Professional Documents
Culture Documents
Background.Diseases that present with protean mani- trum of large-vessel vascular damage, ranging from vas-
festations are the diseases most likely to pose diagnostic culopathy to vasculitis, with stroke. In immunocompro-
challenges for both clinicians and pathologists. Among the mised individuals, especially those with cancer or acquired
most diverse disorders caused by a single known toxic, immunodeficiency syndrome, deeper tissue penetration of
metabolic, neoplastic, or infectious agent are the central the virus may occur (as compared with immunocompetent
and peripheral nervous system complications of varicella- individuals), with resultant myelitis, small-vessel vasculo-
zoster virus (VZV). pathy, ventriculitis, and meningoencephalitis. Detection of
Methods.The pathologic correlates of the neurologic the virus in neurons, oligodendrocytes, meningeal cells, ep-
complications of VZV infection, as well as current methods endymal cells, or the blood vessel wall often requires a
for detecting viral infections, are discussed and presented combination of morphologic, immunohistochemical, in
in pictorial format for the practicing pathologist.
situ hybridization, and polymerase chain reaction (PCR)
Results.Varicella-zoster virus causes chickenpox (var-
icella), usually in childhood; most children manifest only methods. The PCR analysis of cerebrospinal fluid remains
mild neurologic sequelae. After chickenpox resolves, the the mainstay for diagnosing the neurologic complications
virus becomes latent in neurons of cranial and spinal gan- of VZV during life.
glia of nearly all individuals. In elderly and immunocom- Conclusions.Varicella-zoster virus infects a wide vari-
promised individuals, the virus may reactivate to produce ety of cell types in the central and peripheral nervous sys-
shingles (zoster). After zoster resolves, many elderly pa- tem, explaining the diversity of clinical disorders associ-
tients experience postherpetic neuralgia. Uncommonly, ated with the virus.
VZV can spread to large cerebral arteries to cause a spec- (Arch Pathol Lab Med. 2001;125:770780)
nonlatently infected human trigeminal ganglion cells spiked with 1000 copies of plasmid and digested with DNase. Lane VD (positive control)
contains DNA extracted from VZV-infected BSC-1 cells in tissue culture. B, Only occasional cells stain intensely in the largely nonneuronal
population (arrow), and Southern blot hybridization reveals no VZV gene 21 DNA in 10 nonneuronal cell suspensions.
Figure 4. Varicella-zoster virus (VZV) gene 63 protein expression in latently infected ganglionic cells. A, Immunohistochemical staining with
rabbit antiprotein 63 serum shows VZV gene 63 protein in the cytoplasm of a neuron in a section from the thoracic ganglion of a VZV-seropositive
man, indicating at least limited translation of one VZV protein during latency. B, The same ganglion incubated with normal rabbit serum. C,
Thoracic ganglion derived from a VZV-seronegative 2-month-old infant and incubated with rabbit antiprotein 63 serum (alkaline phosphatase
method, new fuschin red chromogen, original magnification 3350 [AC]).
Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden 773
virus is found only in the neurons of ganglia,20,21 zoster is
characterized by viral inclusions and viral particles de-
tectable by light and electron microscopy, respectively, in
neurons, satellite cells, and fibroblast-like cells of gan-
glia.33,34
ZOSTER SINE HERPETE
Rarely, VZV reactivates from latency in dorsal root gan-
glia but fails to reach the skin or cause zoster rash. This
entity, known as zoster sine herpete, is characterized by
severe radicular pain that can be documented only by so-
phisticated virologic testing and may well be underrecog-
nized.36 Virtually nothing is known about the pathologic
correlates of zoster sine herpete. Presumably, however, this
syndrome represents more restricted inflammation at the
level of the ganglion, with unsuccessful transaxonal
spread to skin because of a more effective host response.
POSTHERPETIC NEURALGIA
Most zoster in immunocompetent patients resolves
without sequelae. However, many elderly patients have
prolonged, often debilitating pain, known as postherpetic
neuralgia.3,37 This intractable pain occurring in a derma-
tomal distribution can persist for months or even years.
