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Varicella-Zoster Virus: Atypical Presentations and Unusual Complications

John W. Gnann, Jr.

University of Alabama at Birmingham and Birmingham VA Medical

Center, Birmingham, Alabama

Varicella-zoster virus (VZV) causes two clinically distinct diseases. Primary infection results in varicella (chickenpox), a common and extremely contagious acute infection that occurs in
epidemics among preschool and school-aged children, is characterized by generalized vesicular rash. Like other a-herpesviruses, VZV establishes latency in neural tissue following primary infection. Reactivation of latent VZV from dorsal root
ganglia results in herpes zoster (shingles), a localized cutaneous
eruption accompanied by neuralgic pain that occurs most commonly in older persons. The typical clinical presentations of
varicella and herpes zoster are distinctive and readily recognized
by most experienced clinicians. However, atypical clinical presentations and uncommon complications of these diseases can
pose diagnostic and therapeutic challenges. This review will
address some less common manifestations of VZV infection
that can occur in otherwise healthy immunocompetent persons
and in special populations.

pneumonitis, but only about one-third of those with abnormal

chest radiographs will have respiratory symptoms [36]. As
discussed below, varicella pneumonia appears to be more frequent and more severe in pregnant women [7]. The onset of
respiratory symptoms (including cough, dyspnea, and sometimes hemoptysis) usually occurs within a few days of development of the varicella rash. The chest radiograph reveals a
diffuse interstitial nodular infiltrate [2, 8]. Prior to the availability of antiviral therapy, mortality rates of up to 30% were
reported for varicella pneumonia. However, with the advent of
antiviral treatment and intensive supportive care, the mortality
rate is now probably less than 10%. Although intravenous acyclovir has not been evaluated in controlled trials for treatment
of varicella pneumonia, abundant clinical experience and anecdotal reports indicate the drug is effective in this setting
[911].

Neurologic Complications

Varicella
Pulmonary Complications

Pneumonitis as a complication of varicella is rare in healthy

children but occurs with increased frequency in immunocompromised persons of all ages and in immunocompetent adolescents and adults [1, 2]. Among otherwise healthy adults with
varicella, 2.7%16.3% will have radiographic evidence of VZV
Financial support: GlaxoSmithKline (honoraria and research funding).
Reprints or correspondence: Dr. John W. Gnann, Jr., University of Alabama at Birmingham, Div. of Infectious Diseases, 845 S. 19th St., BBRB
220, Birmingham, AL 35294-2170.
The Journal of Infectious Diseases 2002; 186(Suppl 1):S918
2002 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2002/18608S-0012$15.00

The incidence of neurologic complications associated with

varicella is estimated to be 13 per 10,000 cases [12]. The central
nervous system (CNS) manifestations that occur most frequently with varicella are cerebellar ataxia and encephalitis
[1315]. Other rare neurologic complications include transverse
myelitis, aseptic meningitis, and Guillain-Barre syndrome
[1618]. Few data exist to help define the role of antiviral therapy for neurologic complications of varicella.
Varicella with cerebellar ataxia. Symptomatic cerebellar
ataxia occurs in about 1 in 4000 varicella cases [12]. The pathogenesis of this syndrome is incompletely understood, partly
because the illness is rarely fatal and few pathologic studies
have been reported. Possible mechanisms are direct viral infection of the cerebellum or a parainfectious immunologically
mediated demyelinating process. VZV-specific antibodies and

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Varicella-zoster virus (VZV) is the etiologic agent of varicella (primary infection) and herpes
zoster (reactivation of latent infection). Although varicella is most often a relatively benign
and self-limited childhood illness, the disease can be associated with a variety of serious and
potentially lethal complications in both immunocompetent and immunocompromised persons. One complication of varicella that appears to be increasing in frequency is serious
bacterial soft tissue infections caused by group A streptococci. Issues related to management
of varicella become especially complex when varicella involves pregnant women or susceptible
neonates. Herpes zoster can be associated with a variety of neurologic complications, including
a syndrome of delayed contralateral hemiparesis. Neurologic complications of herpes zoster,
including chronic encephalitis, occur with increased frequency in AIDS patients. VZV retinitis
is a potentially sight-threatening complication that occurs in both immunocompetent and
immunocompromised persons. Current knowledge regarding pathogenesis and antiviral therapy is reviewed.

