Varicella zoster virus vasculopathy
Analysis of virus-infected arteries
M.A. Nagel, MD
I. Traktinskiy, BS
Y. Azarkh, PhD
T. Hedley-Whyte, MD
A. Russman, DO
E.M. VanEgmond, MD
K. Stenmark, MD
M. Frid, PhD
R. Mahalingam, PhD
M. Wellish, BS
A. Choe, BA
R.J. Cohrs, PhD
D. Gilden, MD
Objective: Varicella zoster virus (VZV) is an under-recognized yet treatable cause of stroke. No
animal model exists for stroke caused by VZV infection of cerebral arteries. Thus, we analyzed
cerebral and temporal arteries from 3 patients with VZV vasculopathy to identify features that
will help in diagnosis and lead to a better understanding of VZV-induced vascular remodeling.
Methods: Normal and VZV-infected cerebral and temporal arteries were examined histologically
and by immunohistochemistry using antibodies directed against VZV, endothelium, and smooth
muscle actin and myosin.
Results: All VZV-infected arteries contained 1) a disrupted internal elastic lamina; 2) a hyperplas-
tic intima composed of cells expressing ?-smooth muscle actin (?-SMA) and smooth muscle myo-
sin heavy chain (SM-myosin) but not endothelial cells expressing CD31; and 3) decreased medial
smooth muscle cells. The location of VZV antigen, degree of neointimal thickening, and disruption
of the media were related to the duration of disease.
Conclusions: The presence of VZV primarily in the adventitia early in infection and in the media
and intima later supports the notion that after reactivation from ganglia, VZV spreads transax-
onally to the arterial adventitia followed by transmural spread of virus. Disruption of the internal
elastic lamina, progressive intimal thickening with cells expressing ?-SMA and SM-MHC, and
decreased smooth muscle cells in the media are characteristic features of VZV vasculopathy.
Stroke in VZV vasculopathy may result from changes in arterial caliber and contractility produced
in part by abnormal accumulation of smooth muscle cells and myofibroblasts in thickened neoin-
tima and disruption of the media. Neurology®2011;77:364–370
?-SMA ? ?-smooth muscle actin; PBS ? phosphate-buffered saline; SM ? smooth muscle; VZV ? varicella zoster virus.
Primary varicella zoster virus (VZV) infection usually causes varicella (chickenpox), after which
virus becomes latent in ganglia along the entire neuraxis.1–3A natural decline in cell-mediated
immunity to VZV with age or immunosuppression4–8results in VZV reactivation, manifest as
herpes zoster (shingles). Zoster is common. Approximately 50% of people will have had an
episode by age 85.9
An uncommon but serious complication of virus reactivation is ischemic and hemorrhagic
stroke produced by VZV vasculopathy that affects both immunocompetent and immunocom-
promised individuals and can present as headache and mental status changes with or without
focal neurologic deficits. Both large and small vessels are involved, and MRI shows multifocal
ischemic lesions, commonly at gray–white matter junctions. Importantly, the diagnosis of
VZV vasculopathy is often missed because 1) symptoms and signs may occur months after
zoster10; 2) up to one-third of patients do not have a preceding zoster rash; 3) up to one-third of
patients do not have CSF pleocytosis; and 4) PCR analysis of CSF for VZV DNA is only 30%
From the Departments of Neurology (M.A.N., I.T., Y.A., R.M., M.W., A.C., R.C.-C., R.J.C., D.G.), Pathology (B.K.-D.), Pediatrics (K.S., M.F.),
and Microbiology (D.G.), University of Colorado School of Medicine, Aurora; Department of Pathology (Neuropathology) (T.H.-W.), Massachusetts
General Hospital, Harvard Medical School, Boston; and Departments of Neurology (A.R.) and Pathology and Laboratory Medicine (E.M.V.), Henry
Ford Hospital, Detroit, MI.
Study funding: Supported in part by the NIH (AG006127, D.G.; AG032958, R.M., R.J.C., D.G.; and NS067070, M.A.).
Disclosure: Author disclosures are provided at the end of the article.
