MAJOR ARTICLE

Outcome of and Prognostic Factors for Herpes

Simplex Encephalitis in Adult Patients: Results
of a Multicenter Study
1

Laboratoire de Virologie, Hopital Saint-Vincent-de-Paul, 2Service de Reanimation des Maladies Infectieuses and 3INSERM U13, Hopital
BichatClaude Bernard, and 4Departement de Biostatistiques et Informatique Medicale, Hopital Saint-Louis, Paris; 5Service de Neurologie,
Hopital Delafontaine, Saint-Denis; and 6Service des Maladies Infectieuses, Centre Hospitalier Universitaire Brabois, Nancy, France

Management of herpes simplex encephalitis (HSE) has been considerably improved by the availability of
acyclovir therapy and rapid polymerase chain reaction (PCR)based diagnostic assays. Prognostic factors for
this rare affliction are, however, misestimated. We conducted a large retrospective multicenter study that
included 93 adult patients in whom HSE was diagnosed by PCR from 1991 through 1998 and who were treated
with intravenous acyclovir. Among the 85 patients assessed at 6 months, 30 (35%) had a poor outcome, which
led to death in 13 patients (15%) and severe disability in 17 (20%). The outcome was favorable for 55 patients
(65%). A multivariate analysis identified 2 factors that were found to be independently associated with poor
outcome: a Simplified Acute Physiology Score II 27 at admission and a delay of 12 days between admission
to the hospital and initiation of acyclovir therapy. Early administration of antiviral therapy is the only parameter
that can be modified to improve the prognosis of patients with HSE.
Herpes simplex encephalitis (HSE) is the most common
sporadic necrotizing encephalitis in the Western world
[1]. The spontaneous mortality rate associated with HSE
is 70%, and, before the advent of antiviral therapy, most
survivors had severe neurological impairment [2]. Two
major advances have considerably improved the management of HSE. First, 2 large randomized trials performed in the mid-1980s showed that use of intravenous
acyclovir reduced the 6-month mortality rate to 20%
and significantly decreased morbidity (i.e., minor or no

Received 8 November 2001; revised 8 March 2002; electronically published 10

July 2002.
Financial support: Glaxo-Wellcome (grant 963671).
a

Members of the study group are listed after the text.

Reprints or correspondence: Dr. Flore Rozenberg, Laboratoire de Virologie,

Hopital Saint-Vincent-de-Paul, AP-HP and Faculte Cochin, 82 Avenue DenfertRochereau, 75674 Paris Cedex 14, France (flore.rozenberg@svp.ap-hop-paris.fr).
Clinical Infectious Diseases 2002; 35:25460
 2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3503-0006$15.00

254 CID 2002:35 (1 August) Raschilas et al.

neurological impairment was observed in 37.5% and

55.5% of treated patients, respectively) [3, 4]. Second,
herpes simplex virus (HSV) DNA amplification by PCR
analysis of CSF has been the reference standard for early
diagnosis of HSE since the early 1990s [57], thus greatly
improving early therapeutic decisions [8, 9]. Despite this
marked progress, recent reports have suggested that CNS
sequelae are still frequent [10, 11]. The age of the patient
and the level of consciousness at initiation of therapy
have been identified as major determinants of prognosis
[4]. More recently, the delay between admission of the
patient to the hospital and initiation of acyclovir was
identified as a main predictor of outcome [12]. However,
the rarity of the disease has hampered the design of
studies focused on the long-term outcome of survivors
of HSE or aimed at identifying early prognostic factors.
To further identify parameters independently associated
with poor prognosis, we conducted a large, multicenter,
retrospective study to assess the outcome of HSE for
acyclovir-treated adult patients.