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Gnann

Cutaneous Complications

The most common complication of varicella is bacterial superinfection of skin lesions, caused most often by Staphylo-

coccus aureus or Streptococcus pyogenes [33]. Bacterial cellulitis

can accentuate the scarring associated with varicella and can
be minimized by keeping the patients fingernails trimmed and
by using antibacterial soaps. More serious complications, including staphylococcal and streptococcal toxic shock syndromes, have been reported [34, 35]. Other cutaneous complications of varicella include bullous or hemorrhagic varicella
(more commonly seen in immunocompromised children) or
purpura fulminans, which is associated with thrombocytopenia
and disseminated intravascular coagulation.
A severe form of necrotizing soft tissue infection has been
described following varicella [36, 37]. Although varicella gangrenosa was first described by Hutchison in 1882, several investigators recently reported an increased frequency of severe
soft tissue infections caused by strains of group A b-hemolytic
streptococci, which can elaborate exotoxins and cause extensive
local tissue destruction [38, 39]. Therapy of varicella-associated
necrotizing fasciitis consists of early and aggressive surgical
debridement, appropriate antibiotic therapy, and intensive supportive care [40]. Adjunctive therapy with intravenous immunoglobulin may also be beneficial in patients with streptococcal
toxic shock syndrome and necrotizing fasciitis [41, 42]. Some
authors have suggested a possible association between the use
of nonsteroidal antiinflammatory drugs (NSAIDs; e.g., ibuprofen) and increased risk of varicella-associated necrotizing
fasciitis, although this remains controversial [43, 44]. Nonetheless, it seems prudent to avoid NSAIDs and to use alternative
drugs (e.g., acetaminophen) for relief of pain and fever in patients with varicella.

Maternal and Fetal Varicella Syndromes

Pregnant women, developing fetuses, and neonates are at risk

for mortality and serious morbidity from varicella. Perinatal
transmission of varicella can occur either vertically or horizontally. Vaccinating VZV-susceptible women prior to pregnancy could prevent all of these scenarios.
Maternal varicella. Although based more on case reports
than on prospectively acquired data, the evidence that varicella
in pregnancy is associated with enhanced morbidity is compelling [7, 45]. Women who contract varicella while pregnant
have an estimated 10% risk for developing severe VZV pneumonitis [46]. The risk of varicella during pregnancy is relatively
low in temperate climates, where only about 5% of young
women are VZV seronegative. In the United States, where over
95% of adults are VZV seropositive, varicella is estimated to
occur in about 5 of 10,000 pregnancies [4749]. The risk may
be higher in tropical regions where the incidence of childhood
varicella is lower and thus more young women are susceptible
to primary VZV infection [50, 51].
Aggressive antiviral therapy is recommended for a pregnant
woman with varicella who develops any evidence of pulmonary
involvement (including cough, shortness of breath, or abnormal
chest radiograph). Data from clinical trials are lacking, but

