Journal of Medical Virology 86:1766–1771 (2014)
Comparison of Clinical Manifestations, Outcomes
and Cerebrospinal Fluid Findings Between Herpes
Simplex Type 1 and Type 2 Central Nervous System
Infections in Adults
Song Mi Moon,1 Tark Kim,2 Eun Mi Lee,3 Joong Koo Kang,4 Sang-Ahm Lee,4 and Sang-Ho Choi2*
1
Department of Infectious Diseases, Gachon University Gil Hospital, Incheon, Republic of Korea
2
Departments of Infectious Diseases, University of Ulsan College of Medicine, Seoul, Republic of Korea
3
Department of Neurology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
4
Departments of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
In previous reports on the viral causes of
central nervous system (CNS) infections, it has
been generally recognized that HSV-1 is a
major cause of encephalitis, while HSV-2 is the
predominant cause of aseptic meningitis in
adults. To examine this matter, the clinical
characteristics in the two types of HSV CNS
infections were investigated. In a retrospective
cohort study which included all adult patients
(
16 years) between January 1999 and Decem-
ber 2013 in a 2,700-bed tertiary care hospital,
all the patients in whom PCR of the CSF for
HSV was positive were identified. Ninety-five
patients with positive CSF PCR results for HSV
were included, 21 with HSV-1 and 74 with HSV-
2. Many patients with HSV-1 had encephalitis
(13/21, 61.9%), whereas most patients with
HSV-2 had meningitis (62/74, 83.8%). However,
HSV-1 and HSV-2 accounted for similar propor-
tion of patients with HSV encephalitis (13/25,
52.0% vs. 12/25, 48.0%). Neurological sequelae
were more frequent among patients with HSV-
1 (9/21, 42.9% vs. 6/74, 8.1%; P ¼ 0.001). The
present study suggests that HSV-2 is not only a
major cause of aseptic meningitis, but also it
may cause serious manifestation as HSV-1
encephalitis in adults. J. Med. Virol. 86:
1766–1771, 2014. # 2014 Wiley Periodicals, Inc.
KEY WORDS: herpes simplex virus; meningi-
tis; encephalitis
INTRODUCTION
Herpes simplex virus (HSV), a member of the
herpesviridae family of DNA viruses, is composed of
two types: HSV type 1 (HSV-1) and HSV type 2

C 2014 WILEY PERIODICALS, INC.
(HSV-2). These are closely related with nearly 70%
genomic homology [Knipe and Howley, 2007]. Despite
this, there are significant differences in the clinical
manifestations of these two types of HSV. For exam-
ple, HSV-1 is more commonly associated with herpes
labialis whereas HSV-2 is a more frequent cause of
genital herpes.
It seems that the clinical manifestations of central
nervous system (CNS) infection differ between HSV-1
and HSV-2. CNS infection in neonates is more often
associated with HSV-2 [Berger and Houff, 2008],
whereas almost all cases of HSV encephalitis in
adults reported so far have involved HSV-1 [Kupila
et al., 2006; Frantzidou et al., 2008; Ihekwaba
et al., 2008]. HSV-2 has been more likely caused
aseptic meningitis in adults [Kupila et al., 2006;
Frantzidou et al., 2008; Ihekwaba et al., 2008], but
its role in adult encephalitis is less clear. Cases
of encephalitis caused by HSV-2 have been only
sporadically reported [Wolontis and Jeansson, 1977;
Oommen et al., 1982; Godet et al., 2003; Osih et al.,
2007]. Therefore, it has been generally thought that
the spectrum of CNS diseases is different in between
two types of HSV CNS infections.
However, there have been a few comparative
studies of HSV-1 and HSV-2 CNS infections
[Craig and Nahmias, 1973; Najioullah et al., 2000;
Grant sponsor: Asan Institute of Life Sciences grant 2013-389
Conflicts of interest: All authors report no disclosures.

Correspondence to: Sang-Ho Choi, M.D., Department of
Infectious Diseases, Asan Medical Center, University of Ulsan
College of Medicine, 388-1Pungnap-dong, Songpa-gu, Seoul, 138-
736, Republic of Korea.
