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Atypical Brainstem Encephalitis Caused by Herpes Simplex Virus 2
Kon Chu, MD;
Dong-Wha Kang, MD, PhD;
Jung-Ju Lee, MD;
Byung-Woo Yoon, MD, PhD
Arch Neurol. 2002;59:460-463.
ABSTRACT
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Background Herpes simplex encephalitis is one of the most common and serious sporadic
encephalitides of immunocompetent adults. Herpes simplex virus 2 (HSV-2) infections
of the central nervous system usually manifest as subacute encephalitis, recurrent
meningitis, myelitis, and forms resembling psychiatric syndromes.
Objectives To report and discuss magnetic resonance imaging (MRI) findings and
clinical features in atypical brainstem encephalitis and facial palsy associated
with HSV-2.
Setting Neurology department of a tertiary referral center.
Patient A 37-year-old woman was admitted to the hospital with fever, diplopia,
left hemiparesis, sensory change in the face and limbs, personality changes,
frontal dysexecutive syndrome, and a stiff neck. Brain MRI showed multifocal
high-signal intensities in the pons, midbrain, and frontal lobe white matter
on T2-weighted and fluid-attenuated inversion recovery images. Cerebrospinal
fluid (CSF) polymerase chain reaction (PCR) amplification analysis was positive
for HSV-2. Acyclovir therapy was started, and the encephalitic symptoms disappeared
with a negative conversion of HSV-2 PCR in the CSF. However, after the discontinuation
of acyclovir therapy, peripheral facial palsy occurred on the left side. A
possible relapse or delayed manifestation of the HSV-2 infection was suspected,
and the acyclovir therapy was restarted. A complete remission was achieved
3 days after the treatment. She was discharged without any neurologic sequelae.
Conclusions We describe a patient who developed atypical encephalitis due to HSV-2
and peripheral facial palsy, which could also be related to the HSV-2. This
case suggests that HSV-2 should be considered among the possible causes of
atypical or brainstem encephalitis and that the PCR amplification method of
the CSF can help reveal the possible cause of HSV-2.
INTRODUCTION
HERPES SIMPLEX encephalitis (HSE) is one of the most common and serious
sporadic encephalitides of immunocompetent adults. It can present at any age
and has an estimated incidence of between 1 in 250 000 and 1 in 1 million
persons a year.1-2 Herpes simplex
viruses (HSVs) are ubiquitous human pathogens; they are widespread in the
adult population, with a rate of seropositivity of 60% to 100% for HSV-1 and
10% to 80% for HSV-2.1-2 In the
largest study of HSE to date, HSV-1 or HSV-2 DNA was detected by a nested
polymerase chain reaction (PCR) assay in 82 and 6 of 93 patients, respectively,
with the assay showing a 95% sensitivity.3
The pathologic lesions of classic HSV-1 encephalitis are characteristically
located in the temporal lobes. In addition, the orbital surface of the frontal
lobe and cingulate gyrus may be involved.3
A range of clinical presentations of HSV infection of the nervous system,
including mild disease courses, relapsing and remitting encephalitis, or unusual
neurologic syndromes, sometimes related to specific anatomic locations, has
been described.3 Brainstem encephalitis is
caused mainly by HSV-1.4-15
However, HSV-2 infections in the central nervous system usually manifest as
acute meningitis and not infrequently as subacute encephalitis, recurrent
meningitis, myelitis, and forms resembling psychiatric syndromes3;
they rarely involve the brainstem. Herein, we describe a patient who developed
atypical encephalitis due to HSV-2 involving mainly the brainstem and peripheral
facial palsy caused possibly by a relapse or delayed manifestation of HSV-2
infection.
REPORT OF A CASE
A 37-year-old woman was admitted to the hospital for diplopia and hypesthesia
in the face. She was well until 8 days before admission, when she experienced
the onset of febrile sense and generalized constitutional symptoms. The viral-like
syndrome progressed the following day, with the development of a dull occipital
headache, accompanied by nausea and vomiting. Four days before admission,
mild dysarthria, bilateral facial hypesthesia, and diplopia developed. Gait
instability and personality changes, which were characterized by disinhibition,
were also noticed. Fever developed on the day of admission. She denied any
history of recent infection and other neurologic illnesses. She had a history
of genital herpes, which previously had not been treated. Neurologic examination
revealed mild frontal executive dysfunctions, bilaterally gaze-evoked nystagmus
with small amplitude, diplopia, bilateral facial hypesthesia, dysarthria,
left-sided pronator drift, sensory decrease of the bilateral limbs in all
modalities, generalized hyperreflexia, bilateral cerebellar ataxia, a positive
Romberg test result, and a stiff neck. The gynecologic examination revealed
no evidence of acute or chronic genital lesions. Eye and ear examinations
showed no abnormalities.