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antigens have been found in cerebrospinal fluid (CSF) of patients with varicella-associated cerebellar ataxia, suggesting that
VZV replicates within the CNS [1921].
Ataxia may develop from several days before to 2 weeks after
the onset of varicella, although the neurologic symptoms most
often occur simultaneously with rash [16]. Ataxia is usually
accompanied by vomiting, headache, and lethargy; nuchal rigidity and nystagmus occur in about 25% of patients. When
rash and ataxia occur together, the clinical presentation is sufficient to establish a diagnosis. The CSF is most often normal
but may show moderate lymphocytic pleocytosis (!100 cells/
mL) with mildly elevated protein in 20%30% of cases. The
cerebellar dysfunction associated with varicella is self-limited.
The vast majority of patients recover without apparent sequelae
within 13 weeks. Although there is no substantial evidence
that antiviral therapy alters the natural history of the cerebellar
ataxia syndrome, it is probably appropriate.
Varicella encephalitis. Encephalitis, the most serious CNS
complication of varicella, has an incidence of 12 episodes per
10,000 varicella cases, with the highest incidence in adults and
infants [22, 23]. The role of active VZV replication in the pathogenesis of varicella encephalitis remains uncertain [24]. Some
histopathologic studies have had features suggestive of a postinfectious demyelinating process, while other findings have been
more consistent with direct viral cytopathology [2527].
Neurologic symptoms (headache, fever, vomiting, and altered
sensorium) most often occur about 1 week after the onset of
the varicella rash [13, 14]. The onset of symptoms may be
abrupt or gradual and is accompanied by seizures in 29%52%
of cases [28, 29]. Abnormalities detected by neurologic examination can include ataxia, hypertonia or hypotonia, hyperreflexia or hyporeflexia, positive plantar reflexes, hemiparesis, and
sensory changes. The CSF findings are usually abnormal with
elevated opening pressure, a mild-to-moderate lymphocytic
pleocytosis (usually !100 cells/mL), mildly elevated protein (50
100 mg/dL), and normal glucose levels. Electroencephalography shows slow wave activity consistent with diffuse encephalitis. CNS imaging studies may show edema and areas of low
attenuation consistent with demyelination [25, 30, 31].
The mortality for varicella encephalitis is 5%10%, but the
majority of cases have complete or nearly complete recovery
[32]. Higher mortality rates cited in older literature probably
reflect a significant number of cases of Reyes syndrome. Longterm sequelae, including seizure disorders, may be present in
10%20% of survivors. The value of antiviral therapy for patients with varicella encephalitis has not been established by
prospective clinical trials. However, since no other treatment is
available and because acyclovir is extremely safe and well tolerated, therapy with intravenous acyclovir is warranted in persons with varicella encephalitis.

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VZV Atypical Presentations and Complications

before maternal antibody develops. These babies appear

healthy at birth but develop signs and symptoms of varicella
510 days after delivery. In addition, infants born to VZVseronegative mothers are at risk for severe varicella if infected
during the first few days of life. Conversely, infants who have
varicella lesions at birth or within the first 5 days of life (and
who, thus, received transplacental maternal VZV antibody
prior to delivery) are unlikely to have severe disease.
Perinatally acquired varicella is characterized by visceral organ involvement (including lung, liver, and CNS disease), with
a mortality rate of 30% [67, 68]. Infants delivered during the
high-risk window should receive prophylactic administration of
VZIG [69]. VZIG administration, even when it does not prevent
neonatal infection, appears to significantly reduce the risk of
life-threatening neonatal varicella [70, 71]. Since instances of
severe neonatal varicella have been described even in babies
who received appropriate dosing with VZIG, intravenous acyclovir therapy should be immediately instituted for any perinatally exposed baby who develops characteristic skin lesions.
The utility of other potential interventions, such as acyclovir
therapy for maternal varicella late in pregnancy, preemptive
acyclovir therapy of exposed newborns, or postexposure vaccination of infants, has not been adequately studied.

Varicella in Human Immunodeficiency Virus (HIV)Infected

Persons

The clinical presentation of varicella in HIV-seropositive children is usually similar to that seen in immunocompetent children, although some studies have reported a longer duration
of new lesion formation and higher median lesion counts
[7274]. The most common complication of varicella in this
population is cutaneous bacterial superinfection [75]. Cases of
visceral dissemination of VZV (including pneumonitis, hepatitis, and encephalitis) are uncommon.
After resolution of varicella, HIV-seropositive children are
at high risk for recurrent episodes of cutaneous VZV infection.
In some children with very low CD4 cell counts, the cutaneous
lesions of primary varicella may fail to heal and remain VZVculture positive, resulting in a syndrome of chronic varicella
[76]. About half of HIV-seropositive children who develop varicella will have a VZV recurrence within 2 years [76]. Recurrent
VZV infections may show as classic herpes zoster or as recurrent varicella characterized by a diffuse vesicular rash.
Because more than 95% of HIV-infected US adults are VZV
seropositive, varicella is unusual in this population. However,
when it occurs in HIV-infected adults, the infection may produce significant morbidity, including encephalitis and hepatitis
[77]. For HIV-infected children or adults with varicella, most
clinicians prescribe oral acyclovir or valacyclovir, reserving intravenous acyclovir for those with unusually severe or complicated infections [78]. No published studies have assessed the
efficacy of famciclovir for varicella treatment, but the drug
should theoretically be active.