E-mail: sangho@amc.seoul.kr
Accepted 30 May 2014
DOI 10.1002/jmv.23999
Published online 5 July 2014 in Wiley Online Library
(wileyonlinelibrary.com).
HSV CNS Infection
O’Sullivan et al., 2003; Kupila et al., 2006]. O’Sulli-
van et al. [2003] reported that 89% (32/39) of patients
with HSV-1 DNA detected in CSF had encephalitis,
whereas most patients with HSV-2 had aseptic
meningitis. However, the clinical information was
collected by a questionnaire written by the different
physicians and the diagnosis of encephalitis or asep-
tic meningitis was not strictly defined in that study
[O’Sullivan et al., 2003]. In addition, another recent
study showed that HSV-2 could significantly cause a
wide spectrum of CNS diseases from aseptic meningi-
tis to encephalitis [Omland et al., 2008]. Therefore,
using a retrospective cohort of HSV CNS infections in
adults, the clinical manifestations including spectra
of CNS diseases, outcomes, and CSF findings of HSV-
1 and HSV-2 infections were compared.
PATIENTS AND METHODS
Patient Selection and Study Design
Using our clinical microbiology computerized data-
base, all adult patients (
16 years) with positive PCR
results for HSV in cerebrospinal fluid between Janu-
ary 1999 and December 2013 at the Asan Medical
Center, a 2,700-bed university-affiliated teaching
hospital in Seoul, Republic of Korea were identified
retrospectively. Among them, patients who had other
CNS diseases or concomitant CNS infection were
excluded from the analysis. The Asan Medical Center
Institutional Review Board approved the study and
waived informed consent.
Data Collection
The medical records of all patients were reviewed.
Data were collected on demographics, underlying
diseases or conditions, clinical manifestations (fever,
headache, neck stiffness, nausea/vomiting, memory
impairment, altered mentality, seizure, and mucocu-
taneous lesion, duration of symptoms before admis-
sion), prior history of CNS infections, CSF findings,
treatment, hospital course (intensive care unit hospi-
talization, need for mechanical ventilation, and
length of hospital stay) and outcomes (in-hospital
crude mortality and neurologic sequelae). Neurologi-
cal sequelae were defined as the presence of one or
more of the following: impaired consciousness, cogni-
tive dysfunction, weakness (monoparesis hemiparesis,
quadriparesis), focal or generalized abnormal limb
tone (hypertonia, hypotonia), focal or generalized
abnormal limb reflexes (hypereflexia, hyporeflexia),
diagnosis of new onset or recurrent seizures or new
or recurrent extra pyramidal movement disorders
[Rayamajhi et al., 2011].
Definitions of Aseptic Meningitis
and Encephalitis
The clinical syndromes of patients whose CSF was
HSV PCR positive were classified into aseptic menin-
gitis and encephalitis, as previously defined [Studahl
1767
et al., 1998; Persson et al., 2009]. Briefly, aseptic
meningitis was diagnosed if a patient had: (i) CSF
WBC > 5 cell/mm3, (ii) negative CSF bacterial culture,
(iii) absence of acute signs of parenchymatous brain
dysfunction, such as evidence of focal neurological
deficit, lowered consciousness and disorientation,
and/or seizures, (iv) two or more symptoms or signs
of meningeal inflammation, such as headache, nau-
sea/vomiting, light sensitivity, neck stiffness and
fever >38˚C. Encephalitis was diagnosed if a patient
had: (i) acute signs of parenchymatous brain dys-
function, (ii) at least two of the following: CSF WBC
> 5 cell/mm3, fever >38˚C, and abnormal brain image
findings compatible to encephalitis. Instead of electro-
encephalogram findings, image findings were used as
the definition criteria, because of electroencephalo-
gram was not checked in many of patients.
PCR for Herpes Simplex Virus
All CSFs were processed by the molecular biology
laboratory at Asan Medical Center. Multiplex PCR
assays were performed on all CSFs to detect HSV-1
and HSV-2 DNA as previously described [Lakeman
and Whitley, 1995; Danise et al., 1997]. The PCR
method did not change during the study period.
Statistical Analysis
The clinical, laboratory, and outcome features
of the two antigenic groups were compared.
