Download Case report Successful treatment of Epstein–Barr virus encephalitis

Antiviral Therapy 2013; 18:257–261 (doi: 10.3851/IMP2451)
Case report
Successful treatment of Epstein–Barr virus
encephalitis in the setting of HIV-associated
neurocognitive disorder: a diagnostic and
therapeutic challenge
Janine M Trevillyan1*, Andrew A Mahony1, Catriona McLean2,3, Jennifer F Hoy1,4
Infectious Diseases Department, Alfred Hospital, Melbourne, Australia
Anatomical Pathology Department, Alfred Hospital, Melbourne, Australia
3
Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
4
Department of Infectious Diseases, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
1
2
*Corresponding author e-mail: [email protected]
We report a challenging case of HIV-associated neurocognitive disorder with superimposed Epstein–Barr virus
(EBV) encephalitis. The patient presented with an abnormal MRI brain scan, and EBV DNA that was detected
in the cerebrospinal fluid and brain biopsy, which also
demonstrated histopathological findings consistent with
the diagnosis. This occurred on the background of a
12-month period of gradual cognitive decrease secondary to HIV-associated dementia. Invasive testing was
required to reach the diagnosis in this case, highlighting
the importance of thorough investigation of neurological
impairment in HIV-positive patients. Clinicopathological
recovery was achieved through optimization of antiretroviral therapy and use of valganciclovir.
Introduction
We present the case of a 48-year-old woman with an
acute deterioration in neurological function secondary
to Epstein–Barr virus (EBV) encephalitis on the background of a 12-month period of intermittent neurological symptoms and mild cognitive impairment caused by
HIV-associated neurocognitive disorder (HAND). We
believe this is the first published case of its kind and
highlights the importance of thorough investigation of
neurological symptoms in HIV-infected patients. Management with antiviral therapy targeted at both EBV
and HIV is explored.
Case details
The patient was diagnosed with HIV in 1989 and commenced antiretroviral therapy (ART) in 1994. She had
a CD4+ T-cell nadir of 209 cells/µl. She transitioned
through multiple antiretroviral regimens as the result
of significant side effects, including pancreatitis, rash,
angioedema and lipodystrophy. Despite excellent CD4+
T-cell recovery, except for a short period in 1997, she
failed to maintain full virological suppression and, at the
time of onset of this illness, was receiving didanosine,
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lamivudine and ritonavir-boosted atazanavir, with a
CD4+ T-cell count of 833 cells/µl and a peripheral HIV
viral load of 700 copies/ml (range over previous 5
years of 0–1,250 copies/ml). She had no other significant medical history or previous AIDS-defining illnesses
and was known to be EBV immunoglobulin-G-positive
from 1991. Prior to this presentation, she worked full
time in a care provision capacity, smoked 10–15 cigarettes per day and drank small amounts of alcohol.
In the 12 months leading up to her acute hospital
admission, she was seen by her specialist infectious diseases physician and reported intermittent fluctuating
neurological symptoms characterized by daytime somnolence, anxiety, short-term memory impairment and
episodes of transient asymmetrical upper limb tremor
and paraesthesia that interfered significantly with hand
function. The symptoms progressed until she was unable
to maintain full-time employment. As part of a detailed
work-up, she underwent an MRI brain scan, which
demonstrated on T2-weighted images non-specific discrete areas of high-signal abnormality diffusely throughout both cerebral hemispheres (Figure 1A). Possible
differential diagnoses raised included demyelinating
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conditions, cerebral vasculitis or gliomatosis cerebri.
The patient was reviewed by a neurologist; at that time,
there were self-reported improvements in her cognitive
deficits and no objective neurological findings elicited.
Thus, an approach of close observation and monitoring
was adopted. At this stage, she was reluctant to alter her
currently well-tolerated antiretroviral regiment despite
persisting low-level HIV viraemia.
Figure 1. Axial flair MRI brain images
A
B
C
D
(A) MRI at first presentation: diffuse patchy signals predominantly affecting white matter. (B&C) MRI at time of hospital admission: progression of extensive white
matter signal change, now globally affecting the cerebral hemispheres and cerebellum bilaterally. (D) MRI at 12 months follow-up: moderate resolution of the
supratentorial white matter hyperintensities with resolution of the cerebellar signal abnormality (not shown).
