ndash266)c

MI in subjects 18ndash40 y (n 5 19301) 51 (026) 67 (017) 153 (106ndash220) 149 (104ndash215)c

TIA in subjects 18ndash40 y (n 5 19301) 25 (013) 20 (005) 251 (139ndash452) 242 (134ndash436)c

Abbreviations CI 5 confidence interval HZO 5 herpes zoster ophthalmicus MI 5 myocardial infarctiona Period of follow-up 1 to 237 yearsbHazard ratios were adjusted for sex age obesity (body mass index 30 kgm2) smoking status history of cholesterol 62 mmolL hypertensiondiabetes ischemic heart disease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heart diseasecp 005

210 Neurology 82 January 21 2014

4

significantly decrease the severity of neuropathic com-plications35 Population studies are now needed toevaluate whether immunization to prevent HZ couldalso reduce the incidence of vascular events includingstroke TIA and MI More research is needed to

understand the pathogenesis of increased HZ in pa-tients with risk factors for vascular disease and todetermine the impact of treatment on risk Impor-tantly the role if any of asymptomatic VZV reacti-vation in the pathogenesis of vascular disease and howthis might be affected by zoster immunization needsfurther clarification In the meantime the vaccinecould now be offered to adults with risk factors forvascular disease irrespective of age to reduce the asso-ciated risk of HZ431 At the same time screening forvascular risk factors in patients presenting with HZespecially younger patients in whom interventionmay have the most impact should now be encour-aged Ultimately high-coverage childhood varicellavaccination to reduce latency with wild-type virus isaltogether desirable

AUTHOR CONTRIBUTIONSJudith Breuer conceived and designed the study and wrote the manu-

script Maud Pacou and Aline Gauthier undertook analysis of the THIN

database and contributed to the study design and writing of the manu-

script Martin M Brown contributed to the study design and writing

of the manuscript

STUDY FUNDINGFunded by an unrestricted investigator grant from Sanofi Pasteur MSD to

Judith Breuer JB receives funding from the NIHR UCLUCLH Compre-

hensive Biomedical Research Centre MMBrsquos Chair in Stroke Medicine at

UCL is supported by the Reta Lila Weston Trust for Medical Research

DISCLOSUREJ Breuer has received funding from SPMSD for the VZV Identification

Programme which undertakes genotyping of VZV from vaccine adverse

events JB also heads the VZV reference laboratory which has geno-

typed VZV for GlaxoSmithKline M Pacou A Gauthier and MM

Brown report no disclosures Go to Neurologyorg for full disclosures

Received June 6 2013 Accepted in final form October 8 2013

REFERENCES1 Breuer J Varicella zoster In Zuckerman AJ Banatvala JE

Schoub BD Griffiths PD Mortimer P editors Principles

and Practice of Clinical Virology 6th ed Chichester John

Wiley amp Sons 2009133ndash160

2 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella

zoster virus vasculopathies diverse clinical manifestations

laboratory features pathogenesis and treatment Lancet

Neurol 20098731ndash740

3 Gilden DH Lipton HL Wolf JS et al Two patients

with unusual forms of varicella-zoster virus vasculopathy

N Engl J Med 20023471500ndash1503

4 Kang JH Ho JD Chen YH Lin HC Increased risk

of stroke after a herpes zoster attack a population-based

follow-up study Stroke 2009403443ndash3448

5 Lin HC Chien CW Ho JD Herpes zoster ophthalmicus

and the risk of stroke a population-based follow-up study

Neurology 201074792ndash797

6 Booth N What are the Read Codes Health Libr Rev

199411177ndash182

7 Cegedim Strategic Data Available at httpcsdmruk

cegedimcomour-dataour-datashtml Accessed July 9 2013

8 Heskel NS Hanifin JM ldquoRecurrent herpes zosterrdquo an

unproved entity J Am Acad Dermatol 198410486ndash490

Figure 2 Adjusted risk (hazard ratio and 95 confidence interval) of strokeTIA and MI by age group at index date

Risk of (A) stroke (B) TIA and (C) myocardial infarction (MI) by decade (D) Time to stroke incases and controls younger than 40 years Hazard ratios adjusted for vascular risk factorsfor stroke TIA and MI are significantly higher for cases of herpes zoster occurring before40 years of age compared with matched controls

Neurology 82 January 21 2014 211

4

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

varicella-zoster virus viraemia in patients with herpes zos-

ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

httpwwwneurologyorgcgicollectioncohort_studiesCohort studies

ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

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Page 4: Neurology 2014 Breuer 206 12

whose HZ occurred at ages 18 to 40 years even whenadjusted for vascular risk factors (figure 2) Most riskfactors for vascular disease were also more common insubjects whose HZ occurred at age 18 to 40 years ascompared with matched controls (table e-2) Analysisof BMI cholesterol level and smoking status showedthese to be recorded significantly more frequently incases of HZ than in controls (table e-3) but less fre-quently in subjects aged 18 to 40 years than in oldersubjects (table e-4)

DISCUSSION This retrospective cohort study is thelargest to examine HZ as a risk factor for strokeTIA and MI The study identifies HZ as an indepen-dent risk factor for TIA and MI occurring up to 24years after the acute episode in UK adults older than18 years and for stroke in those aged 18 to 40 yearsThe data also confirm that irrespective of age condi-tions that predispose to vascular disease includinglifestyle factors such as smoking and obesity which

have not previously been examined are significantlymore common in subjects with HZ (table 2)although some of this could be attributable to betterrecording of risk factors in patients who present withHZ (table e-3)

Our study has a number of potential limitationsAlthough representative of UK general practices theTHIN database depends on accurate coding byGPs7 Dermatomal HZ is easily diagnosed and codinghas been shown to be accurate in other database stud-ies13 To reduce miscoding we excluded recurrentHZ which can be confused with herpes simplex89

The THIN database does not require GPs to specifylocation of the HZ which may explain the 10-foldlower than expected percentage of HZO cases in thisstudy compared with previous UK studies (table 1)12

Low levels of HZO recording have also been observedfor another database the UK General PracticeResearch Database13 The low numbers in this studylimited robust evaluation of HZO as a risk factor forstroke or other vascular disease