Fisher’s exact test was used to compare categorical
variables, and the Mann–Whitney U test was used to
compare continuous variables. Data were analyzed
using SPSS for Windows, version 15.0K (SPSS, Inc,
Chicago, IL). P < 0.05 was considered statistically
significant.
RESULTS
During the study period, a total of 151 adult
patients with positive PCR for HSV in the CSF were
identified. Among them, 23 patients with other infec-
tious CNS diseases and 33 patients with non-infec-
tious CNS diseases were excluded from the analysis,
because these patients could not be categorized
appropriately (supplement Fig. S1). Finally, 95 pa-
tients with HSV-1 (21, 22.1%) or HSV-2 (74, 77.9%)
DNA detected in CSF were categorized into those
with HSV CNS infection. Twenty-five (26.3%) of
enrolled patients were considered as having encepha-
litis: 13 (52.0%) with HSV-1 and 12 (48.0%) with
HSV-2. Magnetic resonance image and/or computer-
ized tomography of brain were done in 24 (96.0%)
patients, and abnormalities compatible to encephali-
tis were found in 18 (72.0%) patients. The proportion
of patients with encephalitis was higher in the HSV-
1 group (HSV-1, 61.9% [13/25] vs. HSV-2, 16.2% [12/
74], P < 0.001).
The demographics, underlying diseases or condi-
tions, clinical manifestations, prior history of aseptic
meningitis, treatment, hospital course, and outcomes
J. Med. Virol. DOI 10.1002/jmv
1768 Moon et al.

are summarized in Table I. Eleven (11.6%) patients
had underlying medical conditions: three with diabe-
tes mellitus, one with hepatocellular carcinoma, one
with end-stage renal disease, one on bone marrow
transplantation, one on kidney transplantation, one
on liver transplantation, one with rheumatolid arthri-
tis, one with Sjogren syndrome, and one with Takaya-
sus’s arteritis. There was no HIV-infected patient.
The proportion of underlying diseases or conditions
was not different between HSV-1 and HSV-2 group
(Table I). Male in HSV-1 group and female in HSV-2
were predominant gender. Headache (88.4%, 84/95),
nausea/vomiting (65.3%, 62/95), fever (60.0%, 57/60)
were common symptoms in both groups. Altered
mentality (HSV-1, 47.6% [10/21] vs. HSV-2, 8.1% [6/
74]; P < 0.001), seizure (HSV-1, 38.1% [8/21] vs. HSV-
2, 2.7% [2/74]; P < 0.001), and memory impairment
(HSV-1, 14.3% [3/21] vs. HSV-2, 1.4% [1/74]; P ¼ 0.03)
were more frequent in the HSV-1 group. Simulta-
neous herpetic mucocutaneous lesions were found in
the 17.6% (13/74) of HSV-2 group: 7 (9.6%) with
herpes genitalis, 2 (2.7%) with herpes labialis, and 4
(5.5%) with painless vesicular lesions on their back.
Median duration of symptoms before admission was
3.0 days (range, 1–20 days). Patients in HSV-2 group
only had prior histories of aseptic meningitis.