Address correspondence and
reprint requests to Dr. Don
Gilden, Department of
Neurology, University of
Colorado School of Medicine,
12700 E. 19th Avenue, Box
B182, Aurora, CO 80045
Copyright © 2011 by AAN Enterprises, Inc.
sensitive; in fact, the best laboratory criterion
for diagnosis is detection of anti-VZV anti-
bodies in the CSF.11
Since VZV is an exclusively human virus,
no animal model to study VZV vasculopathy
exists. Morphologic analyses have been lim-
ited to sporadic case reports which noted a
wide range of vascular pathology, ranging
from neointimal proliferation to necrosis with
or without inflammation.12Herein, VZV-
infected cerebral and temporal arteries from
patients with VZV vasculopathy at autopsy
and biopsy were analyzed histologically and
METHODS Clinical features. A normal cerebral artery and
the temporal and middle cerebral arteries containing VZV anti-
gen from 3 subjects with VZV vasculopathy were studied (table).
Subject 1 was an 80-year-old man who developed left
ophthalmic-distribution zoster followed by left ophthalmic ar-
tery occlusion 1 month later; even though the patient had no
symptoms or signs of disease in the left temporal artery, giant cell
arteritis was initially considered to have caused his left-sided loss
of vision, and a temporal artery biopsy was obtained which re-
vealed VZV vasculopathy.13Magnetic resonance angiography re-
vealed left ophthalmic artery occlusion. The CSF was negative
for VZV DNA by PCR, but positive for anti-VZV immuno-
globulin G and immunoglobulin M. The patient improved after
treatment with IV acyclovir for 14 days followed by oral valacy-
clovir. Subject 2 was a 73-year-old man with no history of rash,
who developed an ill-defined protracted multifocal vasculopathy
from which he died 10 months later.14,15He presented initially
with fatigue, anorexia, somnolence, confusion, and headache fol-
lowed 2 weeks later by anterior uveitis of the right eye. MRI
revealed a right parieto-occipital infarct and a small infarct in the
right midbrain. During his hospital course, he developed a tran-
sient internuclear ophthalmoplegia, then a left hemiplegia and
lethargy that improved with IV acyclovir and prednisone. An
angiogram revealed narrowing of the right anterior cerebral ar-
tery and the supraclinoid portion of the right carotid artery ex-
tending into the proximal segment of the right middle cerebral
artery. During the remainder of his hospitalization, he developed
anorexia, headaches, and fluctuating confusion complicated by
pneumonia. He died 316 days from onset of symptoms. Anti-
body to varicella in the CSF was present at a titer of 1:8. The
CSF was not tested for the presence of VZV DNA. Postmortem
analysis of cerebral arteries revealed VZV DNA in the right pos-
terior cerebral and basilar arteries, and VZV antigen was found
in the right middle and posterior cerebral arteries. Subject 3 was
a 37-year-old man with AIDS who developed disseminated her-
pes zoster, followed 10 months later by a right homonomous
hemianopia, confusion, and agitation. Brain imaging revealed
focal disease involving the left midtemporal and inferior parietal
gyri and subcortical white matter. He became increasingly con-
fused and developed a right hemiparesis and left-sided ptosis. A
CT scan showed new areas of low attenuation and swelling in the
right parietal lobe and subcortical white matter with new pete-
chiae and edema in the left frontal and right temporal lobes.
Angiography revealed segmental narrowing of the supraclinoid
portions of both internal carotid arteries at the proximal anterior
cerebral arteries, as well as in the proximal and distal branches of
the left middle cerebral artery, and in the right posterior commu-
nicating artery. His CSF was not examined for either VZV DNA
or anti-VZV antibodies. Postmortem examination revealed VZV
DNA in brain tissue and VZV antigen in the left middle cerebral
Cerebral and temporal arteries examined. The left tem-
poral artery from subject 1 corresponded to the distribution of
zoster and to the ipsilateral vision loss due to left ophthalmic
artery occlusion. The right middle cerebral artery studied in sub-
ject 2 corresponded to the area of arterial narrowing seen in
subject’s angiogram and to the distribution of the bland infarct.
The right middle cerebral artery studied in subject 3 corre-
sponded to CT abnormalities in the right temporal lobe. The
normal cerebral artery was an uninfected middle cerebral artery
obtained from subject 3 that was negative for both VZV DNA
and antigen. Since the morphologies of cerebral and temporal
arteries are similar, including the absence of an external elastic
lamina, no additional temporal artery controls were used.
