Case Report
Herpes Zoster Encephalitis
2 Case Reports and Review of Literature
Rachel Espiritu, MD and Michael Rich, MD
Abstract: Herpes zoster encephalitis (HZE) is a rare complication
of varicella-zoster virus infection. Because of its nonspecific
clinical presentation, HZE is underrecognized. The advent of
polymerase chain reaction for detecting viral particles in cerebro-
spinal fluid provides a rapid and accurate means of diagnosis. Two
patients with HZE diagnosed by a positive cerebrospinal fluid–
polymerase chain reaction and neurological changes are presented,
Downloaded from http://journals.lww.com/infectdis by BhDMf5ePHKbH4TTImqenVI2V1DuJ82ZX0Lr/ajvcsitEnLLUU0MkrmFSp1tUgVCV on 06/29/2018
and the literature is reviewed. We provide a practical approach to
the diagnosis and treatment of HZE and conclude that HZE is
underdiagnosed and should be considered in all patients with
encephalitis even in the absence of a herpes zoster rash.
(Infect Dis Clin Pract 2007;15:284–288)
V aricella-zoster virus (VZV) causes a primary illness
known as varicella or chicken pox that usually occurs in
childhood, becomes latent in the cranial nerve and sensory
nerve ganglia, and can later reactivate to cause herpes zoster
or shingles. In rare occasions, zoster sine herpete occurs,
which is herpes zoster without the characteristic rash.1
It has been estimated that 0.01% to 0.25% of patients
with varicella develop overt neurological complications such
as cerebellar ataxia, encephalitis, transverse myelitis, aseptic
meningitis, polyneuritis, cranial neuropathies, and Reye
syndrome.2,3 Neurological sequelae are more common in
the herpes zoster phase.4 These sequelae include—in order of
decreasing incidence—postherpetic neuralgia, cranial nerve
palsies, peripheral motor neuropathy, myelitis, encephalitis,
thrombotic cerebral vasculopathy, acute ascending polyradi-
culitis, and aseptic meningitis.2,5
Herpes zoster encephalitis (HZE) is an uncommon
complication of herpes zoster.6–8 Immunosuppression is the
principal risk factor for the development of HZE.9–11
Historically, the diagnosis of HZE depended on the presence
of the characteristic rash along with the temporal development
of clinical encephalitis.3 With the advent of the polymerase
chain reaction (PCR) technique for identifying VZV in the
cerebrospinal fluid (CSF), HZE can be definitively diagnosed,
thus allowing for directed therapy.12,13
CASE 1
A 57-year-old man presented with a 6-day history of
localized zoster on the right thigh. Three days after the outbreak
Internal Medicine Center, Summa Health System, Akron, OH.
Address correspondence and reprint requests to Rachel Espiritu, MD,
Internal Medicine Center, Summa Health System, 55 Arch St, Suite 1B,
Akron, OH. E-mail: rach_espiritu@yahoo.com.
Copyright n 2007 by Lippincott Williams & Wilkins
ISSN: 1056-9103/07/1504-0284
284 Infectious Diseases in Clinical Practice  Volume 15, Number 4, July 2007
Copyright @ Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
of the rash, he developed headache, neck pain, and fever, followed
by confusion, memory impairment, and drowsiness with episodes
of agitation and restlessness. He had a history of type 2 diabetes
mellitus and stage I B-cell chronic lymphocytic leukemia. He had
no recent travel, animal exposure, corticosteroid intake, chemo-
therapy, or radiation therapy. Physical examination showed a blood
pressure of 151/66, pulse rate of 75/min, respiratory rate of 20/min,
temperature of 99.58F, nuchal rigidity, and an erythematous
bandlike vesiculopapular rash over the right third lumbar derma-
tome. Neurological examination revealed an altered sensorium and
the presence of asterixis and bilateral ankle clonus. Otherwise,
result of the neurological examination was normal. Results of the
following were normal: serum electrolytes, renal and hepatic
profiles, urinalysis, electrocardiography, chest roentgenography,
and head computed tomography (CT). Complete blood cell count
was significant for leukocytosis (22,600 cells/uL), which consisted
of 75% lymphocytes, 20% neutrophils, 3% monocytes, and 2%
eosinophils. Lumbar tap showed a cloudy CSF. Cerebrospinal fluid
analysis revealed 2110 white blood cell per microliter with 96%
lymphocytes. Cerebrospinal fluid glucose was 52 mg/dL (reference
range, 40–80 mg/dL), which was 44% of the serum glucose of
117 mg/dL (normal, >40%), and protein was elevated at 320 mg/
dL (reference range, 15–60 mg/dL). Intravenous acyclovir (1000
mg every 8 hours) and intravenous ceftriaxone (2 g daily) were
initiated. The patient continued to exhibit a generalized cerebral
impairment with slow speech, disorientation, personality changes,
poor insight and judgment, impaired recent memory, and visual
hallucinations. He did not develop seizures or focal neurological
deficits. Bacterial antigens in CSF for Haemophilus influenzae,
Streptococcus pneumoniae, group B Streptococcus, and Neisseria
meningitidis were not detected. Levels of vitamin B12, folate, and
thyroid-stimulating hormone were all within normal limits. The
finding of a serum fungal immunodiffusion panel for Aspergillus,
Blastomyces, Candida, Coccidioides, and Histoplasma was nega-
tive; the finding of a serum cryptococcal antigen was also negative.