Downloaded from http://cid.oxfordjournals.org/ at University of South Dakota and School of Medicine on June 18, 2014

Franck Raschilas,1,2 Michel Wolff,2 Frederique Delatour,3 Cendrine Chaffaut,4 Thomas De Broucker,5 Sylvie Chevret,4
Pierre Lebon,1 Philippe Canton,6 and Flore Rozenberg,1 for the French Herpes Simplex Encephalitis Study Groupa

METHODS

RESULTS
Study population. Five of the 98 patients enrolled in the
study were excluded from the analyses because incomplete data
were available. The 93 remaining patients originated from 36
hospitals (34 in the Paris area and 2 in Nancy). HSE was associated with HSV type 1 in 92 patients and with HSV type 2
in 1 patient.
Clinical characteristics. The mean patient age was 53.5
years, and there was a slight predominance of male patients. The
first clinical evaluation was performed at the emergency department for 32 patients (34%), in an intensive care unit (ICU)
for 10 patients (11%), in a neurology department for 10 patients
(11%), and in an infectious diseases department for 4 patients
(4%). Thirty-seven patients (40%) were admitted to other medical departments. Overall, 66 (71%) of 93 patients were admitted
to the ICU, either directly or from the ward after a mean delay
of 2.2  2.3 days. At admission, the mean temperature was
38.9C, but 8 patients (8.5%) were not febrile. The mean GCS
score was 13.2  3.1, although the score was !8 for 9 patients,
and the median value was 14. Neurological signs and symptoms
at admission mainly consisted of disorientation (71 patients

Herpes Simplex Encephalitis CID 2002:35 (1 August) 255

Downloaded from http://cid.oxfordjournals.org/ at University of South Dakota and School of Medicine on June 18, 2014

Patients. Patients were traced from records kept by the Virology Department of Saint-Vincent-de-Paul Hospital, where
CSF samples from patients with infections of the CNS were
prospectively assayed by PCR according to a procedure published elsewhere [7]. From January 1991 through June 1998,
CSF samples from 241 adult patients tested positive for HSV
DNA by PCR (180 with HSV type 1 and 61 with HSV type 2).
After the exclusion of patients with HSV type 2associated
meningitis, the study was limited to 98 patients who originated
from 2 geographical centers, Paris and Nancy, France.
Procedures.
Demographic data and information about
previous health status, neurological signs, and symptoms at
hospital admission were retrieved from medical records. The
severity of underlying disease was assessed by the MacCabe
[13] and Knaus [14] scores. The following parameters were
determined within the first 24 h of admission: the Simplified
Acute Physiology Score (SAPS II) [15], the Glasgow Coma Scale
(GCS) score [16], and the need for mechanical ventilation. The
following biological data were obtained: serum sodium concentration, CSF leukocyte count, CSF glucose and protein levels, and IFN-a dosage. CT scan or MRI profiles were reviewed
by a neurologist (T.d.B.). The delay between the onset of symptoms and initiation of treatment, the delay between hospital
admission and initiation of acyclovir, the dose and duration of
antiviral treatment, and the use of drugs to reduce cerebral
edema and/or to control seizures were recorded.
Outcome assessments. Neurological impairment and quality of life were assessed at 6 and 12 months by review of patients
medical charts and by questioning of the patients, their relatives, or their general practitioners about specific items: the
patients professional activity and ability to drive before and
after the onset of HSE; autonomy in daily life, including the
ability to wash him or herself, to cook, to clean the home, and
to shop; the need for permanent home care; impairment in
speaking, fluency, judgment, or memory; the need for antiepileptic treatment and occurrence of seizures after the onset
of HSE; and the need for speech, motor, or any other rehabilitation after the onset of HSE. Ten patients were first evaluated by a member of the team to assess the reliability of the
evaluation. All other patients were then evaluated either by
members of the team or by their general practitioners after
detailed information and the objectives of the study had been
provided to the general practitioner. Handicap and quality of
life were graded according to a 5-grade scale derived from the
Glasgow Outcome Scale [17]: I, good recovery, allowing independent life without any neurological impairment; II, mild
disability, defined by the presence of minimal cognitive alterations (speech disturbances, memory, or attention impairment)
and/or seizures (partially controlled with antiepileptic drugs),

