J Neurooncol (2011) 103:771–776

DOI 10.1007/s11060-010-0438-8

CASE REPORT

Herpes simplex encephalitis following spinal ependymoma

resection: case report and literature review
Daniel M. S. Raper • Alvin Wong •
Paul C. McCormick • Linda D. Lewis

Received: 1 August 2010 / Accepted: 30 September 2010 / Published online: 13 October 2010
Ó Springer Science+Business Media, LLC. 2010

Abstract Herpes simplex encephalitis (HSE) is a rare HSV, though outcomes may be poor even in optimally
complication of neurosurgical procedures but must be con- treated cases. Empiric treatment must be started even in the
sidered in early deterioration of the postoperative patient. absence of serologic evidence of HSV infection if suspicion
This is the first report of HSE following spinal cord tumor for HSE is high.
resection. A 65-year-old woman had C2–C5 laminectomy
for subtotal resection of intramedullary ependymoma. Keywords Herpes simplex
Encephalitis

Six days postoperatively she developed fever, vomiting Ependymoma
Complication
and rapid decline in mental status. Brain MRI revealed
enhancement of left insular cortex. Polymerase chain reac-
Abbreviations
tion on cerebrospinal fluid (CSF) identified herpes simplex
CSF Cerebrospinal fluid
virus type 1 (HSV-1) as the causal agent. Twenty-one days of
DVT Deep vein thrombosis
acyclovir led to improvement. Three subsequent admissions
EVD External ventricular drainage
to neurological intensive care unit were required for deteri-
HSE Herpes simplex encephalitis
oration in mental status, including pneumonia, hydroceph-
HSV Herpes simplex virus
alus and deep vein thromboses. Ventriculoperitoneal shunt
NICU Neurological intensive care unit
(VPS), tracheotomy, percutaneous intravenous central
PCR Polymerase chain reaction
catheter (PICC) line and percutaneous endoscopic gastros-
PEG Percutaneous endoscopic gastrostomy
tomy (PEG) were placed. She was discharged to skilled
PICC Percutaneous intravenous central catheter
nursing home care. Acyclovir is effective therapy against
POD Post operative day
VPS Ventriculoperitoneal shunt

D. M. S. Raper (&)
Graduate Medical Program, University of Sydney, Level 7,
Kolling Building, Royal North Shore Hospital, St Leonards,
NSW 2065, Australia
Introduction
e-mail: drap7157@uni.sydney.edu.au

A. Wong Herpes simplex encephalitis (HSE) is the most common

College of Physicians & Surgeons, Columbia University, cause of sporadic fatal viral encephalitis worldwide yet is a
New York, NY, USA
rare event, with an incidence of 1–4 per million [1].
P. C. McCormick Untreated, the mortality rate is 70% [1]. Even with
Department of Neurological Surgery, Columbia University, appropriate treatment, rates of debilitating neurological
New York, NY, USA sequelae and mortality reach 30% [2]. Risk factors for HSE
include immunosuppression, stress and previous encepha-
L. D. Lewis
Department of Neurology, Columbia University, litis [1, 2]. HSE rarely follows resection of intracranial
New York, NY, USA tumor with only 12 cases reported in the literature [3–13].

123
772 J Neurooncol (2011) 103:771–776

In those cases, stress of surgery and postoperative steroid

use may have triggered reactivation of latent infection.
Here we describe the first reported case of HSE following
incomplete resection of a spinal cord intramedullary
ependymoma. We emphasize the need to use acyclovir
early in the course of such patients.

