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Varicella-Zoster Virus Infections of the Nervous System

Clinical and Pathologic Correlates


B. K. Kleinschmidt-DeMasters, MD; Donald H. Gilden, MD

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)

T he recognition of patterns of symptoms and signs in


patients is essential to the practice of clinical medi-
cine. Pattern recognition also forms the basis for the vi-
and immunocompromised individuals, VZV may reacti-
vate to produce a dermatomal rash and radicular pain
(zoster or shingles). Rarely, VZV reactivates and causes
sually-based specialty of anatomic pathology. Clinicians pain without rash (zoster sine herpete). After zoster re-
selectively obtain corroborating laboratory information af- solves, many elderly patients experience severe persistent
ter formulating a differential diagnosis. Similarly, in the pain (postherpetic neuralgia). Varicella-zoster virus can
morphologically based disciplines of autopsy and surgical also spread to the large cerebral arteries, usually in im-
pathology, the pathologist must recognize patterns of dis- munocompetent and occasionally in immunocompro-
ease to narrow the differential diagnosis and to select the mised individuals, to produce a spectrum of large-vessel
tests or additional stains most likely to be informative. vascular damage, ranging from vasculopathy to vasculitis,
Varicella-zoster virus (VZV), an alpha herpesvirus with stroke. In immunocompromised patients, particular-
found exclusively in humans, can cause a wide spectrum ly those with cancer or the acquired immunodeficiency
of disorders throughout the lifetime of the individual.13 syndrome (AIDS), VZV spreads not only to arteries, but
Varicella-zoster virus causes an acute febrile exanthamous also to the central nervous system (CNS), with varying
illness (varicella or chickenpox), usually in childhood. Af- tissue penetration of the spinal cord (myelitis) and brain
ter chickenpox resolves, VZV becomes latent in neurons (small-vessel vasculopathy). Depending on infection of ol-
of cranial and spinal ganglia of nearly all individuals with igodendrocytes, ovoid mixed ischemic and demyelinative
no corresponding morphologic consequences. In elderly lesions may be seen at any level of the neuraxis. Rarely,
VZV infection in immunocompromised patients produces
Accepted for publication January 31, 2001. lesions that predominantly affect the meninges (menin-
From the Departments of Pathology (Dr Kleinschmidt-DeMasters), goencephalitis) or ependyma (ventriculitis).
Neurology (Drs Kleinschmidt-DeMasters and Gilden), and Microbiol- Detection of the presence of the virus often requires a
ogy (Dr Gilden), The University of Colorado Health Sciences Center, combination of morphologic, immunohistochemical, in
Denver, Colo. situ hybridization, and polymerase chain reaction (PCR)
Reprints: B. K. Kleinschmidt-DeMasters, MD, Department of Pathol-
ogy B216, University of Colorado Health Sciences Center, 4200 East methods.47 Given that the virus may be difficult to doc-
Ninth Avenue, Denver, CO 80262 (e-mail: BK.DeMasters@UCHSC. ument in tissues in association with VZV-associated com-
edu). plications, it is not surprising that the recognition of the
770 Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden
ataxia is one of the most common neurologic abnormali-
ties, and very rarely, transverse myelitis has been report-
ed.2
The vast majority of patients with chickenpox, even
those with neurologic complications, recover from their
illness. Thus, neuropathologic reports on chickenpox are
limited and are derived from the few children who man-
ifest unusual severity of disease and die. Many cases that
were originally clinically classified as having a cerebral
type of CNS complications8 or meningoencephalitis
were found to have only cerebral edema at autopsy. These
cases were subsequently recognized as encephalopathy of
Reye syndrome after varicella, with fatty livers and hep-
atotoxicity, and were not due to direct viral infection or
encephalitis.9 Other cerebral cases manifesting with
meningeal and perivenous lymphocytic inflammation and
limited perivenular demyelination were classified as cases
with indirect, presumably immune-mediated effects of the
virus, known as perivenous (postinfectious) encephalo-
myelitis.10 In cases of aseptic meningitis, the CNS findings
generally consist only of scattered meningeal chronic in-
flammatory cells (Figure 2, A). The virus was virtually
never isolated from cerebrospinal fluid (CSF) or brain.
Only in rare cases, usually in children with cancer, in chil-
dren receiving steroid therapy, or in neonates, have viral
inclusions been seen in the CNS.11,12 Even in children with
cancer, viral inclusions in the CNS have been seen in only
a very small number of patients with visceral dissemina-
tion (2 of 19 patients).12 In fact, most deaths from chick-
enpox are due to pneumonitis (Figure 2, B).
The pathogenesis of acute cerebellitis associated with
chickenpox is unknown. Although originally thought to be
an immune-mediated form of postinfectious encephalo-
myelitis restricted to the cerebellum, magnetic resonance
imaging (MRI) only rarely reveals the focal cerebellar or
Figure 1. Chickenpox (varicella). Typical erythematous vesicular rash brain stem lesions characteristic of postinfectious enceph-