Fourty (42.1%) patients received antiviral agents
(intravenous acyclovir for 38 patients, oral

TABLE I. Comparison of Clinical Characteristics in Patients with Central Nervous System Infections By Herpes Simplex
Virus Type 1 and Type 2

Type

All patients HSV-1 HSV-2

(n ¼ 95) (n ¼ 21) (n ¼ 74) P valuea
Spectrum of CNS diseases
Aseptic meningitis 70 (73.7) 8 (38.1) 62 (83.8) <0.001
Encephalitis 25 (26.3) 13 (61.9) 12 (16.2)
Demographics
Age, median years (range) 34 (16–85) 42 (24–85) 31 (16–77) 0.007
Gender, female 52 (54.7) 6 (28.6) 46 (62.2) 0.012
Underlying diseases or conditions
DM 3 (3.2) 1 (4.7) 2 (2.8) 0.53
Transplantation 2 (2.1) 1 (4.7) 1 (1.4) 0.40
Connective tissue disease 2 (2.1) 1 (4.7) 1 (1.4) 0.40
ESRD 1 (1.1) 1 (1.4) 0 0.22
Malignancy 1 (1.1) 0 1 (1.4) 1.00
Clinical manifestations
Headache 84 (88.4) 15 (71.4) 69 (93.2) 0.013
Nausea/vomiting 62 (65.3) 10 (47.6) 52 (70.3) 0.07
Fever 57 (60.0) 16 (76.2) 41 (55.4) 0.13
Neck stiffness 45 (47.4) 7 (33.3) 38 (51.4) 0.22
Altered mentality 16 (16.8) 10 (47.6) 6 (8.1) <0.001
Seizure 10 (10.5) 8 (38.1) 2 (2.7) <0.001
Memory impairment 4 (4.2) 3 (14.3) 1 (1.4) 0.03
Mucocutaneous lesion 14 (14.7) 1 (4.8) 13 (17.6) 0.18
Genital 8 (8.4) 1 (4.8) 7 (9.6) 0.67
Oral 2 (2.1) 0 2 (2.7) 1.00
Other 4 (4.2) 0 4 (5.5) 1.00
Duration of symptom before admission, median days (range) 3 (1–20) 4 (1–10) 3 (1–20) 0.12
Prior history of aseptic meningitis 12 (12.6) 0 12 (16.2) 0.06
Once 7 (7.4) 0 7 (9.5) 0.34
More than twice 5 (5.3) 0 5 (6.8) 0.58
Treatment
Antiviral agents 39 (41.1) 15 (71.4) 25 (33.8) 0.003
Treatment duration, median days (range) 13 (3–70) 17 (3–70) 11 (3–20) 0.002
Course of illness
ICU hospitalization 12 (12.6) 8 (38.1) 4 (5.4) <0.001
Assisted ventilation 5 (5.3) 5 (23.8) 0 <0.001
Length of the hospital stay, median days (range) 7 (3–231) 17 (3–231) 7 (3–51) 0.007
Neurologic sequelaeb
At discharge 19 (20.0) 12 (57.1) 7 (9.5) <0.001
At the last visit 15 (15.8) 9 (42.9) 6 (8.1) 0.001

Data are no. (%) of patients, unless otherwise indicated; CNS, central nervous system; HSV, herpes simplex virus; DM, diabetes mellitus;
ESRD, end-stage renal disease; ICU, intensive care unit.
a
Comparison of variables between HSV-1 and HSV-2 central nervous system infections: Fisher’s exact test for categorical variables and the
Mann–Whitney U test for continuous variables.
b
Defined by the presence of one or more of the following: (1) impaired consciousness, cognitive dysfunction, weakness (monoparesis hemiparesis,
quadriparesis), (2) focal or generalized abnormal limb tone (hypertonia, hypotonia), (3) focal or generalized abnormal limb reflexes (hypereflexia,
hyporeflexia), (4) diagnosis of new onset or recurrent seizures, or new or recurrent extra pyramidal movement disorders.

J. Med. Virol. DOI 10.1002/jmv

HSV CNS Infection
famciclovir for 1 patient, and oral acyclovir for
1 patient). Most of patient with encephalitis received
antiviral agents (Supplement Table SI) except two
patients. One patient with HSV-2 was considered as
possibly having tuberculous encephalitis and only
received anti-tuberculous regimens, but that patient
had neurologic sequelae of paresthesia. The other
patient with HSV-2 recovered and had no neurologic
sequelae without usage of antiviral agents. Many of
patients with aseptic meningitis (53/70, 75.7%) did
not receive antiviral agents, all of them recovered
without neurologic sequelae. None of patients died
during hospitalization. Fifteen (15.8%) patients suf-
fered from neurologic sequelae at the last visit (motor
weakness in six patients, cognitive dysfunction five
patients, epilepsy in two patients, autonomic dysfunc-
tion in one patient, and facial palsy in one patient).
More patients in the HSV-1 group suffered from
neurologic sequelae (HSV-1, 42.9% [9/21] vs. HSV-2,
8.1% [6/74]; P ¼ 0.001), and most of patients with
neurologic sequelae were diagnosed with HSV en-
cephalitis (Supplement Table SI). In subgroup analy-
sis of patients categorized into having encephalitis,
higher proportion of patients with HSV-1 encephalitis
suffered from neurologic sequelae that those with
HSV-2 encephalitis, although it was not statistically
significant due to small number of patients (HSV-1,
69.2% [9/13] vs. HSV-2, 41.6% [5/12]; P ¼ 0.23).
