Recurrent stroke in varicella zoster associated vasculopathy

Abstract

Varicella zoster virus (VZV) is well known for its neurotropism, primary infection and reactivation after variable latency periods. After reactivation from spinal or cranial nerve ganglia, viruses can affect the central nervous system and cranial vasculature via transaxonal migration followed by transmural spread from the adventitial layer to the intima. Stroke can occur following primary infection by VZV (varicella) or after reactivation (zoster). These infectious vasculitides by VZV can lead to unifocal or multifocal ischemic and hemorrhagic stroke either after cranial nerve or spinal dermatomal zoster. Usual difference between immunocompetent versus immunocompromised individuals is involvement of unifocal large vessel vasculopathy in the former while multifocal small vessel in later. This vasculopathy in some cases may be progressive leading to recurrent stroke even after antiviral treatment. Diagnosis becomes challenging and needs a high degree of suspicion in immunocompetent, younger individuals, in absence of rash and when there are comorbidities. We report a case of elderly immunocompetent women, who developed multifocal infarcts followed by ventricular and subarachnoid haemorrhage after thoracic varicella zoster. Diagnosis was confirmed by the presence of anti-VZV IgG antibodies in the cerebrospinal fluid. In view of the diverse clinic-radiological spectrum of VZV vasculopathy, early recognition of this clinical entity is warranted for improved outcome.

Full text

Nepal Journal of Neuroscience, Volume 18, Number 3, 2021
61
Nepal Journal of Neuroscience 2021;18(3):61-64
Recurrent stroke in varicella zoster associated
vasculopathy
Pradeep Kumar Maurya DM1, Ajai Kumar Singh DM2, Ashutosh Tiwari DM3,
Abdul Qavi DM4
1,2,4 Department of Neurology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3Department of Neurology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
Date of submission: 15th February 2021 Date of acceptance: 16th August 2021 Date of publication: 1st September 2021
Abstract
Varicella zoster virus (VZV) is well known for its neurotropism, primary infection and reactivation after variable
latency periods. After reactivation from spinal or cranial nerve ganglia, viruses can aect the central nervous
system and cranial vasculature via transaxonal migration followed by transmural spread from the adventitial layer
to the intima. Stroke can occur following primary infection by VZV (varicella) or after reactivation (zoster). These
infectious vasculitides by VZV can lead to unifocal or multifocal ischemic and hemorrhagic stroke either after
cranial nerve or spinal dermatomal zoster. Usual dierence between immunocompetent versus immunocompromised
individuals is involvement of unifocal large vessel vasculopathy in the former while multifocal small vessel in
later. This vasculopathy in some cases may be progressive leading to recurrent stroke even after antiviral treatment.
Diagnosis becomes challenging and needs a high degree of suspicion in immunocompetent, younger individuals,
in absence of rash and when there are comorbidities. We report a case of elderly immunocompetent women, who
developed multifocal infarcts followed by ventricular and subarachnoid haemorrhage after thoracic varicella zoster.
Diagnosis was conrmed by the presence of anti-VZV IgG antibodies in the cerebrospinal uid. In view of the
diverse clinic-radiological spectrum of VZV vasculopathy, early recognition of this clinical entity is warranted for
improved outcome.
Key words: Intracerebral bleed, Stroke, Subarachnoid haemorrhage, Varicella zoster, Vasculopathy.
Case Report
This work is licensed under a Creative Commons
Attribution-Non Commercial 4.0 International License.
Address for correspondence:
Dr. Pradeep Kumar Maurya
Department of Neurology,
Dr. Ram Manohar Lohia Institute of Medical Sciences,
Lucknow, Uttar Pradesh, India.
E-mail: pkm730@gmail.com
Phone: +91-9839129968
Access this article online
Website: https://www.nepjol.info/index.php/NJN
DOI: https://doi.org/10.3126/njn.v18i3.34994
HOW TO CITE
Maurya PK, Singh AK, Tiwari A, Qavi A. Recurrent stroke in
varicella zoster associated with vasculopathy. NJNS. 2021;18(3):61-
4.
