Varicella-Zoster Virus
(VZV)
The Neurological Complications of
Varicella Zoster Virus Reactivation
Chickenpox (Varicella)
Latency
Reactivation
Neurologic Disease
Shingles (Zoster)
Postherpetic Neuralgia (PHN)
Myelitis* Vasculopathy* Retinal necrosis*
Zoster Sine Herpete
*may also develop without rash
Cranial nerve ganglia
Dorsal root ganglia
Autonomic ganglia
Latent VZV
VZV is latent is ganglia at all levels of the neuraxis
entire genome is present
VZV is latent in neurons
virus is extrachromosomal, non-linear,
probably circular or concatameric (end-to-end)
abundance varies: 14-1390 copies of VZV DNA per latently
infected neuron
at least 5 VZV genes are transcribed
at least two VZV proteins are present
Primary infection
varicella
Latent
Reactivation
zoster
VZV: Immune Response
loss of cell-mediated immunity leads to virus reactivation
– age
– immunosuppression for patients with cancer and transplant recipients
– prolonged steroid use
– AIDS
concept of reactivation as a continuum of
immunosuppression: mostly aging to AIDS
Age Predicts Postherpetic Neuralgia
Age
Patients
% PHN
References
Adults
590
9
Ragozzino
<70
>70
756
160
4.2
47.5
de Moragas
<60
>60
333
243
15.9
46.9
Rogers
de Moragas et al., Arch. Derm., 1957
Rogers and Tindall, Postgrad. Med., 1971
Ragozzino et al., Medicine, 1982
VZV
Vasculopathy
Nagel et al., Neurol., 2007
progressive outer retinal necrosis (PORN)
Zoster sine herpete
initially described in zoster
patients who had dermatomal
pain distant from rash
(Lewis, Brit. Med. J., 1958)
more strict definition:
dermatomal pain without rash
Zoster Sine Herpete
• 62-year-old man: left T4-5 distribution pain
• exam: left T4-5 increased sensitivity to touch
• labs normal, including MRI and CSF
Zoster Sine Herpete
no history of zoster
radicular pain
VZV DNA in CSF (possibly blood MNCs)
Varicella Zoster Virus Infection without Rash
zoster sine herpete (restricted to dermatomal pain)
vasculopathy
myelitis/myelopathy
ataxia
meningoencephalitis
PORN
Treatment of postherpetic neuralgia with antivirals
prospective, open-label phase I/II clinical trial
15 patients with moderate to severe PHN
interventions: intravenous acyclovir, 10 mg/kg 3X/day for 14 days
followed by oral valacyclovir, 1000 mg 3X/day for one month
main outcome measure: Numeric Rating Scale for Pain score
results: as defined by a ≥ 2-point decrease on Numeric Rating Scale for
Pain, 8 of 15 (53%) patients reported improvement
conclusion: clinical improvement reported by most patients warrants
further investigation in a larger randomized, double-blind, placebocontrolled trial
Quan et al., Arch. Neur., 2006
the SALIVA story
Stress-Induced Subclinical Reactivation of Varicella Zoster Virus in Astronauts
Mehta et al., J Med Virol. 2004
before
during
after
324 total samples
astronaut
days
-265
-263
-261
-259
-255
-253
-249
-247
-243
-241
-239
-237
-236
-234
2
3
4
5
6
7
8
9
10
11
12
13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
-
2
-
3
24
110
-
4
-
-
2
-
800
6000
-
-
5
47
-
6
6800
-