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several case series have reported clinical improvement with intravenous acyclovir given to pregnant women with varicella
pneumonitis [52, 53]. Although acyclovir is not approved for
use during pregnancy for any indication, no fetal toxicity attributable to acyclovir has been documented and the risk-benefit ratio clearly supports use of acyclovir in the setting of
maternal varicella pneumonia [7, 45, 54].
Advisory committees have recommended administration of
varicella-zoster immune globulin (VZIG) to VZV-susceptible
pregnant women who have been exposed to varicella [55]. For
maximal efficacy, VZIG must be administered as soon as possible after exposure (and within 96 h). VZIG (as available in
the United States) is administered by deep intramuscular injection at a dose of 125 U/10 kg of body weight, to a maximum
of 625 U. Intravenous immunoglobulin also contains substantial VZV-specific IgG and may be substituted if VZIG is not
available. Unfortunately, in this time-critical scenario, the true
VZV serologic status of a pregnant woman with a negative
history for varicella is often not known. The clinician may be
faced with a decision to initiate passive immunoprophylaxis
empirically or to wait for serologic testing [56]. The ideal time
to determine VZV serologic status would be before pregnancy
when vaccination could be offered to women confirmed to be
seronegative [57]. Varicella vaccination of pregnant women is
not currently recommended because of the theoretical risk of
the live virus vaccine for both the fetus and mother. Prophylactic therapy with acyclovir for a pregnant woman after VZV
exposure should be effective, but is an unproven approach.
Congenital varicella. A rare but well-defined fetal varicella
syndrome may result when a woman acquires varicella during
the first or second trimester of pregnancy [58, 59]. The embryopathy is characterized by limb hypoplasia, ocular and neurologic abnormalities, and distinctive cicatricial skin scarring
in a dermatomal pattern [60]. The pathogenesis of the syndrome
is thought to be invasion of the fetal nervous system by VZV
during a critical stage of development [61]. Fortunately, fetal
varicella syndrome is uncommon, arising in only 2% of cases
of maternal varicella occurring during the first 20 weeks of
gestation [62]. Due to the rarity of the syndrome, there are no
data to indicate whether antiviral therapy given to a pregnant
woman with varicella can reduce the risk of embryopathy.
A very small number of cases of congenital VZV syndrome
have been reported after maternal herpes zoster [59]. However,
because the mother has preexisting antibody and because herpes zoster results in only low-level viremia, the risk to a fetus
from maternal herpes zoster is extremely low. Babies born to
mothers who have varicella during pregnancy may develop herpes zoster during infancy [63].
Perinatal varicella. VZV infection of neonates may result
from either vertical or horizontal transmission. If maternal varicella appears during a window of about 4 days before to 2
days after delivery, the neonate is at high risk (24%48%) for
developing varicella [6466]. The period of greatest risk is when
the infant is delivered after the onset of maternal viremia but

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Herpes Zoster
Neurologic Complications

amplified from the CSF of encephalitis patients by polymerase

chain reaction (PCR) techniques [79, 97]. The clinical course is
often progressive deterioration and death, although anecdotal
reports have suggested benefit with high-dose intravenous acyclovir therapy [90, 98].
Zoster sine herpete. Clinicians frequently encounter patients who present with zoster-like neuropathic pain but never
develop the characteristic dermatomal rash. Recent detailed
studies of a few patients presenting with dermatomal pain have
established that some of these cases are due to VZV reactivation. Patients with this syndrome, termed zoster sine herpete,
have rising titers of VZV-specific antibody in both serum and
CSF and have VZV DNA in CSF and peripheral blood mononuclear cells detectable by PCR [99, 100]. Since there is no easy
means for making the diagnosis, the incidence of zoster sine
herpete is not known. In anecdotal reports, responses to antiviral therapy have been inconsistent.