Recording by GPs of transient neurologic symp-toms mimicking TIA for example benign positionalvertigo which do not predispose to stroke may haveled to overestimates of the incidence of TIA after HZoccurrence14 However patients with TIA in thisstudy had a 7-fold higher prevalence of stroke com-pared with patients who did not experience TIA(1432 vs 207) This suggests that records ofTIA in the THIN database in the main reflectedtypical disease a finding in line with previousobservations14

Although the overall prevalence of TIA and MIwas in agreement with published data14 the preva-lence of stroke in this population (25) was higherthan for recently reported studies based on other UKpopulation databases15 (table 1) This could be attrib-utable to the comparatively longer time span over

Table 2 Comparison of vascular disease risk factors in cases and controls

Risk factor

Cases Controls

p Value of thex2 testNo No

Obesity 19161 180 35597 167 00001

Smoking 37637 353 71763 337 00001

Cholesterol gt62 mmolL 14962 140 26921 126 00001

Hypertension 26396 238 46928 220 00001

Diabetes 5893 55 10372 49 00001

Ischemic heart disease 6536 61 10274 48 00001

Atrial fibrillation 2775 26 4683 22 00001

Intermittent arterial claudication 1042 10 1754 08 00001

Carotid stenosis 74 01 99 01 00084

Valvular heart disease 1190 11 1977 09 00001

Table 1 Comparison of patients with HZ and matched controls

CharacteristicPatients with HZ(n 5 106601)

Matched controls(n 5 213202) Total (N 5 319803)

Mean age at index date y (SD) 579 (177) 577 (177)

Sex female 63183 (593) 124620 (592)

HZO 1710 (16)

HZ in the head (including HZO) 2324 (21)

Other form of HZnot specified 104277 (978)

Stroke 5252 (246) 2727 (256) 7979 (249)

Myocardial infarction 4835 (227) 2762 (259) 7597 (238)

TIA 3904 (183) 2275 (213) 6179 (193)

Stroke in patients with HZO (n 5 1710) 130 (380) 68 (398) 198 (386)

Abbreviations HZ 5 herpes zoster HZO 5 HZ ophthalmicusData are numbers (percentage) unless otherwise marked

208 Neurology 82 January 21 2014

4

which this analysis was conducted 24 vs 8 years forother studies15 during which time the prevalence ofstroke decreased15

In the UK the incidence of stroke has decreasedby more than 30 in the past 10 years15 This hasbeen attributed in part to government initiativesencouraging GPs to screen opportunistically for and

treat vascular risk factors in subjects older than 45years1516 By contrast in those aged 45 years or youn-ger in whom these policies have not been imple-mented the incidence of stroke has remainedunchanged over the same time period15 The possi-bility that better ascertainment and treatment of vas-cular risk factors in older subjects may underlie thesedifferences is supported by our finding that BMIsmoking status and cholesterol levels were recordedless frequently in the notes of those younger than 40years (tables e-3 and e-4) Better control of vascularrisk factors in older patients presenting with TIAwhich itself increases the risk of stroke would alsoexplain why after HZ the incidence of TIA but notstroke was increased in the THIN patient populationas a whole Together with published data linkingstroke in children with a recent history of chicken-pox17ndash19 these results support a significant role forVZV independently of other vascular risk factorsin the pathogenesis of stroke and cerebrovascular dis-ease in the UK population particularly at youngerages The results are corroborated by populationcohort studies conducted in Taiwan4 and Denmark20

both of which identified HZ as a risk factor forstroke4 or stroke plus TIA20 The Danish study alsoidentified the risk of stroke and TIA to be highest inthose whose HZ occurred when they were youngerthan 40 years20 While the risks identified were higherfor the Danish and Taiwanese studies this may reflectdifferences in the study populations and designs Nei-ther the Danish nor Taiwanese study controlled forsmoking and BMI which may have biased resultswhile the former reported risks for stroke and TIAcombined The Danish study was designed to capturecerebrovascular events associated with acute HZwhereas this and the Taiwanese study excluded sub-jects without a yearrsquos follow-up data The incidence ofstroke was higher in the Taiwanese study (141 at ayear vs 03 in this study) but vascular risk factorswere 3 to 5 times more common in the UK Thiscould either reflect differences between the popula-tions or after current government recommenda-tions more complete ascertainment and treatmentof risk factors in the UK

How then might the findings of long-term in-creases in cerebrovascular and MI after HZ be ex-plained In the case of HZO with which strokesare unequivocally and temporally associated cranialartery pathology arises from direct VZV infectionvia afferent branches of the ophthalmic branch ofthe trigeminal nerve22122 In such cases transmuralspread of virus from the adventitia leads to disruptionof the internal elastic lamina intimal hypertrophyand proinflammatory conditions that increase the riskof stroke21 However these mechanisms cannot easilyexplain the pathogenesis of stroke or TIA after HZ

Figure 1 Kaplan-Meier curves for the risk of stroke TIA and MI over the studyfollow-up period

The time to stroke (A) after the index date does not differ significantly for cases of herpeszoster and matched controls but is significantly shorter for TIA (B) and myocardial infarction(MI) (C) in cases compared with controls

Neurology 82 January 21 2014 209

4

located outside the head and neck or even of MI afterHZ Vascular events occurring within days of HZcould be due to the associated inflammatory responseas has been described for stroke and MI after acuterespiratory or urinary tract infections23 However thiscannot explain the increased risk persisting formonths and years after acute HZ The discovery inrecent years that VZV DNA can be detected in oralfluid and blood both in subjects whose rash is outsidethe head and neck and even in the absence of rashprovides a possible explanation24227 In theoryasymptomatic reactivation of VZV from cranialnerves detectable as virus in saliva could also leadto infection of cranial arteries stroke and TIAincluding in the absence of HZ rash and when therash occurs in noncranial dermatomes26 Thishypothesis is supported by findings from simian var-icella virus infection of macaques a model for VZV28

