Review Article

Herpes Simplex Virus

Address correspondence to
Dr Richard J. Whitley, Suite
303, Children’s Harbor
Building, 1600 7th Avenue
South, Birmingham, AL 35233,
rwhitley@peds.uab.edu.
Relationship Disclosure:
Infections of the Central
Dr Whitley has served on the
board of directors of Gilead
Sciences, Inc, and has
Nervous System
received personal
compensation as a Richard J. Whitley, MD
consultant for the GSK
Watermark Zoster Study,
Merck Letermovir Data and
Safety Monitoring Board,
ABSTRACT
Multiparty Group for Advice Purpose of the Review: This article summarizes knowledge of herpes simplex
on Science (MUGAS) Influenza virus (HSV) infections of the central nervous system (CNS). Disease pathogenesis,
Data Oversight, and N&N
Scientific, Inc. Dr Whitley has detection of DNA polymerase chain reaction (PCR) for diagnosis and prognosis, and
received personal compensation approaches to therapy warrant consideration.
from the Journal of Antiviral Recent Findings: HSV infection of the CNS is one of few treatable viral diseases.
Therapy for serving as section
editor and from the Journal of Clinical trials indicate that outcome following neonatal herpes simplex virus type 2
Infectious Diseases for serving (HSV-2) infections of the CNS is significantly improved when 6 months of suppressive
as associate editor. Dr Whitley oral acyclovir therapy follows IV antiviral therapy. In contrast, herpes simplex virus type
has received personal
compensation for speaking 1 (HSV-1) infections of the brain do not benefit from extended oral antiviral therapy.
engagements from The George This implies a difference in disease pathogenesis between HSV-2 and HSV-1 infections
Washington University of the brain. PCR detection of viral DNA in the CSF is the gold standard for diagnosis.
Continuing Medical Education
Program, Harvard University, Use of PCR is now being adopted as a basis for determining the duration of therapy in
Hospital Pediátrico de Coimbra, the newborn.
Infectious Diseases Society of Summary: HSV infections are among the most common encountered by humans;
America, International
Herpesvirus Workshop, Japan seropositivity occurs in 50% to 90% of adult populations. Herpes simplex encephalitis,
Herpesvirus Infections Forum, however, is an uncommon result of this infection. Since no new antiviral drugs have
The Ohio State University, been introduced in nearly 3 decades, much effort has focused on learning how to
State University of New York,
Plattsburgh, University of Oxford, better use acyclovir and how to use existing databases to establish earlier diagnosis.
and University of Pittsburgh.
Unlabeled Use of Continuum (Minneap Minn) 2015;21(6):1704–1713.
Products/Investigational
Use Disclosure:
Dr Whitley reports no disclosure.
* 2015, American Academy
of Neurology.
INTRODUCTION poral lobe localization of herpes simplex
Herpes simplex virus (HSV) infections encephalitis, which accounts for clinical
of the central nervous system (CNS) are symptoms as a function of duration of
among the most devastating infections disease. This temporal lobe localiza-
acquired by humans, in spite of effica- tion is characteristic of herpes simplex
cious antiviral therapy. Two distinct types encephalitis in individuals older than
of HSV infection of the CNS are recog- 3 months. However, CNS disease in
nized: (1) herpes simplex encephalitis newborns can be either diffuse (blood-
of older children and adults that is re- borne transmission) or focal (neuronal
cognized as the most common cause of transmission). The incidence of both
sporadic fatal encephalitis and is nearly diseases is approximately 1500 to 2000
uniformly caused by herpes simplex virus cases annually.
type 1 (HSV-1); and (2) neonatal herpes
simplex encephalitis that occurs during HERPES SIMPLEX ENCEPHALITIS
the first month of life and is usually OF OLDER CHILDREN AND ADULTS
caused by herpes simplex virus type 2 One of the most perplexing clinical pro-
(HSV-2). Particularly striking is the tem- blems is the evaluation of patients with