Herpes Zoster in the Immunocompromised Host

The risks of cutaneous and visceral dissemination of VZV

in severely immunocompromised patients (e.g., bone marrow
transplant recipients) are well recognized [101]. Commonly reported complications include VZV pneumonia, encephalitis,
and hepatitis. The mortality associated with disseminated zoster
has been substantially reduced by the availability of effective
antiviral therapy [102, 103]. An unusual presentation of herpes
zoster in the immunocompromised host is atypical generalized
zoster. These patients present with diffuse varicella-like skin
lesions with no obvious primary dermatomal involvement [104]
and are VZV seropositive prior to development of the rash, so
the syndrome is not primary varicella. Risk factors for development of atypical generalized zoster appear to be the same as
those for classic herpes zoster. The syndrome most likely represents herpes zoster with a limited area of involvement in the
primary dermatome, followed quickly by generalized cutaneous
dissemination.
A more serious manifestation of herpes zoster in the immunocompromised host is abdominal zoster. These patients
present with severe abdominal pain that may precede the appearance of the cutaneous rash by hours to days [105, 106].
The diagnosis of herpes zoster is usually not considered until
the typical skin vesicles begin to appear, usually in a thoracic
dermatome. The patients have a high mortality rate despite
initiation of appropriate antiviral therapy. Autopsy studies have
revealed a high frequency of abdominal visceral involvement
with VZV.

Herpes Zoster in AIDS

Compared with immunocompetent populations, herpes zoster

is much more common in HIV-infected persons, occurring at a
rate of 3050 cases per 1000 persons-years [107109]. In general,

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Neurologic complications of herpes zoster can occur coincident with the acute eruption or appear weeks to months after
the rash has resolved. The most common neurologic complication of herpes zoster is chronic pain (postherpetic neuralgia),
which occurs with sufficient frequency that it should be considered a part of the natural history of the disease (reviewed
elsewhere in this supplement). Distinct neurologic syndromes
associated with herpes zoster include acute or chronic encephalitis, ophthalmic zoster with contralateral hemiparesis, myelitis, polyradiculitis, motor neuropathies, and a variety of cranial and peripheral nerve palsies, including Bells palsy and
Ramsay Hunt syndrome [79].
Delayed contralateral hemiparesis. Hemiparesis is a rare
but serious complication of herpes zoster that can occur weeks
to months (mean, 7 weeks) after an episode of herpes zoster
involving the first division of the trigeminal nerve [8082]. The
pathogenesis of this syndrome is thought to be direct VZV
invasion of cerebral arteries by extension along intracranial
branches of the trigeminal nerve, resulting in inflammation of
the internal carotid artery or one of its branches on the side
ipsilateral to the rash [83]. The typical presentation is headache
and hemiplegia occurring in a patient with a recent history of
herpes zoster ophthalmicus (HZO). Examination of CSF reveals mononuclear cell pleocytosis (usually !100 cells/mL) and
increased protein [84]. Arteriography is usually diagnostic and
demonstrates inflammation, narrowing, and thrombosis of the
proximal branches of the anterior or middle cerebral artery [85,
86]. Both acyclovir and corticosteroids are used to treat this
syndrome, although no interventions have been evaluated in
controlled trials [87, 88]. Antiviral therapy is warranted because
of the demonstrated presence of VZV in the inflamed arteries,
but benefit of therapy is difficult to assess since irreversible
cerebral infarction has often occurred by the time of diagnosis.
The mortality rate is 20%25% and there is a high probability
of permanent neurologic sequelae among survivors [80, 84].
Chronic VZV encephalitis. This variant of VZV encephalitis
is seen almost exclusively in patients with AIDS or other conditions with depressed cellular immunity. The onset of the encephalitis may occur months after an episode of herpes zoster,
making the diagnosis more difficult [89]. Pathologic studies reveal
multifocal lesions in the white matter near the gray-white junction, with small vessel vasculitis and demyelination [90, 91]. The
clinical presentation is usually subacute with headache, fever,
mental status changes, seizures, and focal neurologic defects, including aphasia, hemiplegia, and visual field cuts [9294]. Magnetic resonance imaging studies demonstrate plaque-like lesions
in deep white matter, changes consistent with demyelination, and
late development of ischemic or hemorrhagic infarcts of cortical
and subcortical gray and white matter [95, 96]. Examination of
CSF reveals mild mononuclear pleocytosis. VZV DNA has been