In this model asymptomatic reactivation of simianvaricella virus from trigeminal ganglia with the poten-tial to spread to cranial arteries has been detected inmacaques with thoracic zoster29 In humans VZVantigen has been demonstrated in arterial adventitialtissue together with intimal hypertrophy within skiplesions present in the cerebral arteries of diabeticswithout a history of HZ30 Notwithstanding the lackof history in these cases diabetics are known to be atincreased risk of HZ31 Furthermore asymptomaticshedding of virus in saliva is significantly more com-mon in those with a history of HZ26 Taken togetherthe possibility remains that certain individuals whoare predisposed to HZ are also more likely to shedvirus asymptomatically and that both represent a riskfor cerebrovascular disease At the same time asymp-tomatic reactivation of VZV from latency in thoracicsympathetic ganglia32 with transaxonal spread viaadrenergic nerves to systemic arteries could explain

the ongoing risk of MI long after an episode of HZAlthough accounting for 15 to 20 of all cases33

the incidence of HZ is comparatively low for thoseyounger than 40 years12 This together with the factthat those whose HZ occurs at ages 18 to 40 years areless likely to have predisposing immunosuppressiveconditions33 suggest a predisposition in this groupto VZV reactivation and a lifetime increased risk ofvascular disease VZV DNA has also been detected inblood for months after the resolution of HZ34 and inasymptomatic children receiving intensive care27 Ifcirculating virus is able to infect arterial tissue partic-ularly when damaged by preexisting risk factors thistoo could contribute to prolonged inflammation withincreased vascular insult In this scenario control ofrisk factors that predispose to arterial damage mightmitigate the risk from HZ which in turn mightexplain our findings that strokes are not more com-mon in UK citizens older than 40 years Takentogether the finding that virus reacts asymptomati-cally from cranial nerves resulting in prolonged oralshedding242534 particularly in subjects with a historyof HZ26 and circulation in the blood2734 provides aset of testable hypotheses to explain the increased riskof TIA MI and in some cases stoke persisting foryears after an episode of HZ particularly in the pres-ence of risk factors for vascular disease The possibilitythat VZV directly exacerbates preexisting arterialdamage would also explain why effective managementof risk factors has reduced the incidence of stroke afterHZ occurrence in the older UK subjects

Overall these data add to the growing body of evi-dence linking VZV a ubiquitous pathogen that es-tablishes persistent infection in more than 95 ofindividuals to vascular disease Immunization withthe licensed zoster vaccine has been shown to signif-icantly reduce the incidence of HZ as well as

Table 3 Hazard ratios (95 CI) for stroke TIA and MI after herpes zoster occurrence

Vascular eventa Cases (n 5 106601) n () Controls (n 5 213202) n ()

Hazard ratio (95 CI)

Unadjusted Adjustedb

Stroke 2727 (249) 5252 (246) 104 (099ndash109) 102 (098ndash107)

MI 2762 (259) 4835 (238) 115 (109ndash120) 110 (105ndash116)c

TIA 2275 (213) 3901 (183) 117 (111ndash123) 115 (109ndash121)c

Stroke in patients with HZO (n 5 2324) 68 (398) 130 (390) 106 (079ndash142) 103 (077ndash139)

Stroke in subjects 18ndash40 y (n 5 19301) 40 (021) 45 (012) 179 (117ndash273) 174 (113ndash266)c

MI in subjects 18ndash40 y (n 5 19301) 51 (026) 67 (017) 153 (106ndash220) 149 (104ndash215)c

TIA in subjects 18ndash40 y (n 5 19301) 25 (013) 20 (005) 251 (139ndash452) 242 (134ndash436)c

Abbreviations CI 5 confidence interval HZO 5 herpes zoster ophthalmicus MI 5 myocardial infarctiona Period of follow-up 1 to 237 yearsbHazard ratios were adjusted for sex age obesity (body mass index 30 kgm2) smoking status history of cholesterol 62 mmolL hypertensiondiabetes ischemic heart disease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heart diseasecp 005

210 Neurology 82 January 21 2014

4

significantly decrease the severity of neuropathic com-plications35 Population studies are now needed toevaluate whether immunization to prevent HZ couldalso reduce the incidence of vascular events includingstroke TIA and MI More research is needed to

understand the pathogenesis of increased HZ in pa-tients with risk factors for vascular disease and todetermine the impact of treatment on risk Impor-tantly the role if any of asymptomatic VZV reacti-vation in the pathogenesis of vascular disease and howthis might be affected by zoster immunization needsfurther clarification In the meantime the vaccinecould now be offered to adults with risk factors forvascular disease irrespective of age to reduce the asso-ciated risk of HZ431 At the same time screening forvascular risk factors in patients presenting with HZespecially younger patients in whom interventionmay have the most impact should now be encour-aged Ultimately high-coverage childhood varicellavaccination to reduce latency with wild-type virus isaltogether desirable

AUTHOR CONTRIBUTIONSJudith Breuer conceived and designed the study and wrote the manu-

script Maud Pacou and Aline Gauthier undertook analysis of the THIN

database and contributed to the study design and writing of the manu-

script Martin M Brown contributed to the study design and writing

of the manuscript

STUDY FUNDINGFunded by an unrestricted investigator grant from Sanofi Pasteur MSD to

Judith Breuer JB receives funding from the NIHR UCLUCLH Compre-

hensive Biomedical Research Centre MMBrsquos Chair in Stroke Medicine at

UCL is supported by the Reta Lila Weston Trust for Medical Research

DISCLOSUREJ Breuer has received funding from SPMSD for the VZV Identification

Programme which undertakes genotyping of VZV from vaccine adverse

events JB also heads the VZV reference laboratory which has geno-

typed VZV for GlaxoSmithKline M Pacou A Gauthier and MM

Brown report no disclosures Go to Neurologyorg for full disclosures

Received June 6 2013 Accepted in final form October 8 2013

REFERENCES1 Breuer J Varicella zoster In Zuckerman AJ Banatvala JE

Schoub BD Griffiths PD Mortimer P editors Principles

and Practice of Clinical Virology 6th ed Chichester John

Wiley amp Sons 2009133ndash160

2 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella

zoster virus vasculopathies diverse clinical manifestations

laboratory features pathogenesis and treatment Lancet

Neurol 20098731ndash740

3 Gilden DH Lipton HL Wolf JS et al Two patients

with unusual forms of varicella-zoster virus vasculopathy

N Engl J Med 20023471500ndash1503

4 Kang JH Ho JD Chen YH Lin HC Increased risk

of stroke after a herpes zoster attack a population-based

follow-up study Stroke 2009403443ndash3448

5 Lin HC Chien CW Ho JD Herpes zoster ophthalmicus

and the risk of stroke a population-based follow-up study

Neurology 201074792ndash797

6 Booth N What are the Read Codes Health Libr Rev

199411177ndash182

7 Cegedim Strategic Data Available at httpcsdmruk

cegedimcomour-dataour-datashtml Accessed July 9 2013

8 Heskel NS Hanifin JM ldquoRecurrent herpes zosterrdquo an

unproved entity J Am Acad Dermatol 198410486ndash490

Figure 2 Adjusted risk (hazard ratio and 95 confidence interval) of strokeTIA and MI by age group at index date