Copyright © 2021 Nepalese Society of Neurosurgeons (NESON)
ISSN: 1813-1948 (Print), 1813-1956 (Online)
a variable latency period and the virus again aects the
nervous system and cranial vasculature. These infectious
vasculitides of VZV can lead to ischemic and hemorrhagic
stroke of various types with variable course which depends
on host immune status.1 Though not a characteristic
feature; the vasculopathy reported to be unifocal large
vessel in immunocompetent and multifocal small vessel
in immunocompromised patients.1 Vasculopathy can be
an isolated event or may be recurrent due to progressive
vasculopathy.2,3 We report a case of immunocompetent
women, who presented with multifocal ischemic stroke
followed by ventricular and subarachnoid haemorrhage
due to progressive vasculopathy after thoracic varicella
zoster. Diagnosis was conrmed by positive anti VZV
IgG antibody in cerebrospinal uid and excluding other
causes. After administration of antiviral treatment, her
clinical course was stabilised.
Case report
A 55-year-old lady with hypertension developed
sudden onset right hemiparesis with speech disturbance
one month back. She was admitted at a local hospital
and magnetic resonance imaging (MRI) of the brain
revealed acute infarct in the left basal ganglia, bilateral
internal capsule and cerebellar vermis (Figure 1a). MR
Introduction
The varicella zoster virus (VZV) is a neurotropic DNA
virus and after primary infection, it remains inactive
in the neural ganglia of cranial or spinal nerves. Due to
altered host immunity the reactivation can occur after

Maurya et al
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Nepal Journal of Neuroscience, Volume 18, Number 3, 2021
angiography of intracranial vessels was unremarkable.
She was improving on antiplatelets, antihypertensive and
supportive treatment. One month after the initial stroke
she again developed sudden-onset altered sensorium with
respiratory distress and was admitted to our institute.
She was put on a mechanical ventilator. Neurological
examination revealed the Glasgow Coma Scale (GCS) of
9/15 (E4M4V1) and right upper motor neuron facial palsy.
Motor examination showed right hemiplegia and ipsilateral
plantars extensor. Old healed zoster rash over left thoracic
region was noted (Figure 1b). History of vesicular lesion
over the same region 2 months back was conrmed by
relatives. Her non-contrast computed tomography (CT)
brain revealed subarachnoid haemorrhage in the left
sylvian ssure, interpeduncular cistern and ventricles
(Figure 1c). CT angiography of the brain revealed a
small aneurysm in the distal branches of the right middle
cerebral artery (Figure 1d). She was detected to be diabetic
and managed with oral hypoglycemic agents. In view of
multifocal infarct in anterior and posterior circulation
followed by subarachnoid and ventricular bleed with past
history of zoster, the possibility of vasculopathy due to
VZV was kept with the aim to rule out other etiologies.
Her haemogram, renal, liver function test and thyroid
prole were normal. Her serum antibody for human
immunodeciency virus, hepatitis B and C were negative.
Her echocardiography and carotid doppler were normal.
Chest X-ray and ultrasonography of the abdomen were
unremarkable. Her ESR was elevated (101), c reactive
protein was positive. Her serum for rheumatoid factor,
antinuclear antibody and rapid plasma reagin (RPR) for
syphilis were negative. Her cerebrospinal uid (CSF)
analysis showed mildly elevated proteins (105 mg/dL)
with normal sugar (74mg/dL), 5 mononuclear cells,
without red blood cells. The CSF was also negative for
bacteria, tuberculosis and cryptococcal infection. Her
CSF came positive for anti-VZV IgG antibody; cut-o
index (COI=2.19; <0.8 Negative and >1.2 Positive) while
IgM was negative suggesting intrathecal synthesis of
antibody. The antibody titres were not available. Her CSF
polymerase chain reaction for VZV and herpes simplex
virus -1 were negative. She was treated with valacyclovir
(3gm/day in three divided doses) for 14 days. She was
discharged after 2&1/2 month of hospitalization in stable
condition. Her modied Rankin score was 3 at 6 month
follow up. Antiviral treatment resulted in stabilization of
disease. Repeat CT angiography of the brain performed at
6 month showed persistence of aneurysm.