without consequences for socioprofessional life; III, moderate

disability, defined by criteria identical to those of group II but
with consequences for socioprofessional life; IV, severe disability, defined by loss of autonomy requiring institutionalization
or constant life aid; and V, death. To identify HSE prognostic
factors, the patients were assigned to 1 of 2 categories, according
to outcome at 6 months: favorable outcome, for patients with
good recovery or mild or moderate disability (grades IIII), or
poor outcome, for patients with severe disability or who died
(grades IV and V).
Statistical methods. For quantitative variables, data were
given as mean  SD; for qualitative variables, data were given
as n/N (%). For the analysis of prognostic factors, outcome at
6 months was the main end point and was considered to be
binary (favorable outcome vs. poor outcome). Univariate prognostic analyses were calculated using Fishers exact test (for
qualitative variables) and the nonparametric Wilcoxon test (for
quantitative variables). Multivariate analysis was then conducted that included the covariates that showed statistical association with the outcome in univariate analysis. A logistic
regression model was used in which the covariates were introduced as binary, using, for each continuous covariate, the median value computed in the whole sample as the cutoff point.
Estimated odds ratios (with 95% CIs) were computed. All statistical tests were 2-sided, and P .05 was considered to be
statistically significant. Statistical analysis was performed using
the SAS version 8.1 software package (SAS, Inc.).

256 CID 2002:35 (1 August) Raschilas et al.

Outcomes. Eighty-five (91%) of 93 patients were available

for evaluation 6 months after the onset of HSE, and 8 were
lost to follow-up. Among these 85 patients, 13 (15%) died, and
8 of those died within the first month of hospitalization. All
deaths that occurred during the first 6 months of follow-up
were due to HSV disease, either as a direct result (7 patients)
or as a consequence of complications (6 patients), mainly nosocomial infections. Only 12 (14%) of 85 patients completely
recovered; 19 (23%) of the 85 patients lived with mild disability,
24 (28%) had moderate disability, and 17 (20%) had severe
disability. Thus, the outcome at 6 months was favorable for 55
(65%) of 85 patients and poor for 30 (35%) of 85 patients. A
relapse of HSE (confirmed by HSV PCR analysis of CSF) occurred in 1 patient 2 months after the end of a first, 24-day
course of acyclovir. This patient had a poor recovery. Fiftythree of 83 patients were assessed 1 year after the onset of HSE.
Among these, 15 (28%) died, 9 (17%) had complete recovery,
12 (23%) had mild disability, 10 (19%) had moderate disability,
and 7 (13%) had severe disability. Two patients living in a longterm care facility died before the end of the first year after the
onset of HSE, 1 patient at 8 months after nosocomial infection
occurred and the other at 10 months after the onset of neurological sequelae of HSE.
Prognostic factors. By univariate analysis, no significant

Table 1.
Demographic characteristics and baseline clinical
and laboratory findings for 93 patients with herpes simplex
encephalitis.
Characteristic
Age, mean years  SD (range)
Male sex, no. (%) of patients
MacCabe score, mean  SD (range)
Knaus score, mean  SD (range)

Value
53.5  17.4 (1688)
56 (60)
0.9  0.33 (02)
1.32  0.6 (13)

Temperature, mean C  SD (range)

38.9  0.9 (36.840.8)

SAPS II, mean  SD (range)

27.8  17.3 (858)

GCS score, mean  SD (range)

13.2  3.1 (315)

Serum sodium concentration,

mean mM  SD (range)

132.2  5.4 (116142)

Neurological features, no. (%) of

patients
Seizures

31 (33)

Focal neurological deficit

22 (24)

CSF parameters, mean  SD (range)

Leukocyte count, cells/mL 103

237  477 (13900)

Mononuclear cell proportion, %

77  22 (13100)

Polymorphonuclear cell proportion, %

12  19 (069)

Protein level, g/L

0.83  0.56 (0.192.98)

IFN-a level,a IU

48.5  48.4 (2200)

NOTE.
Score.
a

GCS, Glasgow Coma Scale; SAPS, Simplified Acute Physiology

Data for IFN-a levels in CSF were available for only 43 patients.