Ceftriaxone was discontinued. Cerebrospinal fluid cytology was
performed and was consistent with reactive pleocytosis from a viral
infection. No virus was isolated from culture of the skin lesion
done on the sixth hospital day. The result of a purified protein
derivative skin test was negative. Results of CSF bacterial,
mycobacterial, and fungal cultures were negative. Results of CSF
herpes simplex virus (HSV) DNA and Enterovirus RNA by PCR
were negative. Varicella-zoster virus DNA PCR was positive. A
magnetic resonance imaging (MRI) of the brain was remarkable
only for the presence of a left choroidal detachment. Ophthalmo-
logic and slit lamp examinations revealed glaucoma that was
attributed to acute scleritis from the choroidal detachment possibly
caused by the patient’s recent VZV infection. There were no
external ophthalmic lesions. The patient was treated with a 3-week
course of intravenous acyclovir and was transferred to an extended
care facility for rehabilitation. One month later, there was
considerable improvement in his neurological function but then
developed another decline in mental status. The CT and MRI
of the head were unremarkable except for a finding of acute
mastoiditis on the right side. A lumbar puncture now revealed only
Infectious Diseases in Clinical Practice  Volume 15, Number 4, July 2007
67 nucleated cells with 92% lymphocytes, a normal glucose
(88 mg/dL), and an elevated protein level (178 mg/dL). The results
of bacterial, fungal, and mycobacterial cultures of CSF were again
negative. Results of PCR testing for HSV and VZV were negative.
Cerebrospinal f luid cytology showed no malignant cells. The
patient has since made little neurological progress. An electroen-
cephalography (EEG) 1 month after revealed a diffuse severe
encephalopathy without focal abnormalities or seizure activity.
CASE 2
A 58-year-old man was admitted with a 2-day history of
bizarre behavior and confusion associated with nausea, vomiting,
and generalized weakness. Five days before, the patient was
evaluated for left axillary chest pain and nausea. The finding on the
initial workup was negative. His medical history included type 2
diabetes mellitus complicated by peripheral neuropathy. Physical
examination was remarkable for a blood pressure of 118/80, pulse
rate of 75/min, respiratory rate of 18/min, temperature of 100.88F,
and a vesicular rash with an erythematous base distributed over the
left third and fourth thoracic dermatomal levels. Neurological
examination was significant for drowsiness, disorientation, and
confusion without focal deficits. Complete blood cell count,
comprehensive drug screen, chest roentgenography, and urinalysis
were unremarkable. A basic metabolic panel revealed acute renal
failure attributed to dehydration. The patient received 2 g of
intravenous cefotaxime, 1 g of intravenous vancomycin, and 800 mg
of intravenous acyclovir and underwent lumbar puncture with CSF
analysis showing a glucose of 136 mg/dL, a protein of 61 mg/dL, 6
red blood cell per microliter, and 127 white blood cell per microliter
consisting of 1% neutrophils, 92% lymphocytes, and 4% monocytes.
Results of Gram stain and bacterial culture were negative.
Vancomycin and cefotaxime were thus discontinued. Intravenous
acyclovir (800 mg) was given continuously every 8 hours. By the
next hospital day, there was dramatic improvement in the patient’s
sensorium. The acute renal failure resolved with hydration. An MRI
of the brain showed mild atrophy with remote small vessel ischemic
changes. Results of blood and urine cultures were negative.
Cerebrospinal fluid PCR for VZV was positive. The patient received
intravenous acyclovir for 1 week and was discharged home with
significant improvement in his symptoms.