of chickenpox (photograph used with parental permission). alomyelitis.13 However, PCR detection of VZV DNA in the
CSF suggests that disease is directly related to the pres-
ence of the virus.14 The unusual CNS complications asso-
patterns of disease caused by VZV has been challenging.4 ciated with chickenpox include transplacental transmis-
Patients often come to biopsy, or especially autopsy, with- sion to the fetus after maternal varicella infection, with
out clinical suspicion of VZV-induced disease. Pathologists viral inclusions demonstrable in the fetal lung and chori-
must recognize these varied patterns of disease caused by onic villi,15 and pseudotumor cerebri in a child with var-
the virus and pursue the correct definitive tests. icella, the pathologic substrate of which is uncertain.16
CHICKENPOX (VARICELLA) VZV LATENCY
Patients in the United States usually become infected After chickenpox resolves, VZV becomes latent in the
with VZV in childhood when they develop acute varicella peripheral nervous system (PNS) ganglia of virtually all
or chickenpox. Humans are the only reservoir for the vi- infected individuals and persists throughout the lifetime
rus. In temperate climates, this highly contagious virus of the host.3 Numerous ganglia are affected, more often
has a seasonal prevalence in winter and spring.1 Chick- the trigeminal cranial ganglia at the skull base but also
enpox is associated with a widespread vesicular exanthe- multiple dorsal root ganglia adjacent to the spinal cord.17
ma that occurs without respect to dermatomal distribution During latency, VZV is not infectious and does not tran-
(Figure 1) and has been well recognized by parents and scribe most of its genetic material, thereby apparently es-
pediatricians alike for more than 100 years. An effective caping detection and clearance of the virus by the immune
vaccine has been developed and, if widespread vaccination system.18 Intense research continues to focus on under-
programs are implemented and continued in the United standing the physical state of the virus during latency, in-
States, uncomplicated chickenpox may become a rare in- cluding the abundance and configuration of viral DNA,
fectious disease seldom encountered by a new generation the identification of cells that harbor the virus in latently
of patients and clinicians. Central nervous system compli- infected ganglia, and the extent of viral transcription and
cations are estimated to occur in less than 1% of cases of translation.1921 Quantitative PCR studies indicate a very
chickenpox, and even this low number may be an over- low copy number of the VZV genome, with 6 to 31 copies
estimate.2 Many children have only mild neurologic se- per 100 000 latently infected ganglionic cells.19 Unlike ret-
quelae, with headache, photophobia, and neck stiffness, roviruses, which incorporate their nucleic acid into host
consistent with mild meningitic symptoms. Cerebellar DNA, VZV remains extrachromosomal but in a noninfec-
Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden 771
Figure 2. A, Fatal varicella with mild meningoencephalitis. In contrast to the histologic features of severe pneumonitis (B), the brain (A) shows
only mild meningitis (curved arrow) and a reactive astrocytosis in the underlying brain (open arrowhead). No viral inclusions are seen (hematoxylin-
eosin, original magnification 3350). B, Fatal varicella pneumonitis. Lung tissue from a 3-month-old child with fatal chickenpox due to lymphocytic
pneumonitis. Note inflammation (curved arrow) and clusters of cells staining positive for varicella antigen (arrowhead) (immunoperoxidaseanti-
immunoperoxidase method with hematoxylin counterstain, original magnification 3350).
Figure 3. Ganglionic cells latently infected with varicella-zoster virus (VZV). A, Localization of VZV DNA predominantly in human dorsal root
ganglionic neurons during viral latency. The neurons were separated from nonneuronal cells by differential filtration methods and identified by
antineurofilament immunostaining. Southern blot hybridization with VZV gene 21 probes (bottom) reveals VZV gene 21 DNA in 3 of 10 aliquots
containing neurons. Polymerase chain reaction (PCR) using VZV gene 21 primers for 40 cycles, followed by nested PCR for 10 cycles using VZV
gene 21 primers internal to the initial pair, produced a 218base pair product. Lane SD (negative control) contains the products of dissociated
772 Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden
tious form. The present understanding of latency derives ness. Involvement of the seventh cranial nerve results in
largely from postmortem studies of trigeminal and dorsal weakness of the ipsilateral facial muscles and a vesicular
root ganglia rapidly harvested at autopsy. Most studies rash in the external ear (zoster oticus) or on the hard pal-
have shown that the virus is present predominantly, if not ate (Figure 6). Such lesions are easily overlooked or mis-
exclusively, in neurons of ganglia (Figure 3).20,21 Despite interpreted by clinicians or autopsy pathologists.
the presence of latent virus within these neurons, little In some cases, the zoster rash must be distinguished
morphologic change and no inflammatory response has from lesions caused by trauma or sexual abuse.26 The latter
