A DIFFICULT CASE

Successful outcome of EpsteinBarr

virus encephalitis managed with
bilateral craniectomy, corticosteroids
and aciclovir
Emma Hayton,1 Benjamin Wakerley,2 Ian CJW Bowler,1 Marko
Bogdanovic,3 Jane Elizabeth Adcock2

Department of Microbiology,
John Radcliffe Hospital,
Oxford, UK
2
Department of Neurology, John
Radcliffe Hospital, Oxford, UK
3
Department of Neurology, Royal
Berkshire Hospital, Reading, UK
Correspondence to
Jane Elizabeth Adcock,
Department of Neurology, John
Radcliffe Hospital, West Wing,
Headley Way, Oxford, Oxon OX3
9DU, UK; jane@fmrib.ox.ac.uk

Summary
We present a 19-year-old woman with severe
encephalitis and raised intracranial pressure
requiring decompressive craniectomy. Her clinical
features were consistent with encephalitis in the
context of acute primary EpsteinBarr virus (EBV)
infection (infectious mononucleosis). Serology,
bone marrow aspirate and PCR of blood and
cerebrospinal uid conrmed the diagnosis.
She was treated with corticosteroids and
aciclovir. She was critically unwell for 3 weeks,
requiring articial ventilation but eventually
made a good recovery. EBV encephalitis is
uncommon, making the diagnosis and decisions
about clinical management challenging.

History

A 19-year-old female university student presented with a 24-h history of

increasing drowsiness and confusion,
preceded by 6 days of fever, malaise,
headache, vomiting and abdominal
pain. On arrival, her Glasgow coma
scale score was 12. Her temperature
was 37.2C. There was no meningism or skin rash, no papilloedema
and no focal neurology. She had a
generalised tonic-clonic seizure in
the emergency department before
being intubated and transferred to
the intensive care unit. CT and MR
scans of brain were both normal, as
was cerebrospinal fluid (CSF) (protein: 0.54 g/dl; glucose: 3.4 mmol/l;
acellular). She was treated empirically with intravenous aciclovir for
suspected viral meningoencephalitis,
with ceftriaxone to cover for bacterial meningitis.
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Two days later, she had elevated

liver enzymes (serum alanine aminotransaminase: 1278 U/l (535)).
She became anaemic (Hb 10.0 g/dl)
and mildly thrombocytopenic (platelet count 112109/l (150400)).
There were atypical lymphocytes on
her blood film. Abdominal ultrasound
demonstrated hepatosplenomegaly.
Monospot and HIV tests were negative. Amoxicillin was added to her
antimicrobial regimen. A maculopapular rash developed the next day.
On day 5, during attempted extubation, she showed reduced left limb
movements. MR brain with gadolinium revealed an ischaemic lesion in the
splenium of the corpus callosum, but
no cerebral oedema or other pathology. Repeat CSF showed opening
pressure of 71 cmH2O, significantly
elevated protein (1.86 g/dl) and white
cell count 64/L (80% mononuclear).
Papilloedema developed on day 7 and
repeat CT brain with contrast showed
generalised cerebral oedema with
early uncal and cerebellar tonsillar
herniation (figure 1). Dexamethasone
8 mg three times daily was started,
and she was transferred urgently to
a neurosurgical centre for bifrontal
decompressive craniectomies.
On day 9 (2 days after craniectomy) we received confirmation of
EpsteinBarr virus (EBV) infection,
with positive serum EBV viral capsid
antigen IgM, and EBV DNA in blood.
Aciclovir was continued for a total

A DIFFICULT CASE

Figure 1 CT brain scan with sagittal and axial views. Day 1: CT brain normal. Day 7: CT brain with contrast: generalised cerebral
oedema with early uncal and cerebellar tonsil herniation.

of 3 weeks and the corticosteroids tapered over

1 month. She was extubated on day 20 and transferred to a neurorehabilitation ward where she
made excellent progress and was discharged with
minimal cognitive and physical disability 6 weeks
later. Repeat MR brain scan showed no parenchymal signal change and the ischaemic lesion in
the splenium had disappeared. At 5 months, she
underwent successful hemicranioplasty and at 6
months follow-up there was no residual neurological or cognitive deficit (Adenbrookes cognitive examination score of 99/100).
Discussion