Postherpetic neuralgia, defined as pain persisting more
than 4 to 6 weeks after the rash resolves, is the most fre-
quent neurologic complication of zoster.37 Age is the most
important predictor of postherpetic neuralgia, with the
risk for postherpetic neuralgia as high as 45% in patients
who develop zoster after age 60 years. The incidence is
also slightly higher in women and in individuals with zos-
ter that has a trigeminal distribution. The pain of post-
herpetic neuralgia is often described by patients as excru-
ciating and debilitating, perhaps best appreciated visually
by the drawing furnished to us by an artist who suffered
from postherpetic neuralgia and who pictured his head
skewered with innumerable nails (Figure 8)! Despite nu-
merous clinical trials of various antiviral agents, steroids,
and pain relievers, there is no proven cure to date.
The pathology of postherpetic neuralgia is just begin-
ning to be understood, and much less morphologic infor-
mation is available for this condition than for zoster. Un-
fortunately, the monograph by Head and Campbell32 did
not address the pathology of postherpetic neuralgia.25
Postmortem microscopic analysis of ganglia from 2 pa-
tients with postherpetic neuralgia revealed the presence
of inflammatory cells, often around dying neurons, that
were still present 1 to 2 years after acute zoster.38,39 Smith38
found gross cystic distortion of thoracic sensory ganglia
Figure 5. Shingles (zoster). Lesions are shown in the ophthalmic (V-
1) branch of the trigeminal nerve, the area of the face involved most
frequently affected by zoster.
Figure 6. Shingles (zoster). Involvement of the seventh cranial nerve.
Note the inability of subject to close the right eye and to wrinkle the
right lower facial muscles and the presence of vesicles in the external
ear (zoster oticus). The combination of peripheral facial weakness and
zoster oticus constitutes the Ramsay Hunt syndrome. Lesions on the
hard palate (right) may also occur and are easily overlooked by clini-
cians or autopsy pathologists.
Figure 7. Cellular pathology of shingles (zoster). In patients with zos-
ter, the dorsal root ganglia often show lymphocytic inflammation
(curved arrows) and neuronal degeneration with phagocytosis (straight
arrow) (hematoxylin-eosin, original magnification 3350).
774 Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden
may develop without concomitant zoster rash, making
clinical recognition and pathologic suspicion even more
challenging.49
Immunocompetent Patients
In immunocompetent patients with reactivated virus,
the virus spreads into the proximal nerve roots adjacent
to dorsal root ganglia, causing neuritis or plexitis.35 The
affected nerves show lymphocytic inflammation, vasculi-
tis, demyelination, and axonal loss. Neuritis at the cranial
level produces various symptoms,3 including the Ramsay
Hunt syndrome. When VZV spreads centrally along pe-
ripheral nerves toward the spinal cord, the virus may en-
ter the spinal cord at levels contiguous with the affected
dorsal root ganglia and nerves, causing myelitis. Patients
with this condition demonstrate the clinical features com-
mon to any myelitis (Figure 9, A). If the cervical spinal
cord is involved, patients exhibit weakness of all 4 extrem-
ities and impaired sphincter function. Bladder and bowel
dysfunction may also be seen with zoster that has a sacral
distribution, even in the absence of myelopathy. Further-
more, zoster that has a cervical or thoracic distribution
may produce diaphragmatic paralysis, which should be
Figure 8. Postherpetic neuralgia. Original drawing by an artist who kept in mind as a potential cause of death in patients with
suffered from postherpetic neuralgia and who pictured his head skew- VZV cervical radiculitis or myelitis. The clinical recogni-
ered with innumerable nails (original drawing by Mr Robert Russin, a tion and diagnosis of zoster myelitis is low, but pathologic
generous gift to Dr D. H. Gilden). involvement may be greater. Before death, the diagnosis
of myelitis can be corroborated by radiographic studies,
usually MRI (Figure 9, B). Pathologically, inflammation of
surgically removed 2.5 months after the onset of a zoster the spinal cord meninges is coupled with varying degrees
rash, persistent chronic inflammatory cells in a ganglion of underlying spinal necrosis, demyelination, and microg-
from a patient who had experienced zoster 1 year previ- lial influx (Figure 9, C). Although clinical recovery is var-
ously, and ghosts of sensory neurons in the ganglia of an iable, many immunocompetent patients improve signifi-
elderly woman 2 years after the patient had experienced cantly. Those with persistent weakness presumably have
postherpetic neuralgia. He hypothesized that the altered greater degrees of spinal cord necrosis and neuronal loss.