Downloaded from http://cid.oxfordjournals.org/ at University of South Dakota and School of Medicine on June 18, 2014

[76%]), behavioral changes (38 [41%]), speech disturbances (55

[59%]), and seizures (31 [33%]). The first neurological examination had no abnormal results for 5 (5.5%) of 93 patients. At
admission to the ICU, the mean SAPS II was 29  14.6, and the
mean GCS score was 11.6  3.6 (table 1).
Laboratory findings. Most of the initial CSF samples exhibited monocytic pleocytosis, but polymorphonuclear cells
were predominant in samples from 2 (2%) of the 93 patients.
The mean protein level was 0.83  0.56 g/L in the initial CSF
samples and reached 1.06  0.64 g/L in the second CSF samples, obtained 4.7  4.03 days later. In 3 patients (3%), the
leukocyte count in the initial CSF samples, obtained at admission, was normal (!5 cells/mm3); protein levels were normal
(!0.50 g/L) in 2 patients and were slightly elevated (0.69 g/L)
in 1 patient. The initial CSF samples were not analyzed with
HSV PCR, but results of PCR were positive for samples drawn
27 (mean  SD, 4.3  3.05) days later, and those samples had
high protein levels and WBC counts. IFN-a levels were high
in the initial CSF sample from 43 patients. The mean level was
48.5  48.4 IU/mL (normal level, !2 IU/mL). Hyponatremia
(serum sodium level, !135 mM) was present in 75 (81%) of
93 patients (table 1).
Brain imaging findings. The mean delay between hospital
admission and the first neuroimaging study was 0.6  1.05 days
(range, 04 days). A CT scan was performed for 91 patients,
and MRI was done for 2 patients (table 2). No abnormalities
were seen on the first CT scan in 19 (21%) of 91 patients. No
other imaging studies were done for 2 (2%) of these 91 patients.
CNS lesions were obvious on a second CT scan obtained
4.7  3 days later for all 17 other patients. Brain imaging revealed temporal involvement in 83 (89%) of the 93 patients,
and this was associated with frontal involvement in 34 (36%)
of 93 patients. In 8 (9%) of 93 patients, radiologic examination
showed only occipital or parietal lesions.
Therapy. All patients received intravenous acyclovir. The
mean delay between hospital admission and the initiation of
acyclovir therapy was 2  2.7 days. In 82 (88%) of 93 patients,
the mean delay between the reported onset of symptoms and
initiation of treatment was 5.5  2.9 days. The intervals were
as follows: 13 (n p 20), 46 (n p 40), 79 (n p 14), 1012
(n p 5), and 1315 days (n p 3). In 11 patients, this information could not be obtained. The mean deduced delay between onset of symptoms and admission was therefore 3.5 days.
The mean dosage of acyclovir was 11.2  8.8 mg/kg 3 times
daily for a mean duration of 18  6.6 days. Seventy-three patients took antiepileptic drugs, and 28 received antiedematous
therapy, either with corticosteroids (n p 12 ) or with hypertonic
mannitol (n p 16). Overall, 66 patients (71%) received care in
the ICU, and 42 patients (45%) required mechanical ventilation, for a mean duration of 15.2  13.4 days (range, 156
days).

Table 2. Findings of CT (91 patients) and

MRI (2 patients) for 93 patients with herpes
simplex encephalitis.

Brain imaging results

No. (%) of
patients

Localization of the lesion

Laterality
Unilateral involvement

53 (57)

Right hemisphere

18

Left hemisphere

35

Bilateral involvement

38 (41)

Temporal

49 (53)

Temporal and frontal

34 (36)

Othera
No abnormal results

8 (9)
2 (2)

Other involved sites were parietal (n p 6) and

occipital (n p 2).

differences between patients with favorable and poor outcome

were found for the following factors: age, MacCabe score, focal
neurological deficit or seizures, need for mechanical ventilation,
serum sodium concentration, and CSF parameters. In contrast,
patients who experienced poor outcome had significantly
higher Knaus and significantly lower GCS scores at admission.
The delay between admission and initiation of acyclovir therapy
was !2 days in 41 (75%) of 55 patients with favorable outcome,
compared with 9 (30%) of 30 patients with poor outcome
(P p .00008). Nosocomial infection occurred significantly
more frequently in the latter group (table 3). On multivariate
analysis, 2 factors were found to be independently associated
with poor outcome of HSE at 6 months: a delay of 12 days
between admission and initiation of acyclovir therapy and a
SAPS II 127 (table 4).

