REVIEW

CURRENT
OPINION Herpes simplex virus encephalitis update
Jean Paul Stahl a,b and Alexandra Mailles c,b

Purpose of review
HSV is the most frequently identified cause of infectious encephalitis, in Western countries. This article is an
update on the topic based on a review of recent studies from 2017 to 2018.
Recent findings
Acyclovir is still the first line treatment, and no new drugs are currently available for clinical use. The major
considerations for HSV encephalitis are as follows: point one, clinical evaluation remains the most
important factor, as though CSF HSV PCR has a good sensitivity, in a small proportion of patients the initial
testing might be negative. MRI brain is the first line imaging test, and mesial temporal lobe involvement
and other typical findings are important for diagnosis; point 2, there should be emphasis on sequela, short-
term, and long-term outcomes, and not just case fatality rated in future studies and clinical management.
Auto-immune encephalitis can be triggered by HSV, and should be considered in patients who are not
responding to treatment; point 3, future studies should be on better management of sequela, and better
treatment regimens including those targeting the immune response.
Summary
Autoimmune encephalitis is a clearly identified complication of HSV encephalitis. Inflammatory mechanisms
are linked to the clinical presentation as well as severity and poor outcome. Initial corticosteroid therapy
has to be evaluated in order to prevent complications.
Keywords
autoimmune encephalitis, brain inflammation, encephalitis, herpes simplex virus sequela

INTRODUCTION of 94% [3]. It can occasionally be false negative, early

Herpes simplex virus (HSV) is the most frequently in the presentation, during the first 4 days of the
identified cause of encephalitis in developed coun- diseases. In such a situation, the CSF HSV PCR
&

tries. It accounts for around 30–40% of cases with an
&
identified cause [1 ], and is the only viral encephalitis
with an effective antiviral treatment. In a study pub-
lished in 2017, HSV encephalitis (HSE) hospitaliza-
tion rate in the United States, was 10.3  2.2 cases/
million in neonates, 2.4  0.3 cases/million in chil-
should be repeated after 4 days or later [4 ]. Never-
theless, less than 0.4% of these PCR in patients
presenting with HSE may be false negatives.
According to recent guidelines, if the CSF HSV
PCR is obtained after 4 days of onset of neurological
symptoms and is negative, empirically started acy-
&

dren and 6.4  0.4 cases/million in adults. Case fatal-
ity rate in neonates, children and adults was 6.9, 1.2
and 7.7%, respectively [2 ].
&
The aim of this update is to report recent devel-
opments in HSVE, published in 2017 and 2018, on
diagnostic tests, treatments especially those target-
ing the immune response, genetic risk factors,
and outcomes.
clovir can be stopped [4 ]. However, recent case
reports highlight the importance of clinical evalua-
tion and when the clinical and imaging findings are
highly suggestive, it might be prudent to continue
treatment with acyclovir. An autopsy-proven HSE
with two false-negative CSF PCRs [5], and another
case with two successive negative PCRs, with a

a
DIAGNOSIS Infectious Diseases Department, University and Hospital Grenoble
Alpes, Grenoble Cedex, France, bEuropean Study Group on Infections
Laboratory diagnostic tests of the Brain (ESGIB). Basel, Switzerland and cInfectious Diseases
Department, Santé Publique France, Saint Maurice Cedex, France
Correspondence to Jean Paul Stahl, Infectious Diseases Department,
Cerebrospinal fluid herpes simplex virus University and Hospital Grenoble Alpes, Grenoble Cedex, France.
PCR E-mail: JPStahl@chu-grenoble.fr
CSF HSV PCR is the best diagnostic test for HSE Curr Opin Infect Dis 2019, 32:239–243
diagnosis, with a sensitivity of 98% and a specificity DOI:10.1097/QCO.0000000000000554