DISCUSSION
The overall age-adjusted annual incidence rate of
herpes zoster has been reported to be 1.3 per 1000 person-
years.2,14 It occurs approximately in 1% of the general
population and in up to 25% of those with underlying
neoplasms.15 However, the incidence of HZE in the general
population is unknown. Among patients infected with VZV,
HZE has been found to occur in approximately 0.1% to
0.2%.16 Reports have shown that neurological complications
of herpes zoster are infrequent except for postherpetic
neuralgia. Herpes zoster accounts for 8% to 13% of the cases
of herpes zoster–associated neurological complications
excluding postherpetic neuralgia.17–19 A recent prospective
study identified VZV as the most common etiology in adult
patients with acute encephalitis.20
Herpes zoster encephalitis has greater prevalence in
such immunocompromised states as acquired immune defi-
ciency syndrome, transplantation, malignancy, and advanced
age.1,5,10,11 Patients with leukemia or lymphoma seem to be
at particular risk for VZV reactivation in general and HZE
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Herpes Zoster Encephalitis
specifically.21 In a retrospective study of 1125 patients with
systemic cancer, HZE occurred in almost 1% of the
population.11 In another cohort study comprising 962 patients
diagnosed with chronic lymphocytic leukemia, 2 patients
developed herpes zoster–related encephalitis.14 In a Finnish
study, HZE was reported to be the leading cause of
encephalitis in patients older than 65 years.22
The severity and location of herpes zoster involvement
affect the risk for development of HZE. In 1 study, 10 of 32
patients with disseminated herpes zoster had encephalitis.23
Disseminated herpes zoster increases the risk of developing
encephalitis by 30%.2 Herpes zoster encephalitis also seemed
to be more common after trigeminal distribution of shingles
compared with other sites.11,15 The presence of 2 or more
prior episodes of herpes zoster and cervical nerve involve-
ment has also been found to predispose to the development
of HZE.2 In both patients presented previously, diabetes
mellitus was present and may have increased the suscepti-
bility to develope HZE. Diabetes has been implicated as a
predisposing factor in the development of herpes zoster–
associated neurological disease.18
Varicella-zoster virus can affect any area of the central
or peripheral nervous system through a vasculopathic
process.10,12 Herpes zoster encephalitis–affected patients
may present with such diverse findings as multiple ischemic
and hemorrhagic infarctions, demyelinating disease, sei-
zures, peripheral neuropathy, and mental status changes.23–25
Generalized cerebral impairment is common and may
include a decreased level of consciousness, behavioral and
personality changes, cognitive decline, and memory impair-
ment. These deficits are suggestive of a subcortical type of
cognitive impairment similar to that reported in 1997 in a
study of 40 patients with HZE.23,26
In HZE, the occurrence of a recent or concomitant
episode of herpes zoster or shingles is important in
distinguishing this entity from other causes of encephalitis.
The onset of central nervous system (CNS) symptoms
usually occurs days to weeks, sometimes up to months after
the herpes zoster eruption.2,5,25 In a small number of cases,
neurological manifestations appear before the appearance of
a rash or, even rarer, in the absence of a rash.5,24,27
Interestingly, Koskiniemi et al17 reported that 40% of 174
patients with HZE had zoster sine herpete. Seizures and
ataxia are infrequent sequelae of HZE.23,28 Fever is usual at
the onset of the rash and CNS symptoms but then resolves
with improvement in neurological status.23
After the development of herpes zoster, the virus can
spread to the spinal cord and brain, leading to CNS
complications.1 Herpes zoster encephalitis exists in any or
a combination of 3 pathological patterns—large vessel
vasculopathy, small vessel vasculopathy, and ventriculitis/
meningitis, thus explaining the variability of the presentation
of the disease.10 In all cases, the main pathological finding is
ganglionic hemorrhage and inflammation.29 Large-vessel
encephalitis predominantly affects elderly immunocompe-
tent patients and is characterized by acute focal neurological
deficits such as hemiplegia or blindness.1,25 Small-vessel
encephalitis is more commonly seen in immunocompro-
mised patients who present with fever, headache, mental
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Espiritu and Rich Infectious Diseases in Clinical Practice  Volume 15, Number 4, July 2007
status changes, seizures, and focal deficits. Imaging shows
multiple deep-seated ischemic or demyelinating lesions in
neural white matter. Ventriculitis, the least common form of
HZE, occurs with VZV infection of ependymal cells and
may produce ataxia and hydrocephalus.1
In the past, diagnosis of HZE was inferred by the
coexistence of an encephalitic state with the herpes zoster
rash. Electroencephalography abnormalities, compatible
CSF results, and exclusion of other causes of encephalitis