DISCUSSION
Although the prognosis for patients with HSE has been dramatically improved by the availability of specific antiviral therapy, sequelae in surviving patients may include severe neurological deficits, seizures, and/or neuropsychological dysfunctions that greatly impair quality of life [1012]. Therefore,
the identification of early factors that are predictive of outcome
might contribute to better management of the disease. Patient
age and level of consciousness at onset of therapy have been
identified elsewhere as major determinants of prognosis [4].
However, in that study, one-half of the patients were between
the ages of 6 months and 20 years. In addition, HSE was diagnosed by cerebral biopsy, which could have slightly modified
the evolution of CNS lesions and also delayed the administration of antiviral treatment, as indicated by the duration of

Herpes Simplex Encephalitis CID 2002:35 (1 August) 257

Downloaded from http://cid.oxfordjournals.org/ at University of South Dakota and School of Medicine on June 18, 2014

Brain lobe involved

disease before therapy. In a more recent study, the delay between

hospital admission and the initiation of acyclovir therapy was
twice as long for patients with poor outcomes as for those with
favorable outcomes [12]. Both studies included pediatric patients, for whom the prognosis might differ from that for adults
[18]. Moreover, patients were included starting in 1983, and
diagnosis was confirmed by heterogeneous methods. Finally,
no multivariate analysis was performed to identify the parameters independently associated with poor outcome. In the present study, we retrospectively analyzed 93 adult patients in whom
HSE was diagnosed by PCR, which is the reference standard
for diagnosis [8], and all patients received acyclovir therapy.
To date, this is the largest series of adults with HSE in whom
prognoses have been evaluated using a multivariate analysis.
The disease of patients in the present study was highly representative of classical adult HSE. The mean age (53.5 years)
was similar to that of patients included in other epidemiological
studies [19]. Mononuclear pleocytosis and mildly elevated protein level were common findings of analysis of CSF samples,
although several CSF samples were acellular or pleocytic, with
polymorphonuclear predominance at the onset of the disease.
However, no correlation was found between CSF abnormalities
and outcome, as reported elsewhere [20]. Neuroimaging
showed temporal lobe involvement in most cases. However,
less typical lesions, such as occipital or parietal lobe involvement, were observed in 11% of patients. Such localizations of
HSE lesions have been recently reported in a detailed radiological study [11]. These previously misdiagnosed cases of HSE
are presently better recognized by PCR [21].
Remarkably, the consciousness level of patients at hospital
admission differed from that usually reported in association
with adult HSE. Indeed, the mean GCS score at admission for
our patients was moderately altered, compared with the high
percentages of comatose patients reported in 2 large studies
elsewhere [3, 4]. However, more recently, the initial GCS score
of patients with HSE was found to be 12 in most cases [22].
Several explanations may account for this high GCS score at
admission: patients may now be referred more rapidly to the
hospital and/or HSE may be suspected earlier, as was suggested
by the short delay (3.5 days) observed in our study between
onset of symptoms and hospital admission. Early use of PCR
may also allow recognition of milder or moderate forms of
HSE [21, 23]. However, despite having a high GCS score at
admission, most patients in the present study exhibited rapid
neurological deterioration, which led to ICU admission in 71%
of the patients.
Surprisingly, despite the use of rapid diagnostic procedures
and effective antiviral therapy, HSE was associated with significant mortality and morbidity in the present series. The 6month fatality rate was only slightly lower than those for acyclovir-treated patients from 3 studies published elsewhere (19%,

Table 3. Univariate analysis of factors associated with outcomes at 6 months for 85 patients with herpes
simplex encephalitis.
Patients with
favorable outcome
(n p 55)

Characteristic
Age, mean years  SD

50  16.2

Patients with
poor outcome
(n p 30)

56.6  16.8

.1

MacCabe score, mean  SD

0.11  0.4

0.1  0.3

.92

Knaus score, mean  SD

1.16  0.4

1.43  0.7

.04

GCS score, mean  SD

13.7  2.5

12.5  3.4

.03

SAPS II, mean  SD

27.6  16.1

29.6  12.1

.45

SAPS II 127, no. (%) of patients

17 (57)

Seizures, no. (%) of patients

18 (33)