Clinical presentation

The major clinical events in this case are summarized in

Fig. 1. Briefly, a 65-year-old woman with diabetes mellitus
noted gradual onset of progressive bilateral hand clumsi-
ness, numbness and increasing gait difficulty. MRI
revealed an intramedullary cervical mass (Fig. 2), which
was treated on at our institution by C2–C5 bilateral cervical
laminectomy, midline myelotomy and radical subtotal
resection of an intramedullary tumor (a WHO grade II
ependymoma). Postoperative dexamethasone was started at
10 mg q 6 h tapering to zero over 7 days. She was dis-
charged on post operative day (POD) 3 to acute inpatient
rehabilitation.
Two days later the patient became febrile with altered
mental status and vomiting, and was admitted to another
hospital. She was initially treated for Klebsiella and
Proteus urosepsis with vancomycin and piperacillin/tazo-
bactam, and cefepime was added on POD 7 on suspicion of
meningitis. Brain and cervical spine MRI demonstrated
subtle meningeal enhancement; an EEG at this time
showed moderate diffuse slowing consistent with multifo-
cal cerebral dysfunction but not definitively ictal in nature.
Due to lack of improvement and cerebrospinal fluid (CSF)
consistent with viral infection (Table 1), acyclovir was
added on POD 8 for suspected herpes encephalitis. She
remained febrile with altered mental status and was trans-
ferred to our institution on POD 10.
Admission examination showed lack of response to all
but noxious stimuli, persistent left facial movements and
extensor posturing of both arms in response to tactile
Fig. 2 Preoperative T1 weighted contrast enhanced cervical MRI
demonstrates intramedullary tumor posterior to C2 vertebra
stimuli. On POD 11 CSF polymerase chain reaction (PCR)
(from sample sent on POD 8 at the referring hospital) was
reported positive for herpes simplex virus type 1 (HSV-1)
PCR. Antibiotics were discontinued; acyclovir 10 mg/kg
IV q 8 h was continued for 21 days. Brain MRI on POD 13
revealed increased signal in left insular, left temporal, left
frontal and bilateral parietal cortices and mild posterior
fossa leptomeningeal enhancement, findings that were
considered consistent with meningoencephalitis, though
atypical for HSV encephalitis (Fig. 3). Repeat PCR of CSF
on POD 17 confirmed the HSV-1 infection. Repeat PCR of
CSF on POD 19 was negative for HSV-1 (Table 1). She
gradually became more responsive, and on POD 29 was
discharged to subacute rehabilitation with normal findings
on repeat CSF studies.

Fig. 1 Clinical course in HSV encephalitis following spinal ependymoma resection

123
J Neurooncol (2011) 103:771–776 773

1.30 9 105
The patient had two subsequent hospitalizations (POD 46
and POD 73) for fever, hypoxemia and altered mental status.

3,000
100
Hydrocephalus, which had not been seen on a CT obtained

74

65
16

0
0
postoperatively during her previous admission, required

1.03 9 105
external ventricular drainage (EVD) and ventriculoperito-
neal shunt (VPS) (POD 51). The patient was admitted to the

12,000
6 p.m.
neurological intensive care unit (NICU) on two separate
59
33

79
21
0
occasions, with pneumonia, C. difficile colitis, bilateral deep

2.54 9 105
vein thrombosis (DVTs), and required tracheostomy for
weaning of ventilation. She was discharged to a skilled
7 a.m.

7,000
nursing facility on POD 80 oriented to place and date, and
51

63
38

74
26
0
able to speak a few words. Arms and legs were profoundly

1.05 9 105
weak, consistent with critical care myoneuropathy.
8,000
64
25

76
24
50

Discussion
6.50 9 104

HSV-1 is carried by approximately 80% of humans, most

2,000

commonly causing oral mucosa lesions [2]; following

73
23

62
38
49

primary infection, the virus is transported through axons to

2.39 9 105

the dorsal root ganglia and trigeminal ganglion where the

infection remains latent. HSV DNA has been amplified
4,000

using PCR from normal brain tissue and may be commonly

62
44

72
10
18
46

found as a latent infection [14]. Recurrent infection results

4.70 9 106

from virus reactivation precipitated by immunosuppres-

89,000

sion, trauma, sunlight, or X-ray irradiation [15]. In contrast,

190

HSV-1 is an infrequent brain infection, annually causing

58

78
21
23

necrotizing encephalitis in about 2,000 people in the USA,

Table 1 CSF characteristics in HSV encephalitis following spinal ependymoma resection