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CNS infections
KEY POINTS
 Clinical evaluation remains a key factor, as CSF PCR
can be false negative rarely.
 Future emphasis should be on sequela and better
evaluation and management of short- and long-term
consequences, and not just reducing the case
fatality rate.
 Need to recognize that autoimmune encephalitis can
be triggered by HSV.
 The essential role of inflammation in disease severity
and outcomes, and the implication of new concepts
on rebatement.
positive result only with the third one [6] have
been reported.
CEREBROSPINAL FLUID CELL COUNTS
AND CHEMISTRY
A German study retrospectively evaluated all conse-
cutive PCR-proven HSV encephalitis cases treated in
&
their hospital for 5 years [7 ]. They included 18
patients with PCR-proven HSV encephalitis present-
ing with altered mental status (77.8%), focal neuro-
logic deficits (72.2%) and fever (72.2%). Four of
these patients (22.2%) had a normal-cellular count
in cerebrospinal fluid (CSF) on admission. Electroen-
cephalography and MRI abnormalities were highly
sensitive for HSV encephalitis independent of CSF
cell count, but initial computed tomography (CT)
scans were normal in 11 out of 16 patients (69%).
In another multicenter study [8], a total of 4404
CSF samples submitted for HSV PCR testing were
analyzed. Among them, 91 (2.1%) were positive for
HSV (75 HSV-1 and 16 HSV-2). Nine patients failed
to meet the Reller criteria (abnormal CSF white
blood cell counts and protein levels, if they were
older than 2 years of age and were not immunocom-
promised), of whom seven were demonstrated to
have HSV encephalitis. The authors observed no
significant correlation between HSV PCR values
and white blood cell (WBC) counts or total protein
levels. They showed that HSV DNA may be detected
in CSF samples with normal WBC and protein levels,
collected from immunocompetent individuals older
than 2 years with HSV encephalitis.
These studies show that normal testing on rou-
tine CSF cell counts and chemistry cannot rule out
diagnosis of HSV encephalitis, and should be con-
sidered in conjunction with clinical as well as
imaging findings.
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Imaging
Imaging, especially MRI brain is an important diag-
nostic tool for diagnosis of HSV encephalitis, as it is
far more sensitive than CT scan, as shown again in a
&
recent German study [7 ]. A recent review [9] sum-
marizes current knowledge about modern imaging
in HSE. Brain MRI has a high sensitivity for the
diagnosis of HSE, showing brain abnormalities in
80–100% of cases. However, normal brain images
on MRI, although rare in HSE patients, does not rule
out HSE diagnosis. HSE most frequently affects the
medial temporal lobes, but can also affect the insu-
lar, cingulate, and frontobasal cortex. Lesions are
unilateral in 64–68% of cases. Brain MRI typically
shows hyperintensities involving the cortex and the
white matter in T2 and FLAIR images. Areas of
contrast enhancement can also be present.
Seizures associated with HSE may lead to a
reversible hyperintense FLAIR signal in the thala-
mus. Isolated brainstem involvement is rare. Diffu-
sion-weighted imaging (DWI) seems to be the most
sensitive sequence for detecting HSE in the acute
phase, typically showing restricted diffusion [hyper-
intense lesions on DWI with hypointensity in the
same areas on apparent diffusion coefficient (ADC)].
Severe presentations of HSE can cause hemorrhagic
necrosis, and are characterized by hypointense T2
signal, but lobar hematomas are rare.
TREATMENT
The most recent guidelines for the treatment of HSE
&
were released by the French ID society [4 ], and are
similar to previous treatment recommendations. In
adults, acyclovir should be administered at a dose of
10 mg/kg/8 h (30 mg/kg/day,) for 14 days in immu-
nocompetent patients, and for 21 days in immuno-
compromised patients. The objective is to achieve
plasma concentrations of 3 mg/l or above to ensure a
CSF concentration of 1 mg/l.
Resistance to acyclovir (mutation in the thymi-
dine kinase gene) can be seen and has been mostly
reported in immunocompromised patients. Very
few case have been reported in immunocompetent
patients [10]. Foscarnet is as an alternative antiviral
when resistance to acyclovir is suspected.
New anti-HSV agents are being studied but are
few. PHA767491 is a new drug with activity against
HSV [11]. It potently blocks the proliferation of HSV
in cells, as well as HSV-induced cell death. In HSV-1-
infected mice, it reduced viral titers in the tissues.
This needs further evaluation, but if its activity is
confirmed, it could be tested vs. acyclovir for
treatment of severe HSV infections, including
encephalitis.
Volume 32  Number 3  June 2019