structure of surviving cells (ie, the neuron ghosts) may The extent to which zoster myelitis in immunocompetent
have contributed to the pathophysiology of her intractable patients is due to a direct viral cytopathic effect is still
pain. Zacks et al40 found no morphologic differences in the unknown. Further clinicopathologic correlation and viro-
nerves from patients with or without postherpetic neural- logic studies of autopsy cases are needed.
gia but did not have access to the corresponding ganglia The virus may also spread to the large blood vessels at
for study. Oaklander et al41 and Rowbotham and col- the base of the brain, causing a process very different from
leagues42 recently demonstrated a greater loss of small cu- meningitis. The most common form of cranial zoster is
taneous nerve endings in skin biopsies obtained from pa- zoster with a trigeminal distribution; this form of zoster
tients with zoster who developed postherpetic neuralgia usually develops in immunocompetent individuals. For
than in those who did not develop this complication. unknown reasons, the ophthalmic division of the trigem-
Additional pathologic studies of ganglia obtained at au- inal nerve (herpes zoster ophthalmicus) is disproportion-
topsy and of nerves and skin obtained at biopsy from in- ately affected as compared with the maxillary and man-
dividuals with postherpetic neuralgia are needed. How- dibular divisions.50 The virus is thought to spread via af-
ever, sophisticated virologic studies at the level of the gan- ferent trigeminal ganglionic fibers to the blood vessels at
glia in these patients are especially desirable. Proof of a the base of the brain. Days to weeks after herpes zoster
greater viral burden and viral reactivation in the neurons ophthalmicus, patients develop stroke with the onset of
of ganglia from such patients would provide a rationale hemiplegia contralateral to the zoster. Angiography and
for aggressive treatment with antiviral reagents. On the pathology examination at autopsy usually reveal involve-
other hand, such therapy implies the intravenous use of ment of the internal carotid artery or its branches ipsilat-
drugs over several weeks, at great cost and inconvenience eral to the zoster, with resultant vessel thrombosis, vary-
to the patient. ing degrees of vessel wall inflammation, and large, ipsi-
lateral brain infarctions.46,5053 This large-vessel involve-
SPREAD OF VZV FROM PNS TO CNS TISSUES ment by VZV is known variously as herpes zoster
Uncommonly, VZV spreads in the CNS in both immu- ophthalmicus, granulomatous angiitis, VZV vasculitis, or
nocompetent and immunocompromised patients, al- simply stroke associated with VZV. Depending on the
though this spread is more likely in the latter group of time elapsed since the onset of viral-mediated damage,
patients.4348 The virus can spread with a centripetal pat- and possibly other as yet unknown factors, there is great
tern (ie, toward the spinal cord or brain), a centrifugal variability in the extent of inflammation in affected blood
pattern (ie, toward the skin), or in both directions. When vessels in cases of VZV meningoencephalitis, myelitis,
the spread is exclusively centripetal, CNS complications neuritis, and large-vessel vasculopathy at the time of au-
Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden 775
Figure 9. Varicella-zoster virus (VZV) myelitis. A, Representation of spastic paraparesis, bilateral extensor plantar responses, and loss of sensation
below the level of the spinal cord lesion (stippled area) characteristic of myelitis. B, Magnetic resonance imaging of the spinal cord shows focal
enhancement (arrow) in a patient with VZV myelitis. C, Histologic features of spinal cord necrosis in VZV myelitis, including meningitis (m),
perivascular inflammation and vasculitis (p), and necrosis (n); the anterior horn cell area (a) is relatively intact at this spinal cord level (hematoxylin-
eosin, original magnification 330). Figure B is used with permission; N Engl J Med. 2000;342:635645. Copyright 2000, Massachusetts Medical
Society. All rights reserved.