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 KEY POINTS
altered mentation, fever, and a variety of detection of viral DNA. Appropriate h Two distinct types of
clinical neurologic findings. Case 9-1 il- blood and urine cultures should also be herpes simplex virus
lustrates the necessary thought processes obtained to test for bacterial infection. infection of the central
for evaluation, diagnosis, and treatment. With herpes simplex encephalitis, bio- nervous system are
For individuals over the age of 20, chemical findings will indicate an ele- recognized: (1) herpes
herpes simplex encephalitis is usually vated protein level and a lymphocytic simplex encephalitis of
the consequence of HSV reactivation, cellular predominance.3 The height of older children and adults
but the real questions of pathogenesis protein elevation is a function of dis- that is recognized as the
remain unanswered. Specifically, does ease duration. Further, CSF protein con- most common cause of
the virus reactivate in the temporal lobe centrations will continue to rise even sporadic fatal encephalitis
or is it transported there from either and is nearly uniformly
with the administration of acyclovir and
caused by herpes simplex
the trigeminal ganglia or olfactory remain elevated even after the comple-
virus type 1; and (2)
bulb? Animal models exist to support tion of acyclovir therapy. Importantly, neonatal herpes simplex
each possibility. approximately 5% of CSF samples will encephalitis that occurs
be totally normal, yet the patient will during the first month of
Diagnosis have herpes simplex encephalitis, as life and is usually caused
When the presentation of herpes sim- confirmed by PCR or historically by by herpes simplex
plex encephalitis is recognized, diagnos- brain biopsy.4 virus type 2.
tic and therapeutic interventions need PCR detection of viral DNA in the h When the presentation
to be initiated immediately.2 In the ab- CSF is the gold standard for diagnosis,5 of herpes simplex
sence of increased intracranial pressure, having replaced brain biopsy and detec- encephalitis is recognized,
CSF examination is mandatory for deter- tion of antibodies in the CSF over time.4 diagnostic and
mining biochemical parameters as well Lakeman and Whitley5 found that the therapeutic interventions
as for having a specimen evaluated by sensitivity and specificity of PCR were need to be initiated
polymerase chain reaction (PCR) for 98% and 94%, respectively. These data immediately.
h With herpes simplex
encephalitis, cerebrospinal
Case 9-1 fluid findings will indicate
A 35-year-old man, who was otherwise healthy, presented to a local emergency an elevated protein level
department with the following history. He had 3 days of low-grade fever and a lymphocytic
and did not go to work on those days. He awoke at 2:00 AM on the fourth day, cellular predominance.
got dressed, went to the kitchen, poured cereal onto the kitchen table,
added milk, got the car keys, and promptly backed his car through the garage h Polymerase chain
door. At that point, his wife immediately took him to the local emergency reaction detection of
department. He had no witnessed seizures. viral DNA in the CSF is
the gold standard for
His temperature on presentation to the emergency department was
diagnosis of herpes
38.5-C (101.3-F), and he was normotensive. On neurologic examination, he
simplex encephalitis,
had an expressive aphasia. There were no focal signs of weakness at presentation.
having replaced brain
Comment. This case represents a classic presentation for herpes simplex
biopsy and detection of
encephalitis, including nonspecific findings such as bizarre behavior and, more
antibodies in the CSF
specifically, expressive aphasia. It is now the responsibility of the emergency
over time.
department physician or neurology consultant to define a course of action.
First, a working differential diagnosis must be established. Numerous diseases
mimic herpes simplex encephalitis, but most are not treatable. Whitley and
colleagues1 summarized those diseases identified following brain biopsy. In
addition to these clinical entities, the recent incursion of West Nile virus
infections of the central nervous system must be included in the differential
diagnosis. Clearly, the expressive aphasia points to a focal neurologic
process. If focal seizures or hemiparesis were present by history or
examination, further evidence of localization would be present.