Patient consents. Arteries from subjects 1 and 2 were archival
autopsy material obtained in 1995 and 1996 and published as
clinicopathological conferences in the New England Journal of
Medicine14,16; the temporal artery from subject 3 was sent to the
neurovirology laboratory at the University of Colorado School of
Medicine for virologic diagnostic evaluation.
Histopathology. Formalin-fixed, paraffin-embedded sections
of cerebral arteries from 3 patients with VZV vasculopathy (ta-
ble) were studied. Sections were cut (5 ?m), baked at 72°C for
30 minutes, and stained with hematoxylin & eosin and
Verhoeff-Van Gieson for elastic fibers.
Immunohistochemistry. Primary antibodies used were as
follows: 1:5,000 polyclonal rabbit anti-VZV 6317; 1:40 mono-
clonal mouse anti-CD31 (Dako, Carpinteria, CA); 1:500 mouse
anti-?–smooth muscle cell actin (?-SMA; Ventana, Tucson,
AZ); and 1:1,000 rabbit anti-smooth muscle myosin heavy chain
(SM-MHC; a gift from Dr. R. Adelstein, NIH). Except when
indicated, all incubations were at room temperature. Sections
were deparaffinized 3 times for 5 minutes each time in 100%
xylene and then in 100% ethanol. After sequential dipping in
95%, 70%, and 50% ethanol, sections were placed in distilled
water, heated in 10 ?m citrate buffer for 20 minutes for antigen
retrieval, and cooled in water. Sections were blocked in
phosphate-buffered saline (PBS) containing 5% normal goat se-
rum for 1 hour, washed 3 times with PBS, and incubated with
primary antibodies against VZV 63 or myosin overnight at 4°C.
After warming to room temperature, sections were rinsed 3 times
with PBS, incubated with 1:100 biotinylated goat antirabbit sec-
ondary antibody (Dako) for 1 hour, rinsed 3 times in PBS, and
incubated with prediluted alkaline phosphatase-conjugated
streptavidin (BD Biosciences, Cat. 551008, San Diego, CA) for
1 hour. The color reaction was developed for 2 minutes using the
TableClinical features of patients with VZV vasculopathy
death, wk Antigen
80M Yes4 Not applicable
73M NoNot applicable 45
Abbreviation: VZV ? varicella zoster virus.
Neurology 77July 26, 2011
fresh fuchsin substrate system (Dako) in the presence of levami-
sole at a final concentration 24 ?g/mL.
For CD31 and ?-SMA immunostaining, sections were
deparaffinized, heated for 36 minutes for epitope retrieval, and
slides were processed using an automated slide stainer according
to the manufacturer’s instructions (reagents/protocol in iVIEW
DAB Detection Kit; Tucson, AZ). Slides were incubated with
the corresponding primary antibody at 37°C for 30 minutes,
rinsed, and incubated with biotinylated secondary antibody fol-
lowed by horseradish peroxidase and DAB (iVIEW DAB Detec-
tion Kit). Slides were rinsed, dehydrated, and mounted on
All slides were viewed using a Nikon Eclipse E800 micro-
scope with Axiovision digital imaging software.
RESULTS Histopathology. A normal middle cere-
bral artery from subject 3 (figure 1) was compared
with VZV-infected temporal and middle cerebral ar-
teries from subjects 1–3. In contrast to normal arte-
rial structure (figure 2A), the intimal layer was
thickened in the arteries of all 3 subjects with VZV
vasculopathy (figure 2, B–D, vertical black lines).
While Verhoeff-Van Gieson staining of the normal
cerebral artery revealed an intact internal elastic lam-
ina (figure 2E, arrow), it was duplicated or disrupted
in all VZV-infected arteries (figure 2, F–H, arrows).
Immunohistochemistry. In contrast to the absence of
VZV antigen in the normal cerebral artery (figure
2I), VZV antigen was seen in the adventitia of sub-
ject 1 at 4 weeks after zoster (figure 2J, arrow), in the
media of subject 2 (who did not have zoster rash)
after 45 weeks of VZV vasculopathy (figure 2K, ar-
row), and in the hyperplastic intima of subject 3 at
48 weeks after zoster (figure 2L, arrow).