3.98 9 106

fatal in up to 70% of cases if untreated [1]. It can manifest

525,000
Tube 4

as altered mental status, seizure or focal deficits such as

dysphasia. It is still unclear whether HSE is caused by
67
23
–
–

primary infection of the central nervous system (CNS) or

3.38 9 106

reactivation of latent virus, and the mechanism of entry

550,000
Tube 1

into the CNS remains unknown. It may be caused by

280

reactivation of the viral genome in the trigeminal ganglion

19

84

69
19
6

with spread to the trigeminal nerve and subsequently to the

2.65 9 107

brain, or by primary infection of the CNS, possibly through

412,000
Tube 4

olfactory nerves [2]. HSE has not been shown to be more

prevalent in immunocompromised hosts except after bone
57
12
31
–
–

marrow transplantation or in patients with AIDS [2].

6.15 9 107

HSE is rare immediately after neurosurgery, and has not

200,000
Tube 1

previously been reported to follow resection of spinal

ependymoma or intramedullary tumor. Table 2 summarizes
45

46
17

–
–

the case reports of HSE in the neurosurgical literature. HSE

1.63 9 106

has occurred following resection of left parasagittal

285,000

meningioma [5], right frontocingular oligodendroglioma

236

[8], right sphenoid wing meningioma [9], right acoustic

56

83
13
4
8

neuroma [10], suprasellar craniopharyngioma [11] and left

Lymphocytes (%)
Glucose (mg/dL)

acoustic neuroma [12]. Perry and colleagues described HSE

Protein (mg/dL)

Monocytes (%)
WBC (per ml)

RBC (per ml)

and bilateral acute retinal necrosis following suprasellar

PMN (%)

craniopharyngioma resection; HSV-2 was the likely culprit

[4]. HSE has also been reported following amygdalo-
POD

hippocampectomy for mesial temporal sclerosis [6].

123
774 J Neurooncol (2011) 103:771–776

Fig. 3 a Parietal cortical

FLAIR hyperintensity on axial
T2 FLAIR sequence. b Axial T2
FLAIR sequence demonstrates
cortical FLAIR hyperintensity
in the left insular cortex

Table 2 Clinical characteristics in reported cases of HSV encephalitis following craniotomy

Author (reference) Year Age Lesion Operation Postoperative Time to Time to treatment
steroids symptoms initiationa (days)
(days)

1 Fearnside 1972 11 Pituitary adenoma Craniotomy Yes 8 No treatment

and Grant [3] before death
2 41 Pituitary adenoma Craniotomy Yes 4 4
3 Perry et al. [4] 1998 64 Craniopharyngioma Craniotomy Yes 2 24
4 Spuler et al. [5] 1999 78 Meningioma Craniotomy Yes 10 5
5 Bourgeois et al. [6] 1999 8 Temporal Seizure Amygdalo- N/A 6 6
hippocampectomy
6 Sheleg et al. [7] 2001 28 GBM Craniotomy Yes 2 No treatment
before death
7 Aldea et al. [8] 2003 28 Oligodendroglioma Craniotomy Yes 7 2
8 Ploner et al. [9] 2005 47 Meningioma Craniotomy Yes 10 2
9 Filipo et al. [10] 2005 33 Acoustic neuroma Mastoidectomy Yes 2 9
10 Kwon et al. [11] 2008 13 Craniopharyngioma Craniotomy Yes 15 7
11 Jalloh et al. [12] 2009 44 Acoustic neuroma Mastoidectomy Yes 1 11
12 Molloy et al. [13] 2000 25 Medulloblastoma Craniotomy N/A 21 No treatment
before death
13 Present report 2010 65 Ependymoma Laminectomy/ Yes 5 3
myelotomy
N/A Not available
a
Time from onset of symptoms to initiation of antiviral treatment