9 (30)

.79

Focal neurological deficit, no. (%) of patients

11 (20)

9 (30)

.3

Serum sodium level, mean mM  SD

132.4  5.5

.0001

131.3  5

.32

CSF parameters, mean  SD

Leukocyte count, cells/mL 103

250  546

170  197

.39

Protein level, g/L

0.83  0.6

0.78  0.4

.39

Less than 2 days between hospital admission and initiation of

acyclovir therapy, no. (%) of patients

41 (75)

9 (30)

Mechanical ventilation, no. (%) of patients

23 (42)

18 (60)

.97

Hospital-acquired infection, no. (%) of patients

17 (31)

20 (67)

.001

NOTE.

.00008

GCS, Glasgow Coma Scale; SAPS, Simplified Acute Physiology Score.

28%, and 19%), which involved a total of 101 patients [3, 4,

12]. Moreover, the 6-month morbidity assessment revealed that
only 37% of our patients returned to conditions of life that
were nearly the same as those preceding the illness; 14% completely recovered and 23% had mild impairment. This percentage was even lower at the 1-year follow-up. These figures
are comparable to those reported in the first trials of acyclovir
treatment, in which the percentages of patients with minor or
no neurological impairment among the entire population of
treated patients were 37.5% and 55.5% [3, 4].
To identify prognostic factors for HSE, patients were assigned
to 1 of 2 categories according to outcome at 6-months (favorable and poor). This categorization was performed before
the statistical analysis of the data set, to distinguish a clear-cut
and clinically relevant group of patients that included those
with very severe neurological disability and those who had died
as result of HSE (poor outcome). A similar categorization
has been used in 2 recent studies that included patients with
bacterial meningitis [24, 25]. Two prognostic factors independently associated with a poor 6-month outcome were identified
for adult patients with HSE: a SAPS II 127 at admission and
a delay of 12 days between admission and initiation of acyclovir
therapy. Our observation that a high SAPS II is associated with
poor outcome is not unexpected, because this score takes into
account many parameters, including age and neurological
status, that have been identified elsewhere as prognostic factors
[4]. The second prognostic factor identified in this study, that
the length of the delay between hospital admission and the
258 CID 2002:35 (1 August) Raschilas et al.

initiation of acyclovir therapy affects outcome, was also reported in a retrospective study by McGrath et al. [12] that
included 42 patients; the study showed that this delay had been
longer for patients with a poor outcome (4 days) than for those
with a good outcome (1.8 days).
Because of the rarity of HSE, the heterogeneous origin of
the patients, and the retrospective design of the study, our
results carry some limitations. First, the precise duration of
symptoms before admission was not taken into account in the
statistical analysis, because it could not be accurately evaluated
in all patients. However, both the high GCS score observed at
hospital admission in patients included in the present study
and the mean delay observed between the onset of symptoms
and initiation of treatment suggest that evolution of the disease
before admission was shorter than that reported by studies
elsewhere [21, 23]. Second, the neurological examination evaluated handicap and quality of life, but neuropsychological

Table 4. Multivariate analysis of factors associated with poor

outcome at 6 months for 85 patients with herpes simplex
encephalitis.
Parameter

OR (95% CI)

SAPS II 127 at hospital admission

3.7 (1.310.6)

.014

More than 2 days between hospital admission and initiation

of acyclovir therapy

3.1 (1.19.1)

.037

NOTE.

SAPS, Simplified Acute Physiology Score.

Downloaded from http://cid.oxfordjournals.org/ at University of South Dakota and School of Medicine on June 18, 2014

9 (16)