To identify the cellular components of the hyper-
plastic intima in VZV-infected arteries, immunohisto-
antigen CD31, and ?-smooth muscle actin (?-SMA)
single cell layer of endothelium is present in a normal
cerebral artery (figure 3A, arrow). In the 3 subjects
with VZV vasculopathy (figure 3, B–D), a thin en-
dothelium (arrows) was seen adjacent to the lumen,
while no endothelial cells were detected in the thick-
ened intima (vertical white lines). Analysis of smooth
muscle cell distribution revealed cells expressing
?-SMA (figure 3E, vertical black line, brown color)
in the media of the normal cerebral artery. In the
VZV-infected temporal artery of subject 1 at 4 weeks
after zoster, cells expressing ?-SMA were present in
the media (figure 3F, vertical black line, brown color)
but at a lower density than in the media of the nor-
mal artery; cells expressing ?-SMA were also present
in the hyperplastic intima (figure 3F, vertical white
line, brown color). In contrast, the middle cerebral
arteries of subjects 2 and 3 with protracted VZV vas-
culopathy showed a striking paucity of cells express-
ing ?-SMA in the media (figure 3, G–H, vertical
black lines, brown color) with a greater abundance of
these cells in the hyperplastic intima (figure 3, G–H,
vertical white lines, brown color). Cells expressing
SM-MHC were present in the media of the normal
cerebral artery (figure 3I, vertical black line, pink
color). Cells expressing SM-MHC were seen in the
media of subject 1 at 4 weeks after zoster, but at a
lower density (figure 3J, vertical black line, pink
Figure 1 Morphology of normal cerebral artery
Movat pentachrome stain reveals the 3 layers of a normal cerebral artery. The intima, adjacent to the lumen, is composed of a
single endothelial layer (arrows indicate endothelial cell nuclei [pink]). The media is composed of smooth muscle cells, and the
Neurology 77July 26, 2011
color) and were even less abundant in the media of
subjects 2 and 3 with protracted VZV vasculopathy
(figure 3, K through L, vertical black lines, pink
color). Like ?-SMA, SM-myosin was expressed by
cells in the hyperplastic intima of the cerebral arteries
of subjects 1–3 with VZV vasculopathy (figure 3,
J–L, vertical white lines, pink color).
DISCUSSION We examined cerebral and temporal
arteries, all of which contained VZV antigen, from 3
patients with VZV vasculopathy, as well as a control
artery that was negative for VZV antigen. Findings
on the VZV-infected arteries were compared to the
uninfected normal cerebral artery (figure 1) which
was composed of a single layer of endothelial cells
adjacent to the lumen (intima), an internal elastic
lamina, a wall of smooth muscle cells (media), and an
outer layer consisting of collagen and adventitial fi-
broblasts (adventitia). Importantly, the arteries repre-
sented early and late infection: the artery from
subject 1 was obtained 4 weeks after zoster before
neurologic symptoms and signs relevant to that ar-
tery developed, while the arteries from subjects 2 and
3 were obtained at autopsy after 45 and 48 weeks of
protracted neurologic illness, respectively. The pres-
ence of most VZV antigen in the adventitia of the
early case, combined with a heavy antigenic burden
in the media and intima of the 2 late cases, supports
the notion that VZV spreads transmurally from the
adventitia to the intima, presumably after transax-
onal spread to the artery via ganglionic afferent fi-
bers.18,19Although it remains unknown why virtually
all cases of VZV vasculopathy involve cerebral arter-
Figure 2 Histologic and virologic analysis of a normal human cerebral artery and varicella zoster virus (VZV)–infected temporal and
cerebral arteries of patients with VZV vasculopathy
Hematoxylin & eosin (H&E) stain of a normal uninfected middle cerebral artery from subject 3 (A); Verhoeff-Van Gieson (VVG) staining shows an intact
internal elastic lamina (E, arrow) devoid of VZV antigen (I). In the temporal artery of subject 1 with early VZV vasculopathy, as well as the right middle
cerebral artery of subjects 2 and 3 (both of whom died of protracted VZV vasculopathy), H&E staining reveals a hyperplastic intima in all 3 arteries (B–D,
vertical black lines), and VVG staining shows duplication or frank disruption of the internal elastic lamina in the arteries of all 3 subjects with VZV vascu-
lopathy (F–H, arrows). VZV antigen (pink) in seen in the adventitia of subject 1 at 4 weeks after zoster (J, arrow), in the media of subject 2 (without a history
of zoster rash) after a 45-week course of VZV vasculopathy (K, arrow), and in the hyperplastic intima of subject 3 at 48 weeks after zoster (L, arrow).