Another patient underwent resection, chemotherapy and
stereotactic radiotherapy for recurrent medulloblastoma
before developing HSE [13]. In these prior reports, the
patients had uncomplicated resections of primary tumors
and all received postoperative steroids, except for one in
which steroids were not mentioned [8]. These cases are
heterogeneous and suggest no clear neurosurgical risk for
development of HSE. Furthermore, since the timing from
surgery to onset of symptoms has been quite variable,
ranging from 36 h [7] to a latency of up to 10 days [9], early
diagnosis may be extremely difficult. Primarily, signs of an
encephalitic process, such as altered mental status and
fever, should prompt rapid investigation.
The etiology of HSE in the present case remains unclear,
but may be due to stress of surgery or immunosuppression
caused by dexamethasone leading to reactivation of latent
HSV. HSV-1 has been shown to be reactivated in mouse
trigeminal ganglion cells treated with dexamethasone in a

123
J Neurooncol (2011) 103:771–776
dose-dependent manner [16]. Despite this risk the rela-
tively small amount of dexamethasone exposure this
patient experienced make steroid-induced immunosup-
pression an unlikely primary etiology for the infection.
HSE is rare, even in patients on immunosuppressive doses
of steroids for unrelated conditions. HSE has been descri-
bed after cardiac [17] or allogeneic bone marrow [18]
transplant, and following Cesarean section in a previously
asymptomatic patient [19]. Encephalitides due to other
similar viruses, such as HHV-6 or Herpes zoster, have also
been described after bone marrow [20–22] or stem cell [23]
transplantation, and following lung transplantation [24] or
laparotomy [25]. Nevertheless, HSE is an extremely rare
postoperative complication, and occurs in the literature as
case reports only. In each of these non-neurosurgical cases,
patients were profoundly immunosuppressed due to oper-
ative protocols or pathological conditions. Neurosurgical
patients suffering HSE in the literature have not been as
immunosuppressed. This raises the possibility that neuro-
surgery may represent an increased risk for reactivation of
latent CNS herpes infection, potentially due to disruption
of CNS homeostasis. Spinal tumor surgery, though
removed from primary handling of the brain itself, never-
theless requires opening of the dura and intramedullary
resection and may represent a similar risk. Finally, a pri-
mary infection in the present case cannot be ruled out; it
may be the case that the patient developed HSE inciden-
tally, closely after her surgery.
MRI imaging, together with PCR of CSF samples for
HSV genomes, has greatly improved the diagnosis of HSE
over the past decade [26]. The MRI findings of increased
signal in left insular, left temporal, left frontal and bilateral
parietal cortices and mild posterior fossa leptomeningeal
enhancement found in this case are not typical of HSE
(Fig. 3). Herpes encephalitis is most often associated with
T2 prolongation and reduced DWI signal in the temporal
lobes and insulas, also commonly causing alterations in
FLAIR sequences in these areas [26]. This makes the
imaging quite atypical in the present case. However, the
combination of clinical, CSF and radiological findings in
this case made an alternate explanation for the MR changes,
such as a bacterial or fungal encephalitis, less likely.
Whereas brain biopsy was previously required for definitive
diagnosis of HSE, this is no longer routinely recommended.
PCR is 98% sensitive and 94% specific [26] and represents
the best diagnostic test currently available. In the present
case, HSV DNA was amplified from CSF drawn at two
different times in different institutions, making it unlikely to
be a contaminant from blood culture in this case. Finally,