then supported the diagnosis.23 Cerebrospinal fluid viral
culture and antibody detection are conclusive, but the delay
in obtaining results compromises timely initiation of
therapy.30 Cerebrospinal fluid analysis typically shows a
lymphocytic pleocytosis with high normal–to-elevated
protein levels and normal glucose levels. Such findings
support the diagnosis of HZE but are not specific, occurring
in other forms of CNS infection and in many as half the
cases of uncomplicated herpes zoster.9,15,31 Rare cases of
HZE with low CSF glucose have been reported.32,33 Cell
counts and protein levels do not seem to correlate with
disease severity.23
Brain computed tomographic scans are generally
unremarkable in patients with HZE and are mainly used to
exclude other diagnoses such as tumor or hemorrhage.28
Magnetic resonance imaging is more sensitive and specific
than CT for evaluating viral encephalitis.12 Magnetic
resonance imaging findings that are suggestive of encepha-
litis from herpes zoster infection include discrete subcortical
nonenhancing spherical lesions that eventually coalesce,
develop enhancement, and spread to the gray matter.8
Autopsy reveals these spherical lesions to be the areas of
demyelination and hemorrhagic infarction.8 However, MRI
abnormalities have also been observed in patients with
uncomplicated herpes zoster, with the CNS lesions
corresponding to the homuncular distribution of the rash.9
Another technique that has been found to be helpful in the
diagnosis of acute encephalitis is single photon emission
computed tomography. In combination with the clinical
presentation, CSF studies, and radiographic results, the
finding of unilateral hyperperfusion on single photon
emission computed tomography has been found to signif-
icantly increase the diagnostic yield for viral encephalitis,
including HZE.34 Most patients with HZE demonstrate mild
diffuse slowing of brain activity without focal abnormalities
on EEG.15,23 This abnormality also lacks specificity for HZE
because nearly 31% of patients with herpes zoster without
neurological manifestations have abnormal EEG findings.28
Diagnosis of VZV CNS infection has also been done using
electron microscopy of CSF through identification of the
characteristic viral cytopathic effect, rate of progression of
this effect, and cell susceptibility. However, this tool does
not provide a rapid means of diagnosis but may be valuable
in confirming viral dissemination into spinal fluid and in
evaluating the efficacy of antiviral therapy.35
The diagnostic armamentarium has been improved with
the recent introduction of VZV PCR.36 Detection of viral
DNA using PCR identifies recent or ongoing CNS infec-
tion.12,37 Polymerase chain reaction, in combination with
detection of intrathecal specific immunoglobulin G antibody,
286
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represents the most accurate method of diagnosis of
neurological infections including HZE.38 A ratio of antibody
levels in serum to CSF of 20 or less indicates intrathecal
antibody production, provided no other antibodies are present
in the CSF.13 In 1 study, VZV antibodies can be measured by
indirect membrane immunofluorescence in up to 94% of
patients with HZE.2 Detection of VZV by PCR provides a
quick, minimally invasive, and accurate diagnostic marker for
HZE especially when there is no concomitant rash.39
Polymerase chain reaction for viral DNA has been observed
to be present as early as day 3 after the appearance of vesicles
with results available within 1 day, unlike viral culture and
serology which take more than a week to obtain results.30,37
Negative PCR results do not rule out the diagnosis. False-
negative results may be due to insufficient DNA in CSF or
variation in viral genome with advanced disease.37 Because
VZV DNA may be undetectable in patients with HZE,
antibody testing of CSF for VZV has been recommended to
confirm the diagnosis.16,17 Cerebrospinal fluid PCR retains
its sensitivity after initiation of antiviral therapy and thus
permits empirical treatment before obtaining CSF.12
Polymerase chain reaction is also very useful in cases
where serological techniques may be equivocal because of
the presence of cross-reactive HSV and VZV antibodies.39
One disadvantage of PCR is the fall in sensitivity in
protracted cases. It was observed that CSF VZV PCR was
positive only in patients with overt neurological deficits
during the acute phase—initial 1 to 2 weeks of the disease—
when the amount of replicating virus is maximal.12 It has
been shown that PCR become negative over time because the
replicating virus and viral DNA do not persist indefinitely in
the CSF.12 Cerebrospinal fluid antibody testing is particularly
useful in this group of patients with neurological symptoms
manifesting weeks to months after the onset of the rash.37
Multiplex PCR, which can detect several viral DNA
simultaneously, is cost effective, although sensitivity and
specificity still need to be determined.30 This test may be
most useful in patients in whom viral encephalitis is
considered, but a specific agent is not clinically evident.