OUTCOMES
Before the use of acyclovir, the case fatality rate of
HSE was up to 70%. With antiviral treatment, it has
decreased to below 20%, but survivors still have
severe sequelae. It was previously demonstrated that
sequelae are a key issue for HSV encephalitis with a
rate of 58% [12]. This point is neglected in guide-
lines, which are focused on the acute phase of the
infection. Future studies and guidelines should
address sequelae and their management, which
are really challenging for both the patients and their
family caregivers.
Another question is the possible correlation
between viral inoculum and the severity of infec-
tion, as well as frequency of unfavorable outcomes.
A study evaluated HSV loads, by real-time PCR, from
the CSF of 33 patients (20 neonates, 5 children, 8
adults) presenting with HSVE, to explore their cor-
relation with disease severity [13]. Initial viral load
did not correlate with lesion volume, subarachnoid
extension, inhospital morbidity, unfavorable dis-
charge, or long-term outcomes. Authors concluded
that the initial HSV viral load does not predict
neuroradiological or clinical outcomes in patients
with HSVE.
HERPES SIMPLEX VIRUS ENCEPHALITIS
AND AUTOIMMUNE ENCEPHALITIS
Armangue et al. recently confirmed the importance
of autoimmune encephalitis triggered by HSE. Their
most recent study concluded that there is a predict-
able time frame of approximately 5 weeks in which
27% of patients with HSE develop an immune
response against N-Méthyl-D-Aspartate receptors
and other neuronal surface proteins, associated with
&&
neurological symptoms [14 ]. Among the remain-
ing patients, 30% developed auto-antibodies in
serum (and some in CSF) without symptoms.
As a consequence, recent guidelines recommend
testing for autoimmune encephalitis in case of fail-
ure to respond to antiviral treatment or when there
is recurrence of symptoms despite appropriate early
&
treatment [4 ].
The pathophysiological explanation for the
auto-immune reaction is still unclear, but several
hypotheses have been entertained [15]: molecular
mimicry, release of antigenic proteins from neuro-
nal injury becoming autoimmune targets, host auto-
inflammatory responses specific to herpesvirus
infection, genetic risk factors, and the role of some
degree of immunodeficiency.
This raises the question of the role of steroid
therapy together with antiviral drugs, which is being
explored in studies [16].
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HSV encephalitis update Stahl and Mailles
PATHOPHYSIOLOGY
There are new studies on pathophysiology of HSVE,
which have implications on the management of
this infection.
The most accepted and studied route of entry of
HSV, into the brain, is neuronal. A recent study
evaluated mechanisms by which the virus could
breach the human brain microvascular endothelial
cells of the blood–brain barrier [17]. The authors
used an electrical cell-substrate impedance-sensing
tool simulating cell system of the blood–brain bar-
rier. They showed that HSV (regardless of type 1 or
2), reduced the cell–cell barrier resistance almost
immediately after virus addition to endothelial cells.
From 30 h after HSV infection, they observed a
viability loss of the infected endothelial cells. They
demonstrate, in this in-vitro model of the blood–
brain barrier, that destruction of brain microvascu-
lar endothelial cells could be another mechanism
for HSV invasion.
Inflammation is an important cause of brain
damage in HSE. Some recent experimental studies
demonstrate the essential role of regulation of the
inflammatory response in pathogenesis.
The impact of a deficiency in interferon regula-
tory factors (IRF3 and IRF7) was evaluated in a HSE
&&
model [18 ]. The case fatality rates of infected IRF3
and IRF7-deficient mice were higher than those
observed in controls and was associated with
increased brain viral loads. At a critical time postin-
fection, IRF7-/- mice exhibited a deficit in IFN-b
production. These results suggest that IRF3 and
IRF7 are important for the efficient control of
inflammatory responses in HSVE.
HSE animal models previously demonstrated
that virus causes damages not only by direct virus-
mediated necrosis but also by the host’s immune
response that contributes to the high mortality of
the disease. The chemokine receptor CXCR3 was
identified to have an important impact on the
course of HSE in mouse models. A recent study
evaluated the role of the chemokine receptor