Risk of (A) stroke (B) TIA and (C) myocardial infarction (MI) by decade (D) Time to stroke incases and controls younger than 40 years Hazard ratios adjusted for vascular risk factorsfor stroke TIA and MI are significantly higher for cases of herpes zoster occurring before40 years of age compared with matched controls

Neurology 82 January 21 2014 211

4

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

varicella-zoster virus viraemia in patients with herpes zos-

ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

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ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

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httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Page 5: Neurology 2014 Breuer 206 12

which this analysis was conducted 24 vs 8 years forother studies15 during which time the prevalence ofstroke decreased15

In the UK the incidence of stroke has decreasedby more than 30 in the past 10 years15 This hasbeen attributed in part to government initiativesencouraging GPs to screen opportunistically for and

treat vascular risk factors in subjects older than 45years1516 By contrast in those aged 45 years or youn-ger in whom these policies have not been imple-mented the incidence of stroke has remainedunchanged over the same time period15 The possi-bility that better ascertainment and treatment of vas-cular risk factors in older subjects may underlie thesedifferences is supported by our finding that BMIsmoking status and cholesterol levels were recordedless frequently in the notes of those younger than 40years (tables e-3 and e-4) Better control of vascularrisk factors in older patients presenting with TIAwhich itself increases the risk of stroke would alsoexplain why after HZ the incidence of TIA but notstroke was increased in the THIN patient populationas a whole Together with published data linkingstroke in children with a recent history of chicken-pox17ndash19 these results support a significant role forVZV independently of other vascular risk factorsin the pathogenesis of stroke and cerebrovascular dis-ease in the UK population particularly at youngerages The results are corroborated by populationcohort studies conducted in Taiwan4 and Denmark20

both of which identified HZ as a risk factor forstroke4 or stroke plus TIA20 The Danish study alsoidentified the risk of stroke and TIA to be highest inthose whose HZ occurred when they were youngerthan 40 years20 While the risks identified were higherfor the Danish and Taiwanese studies this may reflectdifferences in the study populations and designs Nei-ther the Danish nor Taiwanese study controlled forsmoking and BMI which may have biased resultswhile the former reported risks for stroke and TIAcombined The Danish study was designed to capturecerebrovascular events associated with acute HZwhereas this and the Taiwanese study excluded sub-jects without a yearrsquos follow-up data The incidence ofstroke was higher in the Taiwanese study (141 at ayear vs 03 in this study) but vascular risk factorswere 3 to 5 times more common in the UK Thiscould either reflect differences between the popula-tions or after current government recommenda-tions more complete ascertainment and treatmentof risk factors in the UK

How then might the findings of long-term in-creases in cerebrovascular and MI after HZ be ex-plained In the case of HZO with which strokesare unequivocally and temporally associated cranialartery pathology arises from direct VZV infectionvia afferent branches of the ophthalmic branch ofthe trigeminal nerve22122 In such cases transmuralspread of virus from the adventitia leads to disruptionof the internal elastic lamina intimal hypertrophyand proinflammatory conditions that increase the riskof stroke21 However these mechanisms cannot easilyexplain the pathogenesis of stroke or TIA after HZ

Figure 1 Kaplan-Meier curves for the risk of stroke TIA and MI over the studyfollow-up period

The time to stroke (A) after the index date does not differ significantly for cases of herpeszoster and matched controls but is significantly shorter for TIA (B) and myocardial infarction(MI) (C) in cases compared with controls

Neurology 82 January 21 2014 209

4

located outside the head and neck or even of MI afterHZ Vascular events occurring within days of HZcould be due to the associated inflammatory responseas has been described for stroke and MI after acuterespiratory or urinary tract infections23 However thiscannot explain the increased risk persisting formonths and years after acute HZ The discovery inrecent years that VZV DNA can be detected in oralfluid and blood both in subjects whose rash is outsidethe head and neck and even in the absence of rashprovides a possible explanation24227 In theoryasymptomatic reactivation of VZV from cranialnerves detectable as virus in saliva could also leadto infection of cranial arteries stroke and TIAincluding in the absence of HZ rash and when therash occurs in noncranial dermatomes26 Thishypothesis is supported by findings from simian var-icella virus infection of macaques a model for VZV28

In this model asymptomatic reactivation of simianvaricella virus from trigeminal ganglia with the poten-tial to spread to cranial arteries has been detected inmacaques with thoracic zoster29 In humans VZVantigen has been demonstrated in arterial adventitialtissue together with intimal hypertrophy within skiplesions present in the cerebral arteries of diabeticswithout a history of HZ30 Notwithstanding the lackof history in these cases diabetics are known to be atincreased risk of HZ31 Furthermore asymptomaticshedding of virus in saliva is significantly more com-mon in those with a history of HZ26 Taken togetherthe possibility remains that certain individuals whoare predisposed to HZ are also more likely to shedvirus asymptomatically and that both represent a riskfor cerebrovascular disease At the same time asymp-tomatic reactivation of VZV from latency in thoracicsympathetic ganglia32 with transaxonal spread viaadrenergic nerves to systemic arteries could explain

the ongoing risk of MI long after an episode of HZAlthough accounting for 15 to 20 of all cases33

the incidence of HZ is comparatively low for thoseyounger than 40 years12 This together with the factthat those whose HZ occurs at ages 18 to 40 years areless likely to have predisposing immunosuppressiveconditions33 suggest a predisposition in this groupto VZV reactivation and a lifetime increased risk ofvascular disease VZV DNA has also been detected inblood for months after the resolution of HZ34 and inasymptomatic children receiving intensive care27 Ifcirculating virus is able to infect arterial tissue partic-ularly when damaged by preexisting risk factors thistoo could contribute to prolonged inflammation withincreased vascular insult In this scenario control ofrisk factors that predispose to arterial damage mightmitigate the risk from HZ which in turn mightexplain our findings that strokes are not more com-mon in UK citizens older than 40 years Takentogether the finding that virus reacts asymptomati-cally from cranial nerves resulting in prolonged oralshedding242534 particularly in subjects with a historyof HZ26 and circulation in the blood2734 provides aset of testable hypotheses to explain the increased riskof TIA MI and in some cases stoke persisting foryears after an episode of HZ particularly in the pres-ence of risk factors for vascular disease The possibilitythat VZV directly exacerbates preexisting arterialdamage would also explain why effective managementof risk factors has reduced the incidence of stroke afterHZ occurrence in the older UK subjects