electroencephalography may be a helpful adjunct in diag-
nosis of HSE; though less specific than PCR or MRI, it may
be useful in monitoring seizure activity [26]. Abnormal,
nonspecific EEG changes including diffuse or focal slowing
775
were found to be early signs of HSE in a small cohort of
patients in the 1970s [27]. Although HSE is more com-
monly associated with the EEG finding of sharp, high-
amplitude waves in the temporal region [26], the subtle
changes on EEG in our present case may have been a clue to
early encephalitic changes potentially caused by HSE.
The difficulties in diagnosis of HSE may be compounded
by leukocyte and lymphocyte changes in the CSF of post-
operative patients caused by postoperative steroids. CSF
findings, though useful in the diagnosis of HSE, may be
normal early in the course of the disease [26]. When positive,
findings are typical of a viral process, including high lym-
phocytes, increased protein and, most often, normal glucose.
The glucose findings in this case were largely within the
normal range for CSF glucose (50–80 mg/dl), consistent
with a viral meningitis. In a comparison of patients with HSE
treated with acyclovir plus corticosteroids versus acyclovir
alone, there was no significant difference in the initial or
maximum leukocyte count or glucose level in CSF [28].
HSE causes severe neurological sequelae if not treated
expediently, and even in some patients who receive opti-
mal antiviral therapy, neurological outcome remains poor.
Unfortunately, treatment options for HSE are limited.
Acyclovir is an effective antiherpetic drug, but even with
optimal treatment mortality can reach 20–30% [2].
Untreated HSE rapidly replicates in the brain [26], making
prompt treatment of supreme importance. Paradoxically,
steroids have been associated with improved outcomes
following HSE [28]. This is presumed to be due to a
beneficial effect of steroids on brain edema. Nevertheless,
the standard treatment regimen for HSE remains acyclovir,
at a dose of 10 mg/kg for 10–14 days [15].
Although bacteria are the most common cause of
infection in neurosurgical procedures, clinicians must
remain highly suspicious for HSE in the setting of early
postoperative fever with acute mental status changes and
seizures in order to treat in a timely manner to prevent
severe, irreversible damage. Post-neurosurgical HSE is
extremely rare, however, and definitive diagnosis via CSF
examination and PCR should be sought expediently.
Acyclovir can be effective therapy against HSV, is a safe drug
in patients with good renal function, and empiric treatment
must be started even in the absence of serologic evidence
of HSV infection. It may prevent a catastrophic outcome.
References
1. Whitely R, Gnann J (2002) Viral encephalitis: familiar infections
and emerging pathogens. Lancet 359:507–513
2. Steiner I, Kennedy PGE, Pachner AR (2007) The neurotropic
herpes viruses: herpes simplex and varicella zoster. Lancet Neurol
6:1015–1028
123
776
3. Fearnside MR, Grant JMF (1972) Acute necrotizing encephalitis
complicating bifrontal craniotomy and pituitary curettage.
J Neurosurg 36:499–502
4. Perry JD, Girkin CA, Miller NR, Kerr DA (1998) Herpes simplex
encephalitis and bilateral acute retinal necrosis syndrome after
craniotomy. Am J Ophthalmol 126:456–460
5. Spuler A, Blaszyk H, Parisi JE, Davis DH (1999) Herpes simplex
encephalitis after brain surgery: case report and review of the
literature. J Neurol Neurosurg Psychiatr 67:239–242
6. Bourgeois M, Vinikoff L, Lellouch-Tubiana A, Sainte-Rose C
(1999) Reactivation of herpes virus after surgery for epilepsy in a
pediatric patient with mesial temporal sclerosis: case report.
Neurosurgery 44:633–635
7. Sheleg SV, Nedzved MK, Nedzved AM, Kulichkovskaya IV
(2001) Contamination of glioblastoma multiforme with type 1