Figure 1(a): Diusion-weighted magnetic
resonanceimagingofbrainshowingacuteinfarctin
leftputamenandbilateralinternalcapsule.
1(b):Oldzosterrashoverleftthoracicdermatome.
1(c): Computed Tomography (CT) brain showing
subarachnoid haemorrhage (thin arrow),
intraventricularbleed(thickarrow)andoldinfarcts.
1(d): CT angiography brain showing distal right
middlecerebralarteryaneurysm(arrow).

Recurrent stroke associated with VZV vasculopathy
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Nepal Journal of Neuroscience, Volume 18, Number 3, 2021
Discussion
There has been an increased recognition, reporting and
widened clinical spectrum of VZV vasculopathy in recent
years. The pathogenesis of vascular remodelling is yet
unclear. Proposed pathogenic mechanism is transaxonal
migration of VZV form neural ganglia to cerebral arteries
and resultant vasculopathy can easily explains the ipsilateral
zoster ophthalmicus with contralateral hemiplegia, a
classic presentation reported in literature.1 The evidence
came forth form three VZV proven vasculopathy patients,
when immunohistochemical analysis was performed on
cerebral and temporal arteries revealed reactivated VZV
antigen early in outer adventitial layer followed by media
and intima during progression of disease.4 However
cerebral VZV vasculopathy have been documented in
sacral and thoracic dermatomal zoster as well.5.6 As in
our case the vasculopathy at topographically distant site
form preceding zoster rash may be due to simultaneous
reactivation of virus in spinal and cranial ganglia (without
rash) is likely possibility as this hypothesis has been
suggested in the literature.5 Diverse and nonspecic
clinical and neuroimaging features makes the diagnosis
challenging. All of these complications are recognized to
be due to vasculitis aecting small and/or large vessels due
to direct infection of the vessel wall and vasculitis causing
thrombosis. Other causes of infectious and non-infectious
vasculitis to be investigated in appropriate clinical settings.
Giant cell arteritis should be considered in elderly, which
may have clinical features like headache, scalp tenderness
and vision loss along with raised inammatory markers
like ESR and C- reactive protein in absence of rash; needs
therapy with glucocorticoids. Although ESR was elevated
and c-reactive protein was positive in our case, she did
not receive steroids and improved with antiviral treatment.
ANA was negative in our case, which is considered as
the primary screening test for autoimmune disease. The
arterial biopsy may demonstrate the presence of VZV
antigen but it was not performed in our case as she
survived and improved. Disruption of the internal elastic
lamina in cerebral arteries infected with VZV can result
in a weakened vessel wall that leads to dolichoectasia
or aneurysm with subarachnoid or intracerebral
haemorrhage.7,8 Progressive VZV vasculopathy resulting
in recurrent stroke is well reported in literature. A 69
-year-old immunocompromised female developed 3
episodes of ischemic infarct in same arterial territory with
a preceding history of zoster ophthalmicus.9 Diagnosis was
conrmed by demonstration of anti VZV IgG antibody
and positive PCR in CSF. Black blood MRI sequence
was used to document the vasculopathy. In another case
a 51-year-old female with a history of scleroderma had
stepwise progression of focal neurological decit over
the duration of three month despite acyclovir therapy. In
the absence of rash, diagnosis was established by VZV
antibody in CSF. Repeat course of acyclovir along with
steroid resulted in a stabilised course without signicant
clinical improvement.2 Our patient developed recurrent
stroke (ischemic and hemorrhagic) after thoracic zoster
and her CSF anti IgG for VZV came positive. Liberman
AL et al reported a 41-year-old lady with systemic
lupus erythematosus on immunosuppressant developed
headache followed by zoster over multiple dermatomes.