Overall these data add to the growing body of evi-dence linking VZV a ubiquitous pathogen that es-tablishes persistent infection in more than 95 ofindividuals to vascular disease Immunization withthe licensed zoster vaccine has been shown to signif-icantly reduce the incidence of HZ as well as

Table 3 Hazard ratios (95 CI) for stroke TIA and MI after herpes zoster occurrence

Vascular eventa Cases (n 5 106601) n () Controls (n 5 213202) n ()

Hazard ratio (95 CI)

Unadjusted Adjustedb

Stroke 2727 (249) 5252 (246) 104 (099ndash109) 102 (098ndash107)

MI 2762 (259) 4835 (238) 115 (109ndash120) 110 (105ndash116)c

TIA 2275 (213) 3901 (183) 117 (111ndash123) 115 (109ndash121)c

Stroke in patients with HZO (n 5 2324) 68 (398) 130 (390) 106 (079ndash142) 103 (077ndash139)

Stroke in subjects 18ndash40 y (n 5 19301) 40 (021) 45 (012) 179 (117ndash273) 174 (113ndash266)c

MI in subjects 18ndash40 y (n 5 19301) 51 (026) 67 (017) 153 (106ndash220) 149 (104ndash215)c

TIA in subjects 18ndash40 y (n 5 19301) 25 (013) 20 (005) 251 (139ndash452) 242 (134ndash436)c

Abbreviations CI 5 confidence interval HZO 5 herpes zoster ophthalmicus MI 5 myocardial infarctiona Period of follow-up 1 to 237 yearsbHazard ratios were adjusted for sex age obesity (body mass index 30 kgm2) smoking status history of cholesterol 62 mmolL hypertensiondiabetes ischemic heart disease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heart diseasecp 005

210 Neurology 82 January 21 2014

4

significantly decrease the severity of neuropathic com-plications35 Population studies are now needed toevaluate whether immunization to prevent HZ couldalso reduce the incidence of vascular events includingstroke TIA and MI More research is needed to

understand the pathogenesis of increased HZ in pa-tients with risk factors for vascular disease and todetermine the impact of treatment on risk Impor-tantly the role if any of asymptomatic VZV reacti-vation in the pathogenesis of vascular disease and howthis might be affected by zoster immunization needsfurther clarification In the meantime the vaccinecould now be offered to adults with risk factors forvascular disease irrespective of age to reduce the asso-ciated risk of HZ431 At the same time screening forvascular risk factors in patients presenting with HZespecially younger patients in whom interventionmay have the most impact should now be encour-aged Ultimately high-coverage childhood varicellavaccination to reduce latency with wild-type virus isaltogether desirable

AUTHOR CONTRIBUTIONSJudith Breuer conceived and designed the study and wrote the manu-

script Maud Pacou and Aline Gauthier undertook analysis of the THIN

database and contributed to the study design and writing of the manu-

script Martin M Brown contributed to the study design and writing

of the manuscript

STUDY FUNDINGFunded by an unrestricted investigator grant from Sanofi Pasteur MSD to

Judith Breuer JB receives funding from the NIHR UCLUCLH Compre-

hensive Biomedical Research Centre MMBrsquos Chair in Stroke Medicine at

UCL is supported by the Reta Lila Weston Trust for Medical Research

DISCLOSUREJ Breuer has received funding from SPMSD for the VZV Identification

Programme which undertakes genotyping of VZV from vaccine adverse

events JB also heads the VZV reference laboratory which has geno-

typed VZV for GlaxoSmithKline M Pacou A Gauthier and MM

Brown report no disclosures Go to Neurologyorg for full disclosures

Received June 6 2013 Accepted in final form October 8 2013

REFERENCES1 Breuer J Varicella zoster In Zuckerman AJ Banatvala JE

Schoub BD Griffiths PD Mortimer P editors Principles

and Practice of Clinical Virology 6th ed Chichester John

Wiley amp Sons 2009133ndash160

2 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella

zoster virus vasculopathies diverse clinical manifestations

laboratory features pathogenesis and treatment Lancet

Neurol 20098731ndash740

3 Gilden DH Lipton HL Wolf JS et al Two patients

with unusual forms of varicella-zoster virus vasculopathy

N Engl J Med 20023471500ndash1503

4 Kang JH Ho JD Chen YH Lin HC Increased risk

of stroke after a herpes zoster attack a population-based

follow-up study Stroke 2009403443ndash3448

5 Lin HC Chien CW Ho JD Herpes zoster ophthalmicus

and the risk of stroke a population-based follow-up study

Neurology 201074792ndash797

6 Booth N What are the Read Codes Health Libr Rev

199411177ndash182

7 Cegedim Strategic Data Available at httpcsdmruk

cegedimcomour-dataour-datashtml Accessed July 9 2013

8 Heskel NS Hanifin JM ldquoRecurrent herpes zosterrdquo an

unproved entity J Am Acad Dermatol 198410486ndash490

Figure 2 Adjusted risk (hazard ratio and 95 confidence interval) of strokeTIA and MI by age group at index date

Risk of (A) stroke (B) TIA and (C) myocardial infarction (MI) by decade (D) Time to stroke incases and controls younger than 40 years Hazard ratios adjusted for vascular risk factorsfor stroke TIA and MI are significantly higher for cases of herpes zoster occurring before40 years of age compared with matched controls