7
7
-
8
5
-
VZV DNA in astronaut saliva
VZV copies / ml saliva
flight days subject 1 subject 2 subject 3
before
0 / 42
during
11 / 36
after
7 / 27
105 total samples
AME
-133
-131
-129
-127
-125
-123
-121
-119
-125
-117
-115
-113
-111
-109
-10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
3
4
5
6
7
8
9
10
11
12
13
224
0
0
128
0
200
0
2500
0
450
0
120
18
247
0
0
0
0
0
650
75
0
0
23
0
0
0
0
0
0
0
0
0
0
0
0
14
15
16
17
18
19
20
21
22
23
1250
45
0
110
0
0
0
0
0
560
0
340
45
23
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
VZV Antibody titer
subject 1
subject 2
subject 3
1 : 80
1 : 80
1 : 80
1 : 320
1 : 640
1 : 80
1 : 320
1 : 320
1 : 80
0
0
0
0
0
0
0
0
0
0
0
0
0
0
HFL cells inoculated with astronaut saliva
days post
flight
subject 1
subject 2
2
3
4
5
6
VZV from zoster vesicle
anti-VZV-IE63
anti-HSV-1-ICP22
subject 3
PCR analysis of HFL cells inoculated with astronaunt saliva
subject
1
2
3
days post flight
VZV
HSV
VZV
HSV
VZV
HSV
2
+
-
-
+
-
-
-
-
3
4
5
6
Summary
VZV DNA was detected in saliva of astronauts during and shortly after
space flight
Infectious VZV was isolated from saliva of healthy astronauts shortly
after landing
VZV, like HSV-1 and HSV-2, can reactivate and shed infectious virus
in the absence of clinical disease
Cohrs et al., J. Med. Virol., 2008
Analysis of Saliva in Patients with Zoster
54 zoster patients
6 patients with chronic pain
14 healthy control subjects
saliva collected 3 times from every subject over 2-week period
Results
• VZV DNA found in saliva of all 54 zoster patients, never in controls
• both presence & abundance of VZV DNA correlated with pain
• VZV DNA was also found at times after rash and pain resolved
Mehta et al., J. Inf. Dis., 2008
VZV DNA in saliva of zoster patients
54 subjects, 3 samples per subject collected over a 2 week period
ophthalmic
Patient
Age/Sex
cervical
Zoster site VZV DNA
Patient
Age/Sex
thoracic
Zoster site VZV DNA
Patient
Age/Sex
lumbar
Zoster site VZV DNA
Patient
Age/Sex
8.0 x 10
1
49
51/F
L1
2.9 x 10
1
2.0 x 10
4
50
58/F
L2-3
4.3 x 10
1
T2-3
6.6 x 10
3
51
72/M
L3
1.5 x 10
2
T3
6.9 x 10
1
52
67/F
L3
1.4 x 10
2
4.2 x 10
1
53
44/F
L4-5
4.5 x 10
4
54
74/M
L5
1.4 x 10
2
1
64/F
V1
1.4 x 10
7
2
52/M
V1
3.2 x 10
4
11
79/M
C2-3
6.5 x 10
3
12
49/F
C3
1.4 x 10
7
1.2 x 10
6
25
75/M
T3-4
4.3 x 10
2
9
75/M
C2
10
65/M
C2
7.2 x 10
4
20
47/F
T1
5.0 x 10
5
21
58/F
T2
22
53/F
23
66/F
3
44/M
V1
1.0 x 10
5
4
48/F
V1
1.8 x 10
5
6.3 x 10
2
14
53/F
C3
8.0 x 10
0
15
44/F
C3
5.8 x 10
5
26
39/F
T4
2.3 x 10
1
27
48/M
T4-5
8.8 x 10
4
5
59/F
V1
6
62/M
V1
2.5 x 10
4
7
41/M
V1
1.0 x 10
3
5.5 x 10
3
8
82/F
V1
13
41 - 82
median
2.9 x 10
4
24
51/M
T3-4
16
48/M
C3
4.5 x 10
17
63/M
C3-4
6.5 x 10
4
28
30/F
T5
4.4 x 10
1
8.2 x 10
4
29
56/F
T5
6.5 x 10
1
4.5 x 10
4
30
60/M
T5
9.0 x 10
0
31
65/M
T5
1.9 x 10
4
32
59/M
T5
1.6 x 10
1
33
62/M
T5
1.6 x 10
2
34
62/M
T5-6
1.2 x 10
2
35
58/F
T6
1.3 x 10
2
36
43/F
T6
2.1 x 10
1
37
61/M
T6
5.8 x 10
2
38
40/M
T6
1.9 x 10
3
39
39/M
T6
2.7 x 10
7
40
35/F
T6-7
7.6 x 10
3
41
59/F
T7
2.7 x 10