Because of the rarity of HZE, randomized control trials
have not been performed to assess medical treatment.
Moreover, the significant morbidity of HZE coupled with
the benign side-effect profile of antiherpetic therapy make it
unlikely that a placebo-controlled study could be ethically
performed. Numerous case reports and case series have
illustrated the effectiveness of acyclovir in HZE.40 However,
other case reports suggest that acyclovir may be ineffective
in HZE.18 Acyclovir administration is standard therapy
despite limited data because of its relatively benign side-
effect profile and the significant morbidity associated with
HZE.3 Although not proven to eradicate VZV, treatment with
acyclovir prohibits active infection and presumably keeps the
virus in its latent state.24 Doses used for VZV encephalitis
have been similar to that proven to be effective for herpes
simplex encephalitis—10 to 15 mg/kg intravenously every
8 hours for a duration of 10 to 14 days.13,41 The efficacy of
therapy is implied by the disappearance of VZV DNA with
antiviral treatment. One study revealed undetectable VZV
DNA by PCR in patients treated with acyclovir for at least
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Infectious Diseases in Clinical Practice  Volume 15, Number 4, July 2007
2 days but persistence of viral DNA in a third of patients with
less than 2 days of treatment or those without treatment.9
Cerebrospinal fluid PCR may thus be useful in monitoring
therapeutic response and determining prognosis in patients
with HZE.12,29 Clinical failure after treatment with acyclovir
may be due to persistence of the virus in the CSF, inadequate
CNS drug concentration, or development of acyclovir-
resistant strains.41 Alternative approaches such as the use of
drug combinations or other drugs including famciclovir or
sorivudine have been successfully used for VZV infection, but
no information is available for cases with associated neurolog-
ical complications.41 Another antiviral agent, ganciclovir, has
been shown to be effective in some patients with varicella
zoster encephalitis.40 In 1 case of HZE where acyclovir
resistance occurred, vidarabine was found to be effective.42
The use of corticosteroids in HZE is controversial,
perhaps best suited for immunocompetent patients with
severe encephalitis or evolving cerebral edema.13 It is
unknown if antiviral therapy prevents the development of
HZE in patients with shingles. A recent multicenter trial
proved the efficacy of the zoster vaccine, a vaccine 14 times
the potency of the current live varicella virus vaccine
(VARIVAX), in markedly reducing the incidence of herpes
zoster (by 51.3%) in older adults.43 This vaccine should thus
potentially reduce the incidence of HZE, especially in
susceptible immunocompetent patients who can receive the
vaccine.
In a 1983 study evaluating 25 patients with HZE, the
average length of neurological symptoms was approximately
16 days, with note of longer duration in cases of dissemi-
nated herpes zoster and immunocompromised states.23 In
another report, the mean duration of CNS symptoms was 3
and 7 days, respectively, for acyclovir-treated and nontreated
patients.28 The clinical outcome in patients with HZE has
been variable. In a study by Jemsek et al,23 patients con-
sistently returned to their preencephalitic mental status
regardless of severity of disease. Normal cognitive function
resulted in 90% of cases.23 This was comparable with other
studies wherein most patients with HZE recovered com-
pletely with26 or without44 antiviral therapy. A slow but
eventual return to baseline cognitive state was the trend
in 12 cases of HZE.23A separate study reported long-term
neurological sequelae of HZE to be present in up to 30%
of patients.5 Other studies have found the rate of HZE
mortality to be as high as 20% to 50%.5,15 Deaths from HZE
have been mainly attributed to nonneurological complica-
tions such as pneumonia.5
CONCLUSIONS
The clinical manifestations of HZE are variable,
nonspecific, and often indistinguishable from other forms
of encephalitis. Older and immunosuppressed individuals are
more prone to acquiring the disease. The finding of an
antecedent or concurrent episode of herpes zoster rash is a
key in the diagnosis but is not always present. The CSF VZV
PCR, a rapid and highly sensitive test, is most valuable in
proving the diagnosis of HZE and thus should be used when
HZE is being considered. Timely treatment with acyclovir
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Herpes Zoster Encephalitis
may be beneficial and should be instituted empirically in
suspected cases.
ACKNOWLEDGMENT
The authors thank Dr Joseph Myers for his valuable
comments and suggestions.
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