The spread of VZV beyond the small vessels and into ulitis (Figure 13) or small-vessel vasculopathy (multifocal
oligodendrocytes adds a demyelinative component to the leukoencephalopathy).
lesions of multifocal leukoencephalopathy; these lesions
are often small, located deep in the white matter or at DETECTION OF VZV IN CSF AND BRAIN TISSUE BY
junctions of the gray and white matter (Figure 11, B and PCR AND ANTIBODY TESTING
D), and are less coalescent than the demyelinative lesions Polymerase chain reaction is now the standard method
of progressive multifocal leukoencephalopathy.45,46 The of diagnosis for many viral CNS infections.60,61 Compared
greater abundance of virus in the lesions, apparently due with viral isolation of VZV by culture, PCR detection is
to an inability of the severely immunocompromised host more rapid and sensitive, and the methodology can be
to mount an effective immune response, results in readily adapted to a wide variety of fluid and tissue specimens
visible intranuclear owls eye Cowdry type A viral in- to detect infection.62 Cerebrospinal fluid PCR for VZV
clusion bodies (Figures 11, E and 12, B). The lesions often DNA has considerably broadened our understanding of
lack inflammation that might hint at the infectious etiol- the neurologic complications due to VZV. In one study of
ogy of the small-vessel vasculopathy.46 Some AIDS pa- the prevalence of CNS disease due to VZV, PCR was used
tients develop overwhelming ventriculitis that may be ra- to test CSF specimens from 84 consecutive patients in-
diographically demonstrable (Figure 12, A), with innu- fected with the human immunodeficiency virus (HIV)
merable Cowdry A viral inclusions in the ependymal cells who had new neurologic symptoms.63 Six patients had
lining the ventricles47, 57 (Figure 12, B). Such patients usu- positive results for VZV DNA in CSF, and all had clinical
ally clinically manifest not only headache and mental sta- presentations consistent with ocular or other CNS VZV-
tus changes, but also gait disturbances and hydrocepha- associated diseases, indicating a tight correlation between
lus. In an unusual case, severe meningoencephalitis (Fig- positive results and disease. Importantly, 4 patients did
ure 12, C) has been reported to be associated with a pro- not have a zoster rash at the time, underscoring the critical
found elevation of CSF protein levels and vasculitis with role of CSF PCR testing in cases that may be clinically
an extensive fibrinoid necrosis (Figure 12, D).58 Myelitis is confusing.63 In another study, CSF PCR results from 514
well documented in AIDS patients59 and is often insidious, consecutive HIV-infected patients with neurologic disease
progressive, and sometimes fatal. Autopsy studies in these were positive for VZV DNA in 13 (2.5%) of the patients.64
cases have shown frank spinal cord invasion by the virus, Four of the 13 patients had VZV encephalitis or menin-
sometimes with more extensive necrosis and inflamma- goencephalomyelitis and received appropriate antiviral
tion than that seen in immunocompetent patients.4 In situ therapy; in 2 patients, viral DNA could no longer be de-
hybridization studies in immunocompromised patients tected in the CSF after therapy, and the patients clinical
have demonstrated large numbers of cells in CNS lesions conditions improved. In the other 2 patients, PCR analysis
that contain VZV DNA, especially in cases with ventric- showed the persistence of VZV DNA in the CSF; these
Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden 777
patients deteriorated clinically and died.64 Thus, CSF PCR
may be useful in monitoring therapeutic response. In that
same study, 9 of the 13 patients with neurologic symptoms
who had positive results on CSF PCR analysis were
thought to have symptoms caused by complications of
HIV other than VZV meningoencephalomyelitis and were
subsequently diagnosed with subclinical reactivation of
VZV.64 Thus, in some cases, positive results on CSF PCR
testing may antedate clinically recognizable disease. The
results of CSF PCR became negative in patients who re-
ceived appropriate antiviral therapy, suggesting a prog-
nostic utility for testing patients in whom disease might
be averted by prophylactic therapy. Together, these studies
indicate that CSF PCR testing for VZV DNA can influence
therapeutic decision making.
Cerebrospinal fluid PCR testing for VZV DNA has also
been critical in identifying VZV as a causative factor in
cases of CNS infections without skin manifestations,49,65
cases of arteritis,6 and cases of Ramsay Hunt syndrome
(with testing of both CSF and the fluid from vesicles in
the ears).66 This testing has also been critical in excluding
VZV as a causative factor in multiple sclerosis67 and in
most cases of Bells palsy (with testing of the endoneurial
fluid).68 Polymerase chain reaction testing for VZV DNA
on tissues obtained at biopsy or autopsy also has diag-
nostic utility. Unlike other members of the herpesvirus
family such as HSV-1, which have been detected in some
brain tissues obtained at autopsy from patients without
neurologic diseases,69 VZV has not been found incidental-
ly in such specimens. This absence of detectable VZV in
the brain suggests that, after chickenpox or zoster, the vi-
rus becomes latent only in the PNS, at the level of the
cranial or dorsal root ganglia, and that the virus does not
normally gain access to the CNS.