CXCR3 after infection with a HSV encephalitis-caus-
ing strain [19]. The authors compared CXCR3-defi-
cient mice with wild-type controls. They
demonstrated that CXCR3-deficient mice cleared
HSV-1 more efficiently 14 days after infection. Inhi-
bition of CXCR3 signalling reduced T-cell infiltra-
tion and microglial activation. They conclude that,
surprisingly, interruption of the CXCR3 pathway
leads paradoxically to an enhanced viral clearance
after intranasal infection. These results have
implications for an ongoing study [16] evaluating
the role of immunomodulation (namely steroids)
in HSVE.
www.co-infectiousdiseases.com 241
CNS infections
TLR3 is a sensor of double-stranded RNA,
required for innate immune responses to HSV-1 in
& &
neurons and astrocytes [20 ]. In a recent study [21 ],
authors demonstrated that TLR3 recruited
mTORC2, the metabolic checkpoint kinase complex
leading to the induction of chemokines and traffick-
ing of TLR3 to the cell periphery. Such trafficking
activated required molecules for the induction of
type I interferons. They showed that HSV-1 brain
infection of animals was increased when TLR3
responses were impaired by an mechanistic target
of rapamycin inhibitor. This effect was antagonized
by the use of an agonistic antibody to TLR3.
A study on human cells obtained from CSF con-
&
firms those results [22 ]. Authors used trigeminal
(TG) neurons, as control and TRL3-deficient trigemi-
nal neurons. Both control and TLR3-deficient neu-
rons were highly susceptible to HSV-1. The
pretreatment of control neurons with poly (I:C)
induced HSV-1 resistant cells. Moreover, both control
and TLR3-deficient TG neurons developed resistance
to HSV-1 when pretreated with IFN-b but not IFN-l.
Authors conclude that trigeminal neurons are natu-
rally sensitive to HSV-1 and they need previous stim-
ulation of the TLR3 or IFN-a/b receptors to induce
antiviral immunity, whereas cortical neurons have a
TLR3-dependent constitutive resistance, sufficient
enough to block incoming HSV-1 even in case of lack
of prior antiviral information. The lack of constitu-
tive resistance in trigeminal neurons in vitro could
explain the latency of the virus in this reservoir in
vivo. These results corroborate the importance of the
constitutive TLR3-dependent response of cortical
neurons in the pathogenesis of HSE.
Recently, in a human study, other authors con-
firmed that mutations in TLR3 gene or in other
genes involved in the TLR3 pathway (TLR3,
TICAM1, TRAF3, UNC93B1, TBK1, and IRF3) are
& patients and correlation with disease. J Infect Dis 1995; 171:857–863.
risk factors for HSE [23 ]. This needs to be validated
in larger studies, but it highlights the role of genetic
risk factors in HSE.
These studies suggest that the TLR3 might be a
therapeutic target in the future for better manage-
ment of HSVE.
In a rat model, HSV-1 infection caused an inter-
action between complement factors and protea-
somes, resulting in the formation of proteasome/
complement complexes (so called compleasomes).
The exposure to the proteasome regulatory subunit
anti secretory factor 1 reduces the intracranial pres-
& infectious encephalitis. Med Mal Infect 2017; 47:195–205.
sure [24 ]. A human study was performed in order to
&
confirm this feature in clinical practice [24 ]. The
acute and prolonged formation of compleasomes in
cerebrospinal fluid (CSF) was evaluated in 55 CSF
samples from 24 HSE patients. They were compared
with healthy controls (n ¼ 23) and patient controls
242 www.co-infectiousdiseases.com
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(n ¼ 27). There was a significant increase in com-
pleasome formation in CSF samples obtained from
HSE patients compared with the control group. The
levels were significantly higher in the acute phase
compared with late samples. This early increased
formation of compleasomes in CSF suggests that this
complex may be important in host defense against
HSV in the brain.
CONCLUSION
Acyclovir remains the first line treatment, and there
are few new drugs available. New treatments will
probably target modulation of the inflammatory
response in HSE, and treatment of autoimmune
encephalitis following HSE.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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READING
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& of special interest
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