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EBV encephalitis in the setting of HIV-associated neurocognitive disorder
There was a significant resurgence in symptoms 6
months later. She was the driver in a single-car lowspeed motor vehicle accident (during which no major
injuries were sustained) and became progressively
ataxic, leading to a number of unprovoked falls. Family members reported increasing impulsiveness and
disorientation with episodes of dysarthria and lower
limb weakness, prompting hospital admission. Her
neurological examination now demonstrated a fine
tremor with slowed coordination and truncal ataxia.
There was a progressive worsening of the lower limb
findings with subtly increased tone and hyper-reflexia
bilaterally. She underwent a lumbar puncture and cerebrospinal fluid (CSF) sampling, which demonstrated
an elevated total protein count of 1.13 g/l and a reactive lymphocytosis (24×106 cells/l). The HIV viral load
in the CSF was 7,000 copies/ml and a real-time PCR
(RT-PCR) for EBV was positive. Culture for bacterial
and fungal pathogens was negative, as was PCR testing for polyomaviruses, herpes simplex viruses 1 and 2,
varicella zoster virus, cytomegalovirus, human herpesvirus-6 and Tropheryma whippeli. There was no detectable cryptococcal antigen.
Repeat MRI brain scan (Figure 1B and 1C) demonstrated progressive extensive, asymmetrical and confluent white matter changes in the cerebral hemispheres
and cerebellum bilaterally.
The ART regimen was changed to maximize peripheral viral control and CSF drug penetration. Given her
extensive treatment experience and known archived
resistance mutations, she commenced a regiment of lamivudine, raltegravir, etravirine and ritonavir-boosted darunavir (twice daily). Genotyping (ViroSeq®) subsequently
showed major protease inhibitor (D30N and N88D) and
reverse transcriptase mutations (M41L, E44D, D67N,
T69D, V118I, M184V, L210W, T215Y and K219Q).
Although the radiological findings were felt to be
consistent with a viral encephalopathy, the presence of
EBV by PCR in the CSF (with its known associations
with primary central nervous system lymphoma), the
tempo of the illness and the unusual pattern of neurological findings mandated a brain biopsy to rule out
underlying malignancy. Histopathologically, this demonstrated a florid reactive meningoencephalitis and
­leukoencephalitis, which was not consistent with a diagnosis of HAND. EBV immunoperoxidase studies demonstrated scattered positively reactive cells, and EBV
PCR on the tissue samples was also positive (Figure 2A,
2B and 2C). Immunoperoxidase studies and PCR for
other infectious aetiologies, including herpes simplex
virus, varicella zoster virus, cytomegalovirus and polyomaviruses, as well as culture for Cryptococcus, were
negative. No evidence of lymphoma was found.
She commenced oral valganciclovir 900 mg twice
daily and over the following 2 weeks made a significant
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recovery with improved memory, mood and complete
resolution of physical findings, including balance and
coordination. Subjectively, there were increased energy
levels and appetite, and, objectively, she recorded
improved scores on formal neuropsychological testing. One month into therapy her peripheral HIV viral
load was <50 copies/ml, with a CD4+ T-cell count of
968 cells/ml. Repeat lumbar punctures showed a normalization of total protein, an absence of EBV DNA
on PCR and durable HIV suppression within the CSF.
There has been a slow improvement in imaging findings
on serial MRI brains to date (Figure 1D).
She completed a 6-month course of valganciclovir
and, following 12 months post-completion of therapy,
is living independently at home with only minor residual neurocognitive deficits, predominantly short-term
memory impairment.
Discussion
Despite the high EBV seroprevalence in the community
[1], EBV encephalitis is rare, with neurological complications estimated to occur in 0.7–7.3% of all cases of
acute EBV infection [2].
In HIV-infected patients, it has been thought that the
detection of EBV DNA in the CSF is both a sensitive
and specific marker of primary central nervous system lymphoma (PCNSL) [3]. However, with increasing
awareness and availability of PCR testing, EBV DNA
has been detected within the central nervous system of
patients with a wide variety of clinical presentations [4].