Data on CSF findings are presented in Table II.
Lymphocytic CSF pleocytosis was present in most of
patients. In patients with HSV-1, median CSF WBC
count (HSV-1, 43 cell/mm3 vs. HSV-2, 400 cell/mm3;
P ¼ 0.002), CSF glucose level (HSV-1, 62 mg/dl vs.
HSV-2, 74 mg/dl; P ¼ 0.002), and CSF protein level
(HSV-1, 62 mg/dl vs. HSV-2, 74 mg/dl; P ¼ 0.002) was
lower. However in a subgroup analysis of the patients
with encephalitis, CSF findings were not significantly
different in patients with HSV-1 versus HSV-2
(Supplementary Table SII).
DISCUSSION
The present study, one of the largest study compar-
ing the characteristics of HSV-1 and HSV-2 CNS
infections, has several important implications. As
TABLE II. Comparison of Cerebrospinal Fluid Findings between Patients with Central Nervous Infections Caused By
Herpes Simplex Virus Type 1 and Herpes Simplex Virus Type 2
CSF findings HSV-1 (n ¼ 21)
3
WBC (cell/mm ) 50 (6–800)
Neutrophil percent 3 (0–35)
Lymphocyte percent 71 (15–98)
Monocyte percent 19 (1–50)
Glucose (mg/dl) 62 (40–106)
CSF/serum glucose ratio 0.50 (0.38–0.73)
Protein (mg/dl) 72 (27–264)
ADA (U/L) 3.0 (4.0–12.0)
Data are medians (range), unless otherwise indicated; CNS, central nervous system; HSV, herpes simplex virus; CSF, cerebrospinal fluid;
WBC, white blood cell; ADA, adenosine deaminase.
1769
expected, a higher proportion of the patients with
HSV-1 CNS infections had encephalitis and suffered
from neurologic sequelae than of those with HSV-2
infections. However, HSV-2 also was the significant
cause of HSV encephalitis. Prior studies have re-
ported that HSV-2 is the dominant cause of aseptic
meningitis [Danise et al., 1997; Kupila et al., 2006;
Ihekwaba et al., 2008], and HSV-2 was rarely identi-
fied in the CSF of adults with encephalitis. HSV-2
was not found in any patients with encephalitis in
recent small-scale studies in Finland [Kupila
et al., 2006] and Greece [Frantzidou et al., 2008].
However, a recent study from Denmark reported that
12% (6/49) of patients with HSV-2 CNS infections
had encephalitis [Omland et al., 2008]. Also, O’sulli-
van et al. reported that 26% (19/74) of patients with
HSV-2 CNS infection had altered mentality and
drowsiness. Although the spectrum of CNS diseases
was not strictly defined, some of those complaining of
altered mentality and drowsiness with HSV-2 infec-
tion might have encephalitis [O’Sullivan et al., 2003].
The discordant findings may result from ethnic or
regional differences between the study populations.
In addition, the severity of HSV-2 CNS infection can
be variously reported according to comorbidity or
immune status of study population. Mommeja-Marin
et al. [2003] reported that HSV-2 can cause severe
meningitis in immunocompromised patients such as
malignancy on chemotherapy and acquired immuno-
deficiency syndrome. However, in the present study,
the association of higher proportion of HSV-2 enceph-
alitis with comorbidity or immunocomprosed status
was not found, because most of patients with HSV
CNS infection were immunocompetent, regardless of
HSV types (Table I). Large-scale studies should be
carried out in various population to obtain a more
comprehensive understanding.