Neurology 82 January 21 2014 211

4

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

varicella-zoster virus viraemia in patients with herpes zos-

ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

httpwwwneurologyorgcgicollectioncohort_studiesCohort studies

ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

Reprints

httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Page 6: Neurology 2014 Breuer 206 12

located outside the head and neck or even of MI afterHZ Vascular events occurring within days of HZcould be due to the associated inflammatory responseas has been described for stroke and MI after acuterespiratory or urinary tract infections23 However thiscannot explain the increased risk persisting formonths and years after acute HZ The discovery inrecent years that VZV DNA can be detected in oralfluid and blood both in subjects whose rash is outsidethe head and neck and even in the absence of rashprovides a possible explanation24227 In theoryasymptomatic reactivation of VZV from cranialnerves detectable as virus in saliva could also leadto infection of cranial arteries stroke and TIAincluding in the absence of HZ rash and when therash occurs in noncranial dermatomes26 Thishypothesis is supported by findings from simian var-icella virus infection of macaques a model for VZV28

In this model asymptomatic reactivation of simianvaricella virus from trigeminal ganglia with the poten-tial to spread to cranial arteries has been detected inmacaques with thoracic zoster29 In humans VZVantigen has been demonstrated in arterial adventitialtissue together with intimal hypertrophy within skiplesions present in the cerebral arteries of diabeticswithout a history of HZ30 Notwithstanding the lackof history in these cases diabetics are known to be atincreased risk of HZ31 Furthermore asymptomaticshedding of virus in saliva is significantly more com-mon in those with a history of HZ26 Taken togetherthe possibility remains that certain individuals whoare predisposed to HZ are also more likely to shedvirus asymptomatically and that both represent a riskfor cerebrovascular disease At the same time asymp-tomatic reactivation of VZV from latency in thoracicsympathetic ganglia32 with transaxonal spread viaadrenergic nerves to systemic arteries could explain

the ongoing risk of MI long after an episode of HZAlthough accounting for 15 to 20 of all cases33

the incidence of HZ is comparatively low for thoseyounger than 40 years12 This together with the factthat those whose HZ occurs at ages 18 to 40 years areless likely to have predisposing immunosuppressiveconditions33 suggest a predisposition in this groupto VZV reactivation and a lifetime increased risk ofvascular disease VZV DNA has also been detected inblood for months after the resolution of HZ34 and inasymptomatic children receiving intensive care27 Ifcirculating virus is able to infect arterial tissue partic-ularly when damaged by preexisting risk factors thistoo could contribute to prolonged inflammation withincreased vascular insult In this scenario control ofrisk factors that predispose to arterial damage mightmitigate the risk from HZ which in turn mightexplain our findings that strokes are not more com-mon in UK citizens older than 40 years Takentogether the finding that virus reacts asymptomati-cally from cranial nerves resulting in prolonged oralshedding242534 particularly in subjects with a historyof HZ26 and circulation in the blood2734 provides aset of testable hypotheses to explain the increased riskof TIA MI and in some cases stoke persisting foryears after an episode of HZ particularly in the pres-ence of risk factors for vascular disease The possibilitythat VZV directly exacerbates preexisting arterialdamage would also explain why effective managementof risk factors has reduced the incidence of stroke afterHZ occurrence in the older UK subjects

Overall these data add to the growing body of evi-dence linking VZV a ubiquitous pathogen that es-tablishes persistent infection in more than 95 ofindividuals to vascular disease Immunization withthe licensed zoster vaccine has been shown to signif-icantly reduce the incidence of HZ as well as

Table 3 Hazard ratios (95 CI) for stroke TIA and MI after herpes zoster occurrence

Vascular eventa Cases (n 5 106601) n () Controls (n 5 213202) n ()

Hazard ratio (95 CI)

Unadjusted Adjustedb

Stroke 2727 (249) 5252 (246) 104 (099ndash109) 102 (098ndash107)

MI 2762 (259) 4835 (238) 115 (109ndash120) 110 (105ndash116)c

TIA 2275 (213) 3901 (183) 117 (111ndash123) 115 (109ndash121)c

Stroke in patients with HZO (n 5 2324) 68 (398) 130 (390) 106 (079ndash142) 103 (077ndash139)

Stroke in subjects 18ndash40 y (n 5 19301) 40 (021) 45 (012) 179 (117ndash273) 174 (113ndash266)c

MI in subjects 18ndash40 y (n 5 19301) 51 (026) 67 (017) 153 (106ndash220) 149 (104ndash215)c

TIA in subjects 18ndash40 y (n 5 19301) 25 (013) 20 (005) 251 (139ndash452) 242 (134ndash436)c

Abbreviations CI 5 confidence interval HZO 5 herpes zoster ophthalmicus MI 5 myocardial infarctiona Period of follow-up 1 to 237 yearsbHazard ratios were adjusted for sex age obesity (body mass index 30 kgm2) smoking status history of cholesterol 62 mmolL hypertensiondiabetes ischemic heart disease atrial fibrillation intermittent arterial claudication carotid stenosis and valvular heart diseasecp 005

210 Neurology 82 January 21 2014

4

significantly decrease the severity of neuropathic com-plications35 Population studies are now needed toevaluate whether immunization to prevent HZ couldalso reduce the incidence of vascular events includingstroke TIA and MI More research is needed to

understand the pathogenesis of increased HZ in pa-tients with risk factors for vascular disease and todetermine the impact of treatment on risk Impor-tantly the role if any of asymptomatic VZV reacti-vation in the pathogenesis of vascular disease and howthis might be affected by zoster immunization needsfurther clarification In the meantime the vaccinecould now be offered to adults with risk factors forvascular disease irrespective of age to reduce the asso-ciated risk of HZ431 At the same time screening forvascular risk factors in patients presenting with HZespecially younger patients in whom interventionmay have the most impact should now be encour-aged Ultimately high-coverage childhood varicellavaccination to reduce latency with wild-type virus isaltogether desirable

AUTHOR CONTRIBUTIONSJudith Breuer conceived and designed the study and wrote the manu-

script Maud Pacou and Aline Gauthier undertook analysis of the THIN

database and contributed to the study design and writing of the manu-

script Martin M Brown contributed to the study design and writing

of the manuscript

STUDY FUNDINGFunded by an unrestricted investigator grant from Sanofi Pasteur MSD to