In fact, although the sensitivity for PCNSL may indeed
be as high as 97%, as initially reported, the specificity
has been shown to be much lower in a number of studies [5–7]. Detection of high levels of EBV DNA in the
CSF of patients with concurrent low peripheral plasma
levels is consistent with intracerebral EBV reactivation
and, in the setting of clinical symptoms and CSF lymphocytosis, supports the diagnosis of viral encephalitis.
Intrathecal EBV replication is often detected in the presence of other infectious pathogens and diagnoses, and,
although this interaction is yet to be fully explained, it
raises the possibility that latent intracerebral EBV infection can be reactivated by concurrent viral (including
HIV) and bacterial infections, leading to poorer outcomes in some instances [4,8].
Aciclovir, ganciclovir and valganciclovir have each
been successfully used in a variety of clinical settings
for the treatment of EBV infections [9–12]. Ganciclovir
has been shown to decrease the quantitative EBV PCR
in the CSF of HIV-infected patients, but this has not
been correlated with clinical outcomes [13].
In 2007, Katramados et al. [14] described the case of
a 39-year-old woman with well-controlled HIV presenting with progressive neurological signs, an abnormal
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Figure 2. Photomicrographs showing the histopathology of cerebral biopsy
A
B
C
(A) CD3 immunoperoxidase studies: numerous small reactive T-cells are present. (B) Representative slice of white matter demonstrating florid perivascular lymphocytic
cuffing with reactive microglia and macrophage infiltration; consistent with leukoencephalitis. (C) Epstein–Barr virus (EBV) latent membrane protein immunoperoxidase
studies; fine cytoplasmic EBV immunoreactive granules within glial cells suggests EBV infection of cells. Hematoxylin and eosin staining, original magnification ×400.
MRI and EBV DNA detectable in the CSF. As in our
case, a brain biopsy demonstrated diffuse lympho- and
plasma-cytic infiltration with mononuclear perivascular cuffing. With no change in ART, the patient made
a full recovery, with one episode of relapse, following
treatment with intravenous ganciclovir.
Our patient’s rapid clinical deterioration, abnormal
MRI brain scan and positive EBV PCR in the CSF
and brain tissue, along with the histopathological
findings, support the diagnosis of EBV encephalitis.
The CSF lymphocyte count (24×109 cells/l) was lower
than expected for an acute viral encephalitis but does
not exclude the diagnosis and may have been affected
by HIV coinfection. Our case is unique in that the
encephalitis occurred in the setting of chronic HAND.
Prior to her acute hospital admission, she was documented to have had a slow 12-month decline in
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multiple domains of higher cognitive function, associated with persistent HIV viraemia and non-specific
imaging findings: all consistent with a diagnosis of
HAND [15].
It has been suggested that the optimal treatment for
HAND includes antiretroviral agents with enhanced
central nervous system penetration. In particular,
agents such as abacavir, zidovudine, ritonavir-boosted
protease inhibitors and nevirapine are commonly recommended [16]. However, clinical studies have not
demonstrated consistent improvement in neurological function when patients are changed to these agents
[17]. In our case, the decision was made to change her
regimen because of persisting low grade viraemia (both
peripherally and within the CSF). In combination with
EBV-targeted antiviral therapy, this led to a significant
and sustained clinical recovery.
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EBV encephalitis in the setting of HIV-associated neurocognitive disorder
Conclusions
7.
EBV encephalitis is rare and has not previously been
reported in the setting of HAND. This case highlights
the importance of a thorough investigation of neurological impairment in HIV-positive patients and proposes the use of both antiviral and antiretroviral agents
in this setting.
8.
9.
10.
Disclosure statement
JFH has served on advisory boards for Gilead Sciences,
ViiV Healthcare, Janssen Cilag and Merck, Sharp &
Dohme. Her institution has received research support
from Merck, Sharp & Dohme and Gilead Sciences, and
honoraria for speaking or chairing engagements from
Gilead Sciences and Janssen Cilag. All other authors
declare no competing interests.
2.
3.
4.
5.
6.
12.
13.
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Accepted 23 July 2012; published online 6 November 2012
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