been noted during latency. Again, however, relatively few distinction is of special interest to forensic pathologists.
pathologic reports exist detailing any subtle changes that Although zoster is relatively uncommon in children, oc-
may occur in ganglia during VZV latency when the pa- casional cases of a vesicular perianal zoster rash, a rash
tient develops intercurrent systemic diseases (such as ma- with a sacral nerve distribution, have been mistaken clin-
lignancy) or undergoes transplantation. Four VZV genes ically for genital herpes simplex virus (HSV) lesions. The
(genes 21, 29, 62, and 63) are known to be transcribed in presence of sexually transmitted diseases in young chil-
latently infected human ganglia, but it is not yet clear dren, such as genital HSV, should always prompt suspi-
which of these genes are translated into proteins during cion of sexual abuse.27,28 The phenomenon of zoster after
latency.22 The protein product of VZV gene 63 has been trauma is also of interest to forensic and autopsy pathol-
identified immunohistochemically in latently infected gan- ogists. Atypical varicella exanthems have been associated
glionic neurons (Figure 4).23 A better understanding of ex- with childhood cutaneous injuries such as antecedent
actly which genes are transcribed and translated during wasp stings,29 and classic dermatomal zoster has been re-
VZV latency may lead to strategies that prevent viral re- ported in adults after spinal surgery30 and even after triv-
activation. This prevention is important since zoster and ial external musculoskeletal trauma.31
its attendant complications are difficult to treat, especially Zoster in immunocompromised patients develops after
if patients develop postherpetic neuralgia or if the virus radiation therapy; bone marrow transplantation; or in as-
spreads to the CNS or cerebral arteries. Although VZV sociation with lymphoma, leukemia, cancer, AIDS, or even
vaccination prevents chickenpox, the effect of vaccination prolonged steroid use. In contrast to the course of zoster
on the incidence of zoster in the elderly will not be known in immunocompetent patients, zoster is often recurrent or
for decades. Varicella-zoster virus vaccine is a live atten- protracted in the immunocompromised population, espe-
uated virus that becomes latent after vaccination.24 cially in patients with AIDS.3 In immunocompromised pa-
tients, VZV is also considerably more likely to disseminate
SHINGLES (ZOSTER) after zoster to multiple cutaneous sites and internal or-
Varicella-zoster virus appears to become latent in nearly gans and to spread to the CNS causing complications that
all infected individuals, and the likelihood of viral reac- will be described further.
tivation to shingles (zoster) increases with each advancing In all cases, the pathologic substrate for zoster is varying
decade of age. Zoster is common, with an incidence of degrees of ganglionic hemorrhage and inflammation. In
more than 300 000 cases annually in the United States, al- 1900, Head and Campbell32 published their classic and de-
beit without a seasonal predilection like chickenpox.13 tailed autopsy studies on 21 patients with shingles; their
Zoster usually develops in elderly individuals and is 8 to monograph was recently reviewed by Oaklander,25 who
10 times more frequent after age 60 years than before. noted the near impossibility of duplicating such extensive
Immunocompromised patients are also at high risk. CNS and PNS dissections today. More recently, Nagashi-
With reactivation, the virus spreads transaxonally to the ma and coworkers33 and Ghatak and Zimmerman34 also
skin, causing a rash with a dermatomal distribution; the reported hemorrhage, necrosis, and inflammation within
rash is characterized by vesicles on an erythematous base. affected spinal ganglia of patients with zoster. Collectively,
In immunocompetent individuals, the zoster rash is usu- these reports and our own experience suggest consider-
ally confined to 1 or 2 dermatomes25 and is associated with able variability among patients and among multiple gan-
severe radicular pain. Zoster is nearly always monophasic, glia from a single patient in the degree of changes present
with recurrence occurring in less than 5% of zoster pa- in individual ganglia; this variability underscores the need
tients. Because the rash can occur anywhere on the trunk, for extensive dissection of the ganglia at autopsy. The his-
face, ear, mouth, extremities, or genitalia, patients are like- tologic features may include mononuclear and lympho-
ly to seek medical attention from various medical special- cytic inflammation, neuronal degeneration, neuronal
ists. Any level of the neuraxis can be involved, but thoracic phagocytosis by satellite cells, and empty neuronal cell
zoster is most often seen clinically, followed by lesions on beds, with eventual fibrous scarring of the ganglia 4,25 (Fig-
the face (Figure 5). The latter usually involves the oph- ure 7). Vasculitis in the adjacent nerve results in the loss
thalmic division of the trigeminal nerve and may be as- of myelin and axons,4 which can result in limb paresis.35
sociated with zoster keratitis, a potential cause of blind- Interestingly, in contrast to latent VZV during which the