Magnification ? ?100 in panels A–H and ?600 in panels I–L.
Neurology 77 July 26, 2011
ies rather than systemic arteries, it is possible that the
absence of an external elastic lamina in cerebral arter-
ies, unlike systemic arteries,20facilitates transmural
spread of virus in cerebral arteries with continued
virus production in a thickened intima.
Results of histologic and immunohistochemical
analyses of cerebral and temporal arteries from sub-
jects with VZV vasculopathy were similar. All arter-
ies contained a hyperplastic intima with a duplicated
or disrupted internal elastic lamina. The degree of
neointimal thickening was greater in the late cases
(subjects 2 and 3) than in the early case (subject 1),
suggestive of vascular remodeling that continues for
months after initial VZV infection. Although a thin
endothelial layer was readily seen on the luminal sur-
face of the 3 VZV-infected arteries, the thickened
intima did not contain CD31-positive cells, thus
making endothelial cells an unlikely source of the
hyperplastic intima. Instead, the thickened intima
contained cells expressing both ?-SMA and SM-
MHC, indicating a smooth muscle cell origin. Fur-
thermore, far fewer cells expressing ?-SMA and
SM-MHC were seen in the media of the late cases
(subjects 2 and 3) compared to the early case (sub-
ject 1) or in the normal cerebral artery. Together,
these findings suggest that some neointimal cells
Figure 3Immunohistochemical analyses of a normal cerebral artery and varicella zoster virus (VZV)–infected arteries from patients with
subjects 1–3 with VZV vasculopathy (B–D, vertical white lines) does not contain endothelial cells expressing CD31; however, a thin endothelium is seen
adjacent to the lumen (B–D, brown color, arrows). In the normal artery, ?–smooth muscle actin (?-SMA) is present exclusively in smooth muscle cells of the
media (E, vertical black line, brown color). In the VZV-infected artery of subject 1 at 4 weeks after zoster, cells expressing ?-SMA are present but less
dense in the media and also seen in the hyperplastic intima (F, vertical black and white lines, brown color, respectively); in contrast, the cerebral arteries of
subjects 2 and 3 with protracted VZV vasculopathy revealed a striking paucity of cells expressing ?-SMA in the media (G, H, vertical black lines, brown
chain (SM-MHC) are abundant in the media of the normal artery (I, vertical black line, pink color); such cells are also present but less dense in the arterial
media in subject 1 at 4 weeks after zoster (J, vertical black line, pink color) and sparse in the media of subjects 2 and 3 with protracted VZV vasculopathy
(K, L, vertical black lines, pink color). Like ?-SMA, SM-MHC is expressed by cells in the hyperplastic intima of the cerebral arteries of subjects 1–3 with VZV
vasculopathy (J–L, vertical white lines, pink color). Magnification ? ?200 in all panels.
Neurology 77July 26, 2011
originated from smooth muscle cells in the media
after VZV infection. The thickened intima also con-
tained abundant cells that expressed ?-SMA but not
SM-MHC (myofibroblasts). While dedifferentiated
smooth muscle cells can retain ?-SMA and lose SM-
MHC expression, it is also possible that these myofi-
broblasts originated from resident or circulating
progenitor cells or adventitial fibroblasts. Unfortu-
nately, there are no specific markers to identify the
origin of these neointimal myofibroblasts.
The VZV-infected arteries did not contain a dis-
tinct core of extracellular lipid in the thickened in-
tima characteristic of atheromatous lesions21or
medial hypertrophy seen in hypertensive vascular dis-
ease.22Although intimal hyperplasia and a frag-
mented internal elastic lamina may be seen in
cerebral arteries of patients with HIV-associated vas-
culopathy, other diverse pathologic changes charac-
teristic of HIV vasculopathy—perivascular space
dilatation, rarefaction, pigment deposition with ves-
sel wall mineralization, and perivascular inflamma-
tory cell infiltrates23—as well as aneurysmal
formation and fibrosis24were conspicuously absent.