Her CSF was inammatory and CT brain revealed SAH at
multiple locations.7 PCR revealed VZV deoxyribonucleic
acid in CSF. She was treated with intravenous acyclovir
for 21 days but two months later her headache worsened.
Repeat CT brain revealed SAH at multiple locations
and digital subtraction angiography (DSA) revealed
9 aneurysms. A repeat course of acyclovir and steroid
resulted in the resolution of a few aneurysms. Pathogenic
mechanism for development of aneurysm was supposed
to be intense inammatory response which led to damage
of vessel wall.7 As only CT angiography was performed
and repeated in our case which revealed persistence
of single aneurysm, whereas DSA can detect smaller
aneurysm but could not be done in our case. Takeshita J et
al reported simultaneous ischemic and hemorrhagic stroke
in a patient with zoster rash over buttocks and it was
consistent with VZV vasculopathy; diagnosis was made
by positive zoster DNA in CSF.10 Cerebellar haemorrhage
due to VZV vasculitis following zoster has also been
reported.11 As entry of virus to anterior circulation can
be easily explained by spread from trigeminal ganglia,
whereas aiction of posterior circulation arteries lies on
other proposed mechanism of viral spread from other
pathways.11 This clinical entity may constitute a diagnostic
challenge to clinicians as stroke may occur weeks or
months after stroke, absence of rash and CSF pleocytosis
in 1/3rd of patients.12 The sensitivity of VZV PCR and
anti VZV IgG in CSF are reported to be 30% and 93%
respectively.13 The determination of anti VZV antibody
in the CSF amid the course of vasculopathy strongly
indicate that the incident stroke is related to concurrent
VZV infection. It is further supported by the fact that
the production and circulation of CSF is 3 times of total
volume present in normal adults.5 The VZV antibody
would be undetectable unless the infectious vasculopathy
has a protracted course. The presence of antibody against
VZV is considered diagnostic even though the PCR for
VZV DNA is not identied as it is detectable early in the
course.13 Although the detection of VZV DNA by PCR and
IgG antibody against VZV are both considered diagnostic
but negative PCR does not exclude the diagnosis; the
only negative result for both can rmly exclude the
possibility of VZV vasculopathy.13 As in our patient the
IgG antibody against VZV was detected 2 month after
the zoster rash suggesting active vasculopathy. Due to

Maurya et al
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Nepal Journal of Neuroscience, Volume 18, Number 3, 2021
productive infection of VZV, treatment with acyclovir/
valacyclovir is justied and should be promptly instituted.
Optimal therapeutic regimen is yet to be determined in the
absence of controlled clinical trials. However intravenous
acyclovir for 14 days along with short course of prednisone
(5 days) have been advocated by some authors based on
clinical experience.13 In selected cases higher doses of
acyclovir (15 mg/kg q8h) and extended duration (21 days)
and repeat course of treatment have been used.2,14
Our case highlights that diagnosing VZV vasculopathy
in elderly may be dicult in the presence of other comorbid
risk factors. This rare clinical entity should be considered
even in dermatomal zoster. The awareness regarding the
protean manifestations of VZV vasculopathy can lead to
early diagnosis and treatment.
Conict of interest: None
Financial support: Nil
References
1. Gilden D, Cohrs RJ, Mahalingam R, Nagel MA.
Varicella zoster virus vasculopathies: Diverse clinical
manifestations, laboratory features, pathogenesis,
and treatment. Lancet Neurol. 2009;8(8):731-40.
https://doi.org/10.1016/S1474-4422(09)70134-6
2. Russman AN, Lederman RJ, Calabrese LH, Embi
PJ, Forghani B, Gilden DH. Multifocal varicella-
zoster virus vasculopathy without rash. ArchNeurol.