EBV was suspected initially on demographic

grounds, with an acute (likely viral) illness in a

previously healthy young adult in the social context of undergraduate life. Monospot test was
negative on day 2 of admission: this test has lower
sensitivity early in the illness. Subsequent serology was consistent with acute primary EBV infection (figure 2). Bone marrow aspirate on day 11
also showed typical EBV changes, and excluded
the haemophagocytic syndrome.
Typical features of EBV included elevated liver
enzymes, bone marrow suppression and abnormal
blood film with atypical lymphocytes, splenomegaly and a rash followed amoxicillin. The severe
encephalitis was atypical and dominated her clinical presentation.
Encephalitis is relatively rare and large studies
tell us that the cause often remains elusive. The

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A DIFFICULT CASE

Figure 2 Graphical representation of clinical, serological and haematological progression of a young woman with EBV encephalitis.
Note that WCC refers to cerebrospinal uid white cells.

California Encephalitis Project1 found a specific

cause in 38% cases, and a nationwide French
study2 in 52%. A recent UK study, which included
immune-mediated cases,3 attributed a cause to
63% cases. EBV accounted for 4/325, 3/253
and 1/203 in these studies, respectively, a range
of 0.5%1.2%. The ongoing EncephUK study,
including an epidemiological approach to the
aetiology of encephalitis, will help to determine
the true incidence of EBV encephalitis (http://
www.encephuk.org).
Some studies list EBV as a probable cause of
encephalitis on the basis that serology was positive
whereas PCR of the CSF was not. Our literature
review suggests that positive EBV serology in an
appropriate clinical context is more reliable than
PCR of the CSF. The second of our patients CSF
samples was positive for EBV at the limit of the sensitivity of the assay, whereas the first (acellular) sample was negative. PCR of CSF is most likely to give
a diagnosis between days 3 and 14 of an illness, and
when leucocytes are present in the sample.4 There
is no evidence of a strong association between CSF
and serum white cell counts, and it is the former
that is most closely associated with prognosis.
Published case reports suggest that EBV can
cause a very diverse range of central nervous
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system (CNS) disease, including encephalitis,

meningitis, myelitis and neuropathy.5 The mechanisms by which the virus exerts its effects on the
CNS remain to be elucidated. EBV is also reported
as the causative agent in postinfectious acute disseminated encephalomyopathy (ADEM),6 where
the pathogenesis is likely to be different.
Although there are theoretical reasons for using
aciclovir, which reduces replication and nasopharyngeal shedding of EBV,7 there is no evidence
that it confers clinical benefit in EBV encephalitis. Nevertheless, because of its low toxicity and
potential benefit, the consensus is to give a 23
week course, as for herpes simplex virus (HSV)
encephalitis. Twenty-one days treatment is recommended for patients aged 3 months to 12 years
or those with immune compromise. The soon to
be published UK national encephalitis guidelines
recommend 14 days of treatment, followed by
repeat LP to assess for viral clearance.
Corticosteroids are widely used to modify the
inflammatory process of ADEM but their role in
viral encephalitis is debated. The German Trial of
Acyclovir and Corticosteroids in HSV-Encephalitis
study,8 once published, should clarify the role
of early adjuvant corticosteroids in encephalitis
caused by HSV. We found one case report where

A DIFFICULT CASE

they were used as part of the successful treatment

of EBV encephalitis (although the time course and
presence of inflammatory lesions on MRI in this
case from Japan might suggest a postinfectious
aetiology).9
Decompressive craniectomy in cases of cerebral oedema refractory to medical management
is better established, with several case reports
describing excellent outcome in the context of
meningitis or encephalitis.1012 We found only
one other report of decompressive surgery specifically in EBV encephalitis, also in an immunocompetent man who went on to make a full
recovery.13
There are too few data (mostly anecdotal)
to predict outcomes in encephalitis caused by
EBV. Death and disability have certainly been
reported,14 but there are sufficient reports of full
recovery even in severe disease to give hope to the
families of those afflicted.15 16
Conclusion

EBV should be considered as a cause of encephalitis and serological tests carried out where firstline investigations have failed to give a diagnosis.
Negative tests, and in particular lumbar puncture,
taken early in the course of an illness may need to
be repeated. Craniotomy and the use of corticosteroids should be considered in selected cases.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned;
externally peer reviewed. This paper was reviewed
by Benedict Michael, Liverpool, UK.

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