Cerebrospinal fluid (CSF) examination revealed an elevated opening pressure
(21 cm H2O), a white blood cell count of 29 cells/µL (polymorphonuclear
leukocytes, 3 cells/µL; lymphocytes, 11 cells/µL; monocytes, 15
cells/µL), no red blood cells, and a slightly elevated protein level
(0.054 g/dL) (Table 1). The CSF
PCR was performed in our infection laboratory as previously described.16 The presence on an ethidium bromide–stained
gel of PCR products of the expected size (518, 524, and 589 base pairs corresponding
to HSV-1 and HSV-2, Epstein-Barr virus [EBV], and cytomegalovirus [CMV], respectively)
attested to the specificity of the PCR assay. Although the CMV-amplified product
was accurately identified by its molecular weight, HSV and EBV, which led
to PCR products of similar sizes, needed further characterization. The specific SmaI and BamHI patterns of these
amplified PCR products clearly distinguished HSV from EBV. In addition, this
restriction analysis permitted an unambiguous discrimination between HSV-1
and HSV-2 genomes by comparing sizes. The PCR methods for searching for enterovirus
were performed as previously described.17 Results
of a PCR test of the CSF were positive for HSV-2, which was confirmed by direct
sequencing. The PCRs for other viral pathogens, such as CMV, EBV, and enterovirus,
revealed no abnormalities. Electroencephalography results were normal. Magnetic
resonance imaging (MRI) of the brain (Figure
1) showed multifocal high-signal intensities in the pons, midbrain,
subcortical white matter of the frontal lobe, and external capsule on fluid-attenuated
inversion recovery imaging. The main lesion was situated in the brainstem.
However, there was no involvement of the medial temporal lobes.
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Table 1. Summary of CSF Findings and Clinical Courses*
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Figure 1. A, Fluid-attenuated inversion
recovery magnetic resonance imaging shows multifocal hyperintensities in the
pons with swelling. B, Additional lesions are shown in external capsule and
frontal white matter.
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Intravenous administration of acyclovir, 30 mg/kg, was started on the
third hospital day (HD). Her encephalitic symptoms disappeared in 10 days.
Follow-up PCR of the CSF on the seventh HD revealed negative conversion for
HSV-2. However, mild lymphocytic pleocytosis, with a blood cell count ranging
from 24 cells/µL to 202 cells/µL, remained in follow-up CSF examinations
and protein values were normal (Table 1). Intermittent fever, a slightly stiff neck, and mild headache
persisted during acyclovir therapy. Other neurologic symptoms improved completely
by the 27th HD.
One day after the discontinuation of acyclovir (28th HD), sudden peripheral
facial palsy developed on the left side without facial sensory or taste changes.
A blink reflex test showed an efferent pathway abnormality of the left facial
nerve. In addition, MRI of the internal auditory canal, performed on the 28th
HD, demonstrated a focal enhancement and enlargement of the left facial nerve
between the geniculate ganglion and the descending part of facial nerve (Figure 2). At that time, CSF PCR test results
were negative for HSV and mild lymphocytic pleocytosis. A presumptive diagnosis
of facial neuritis, caused possibly by the relapse or delayed manifestation
of HSV-2 infection was made, and the patient again starting taking acyclovir
intravenously with oral prednisone. Facial palsy disappeared completely by
the 31st HD, 3 days after the acyclovir therapy was reinitiated. She was discharged
without any neurologic complications.
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Figure 2. Magnetic resonance image of the
internal auditory canal shows the enlargement and focal gadolinium enhancement
of the left facial nerve (white arrow).
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COMMENT
Atypical presentations have been reported in 20% of HSE patients in
a large series confirmed by PCR amplification of viral DNA from the CSF.18 Widespread use of the CSF PCR amplification method
might improve recognition of mild or atypical cases of HSE with excellent
sensitivity and specificity. Our case presents several interesting occurrences.
First, although HSV-2 has rarely been reported to cause brainstem encephalitis,
the HSV-2 encephalitis in our patient involved mainly the brainstem. There
has been just one previous case reported by a group of Japanese investigators.19 In the Japanese study, the MRI results of the patient
were normal, and the diagnosis of brainstem HSE was made on the basis of the
clinical symptoms and a CSF PCR test result positive for HSV-2. In our patient,
MRI of the brain showed atypical findings for HSE owing to HSV-2: bilateral
involvement of the pons, midbrain, and white matter of frontal lobe. The frontal
dysexecutive syndrome and personality change could be explained by the involvement
of frontal lobe white matter and the sensory symptoms, diplopia, and increased
deep tendon reflexes by the bilateral involvement of the pons and midbrain.
Second, the clinical course of our patient was mild compared with the
usual course of HSE, which is usually devastating. The initially positive
CSF PCR test result in our patient was converted to negative in 10 days with
acyclovir therapy, and neurologic symptoms and signs resolved completely while
the patient was undergoing acyclovir therapy, except for the remaining CSF
pleocytosis and a mild headache.