herpes simplex virus. J Neurosurg 95:721
8. Aldea S, Joly LM, Roujeau T, Oswald AM, Devaux B (2003)
Postoperative herpes simplex virus encephalitis after neurosur-
gery: case report and review of the literature. Clin Infect Dis
36:e96–e99
9. Ploner M, Turowski B, Wöbker G (2005) Herpes encephalitis
after meningioma resection. Neurology 65:1674–1675
10. Filipo R, Attanasio G, De Seta E, Viccaro M (2005) Post-oper-
ative herpes simplex virus encephalitis after surgical resection of
acoustic neuroma: a case report. J Laryngol Otol 119:558–560
11. Kwon JW, Cho BK, Kim EC, Wang KC, Kim SK (2008) Herpes
simplex encephalitis after craniopharyngioma surgery. J Neuro-
surg Pediatr 2:355–358
12. Jalloh I, Guilfoyle MR, Lloyd SKW, Macfarlane R, Smith C
(2009) Reactivation and centripetal spread of herpes simplex
virus complicating acoustic neuroma resection. Surg Neurol
72:502–504
13. Molloy S, Allcutt D, Brennan P, Farrell MA, Perryman R, Brett
FM (2000) Herpes simplex encephalitis occurring after chemo-
therapy, surgery, and stereotactic radiotherapy for medulloblas-
toma. Arch Pathol Lab Med 124:1809–1812
14. Gordon L, McQuaid S, Cosby SL (1996) Detection of herpes
simplex virus (types 1 and 2) and human herpesvirus 6 DNA in
human brain tissue by polymerase chain reaction. Clin Diagn
Virol 6:33–40
15. Kennedy PGE, Chaudhuri A (2002) Herpes simplex encephalitis.
J Neurol Neurosurg Psychiatr 73:237–238
123
J Neurooncol (2011) 103:771–776
16. Halford WP, Gebhardt BM, Carr DJJ (1996) Mechanisms of
herpes simplex virus type 1 reactivation. J Virol 70:5051–5060
17. Hotson JR, Pedley TA (1976) The neurological complications of
cardiac transplantation. Brain 99:673–694
18. Romee R, Brunstein CG, Weisdorf DJ, Majhail NS (2010) Herpes
simplex virus encephalitis after allogeneic transplantation: an
instructive case. Bone Marrow Transpl 45:776–778
19. Godet C, Beby-Defaux A, Agius G, Pourrat O, Robert R (2003)
Maternal Herpes simplex virus type 2 encephalitis following
Cesarean section. J Infect 47:174–175
20. Janoly-Dumenil A, Galambrun C, Basset T, Mialou V, Bertrand
Y, Bleyzac N (2006) Human herpes virus-6 encphalitis in a
pediatric bone marrow recipient: successful treatment with
pharmacokinetic monitoring and high doses of ganciclovir. Bone
Marrow Transpl 38:769–770
21. MacLean HJ, Douen AG (2002) Severe amnesia associated with
human herpesvirus 6 encephalitis after bone marrow transplan-
tation. Transplantation 73:1086–1089
22. Mookerjee BP, Vogelsang G (1997) Human herpes virus-6
encephalitis after bone marrow transplantation: successful treat-
ment with ganciclovir. Bone Marrow Transpl 20:905–906
23. Bommer M, Pauls S, Greiner J (2009) Challenging complications
of treatment—human herpes virus 6 encephalitis and pneumonitis
in a patient undergoing autologous stem cell transplantation for
relapsed Hodgkin’s disease: a case report. Virol J 6:111–113
24. Bollen AE, Wartan AN, Krikke AP, Haaxma-Reiche H (2001)
Amnestic syndrome after lung transplantation by human herpes
virus-6 encephalitis. J Neurol 248:619–620
25. Wayne ER, Kosloske A, Holton CP, Burrington JD, Hatch EI
(1975) Complications of abdominal exploration and splenectomy
in staging children with Hodgkin’s disease. J Ped Surg 10:
677–684
26. Baringer JR (2008) Herpes simplex infections of the nervous
system. Neurol Clin 26:657–674
27. Ch’ien LT, Boehm RM, Robinson H, Liu C, Frenkel LD (1977)
Characteristic early electroencephalographic changes in Herpes
simplex encephalitis. Arch Neurol 34:361–364
28. Kamei S, Sekizawa T, Shiota H, Mizutani T, Itoyama Y, Takasu
T, Morishima T, Hirayanagi K (2005) Evaluation of combination
therapy using acyclovir and corticosteroid in adult patients with
herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatr
76:1544–1549
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.