Judith Breuer JB receives funding from the NIHR UCLUCLH Compre-

hensive Biomedical Research Centre MMBrsquos Chair in Stroke Medicine at

UCL is supported by the Reta Lila Weston Trust for Medical Research

DISCLOSUREJ Breuer has received funding from SPMSD for the VZV Identification

Programme which undertakes genotyping of VZV from vaccine adverse

events JB also heads the VZV reference laboratory which has geno-

typed VZV for GlaxoSmithKline M Pacou A Gauthier and MM

Brown report no disclosures Go to Neurologyorg for full disclosures

Received June 6 2013 Accepted in final form October 8 2013

REFERENCES1 Breuer J Varicella zoster In Zuckerman AJ Banatvala JE

Schoub BD Griffiths PD Mortimer P editors Principles

and Practice of Clinical Virology 6th ed Chichester John

Wiley amp Sons 2009133ndash160

2 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella

zoster virus vasculopathies diverse clinical manifestations

laboratory features pathogenesis and treatment Lancet

Neurol 20098731ndash740

3 Gilden DH Lipton HL Wolf JS et al Two patients

with unusual forms of varicella-zoster virus vasculopathy

N Engl J Med 20023471500ndash1503

4 Kang JH Ho JD Chen YH Lin HC Increased risk

of stroke after a herpes zoster attack a population-based

follow-up study Stroke 2009403443ndash3448

5 Lin HC Chien CW Ho JD Herpes zoster ophthalmicus

and the risk of stroke a population-based follow-up study

Neurology 201074792ndash797

6 Booth N What are the Read Codes Health Libr Rev

199411177ndash182

7 Cegedim Strategic Data Available at httpcsdmruk

cegedimcomour-dataour-datashtml Accessed July 9 2013

8 Heskel NS Hanifin JM ldquoRecurrent herpes zosterrdquo an

unproved entity J Am Acad Dermatol 198410486ndash490

Figure 2 Adjusted risk (hazard ratio and 95 confidence interval) of strokeTIA and MI by age group at index date

Risk of (A) stroke (B) TIA and (C) myocardial infarction (MI) by decade (D) Time to stroke incases and controls younger than 40 years Hazard ratios adjusted for vascular risk factorsfor stroke TIA and MI are significantly higher for cases of herpes zoster occurring before40 years of age compared with matched controls

Neurology 82 January 21 2014 211

4

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

varicella-zoster virus viraemia in patients with herpes zos-

ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

httpwwwneurologyorgcgicollectioncohort_studiesCohort studies

ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

Reprints

httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Page 7: Neurology 2014 Breuer 206 12

significantly decrease the severity of neuropathic com-plications35 Population studies are now needed toevaluate whether immunization to prevent HZ couldalso reduce the incidence of vascular events includingstroke TIA and MI More research is needed to

understand the pathogenesis of increased HZ in pa-tients with risk factors for vascular disease and todetermine the impact of treatment on risk Impor-tantly the role if any of asymptomatic VZV reacti-vation in the pathogenesis of vascular disease and howthis might be affected by zoster immunization needsfurther clarification In the meantime the vaccinecould now be offered to adults with risk factors forvascular disease irrespective of age to reduce the asso-ciated risk of HZ431 At the same time screening forvascular risk factors in patients presenting with HZespecially younger patients in whom interventionmay have the most impact should now be encour-aged Ultimately high-coverage childhood varicellavaccination to reduce latency with wild-type virus isaltogether desirable

AUTHOR CONTRIBUTIONSJudith Breuer conceived and designed the study and wrote the manu-

script Maud Pacou and Aline Gauthier undertook analysis of the THIN

database and contributed to the study design and writing of the manu-

script Martin M Brown contributed to the study design and writing

of the manuscript

STUDY FUNDINGFunded by an unrestricted investigator grant from Sanofi Pasteur MSD to

Judith Breuer JB receives funding from the NIHR UCLUCLH Compre-

hensive Biomedical Research Centre MMBrsquos Chair in Stroke Medicine at

UCL is supported by the Reta Lila Weston Trust for Medical Research

DISCLOSUREJ Breuer has received funding from SPMSD for the VZV Identification

Programme which undertakes genotyping of VZV from vaccine adverse

events JB also heads the VZV reference laboratory which has geno-

typed VZV for GlaxoSmithKline M Pacou A Gauthier and MM

Brown report no disclosures Go to Neurologyorg for full disclosures

Received June 6 2013 Accepted in final form October 8 2013

REFERENCES1 Breuer J Varicella zoster In Zuckerman AJ Banatvala JE

Schoub BD Griffiths PD Mortimer P editors Principles

and Practice of Clinical Virology 6th ed Chichester John

Wiley amp Sons 2009133ndash160

2 Gilden D Cohrs RJ Mahalingam R Nagel MA Varicella

zoster virus vasculopathies diverse clinical manifestations

laboratory features pathogenesis and treatment Lancet

Neurol 20098731ndash740

3 Gilden DH Lipton HL Wolf JS et al Two patients

with unusual forms of varicella-zoster virus vasculopathy

N Engl J Med 20023471500ndash1503

4 Kang JH Ho JD Chen YH Lin HC Increased risk

of stroke after a herpes zoster attack a population-based

follow-up study Stroke 2009403443ndash3448

5 Lin HC Chien CW Ho JD Herpes zoster ophthalmicus

and the risk of stroke a population-based follow-up study

Neurology 201074792ndash797

6 Booth N What are the Read Codes Health Libr Rev

199411177ndash182

7 Cegedim Strategic Data Available at httpcsdmruk

cegedimcomour-dataour-datashtml Accessed July 9 2013

8 Heskel NS Hanifin JM ldquoRecurrent herpes zosterrdquo an

unproved entity J Am Acad Dermatol 198410486ndash490

Figure 2 Adjusted risk (hazard ratio and 95 confidence interval) of strokeTIA and MI by age group at index date

Risk of (A) stroke (B) TIA and (C) myocardial infarction (MI) by decade (D) Time to stroke incases and controls younger than 40 years Hazard ratios adjusted for vascular risk factorsfor stroke TIA and MI are significantly higher for cases of herpes zoster occurring before40 years of age compared with matched controls

Neurology 82 January 21 2014 211

4

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

varicella-zoster virus viraemia in patients with herpes zos-

ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

httpwwwneurologyorgcgicollectioncohort_studiesCohort studies

ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

Reprints

httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Page 8: Neurology 2014 Breuer 206 12