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 Herpes Simplex Virus Infections
KEY POINT
h Polymerase chain reaction
evaluation of the CSF
and an MRI are important
components of the
diagnostic evaluation
for herpes simplex
encephalitis.
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were generated by comparing brain
biopsy results (HSV culture positive or
negative) with CSF PCR evaluation. Three
points require iteration. First, heme con-
tamination of the CSF will lead to a false
negative. Second, three patients had
biopsy specimens either obtained from
a noninvolved area of the brain or tissue
fixed in formalin prior to an attempt to
isolate virus. As to these three cases, if
studies had been performed appropri-
ately, the specificity would have been
higher. Third, not all laboratories that
perform CSF evaluations for HSV DNA
are reliable, including some academic
units. Thus, it is incumbent upon the at-
tending physician to first find an out-
standing laboratory and then, even if
the PCR is negative but with a compatible
clinical picture, institute therapy and treat
until an alternative diagnosis is estab-
lished. It is prudent to repeat the CSF
examination if the initial evaluation is
negative for detection of HSV DNA by
PCR. Assessment for increasing protein
and repeat PCR may prove valuable.
Ideally, the results of PCR testing should
FIGURE 9-1 T2-weighted MRI illustrating the classic findings
of herpes simplex encephalitis, including
hyperintensity involving the right insular cortex.
be available within 24 to 48 hours. If virus
typing is required, it can be performed
on the PCR DNA preparation.
As it relates to additional diagnostic
tests, EEG and radiologic imaging have
been utilized to varying extents. Histor-
ically, both EEG and CT scans were uti-
lized. EEG evidence of spike and slow
wave localization to the temporal lobe
has been considered excellent evidence
of disease being caused by herpes
simplex encephalitis, but it has a sensi-
tivity of only about 60% and a specificity
of 80%.6 CT scans have given way to
MRI scans. As shown in Figure 9-1,
the classic findings of herpes simplex
encephalitis are illustrated with a
T2-weighted MRI. A few comments are
in order. First, these MRI findings have
been reiterated by the California En-
cephalitis Project.7 Second, as with CSF
evaluations, about 5% will have a
normal MRI at presentation but subse-
quently develop abnormalities. Finally,
at the present, no data exist as to the
correlation of volume of involvement
by MRI and outcome. In summary, PCR
December 2015

evaluation of the CSF and an MRI are
important components of the diagnos-
tic evaluation.
Treatment
Acyclovir is the only US Food and Drug
Administration (FDA)-approved therapy
for the treatment of herpes simplex
encephalitis. The recommended dose
is 10 mg/kg IV every 8 hours for 14 to
21 days.8 Some physicians have attemp-
ted to increase the dose to 15 mg/kg
per dose, but usually elevated creatinine
levels preclude long-term administration.
Adjunct therapy has not proven useful,
although some clinicians utilize a short
3-day burst of corticosteroids. Neuro-
intensive care unit management for in-
creased intracranial pressure is essential.
Overall, the mortality at 3 months
after treatment is 15% but increases to
25% by 18 months post-therapy. The
late-onset deaths were attributed to
neurologic complications. Neurologic
outcome is dependent upon two fac-
tors: age and level of consciousness at
the time of initiation of therapy. The
stratifications are ages less than or greater
than 30 years and a Glasgow Coma
Scale score less than or greater than 6.
For young patients under 30 years of
age with a score greater than 6, the pro-
bability of returning to normal function
is 60%, a figure decreased to 30% for
patients older than 30 years of age.9
The National Institute of Allergy
and Infectious Diseases (NIAID) Colla-
borative Antiviral Study Group (CASG)
recently completed a randomized con-
trolled study of long-term valacyclovir
therapy in patients with PCR-confirmed
HSV-1 infection to test the hypothesis
that chronic replication of HSV in the
CNS might contribute to morbidity.10
Medication was administered orally.
While there was no added benefit to
long-term therapy, the natural history
became clearer. Notably, there was sig-
nificant improvement over 1 year in all
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KEY POINTS
populations, if medication could be h Acyclovir is the only
swallowed; 70% of these subjects were licensed therapy for the
determined to be functioning normally. treatment of herpes
Clearly, this is a self-selected popula- simplex encephalitis.
tion and may not represent all patients The recommended dose
with herpes simplex encephalitis. Al- is 10 mg/kg IV every
though another study reported a similar 8 hours for 14 to 21 days.
outcome with just IV acyclovir therapy, h Therapy should be
notably, duration of disease contributed instituted as quickly as
to influence outcome.11 No data exist possible after herpes
to indicate that the combination of acy- simplex encephalitis
clovir with other antiherpetic drugs is is suspected.
either synergistic or additive. h Herpes simplex virus
In summary, therapy should be in- type 2 causes aseptic
stituted as quickly as possible after her- meningitis and is
pes simplex encephalitis is suspected. usually benign.
Long-term rehabilitation is indicated
and will improve outcome. Thus, speech,
occupational, and physical therapy
specialists need to be participating in
the care of these patients. The percent-
age of patients who appear to return to
normal function is higher than in the
original controlled studies. In the ab-
sence of brain biopsy, noninvasive di-
agnosis may contribute to improved
neurologic status.
Virus Type
In the studies done by the NIAID CASG,
virtually all cases of herpes simplex en-
cephalitis were attributed to HSV-1. More
recently, reports have shown HSV-2
causing herpes simplex encephalitis
at a higher percentage,12 accounting for
as many as 50% of cases in Korea.
Other Considerations of Herpes
Simplex Virus Infections of
the Central Nervous System
Two other considerations are warranted.
First, HSV-2 causes aseptic meningitis
and is usually benign. For the most part,
these patients present with nuchal
rigidity and fever. A lumbar puncture
will identify mononuclear cells but only
a very slight increase in CSF protein.
When the CSF is evaluated by PCR,
many care providers are surprised by
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 Herpes Simplex Virus Infections