Third, peripheral facial palsy developed after the discontinuation of
acyclovir therapy. In addition, MRI of the internal auditory canal showed
a mildly enlarged facial nerve with gadolinium–diethylenetriamine penta-acetic
acid enhancement, consistent with the findings of facial neuritis. The clinical
usefulness of internal auditory canal MRI in facial neuritis has been reported
previously.20-21 This occurrence
raises the questions of the possibility of the causative role of HSV-2. At
this time we can only speculate that a relapse or a delayed manifestation
of HSV-2 infection may have been the possible cause of the facial palsy, because
we were not able to clarify the probable mechanism; at the onset of the facial
palsy, the CSF PCR test result was negative for HSV, and a salivary fluid
PCR was not performed. However, the immediate response to the prednisone and
acyclovir suggests an inflammatory mechanism.
Herpes simplex virus infection has long been postulated as a cause of
peripheral facial palsy. However, a direct relationship between HSV-1 reactivation
and peripheral facial palsy has been demonstrated in only a few cases. Some
authors22-25
have reported viral DNAs for HSV-1 in endoneurial fluid, muscle, saliva, and
geniculate ganglion in patients with peripheral facial palsy and experimental
models. Recently, Kohler et al26 investigated
CSF abnormalities in 265 patients with acute peripheral facial palsy, using
antibody responses in the CSF. In their series, 35 of the 265 patients had
nonidiopathic causes of facial palsy: herpes zoster (n = 17), Lyme disease
(n = 8), human immunodeficiency virus infection (n = 8), sarcoidosis (n =
1), and HSV-1 (n = 1). In the assessment of acute-onset cases, clinical presentation
is the most important clue as to a specific cause, and a CSF analysis may
provide additional information early in the disease. The validity of this
relationship between HSV-1 and facial nerve palsy is difficult to prove, because
it is impossible to definitively confirm an etiologic mechanism involving
the facial nerve since a biopsy cannot be performed without causing permanent
nerve damage. The indirect diagnosis of HSV-1 relapse by serologic tests is
itself problematic because there are no specific elevations of antibodies
in HSV-1 reactivation.27-28 However,
using the PCR amplification method, Murakami et al25
found HSV-1 DNA in 79% of the patients with Bell palsy and 89% with Ramsay-Hunt
syndrome. They suggested that facial palsy with a CSF PCR test result negative
for HSV-1 might have been caused in part by etiologic agents other than HSV-1,
such as HSV-2 or herpes zoster virus.
Finally, another distinctive feature of this case report is that we
used the PCR amplification method to detect viral DNA in the CSF. The PCR
amplification method has been suggested as the gold standard for diagnosing
HSE.16, 18 In previous literature
on brainstem HSE, mainly caused by HSV-1, diagnoses were made by the serum
and CSF viral antibody testing.18 However,
PCR-proven brainstem encephalitis is rare. The clinical profiles and salient
features of the herpetic brainstem encephalitis, proven by CSF PCR, are summarized
in Table 2.
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Table 2. Summary of Recent Cases With Herpetic Brainstem Encephalitis
Proven by CSF PCR*
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Herein, we describe a patient who developed atypical encephalitis due
to HSV-2 and peripheral facial palsy, which could also be related to HSV-2.
This case suggests that HSV-2 should be considered among the causes of atypical
or brainstem encephalitis and that the PCR amplification method of the CSF
can help reveal the possible cause.
AUTHOR INFORMATION
Accepted for publication January 17, 2001.
Author contributions: Study
concept and design (Drs Chu, Lee, and Yoon); acquisition
of data (Drs Chu, Lee, and Yoon); analysis and interpretation
of data (Drs Chu, Kang, and Yoon); drafting of the
manuscript (Drs Chu, Lee, and Yoon); critical revision
of the manuscript for important intellectual content (Drs Chu, Kang,
Lee, and Yoon); administrative, technical, and material
support (Drs Chu, Kang, Lee, and Yoon); study supervision (Dr Yoon).
This study was supported by the Seoul National University Hospital Research
Fund.
We thank Grace Wang, PharmD, for her editorial support.
Corresponding author and reprints: Byung-Woo Yoon, MD, PhD, Department
of Neurology, Seoul National University Hospital, 28, Yongon-Dong, Chongno-Gu,
Seoul 110-744, South Korea (e-mail: bwyoon{at}snu.ac.kr).
From the Department of Neurology and Clinical Research Institute (Drs
Chu, Kang, and Lee), and Neuroscience Research Institute (Dr Yoon), Seoul
National University Hospital, Neuroscience Research Institute of SNUMRC (Drs
Chu, Kang, Lee, and Yoon), Seoul, Korea.
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