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VZV Atypical Presentations and Complications

Acute Retinal Necrosis (ARN)

VZV-associated ARN has been described in both immunocompetent and immunocompromised persons. Since the advent
of the AIDS epidemic, a more aggressive variant of this disease
(sometimes termed rapidly progressive herpetic retinal necrosis
[RPHRN]) has been identified [118, 119]. Visual changes are
usually noted weeks to months after the antecedent herpes zoster. ARN can follow either HZO or herpes zoster in a remote
dermatome. Furthermore, retinal involvement is bilateral in
over half of cases, suggesting that VZV reaches the CNS via
hematogenous spread, possibly with extension along nerve
pathways within the anterior visual system [118]. VZV retinitis
presents with multifocal necrotizing lesions, often initially involving the peripheral retina. The granular, nonhemorrhagic
lesions rapidly extend and coalesce, accompanied by relatively
little intraocular inflammation [120122].
In AIDS patients, VZV retinitis rapidly progresses to full
thickness retinal necrosis, usually with retinal detachment, resulting in blindness in 75%85% of involved eyes [118]. Since
the involved eye is rarely salvageable in HIV-infected patients
with RPHRN, the goal is to try to prevent disease progression
in the uninvolved eye. Intravenous acyclovir alone is ineffective
[122]. Some experts recommend intravenous therapy with gan-

ciclovir or foscarnet (or a combination of the two) together

with intravitreal injections of ganciclovir [123, 124]. Anecdotal
success with cidofovir has also been reported. Results of antiviral therapy for VZV retinitis in HIV-infected patients, regardless of regimen, have been disappointing.
ARN in immunocompetent patients is a less virulent disease
and more responsive to antiviral therapy. In this setting, acyclovir is clearly beneficial for preserving useful vision [125, 126].
A suggested antiviral regimen for ARN in the otherwise healthy
host is intravenous acyclovir 1015 mg/kg every 8 h for 1014
days, followed by oral valacyclovir 1 g 3 times daily for 46
weeks, although this treatment approach has never been studied
in a controlled fashion.

Conclusion
Most clinicians readily recognize typical clinical signs and
symptoms of varicella and herpes zoster. However, in certain
circumstances and in special populations, VZV infection can
present with unusual manifestations and can cause potentially
life-threatening complications. Clinicians must be aware of
these presentations and be prepared to perform appropriate
diagnostic studies. For example, a patient presenting with delayed contralateral hemiparesis may not be appropriately
treated unless the acute clinical presentation is linked to the
history of recent trigeminal zoster. Fortunately, most unusual
manifestations of VZV are rare. The complications of varicella
will become even less common as use of the varicella vaccine
becomes more widespread.
The low incidence of VZV-related disorders means that attempts to conduct traditional controlled therapeutic trials with
adequate numbers of patients are fraught with difficulty. Even
with multicenter clinical trials networks, performing prospective studies on diseases like varicella encephalitis or congenital
varicella are probably impossible. Since the morbidity associated with many of these complications is substantial and the
risks associated with antiviral therapy are low, many physicians
appropriately initiate antiviral therapy on the basis of limited
anecdotal data. Although rigorous prospective controlled clinical trials are likely not feasible, it is still critical to collect
information regarding the utility of antiviral therapy for these
complications of varicella and herpes zoster. Well-documented
case series (e.g., valacyclovir therapy for varicella in pregnancy
or for varicella cerebellar ataxia) can still provide extremely
valuable data and should be actively pursued.

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