FRENCH HERPES SIMPLEX ENCEPHALITIS

STUDY GROUP MEMBERS
Prof. Agid, Dr. Bolgert, Prof. Bricaire, Prof. Lyon-Caen, and
Prof. Pierrot-Deseilligny (Hopital Pitie-Salpetriere, Paris); Dr.
Akrouf and Dr. Meignan (Hopital Sainte-Anne, Paris); Prof.
Bousser (Hopital Lariboisie`re, Paris); Prof. Degos (FondationHopital Saint-Joseph, Paris); Prof. Degos (Hopital Henri Mondor, Paris); Prof. Dhainaut (Hopital Cochin, Paris); Prof. Offenstadt (Hopital Saint-Antoine, Paris); Prof. Roullet (Hopital
Tenon, Paris); Prof. Safar (Hopital Broussais, Paris); Prof.
Valcke (Hopital Boucicaut, Paris); Prof. Bleichner and Dr. Davous (Hopital Victor Dupouy, Argenteuil); Dr. Fouet, Dr. Hilpert, and Dr. Lanoe (Hopital Robert Ballanger, Aulnay-sousBois); Dr. Hoang The Duan and Prof. Robineau (Hopital
Avicenne, Bobigny); Prof. Jardin (Hopital Ambroise Pare, Boulogne-Billancourt); Prof. Chaput and Prof. Galanaud (Hopital
Antoine Becle`re, Clamart); Prof. Dreyfuss (Hopital Louis
Mourier, Colombes); Prof. Lemaire (Hopital Henri Mondor,
Creteil); Dr. Tenaillon (Hopital Louise Michel, Evry); Dr. Clair
and Prof. Gajdos (Hopital Raymond Poincarre, Garches); Prof.
Nouhaillat (Hopital Leon Touladjian, Mantes-la-Jolie); Dr. Loriferne (Centre Hospitalier, Montfermeil); Prof. Canton, Prof.
Gerard, and Prof. May (Hopital Brabois, Nancy); and Prof.
Weber (Hopital Central, Nancy); Dr. Cambon and Dr. Ricome
(Centre Hospitalier Intercommunal, Poissy-Saint-Germain-enLaye); Dr. Trouillet (Hopital Rene Dubos, Pontoise); Dr. Fraisse
(Hopital Delafontaine, Saint-Denis); Dr. Graveleau, Dr. Loirat,
and Dr. Truelle (Hopital Foch, Suresnes); Dr. Vuong (Clinique
du Vert Galant, Tremblay-en-France); Dr. Blin (Hopital de Gonesse); Dr. Caen (Hopital de Corbeil); Dr. Casciani and Dr.

Patey (Hopital de Villeneuve-Saint-Georges); and Dr. Coudray

(Centre Hospitalier General de Longjumeau).

Acknowledgment

We thank Glaxo-Wellcome for supporting this study.

References
1. Whitley RJ. Viral encephalitis. N Engl J Med 1990; 323:24250.
2. Whitley RJ, Soong SJ, Dolin R, Galasso GJ, Chien LT, Alford CA.
Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N Engl J Med 1977; 297:28994.
3. Skoldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine
in herpes simplex encephalitis: randomised multicentre study in consecutive Swedish patients. Lancet 1984; 2:70711.
4. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir
therapy in herpes simplex encephalitis. N Engl J Med 1986; 314:1449.
5. Powell KF, Anderson NE, Frith RW, Croxson MC. Non-invasive diagnosis of herpes simplex encephalitis. Lancet 1990; 335:3578.
6. Aurelius E, Johansson B, Skoldenberg B, Staland A, Forsgren M. Rapid
diagnosis of herpes simplex encephalitis by nested polymerase chain
reaction assay of cerebrospinal fluid. Lancet 1991; 337:18992.
7. Rozenberg F, Lebon P. Amplification and characterization of herpesvirus DNA in cerebrospinal fluid from patients with acute encephalitis.
J Clin Microbiol 1991; 29:24127.
8. Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis:
application of polymerase chain reaction to cerebrospinal fluid from
brain-biopsied patients and correlation with disease. National Institute
of Allergy and Infectious Diseases Collaborative Antiviral Study Group.
J Infect Dis 1995; 171:85763.
9. Cinque P, Cleator GM, Weber T, Monteyne P, Sindic CJ, van Loon
AM. The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and
Encephalitis. J Neurol Neurosurg Psychiatry 1996; 61:33945.
10. Gordon B, Selnes OA, Hart J, Hanley DF, Whitley RJ. Long-term
cognitive sequelae of acyclovir-treated herpes simplex encephalitis.
Arch Neurol 1990; 47:6467.
11. Kapur N, Barker S, Burrows EH, et al. Herpes simplex encephalitis:
long term magnetic resonance imaging and neuropsychological profile.
J Neurol Neurosurg Psychiatry 1994; 57:133442.
12. McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex
encephalitis treated with acyclovir: diagnosis and long term outcome.
J Neurol Neurosurg Psychiatry 1997; 63:3216.
13. MacCabe WR, Jackson GG. Gram negative bacteriemia: etiology and
ecology. Arch Intern Med 1962; 110:8391.
14. Knaus WA, Zimmerman JE, Wagner DP, Draper EA, Lawrence DE.
APACHEacute physiology and chronic health evaluation: a physiologically based classification system. Crit Care Med 1981; 9:5917.
15. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology
Score (SAPS II) based on a European/North American multicenter
study. JAMA 1993; 270:295763.
16. Teasdale G, Jennett B. Assessment of coma and impaired consciousness:
a practical scale. Lancet 1974; 2:814.
17. Jennett B, Bond M. Assessment of outcome after severe brain damage.
Lancet 1975; 1:4804.
18. Lahat E, Barr J, Barkai G, Paret G, Brand N, Barzilai A. Long term
neurological outcome of herpes encephalitis. Arch Dis Child 1999; 80:
6971.
19. Koskiniemi M, Piiparinen H, Mannonen L, Rantalaiho T, Vaheri A.
Herpes encephalitis is a disease of middle aged and elderly people:
polymerase chain reaction for detection of herpes simplex virus in the