Few studies have directly addressed the incidence of
VZV DNA detection in autopsy tissues from healthy in-
dividuals. Liedtke et al70 used PCR to determine the pres-
ence of the DNA of HSV-1 and VZV in trigeminal ganglia
and olfactory bulbs of 109 forensic postmortem cases.
HSV-1 DNA was found in 15.5% of olfactory bulbs, but
VZV DNA was found in only 1% of olfactory bulbs. Sev-
eral studies that have evaluated the role of VZV in various
neurologic diseases provide additional evidence that VZV
DNA is not incidentally, widely detectable in postmortem
brain tissues. Analysis by PCR failed to reveal VZV DNA
in temporal lobe cortex from 8 schizophrenic patients, 8
nonschizophrenic suicide victims, and 8 healthy controls.71
Figure 12. Varicella-zoster virus ventriculitis and meningitis. A, Mag- Similarly, no VZV DNA was demonstrated by PCR in
netic resonance imaging (MRI) shows ventriculitis (white arrowhead) brain tissues from epileptic children with Rasmussen
in a patient with the acquired immunodeficiency syndrome (AIDS), as chronic encephalitis72 and in brain tissues from healthy
well as a lesion in the basal ganglia (black arrow). The poor scan qual-
ity reflects the patients agitation and movement in the scanner. B, Nu-
elderly individuals and patients with Alzheimer disease.73
merous Cowdry A viral herpetic inclusions in the ependymal cells in Only a single study reported detection of VZV DNA in a
tissue obtained at autopsy from the same patient (hematoxylin-eosin, significant proportion of brains from patients with mul-
original magnification 3350). C, An MRI scan showing meningeal en- tiple sclerosis and control individuals,74 but those results
hancement in the interpeduncular cistern (arrow). D, In this patient have never been confirmed. Polymerase chain reaction
(same patient as depicted in part C), on pathologic examination, ex- testing of various tissue specimens has excluded VZV as
tensive lymphocytic meningitis was associated with vasculitis and eo-
sinophilic fibrinoid necrosis of leptomeningeal vessels (hematoxylin- the cause of giant cell arteritis75 and multifocal encepha-
eosin, original magnification 3150). lomalacia76 but has verified the role of the virus in some
congenital infections.77
Figure 13. Varicella-zoster virus ventriculitis. In situ hybridization stud-
ies for varicella-zoster virus performed on brain tissue from a patient with Testing of CSF for VZV antibodies helps to confirm the
the acquired immunodeficiency syndrome; the patient had small-vessel role of VZV in producing the varied clinical syndromes
arteriopathy and focal ventriculitis. The tissue contains a denuded area of the PNS and CNS. In the appropriate clinical setting
of ependyma (straight arrow) and abundant blue-black signal in the nu- (ie, acute or subacute spinal cord disease, acute or chronic
clei of the adjacent, residual infected ependymal cells (open arrow). Note progressive encephalitis, or chronic radicular pain with or
numerous glial cells containing the virus at the edge of the nearby pale
mixed ischemic and demyelinative lesion (curved arrows) (in situ hy-
without rash), the presence of VZV antibody in the CSF
bridization probe for VZV, with NBT [nitroblue tetrazolium]/BCIP chro- is strong presumptive evidence of VZV infection. The di-
mogen, original magnification 3350). agnosis of VZV infection of the nervous system is sup-
778 Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden
ported by the detection of VZV antibody in the CSF, even 14. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz C.
Detection of varicella-zoster virus DNA by polymerase chain reaction in the ce-
in the absence of PCR-amplifiable VZV DNA.78 The anal- rebrospinal fluid of patients suffering from neurological complications associated
ysis of serum anti-VZV antibody is of no value since VZV with chickenpox or herpes zoster. J Clin Microbiol. 1991;29:15131516.
antibodies persist in the serum of nearly all adults.79 15. Robertson NJ, McKeever PA. Fetal and placental pathology in two cases
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predict from clinical information whether CSF testing will inal and thoracic ganglia. J Infect Dis. 1992;166(suppl 1):S24S29.
19. Mahalingam R, Wellish M, Lederer D, Forghani B, Cohrs R, Gilden D.
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