2003;60(11):1607-9. https://doi.org/10.1001/
archneur.60.11.1607
3. West SL, Newton RW, Baildam EM, Turner AJ,
Arkwright PD. Recurrent hemiplegia associated
with cerebral vasculopathy following third trimester
maternal herpes zoster infection. Dev Med Child
Neurol. 2006;48(12):991-3. https://doi.org/10.1017/
S0012162206002179
4. Nagel MA, Traktinskiy I, Azarkh Y, Kleinschmidt-
DeMasters B, Hedley-Whyte T, Russman A, et al.
Varicella zoster virus vasculopathy: Analysis of virus
infected arteries. Neurology. 2011 Jul;77(4):364-70.
https://doi.org/10.1212/WNL.0b013e3182267bfa
5. Gilden DH, Lipton HL, Wolf JS, Akenbrandt W,
Smith JE, Mahalingam R, et al. Two patients with
unusual forms of varicella-zoster virus vasculopathy.
N Engl J Med. 2002 Nov;347(19):1500-3. https://doi.
org/10.1056/NEJMoa020841
6. Horten B, Price RW, Jimenez D. Multifocal varicella-
zoster virus leukoencephalitis temporally remote
from herpes zoster. Ann Neurol. 1981 Mar;9(3):251-
66. https://doi.org/10.1002/ana.410090308
7. Liberman AL, Nagel MA, Hurley MC, Caprio
FZ, Bernstein RA, Gilden D. Rapid development
of 9 cerebral aneurysms in varicella-zoster virus
vasculopathy. Neurology. 2014;82:2139–41. https://
doi.org/10.1212/WNL.0000000000000503
8. Jain R, Deveikis J, Hickenbottom S, Mukherji
SK. Varicella-zoster vasculitis presenting with
intracranial hemorrhage. AJNR Am J Neuroradiol.
2003;24:971–4.
9. Shah J, Poonawala H, Keay SK, Serulle Y, Steven A,
Gandhi D, et al. Varicella-Zoster Virus vasculopathy:
A case report demonstrating vasculitis using black-
blood MRI. J Neurol Neurophysiol. 2015;6(6).
https://doi.org/10.4172/2155-9562.1000342
10. Takeshita J, Nomura E, Takemaru M, Himeno T,
Shimoe Y, Kuriyama M. Rapidly deteriorated lobar
intracerebral hemorrhages: Possible association
of Varicella Zoster Virus-Vasculopathy. Rinsho
Shinkeigaku. 2018;58(4):245-8. https://doi.
org/10.5692/clinicalneurol.cn-001144
11. Matsuo K, Uozumi Y, Miyamoto H, Tatsumi S,
Kohmura E. Varicella-zoster vasculitis presenting
with cerebellar hemorrhage. J Stroke Cerebrovasc
Dis. 2015;24(6):e153e155. https://doi.org/10.1016/j.
jstrokecerebrovasdis.2015.03.00
12. Nagel MA, Cohrs RJ, Mahalingam R, Wellish MC,
Forghani B, Schiller A, et al. The varicella zoster virus
vasculopathies: Clinical, CSF, imaging, and virologic
features. Neurology. 2008 Mar;70(11):853-60.
https://doi.org/10.1212/01.wnl.0000304747.38502.
e8
13. Nagel MA, Bubak AN. Varicella Zoster Virus
vasculopathy. J Infect Dis. 2018;218(suppl
2):S107,S112. https://doi.org/10.1093/infdis/jiy425
14. Osiro S, Salomon N. Varicella-zoster virus (VZV)
multifocal vasculopathy in a patient with systemic
lupus erythematosus: A diagnostic and treatment
dilemma. IDCases. 2017;8:81 -3. https://doi.
org/10.1016/j.idcr.2017.04.010