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.

topsy.46, 5053 A spectrum of vascular involvement exists,


ranging from necrotizing arteritis to modest, chronic vas-
cular inflammation, to thrombosis without inflammation,
to remote vascular occlusion resembling atherosclerosis at
the level of small blood vessels in the brain, spinal cord,
peripheral nerves, and large vessels in the circle of Willis.
Immunocompromised Patients
Recognition of the ability of VZV to directly infect
blood vessel walls has been slow to occur46,5054 despite a
seminal report by Linnemann and Alvira54 in 1980 dem-
onstrating the virus in the outer layers of vessel walls in
a patient with Hodgkin disease and granulomatous angi-
itis after ophthalmic zoster. The use of immunohistochem-
istry, in situ hybridization, and PCR techniques has con-
firmed the presence of the virus in cranial blood vessels.5,6
Like Linnemann and Alvira,54 our laboratory has usually Figure 10. Varicella-zoster virus (VZV) arteriopathy in a 17-year-old
found evidence of virus in the outer vessel wall and not adolescent with acquired immunodeficiency syndrome (AIDS). A large
in the endothelium. Interestingly, the role of direct vas- meningeal blood vessel, showing intimal fibroblast proliferation, dis-
cular involvement by VZV as the underlying cause of dis- ruption of the internal elastic lamina (arrows), and compromise of the
ease has been underscored by the demonstration of viral luminal diameter without inflammation (hematoxylin-eosin, original
magnification 3150).
inclusions in abdominal blood vessels in an elderly cancer
patient with intestinal necrosis.55 In more remote cases,
particularly in cases of childhood AIDS associated with Such patients present clinically with headache, confusion
VZV, the vessel wall may develop a fibrotic, intimal pro- (Figure 11, A), focal weakness, or combinations thereof.
liferative lesion without inflammation, and the virus may AIDS patients with very low CD4 counts often develop a
or may not be demonstrable56 (Figure 10). greater extent of tissue penetration by VZV than do im-
In AIDS patients, VZV tends to reactivate from multiple munocompetent patients. In the brain, VZV involvement
dorsal root ganglia levels, and the disease is often dissemi- of small blood vessels or ependymal cells results in small-
nated. Skin lesions extend beyond 1 or 2 dermatomes, and vessel vasculopathy (Figure 11, B, D, and E) (multifocal
the viscera, spinal cord, and brain are often involved, with leukoencephalopathy) or ependymitis (ventriculitis), re-
or without concomitant rash. AIDS patients and other se- spectively.46,4549 Both MRI (Figure 11, B) and PCR of the
verely immunocompromised individuals often manifest un- CSF for VZV DNA (Figure 11, C) are helpful in the di-
duly dramatic and sometimes protracted infections.3,4,4549 agnosis.
776 Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden
Figure 11. Varicella-zoster virus (VZV) en-
cephalitis (small vessel arteriopathy). A, Clin-
ically, this condition usually manifests with
headache, fever, confusion, and focal deficits.
B, A magnetic resonance imaging scan shows
enhancing lesions deep in the cerebral white
matter and at the junctions of the gray and
white matter. C, Cerebrospinal fluid that is
positive for VZV, but not for herpes simplex
virus (HSV) or cytomegalovirus (CMV), by
premortem polymerase chain reaction. D, On
pathologic examination, ovoid areas of pallor
and demyelination contrast with the intense
blue of normal myelin (luxol fast blue and pe-
riodic acidSchiff stain, original magnifica-
tion 330). E, The perimeter of the demyelin-
ated areas shows herpetic owls eye viral
inclusions in glia (arrow) and endothelial
swelling in a small vessel (v) (hematoxylin-
eosin, original magnification 3350). Figure B
is used with permission; N Engl J Med. 2000;
342:635645. Copyright 2000, Massachu-
setts 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
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780 Arch Pathol Lab MedVol 125, June 2001 VZV Infections of the Nervous SystemKleinschmidt-DeMasters & Gilden

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