One of interesting findings of the present study is
that there was a predominance of males in HSV-1
CNS infection, while a predominance of females was
found in patients with HSV-2 CNS infection. Previ-
ous reports also reported that HSV-2 CNS infections
are more common in females [Tedder et al., 1994;
Kupila et al., 2004]. This female predominance in
HSV-2 CNS infections has been explained by the
HSV-2 (n ¼ 74) P value
400 (6–4,000) 0.002
1 (0–89) 0.26
78 (3–99) 0.13
14 (0–57) 0.11
74 (27–117) 0.01
0.49 (0.26–0.69) 0.25
95 (25–335) 0.018
3.1 (4–10.5) 0.55
J. Med. Virol. DOI 10.1002/jmv
1770
greater susceptibility of females to HSV-2 infection
in the context of genital infections [Langenberg et al.,
1999; Gupta et al., 2007]. Male predominance and
rare mucocutaneous lesions in HSV-1 group suggest-
ing that the pathogenesis of HSV CNS infection may
be different between two types. Indeed, some previ-
ous studies support this hypothesis. The isolation of
different HSV-1 strains from the oropharynx and
brain tissue in some of patients with encephalitis
implicating that some HSV-1 encephalitis may result
from reinfection than reactivation [Whitley et al.,
1982]. Another experimental study in which increas-
ing reactivation in sacral nerve root ganglia was
found when the region containing the latency-associ-
ated transcripts of HSV-2 was inserted in an HSV-1
virus indicates that viral types may influence site of
reactivation [Yoshikawa et al., 1996]. Further studies
should be followed to investigate the difference of
pathogenesis of HSV CNS infection between two
types.
Intravenous acyclovir is recommended for the treat-
ment of HSV encephalitis, but there was no study of
systemic antiviral agents for HSV aseptic meningitis
[Cernik et al., 2008]. Many of patients with HSV-2
aseptic meningitis who did not receive antiviral
agents were recovered without neurologic sequelae.
Even, a patient with HSV-2 encephalitis who was
conservatively treated without an antiviral agent had
no neurologic sequelae. This finding suggests that the
usage of antiviral agents may not be mandatory for
patients with HSV-2 aseptic meningitis.
With regard to the CSF laboratory findings, CSF
leukocyte counts, CSF protein, and glucose level were
lower in patients with HSV-1 than in those with HSV-
2 infections (Table I). This finding may simply reflect
the disease categories of CNS infection. That is to say,
the differences in CSF findings may be explained by
the higher frequency of encephalitis in the patients in
the HSV-1 group. Simko et al. [2002] observed higher
leukocyte counts (encephalitis group, 202 [range 2–
667] cells/mm3 vs. meningitis group, 484 [range 58–
1,888] cell/mm3; P < 0.04) and protein levels (encepha-
litis group, 73 [range 22–146] mg/dl vs. meningitis
group, 129 [range 75–281] mg/dl; P < 0.001) in the
CSF of patients with meningitis than of those with
encephalitis. The absence of a significant difference
in CSF laboratory findings between the two groups
in a subgroup analysis of patients with encephalitis
supports this explanation (Supplementary Table SII).
This study has some limitations. First, the patients
in the current study have been identified in a single
tertiary care center in which there might be a higher
prevalence of patients in some sort of immunocom-
promised state than a regional hospital. Indeed,
HSV-2 CNS infection resulted in severe outcomes or
encephalitis in immunocompromised adults [Mom-
meja-Marin et al., 2003]. Hence, the generalization of
the current study is limited. Second, it is a retrospec-
tive study and the relevant information has been
collected from patients’ medical records. The conclu-
J. Med. Virol. DOI 10.1002/jmv
Moon et al.
sion of study is flawed by the retrospective assign-
ment of disease category. Among the patients
categorized into having encephalitis, higher propor-
tion of patients with HSV-1 encephalitis suffered
from neurologic sequelae that those with HSV-2
encephalitis, although it was not statistically signifi-
cant due to small number of patients (HSV-1, 69.2%
[9/13] vs. HSV-2, 41.6% [5/12]; P ¼ 0.23). It suggests
that encephalitis caused by HSV-2 may not be the
same disease category as that caused by HSV-1. Also,
histories of CNS infection and mucucutanous herpes
infection may have been underreported. Third, some
of HSV infection might be omitted. A result of PCR
performed on early CSF samples of patients with
HSV encephalitis can be negative [Weil et al., 2002].
In conclusion, the present study suggests that
HSV-2 is not only a major cause of aseptic meningi-
tis, but also it may cause serious manifestation as
HSV-1 encephalitis although a higher proportion of
patients with HSV-1 CNS infections have encephali-
tis than of those with HSV-2. Well-designed prospec-
tive studies using more strict and well-defined
criteria for categorization of CNS diseases should be
conducted in multiple regions and multiple centers to
confirm these findings.
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