Analysis of the morphology and composition of the
thickened intima and media, and the location of viral
antigen in the adventitia in early VZV vasculopathy,
revealed clues to the possible mechanisms of VZV-
induced vascular remodeling that leads to stroke. Previ-
ous studies of pulmonary and coronary vascular wall
remodeling revealed that the adventitia is a key regula-
tor in vascular wall structure and function.25–36After
vascular injury (i.e., balloon injury,25,26,28pulmonary
hypertension,29,31,33hypoxia30,32), adventitial fibroblasts
migrate to the intima. In addition, these “activated” ad-
ventitial fibroblasts can 1) secrete factors that create a
proinflammatory environment, further contributing to
vascular wall remodeling,29,30,32–34and 2) affect adjacent
adventitial fibroblasts and medial smooth muscle cells
such that they acquire a proliferative, migratory, and
dritic cells have been shown to become activated and
contribute to a proinflammatory environment leading
to vascular wall remodeling, as seen in giant cell arteri-
tis.36,37It is possible that VZV infection of adventitial
cells might lead to cerebrovascular wall remodeling in a
similar manner. Further studies are under way to ana-
lyze the inflammatory environment and dendritic cell
activation in VZV-infected arteries.
Dr. Nagel: drafting/revising the manuscript, study concept or design, analysis
tion of data, study supervision. I. Traktinskiy: study concept or design, analy-
sis or interpretation of data, contribution of vital reagents/tools/patients,
data. Dr. Kleinschmidt-DeMasters: drafting/revising the manuscript, analysis
or interpretation of data. Dr. Hedley-Whyte: drafting/revising the manu-
script, contribution of vital reagents/tools/patients. Dr. Russman: drafting/
revising the manuscript, analysis or interpretation of data, acquisition of data.
Dr. VanEgmond: analysis or interpretation of data. Dr. Stenmark: drafting/
revising the manuscript, study concept or design, analysis or interpretation of
data, obtaining funding. Dr. Frid: drafting/revising the manuscript, study
sion. Dr. Mahalingam: drafting/revising the manuscript, study concept or
design, analysis or interpretation of data, contribution of vital reagents/tools/
patients, acquisition of data. M. Wellish: study concept or design. A. Choe:
statistical analysis. Dr. Cordery-Cotter: analysis or interpretation of data, contri-
bution of vital reagents/tools/patients, study supervision. Dr. Cohrs: drafting/
contribution of vital reagents/tools/patients, acquisition of data, obtaining fund-
sis or interpretation of data, contribution of vital reagents/tools/patients,
The authors thank Marina Hoffman for editorial assistance and Cathy
Allen for word processing and formatting the manuscript.
Dr. Nagel receives research support from the NIH. I. Traktinskiy reports
no disclosures. Dr. Azarkh receives research support from the NIH. Dr.
Kleinschmidt-DeMasters reports no disclosures. Dr. Hedley-Whyte serves
on the editorial board of Human Pathology and holds stock/stock options
in Becton Dickinson. Dr. Russman serves on speakers’ bureaus for Boehr-
inger Ingelheim and Pfizer Inc and receives research support from the
NIH. Dr. VanEgmond reports no disclosures. Dr. Stenmark serves on the
editorial boards of the American Journal of Respiratory and Critical Care
Medicine, the American Journal of Respiratory Cell and Molecular Biology,
the American Journal of Physiology–Lung Cellular and Molecular Physiology,
and as an Associate Editor for Pulmonary Circulation; and receives re-
search support from the NIH. Dr. Frid reports no disclosures. Dr. Ma-
halingam serves on the editorial board of the Journal of Neurovirology and
receives research support from the NIH. M. Wellish and A. Choe report
no disclosures. Dr. Cordery-Cotter reports no disclosures. Dr. Cohrs
serves on the editorial board of Archives of Clinical Microbiology and re-
ceives research support from the NIH. Dr. Gilden has received a speaker
honorarium from Merck & Co., Inc.; serves as Senior Associate Editor for
the Journal of Neurovirology and on the editorial boards of In Vivo, the
Journal of Virology, Scientific American Medicine, Virus Genes, and Neurol-
ogy®; has served as a consultant for Teva Pharmaceutical Industries Ltd.
and Epiphany Laboratories; and receives research support from the NIH.
Received February 18, 2011. Accepted in final form April 6, 2011.
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