1
42
23/F
T7-8
2.6 x 10
4
43
50/M
T8
1.5 x 10
3
44
35/M
T8
6.5 x 10
1
45
72/F
T11
2.2 x 10
2
46
69/F
T11
3.5 x 10
1
47
65/F
T12
5.7 x 10
3
48
29
21/F
21 - 75
T12
5.5 x 10
median
2
1.0 x 10
19
4(F) / 4(M)
C3
1
18
8
40/M
11
26/F
26/F
26 - 79
5(F) / 6(M)
C4
C4
median
4
7.4 x 10
16(F) / 13(M)
Zoster site VZV DNA
3
6
44 - 74
4(F) / 2(M)
median
2
1.4 x 10
Control Subjects
3 samples per subject collected over a 2 week period
Chronic Pain
Subject
1
2
3
4
5
6
Age/Sex
Disease
53/F
43/F
24/M
64/F
38/M
58/F
Stomach cancer
Autoimmune connective tissue disorder
Prostate cancer and hepatitis
Autoimmune hepatitis
Leukemia
Hepatitis B
Healthy subjects:
14 individual (42 saliva samples)
VZV DNA detected in saliva of all 54 patients on first day of rash
VZV DNA in saliva disappeared during 14 day study period in 82%
patients
There was significant positive correlation between:
pain and the presence of VZV DNA in saliva (P<0.0005)
pain and the VZV DNA burden in saliva (P<0.0005)
Infectious VZV was isolated from saliva in 1 of 2 patients
THE WIDENING SPECTRUM OF
VZV REACTIVATION
pr
im
ary
in f
ec
ti o
n
r)
e
t
s
( zo
h
as
r
it h
sh
w
a
r
on
i
ut
t
o
a
it h
tiv
c
w
a
re
on
on
i
i
t
t
va
a
va
i
i
t
t
c
l iv
c
a
a
a
re
l re
ns
va
i
i
a
l
c
sa
ni
NA
i
l
n
D
i
bc
us
ZV
r
su
i
V
v
us
o
i
ct
e
f
in
VZV Laboratory
Collaborators
Clinical Neurologists
Randy Cohrs, PhD
Ravi Mahalingam, PhD
Subbiah Pugazhenthi, PhD
Jeffrey Cohen – NIH
Bagher Forghani – CA Dept. Health
Peter Kennedy – Glasgow
Krishman Kolappaswamy and
Louis deTolla – U. Maryland
Vicki Traina-Dorge – Tulane
Satish Mehta – NASA
Duane Pearson – NASA
Stephen Tyring –U. Texas
Catherine Amlie-Lefond - MCW
Richard Baringer – U. Utah
Brad Beinlich - U. Wisconsin
Jeffrey Bennett - U. Colorado
Deborah Blumenthal – U. Utah
Louis Caplan - Harvard
Shari de Silva - Georgetown U.
Robert Fox - U. Pennsylvania
Craig Gardner – Jefferson
Steve Galetta - U. Pennsylvania
Gwen Garden – U. Washington
Jack Gwaltney - U. Virginia
Irene Katzan – Cleveland Clinic
Andreas Kronenberg – U. Hosp., Zurich
Michael Levy – Johns Hopkins
Howard Lipton – U. Ilinois
Howard Moses – Johns Hopkins
Heidi Orme – U. Utah
Lyle Ostrow – Johns Hopkins
Diana Quan – U. Colorado
Andy Russman – Henry Ford
Joseph Safdieh - Cornell
Stuart Schneck - U. Colorado
Elijah Stommel - Dartmouth
Charlene Sweeney - U. Colorado
Jim Wolf – Johns Hopkins
Maria Nagel, MD
Niklaus Mueller, PhD
Elizabeth Brazeau
Mary Wellish
Laurie Graf
Dianna Quan, MD
Barbara Hammack, PhD
Penny Clarke, PhD
Steven Deitch, MD
Bette DeMasters, MD
Aud Dueland, MD, PhD
Jim LaGuardia, MD
Abbas Vafai, PhD
Tiffany White, PhD
Sophie Wroblewska, MD, PhD
Mike Barbour
John Brucklier
Mary Devlin
Kathy Reilly
Katie Srock
John Smith
Helene Van Trieste-Schmidt
Bill Wolf
Neuropathologists
Robert Hevner – U. Wash
Tessa Hedley-Whyte - Harvard
John Martin – NIH
Jeannette Townsend – U. Utah
Hebrew University
Yechiel Becker
Yaacov Rozenman
Yehuda Stram
Laboratory Colleagues
Mark Burgoon, PhD
Greg Owens, PhD
Xiaoli Yu, PhD