Herpes Simplex Encephalitis CID 2002:35 (1 August) 259

Downloaded from http://cid.oxfordjournals.org/ at University of South Dakota and School of Medicine on June 18, 2014

status was not precisely assessed. In a study by McGrath et al.

[12], all but 1 of 34 surviving patients had neurological symptoms and abnormal results of neurological examination, but
nearly one-half of patients were able to perform everyday activities as before HSE. Thus, the handicap and quality-of-life
scores defined in our study may have underevaluated the occurrence of neurological sequelae in patients with HSE.
In conclusion, although the availability of PCR has greatly
facilitated early diagnosis of HSE, a number of patients die or
do not recover completely, despite administration of early acyclovir therapy, and have severe sequelae. Our results underline
the fact that HSE prognosis is correlated with the delay between
hospital admission and initiation of acyclovir. In the future,
further reduction of mortality and morbidity due to HSE might
be achieved with use of more-effective antiviral agents. However, because the early administration of antiviral therapy is, at
present, the only parameter that can be modified to improve
the prognosis for patients with HSE, acyclovir treatment should
be initiated as soon as HSE is suspected.

CSF of 516 patients with encephalitis. The Study Group. J Neurol

Neurosurg Psychiatry 1996; 60:1748.
20. Koskiniemi M, Vaheri A, Taskinen E. Cerebrospinal fluid alterations
in herpes simplex virus encephalitis. Rev Infect Dis 1984; 6:60818.
21. Domingues RB, Tsanaclis AM, Pannuti CS, Mayo MS, Lakeman FD.
Evaluation of the range of clinical presentations of herpes simplex
encephalitis by using polymerase chain reaction assay of cerebrospinal
fluid samples. Clin Infect Dis 1997; 25:8691.
22. Domingues RB, Fink MC, Tsanaclis AM, et al. Diagnosis of herpes
simplex encephalitis by magnetic resonance imaging and polymerase
chain reaction assay of cerebrospinal fluid. J Neurol Sci 1998; 157:

14853.
23. Fodor PA, Levin MJ, Weinberg A, Sandberg E, Sylman J, Tyler KL.
Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology 1998; 51:5549.
24. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial
meningitis: risk stratification for adverse clinical outcome and effect
of antibiotic timing. Ann Intern Med 1998; 129:8629.
25. Auburtin M, Porcher R, Bruneel F, et al. Pneumococcal meningitis in
the intensive care unit: prognostic factors of clinical outcome in a series
of 80 cases. Am J Respir Crit Care Med 2002; 165:7137.

Downloaded from http://cid.oxfordjournals.org/ at University of South Dakota and School of Medicine on June 18, 2014

260 CID 2002:35 (1 August) Raschilas et al.