9 Koh MJ Seah PP Teo RY Zosteriform herpes simplex

Singapore Med J 200849e59ndashe60

10 Fisher M Stroke and TIA epidemiology risk factors and

the need for early intervention Am J Manag Care 2008

14S204ndashS211

11 Rodgers H Greenaway J Davies T Wood R Steen N

Thomson R Risk factors for first-ever stroke in older peo-

ple in the North East of England a population-based

study Stroke 2004357ndash11

12 Hope-Simpson RE The nature of herpes zoster a long-

term study and a new hypothesis Proc R Soc Med 1965

589ndash20

13 Gauthier A Breuer J Carrington D Martin M Remy V

Epidemiology and cost of herpes zoster and post-herpetic

neuralgia in the United Kingdom Epidemiol Infect 2009

13738ndash47

14 Bots ML van der Wilk EC Koudstaal PJ Hofman A

Grobbee DE Transient neurological attacks in the general

population prevalence risk factors and clinical relevance

Stroke 199728768ndash773

15 Lee S Shafe AC Cowie MR UK stroke incidence mor-

tality and cardiovascular risk management 1999ndash2008

time-trend analysis from the General Practice Research

Database BMJ Open 20111e000269

16 Department of Health Putting prevention first vascular

checksmdashrisk assessment and management [online] Avail-

able at wwwhealthchecknhsukdocumentphpo5227

Accessed in 2008 no longer available online

17 Miravet E Danchaivijitr N Basu H Saunders DE

Ganesan V Clinical and radiological features of childhood

cerebral infarction following varicella zoster virus infection

Dev Med Child Neurol 200749417ndash422

18 Sebire G Meyer L Chabrier S Varicella as a risk factor for

cerebral infarction in childhood a case-control study Ann

Neurol 199945679ndash680

19 Askalan R Laughlin S Mayank S et al Chickenpox and

stroke in childhood a study of frequency and causation

Stroke 2001321257ndash1262

20 Sreenivasan N Basit S Wohlfahrt J et al The short- and

long-term risk of stroke after herpes zoster a nationwide

population-based cohort study PLoS One 20138e69156

21 Nagel MA Traktinskiy I Azarkh Y et al Varicella zoster

virus vasculopathy analysis of virus-infected arteries Neu-

rology 201177364ndash370

22 Kleinschmidt-DeMasters BK Gilden DH The expanding

spectrum of herpesvirus infections of the nervous system

Brain Pathol 200111440ndash451

23 Smeeth L Thomas SL Hall AJ Hubbard R Farrington P

Vallance P Risk of myocardial infarction and stroke after

acute infection or vaccination N Engl J Med 2004351

2611ndash2618

24 Mehta SK Cohrs RJ Forghani B Zerbe G Gilden DH

Pierson DL Stress-induced subclinical reactivation of

varicella zoster virus in astronauts J Med Virol 2004

72174ndash179

25 Cohrs RJ Mehta SK Schmid DS Gilden DH

Pierson DL Asymptomatic reactivation and shed of infec-

tious varicella zoster virus in astronauts J Med Virol 2008

801116ndash1122

26 Gilden D Nagel MA Cohrs RJ Persistence of varicella

zoster virus DNA in saliva after herpes zoster J Infect Dis

20122051178

27 Papaevangelou V Quinlivan M Lockwood J et al Sub-

clinical VZV reactivation in immunocompetent children

hospitalized in the ICU associated with prolonged fever

duration Clin Microbiol Infect 201319E245ndashE251

28 Mahalingam R Messaoudi I Gilden D Simian varicella

virus pathogenesis Curr Top Microbiol Immunol 2010

342309ndash321

29 Mahalingam R Traina-Dorge V Wellish M et al Latent

simian varicella virus reactivates in monkeys treated with

tacrolimus with or without exposure to irradiation

J Neurovirol 201016342ndash354

30 Nagel MA Traktinskiy I Choe A Rempel A Gilden D

Varicella-zoster virus expression in the cerebral arteries of

diabetic subjects Arch Neurol 201269142ndash144

31 Heymann AD Chodick G Karpati T et al Diabetes as a

risk factor for herpes zoster infection results of a

population-based study in Israel Infection 200836

226ndash230

32 Mahalingam R Wellish M Wolf W et al Latent

varicella-zoster viral DNA in human trigeminal and tho-

racic ganglia N Engl J Med 1990323627ndash631

33 Yawn BP Saddier P Wollan PC St Sauver JL

Kurland MJ Sy LS A population-based study of the

incidence and complication rates of herpes zoster before

zoster vaccine introduction Mayo Clin Proc200782

1341ndash1349

34 Quinlivan ML Ayres KL Kelly PJ et al Persistence of

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ter J Clin Virol 201150130ndash135

35 Oxman MN Levin MJ Johnson GR et al A vaccine to

prevent herpes zoster and postherpetic neuralgia in older

adults N Engl J Med 20053522271ndash2284

212 Neurology 82 January 21 2014

4

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

httpwwwneurologyorgcgicollectioncohort_studiesCohort studies

ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

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httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

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Page 9: Neurology 2014 Breuer 206 12

DOI 101212WNL0000000000000038201482206-212 Published Online before print January 2 2014Neurology

Judith Breuer Maud Pacou Aline Gauthier et al the UK

Herpes zoster as a risk factor for stroke and TIA A retrospective cohort study in

This information is current as of January 2 2014

ServicesUpdated Information amp

httpwwwneurologyorgcontent823206fullhtmlincluding high resolution figures can be found at

Supplementary Material

00000000038DC3htmlhttpwwwneurologyorgcontentsuppl20140312WNL00000

00000000038DC2htmlhttpwwwneurologyorgcontentsuppl20140205WNL00000

00000000038DC1htmlhttpwwwneurologyorgcontentsuppl20140102WNL00000Supplementary material can be found at

References

httpwwwneurologyorgcontent823206fullhtmlref-list-1at This article cites 32 articles 8 of which you can access for free

Subspecialty Collections

httpwwwneurologyorgcgicollectionviral_infectionsViral infections s

httpwwwneurologyorgcgicollectionstroke_in_young_adultStroke in young adults

iologyhttpwwwneurologyorgcgicollectionrisk_factors_in_epidemRisk factors in epidemiology

httpwwwneurologyorgcgicollectioncohort_studiesCohort studies

ease_strokehttpwwwneurologyorgcgicollectionall_cerebrovascular_disAll Cerebrovascular diseaseStrokefollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgmiscaboutxhtmlpermissionsor in its entirety can be found online atInformation about reproducing this article in parts (figurestables)

Reprints

httpwwwneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online