KEY POINT
h Herpes simplex
encephalitis has been
associated with the
autoimmune entity
anti-N-methyl-D-aspartate
receptor antibody
encephalitis.
the identification of HSV-2. By the time
the attending physician becomes aware
of the PCR results, the patient is usually
well, indicating that the overwhelming
majority of such patients do not warrant
either IV or oral therapy. Some of these
patients will develop recurrent aseptic
meningitis, namely Mollaret meningi-
tis. Suppressive antiviral therapy of
Mollaret meningitis has not been proven
efficacious despite anecdotal reports.13
Second, herpes simplex encephalitis has
been associated with the autoimmune
entity anti-N-methyl-D-aspartate (NMDA)
receptor antibody encephalitis.14 This
observation certainly warrants further
follow-up.
Summary
The above review summarizes presen-
tation, diagnosis, and management of
herpes simplex encephalitis. Of greatest
importance, time is of the essence in
making a diagnosis and initiating anti-
viral therapy. Because emergency de-
partment physicians and neurologists
in community practice may only see
one or two cases a year, a high index
of suspicion is warranted. It is reason-
able to initiate antiviral therapy prior
to obtaining PCR results and data from
other diagnostic tests. The need for
improved therapies is obvious. Acy-
clovir is not lipophilic and, therefore,
does not cross the blood-brain barrier
as would be desired. It is hoped that
newer drugs will address this need. If
herpes simplex encephalitis cannot be
confirmed, it is prudent to obtain acute
and convalescent sera to determine ev-
idence of seroconversion to other neu-
rotrophic viruses.
NEONATAL HERPES
SIMPLEX VIRUS
Infections of the newborn are usually
associated with irritability, fever, and,
ultimately, lethargy. While initial con-
siderations focus on bacterial infections,
those caused by viruses, in particular
HSV, must be considered in the differ-
ential diagnosis (Case 9-2).

Case 9-2
A 30-year-old woman delivered a daughter at 37 weeks of gestation. Her pregnancy, labor, and delivery
were unremarkable. She denied a history of fever, sexually transmitted infection, or vaginal discharge
at any time during pregnancy. The child weighed 2.3 kg (5 lb) and had a normal Apgar score. No cultures
of either mother or baby were obtained at delivery or postnatally. The mother elected to breast-feed
her child and was discharged home at 48 hours postpartum.
At home, the child was alert and active and took the breast well. At 12 days of life, mom reported
that the child was more lethargic but still took the breast. On the morning of presentation to the
emergency department, day 15 of life, the child had become febrile and irritable. In the car en route to
the emergency department, the child seemed to have uncontrolled shaking of the upper extremities.
In the emergency department, the child was febrile to 39-C (102.2-F) with a pulse of 150. Physicians
confirmed that the child was irritable and inconsolable and would not feed. The only other relevant
clinical findings were a bulging fontanel, nuchal rigidity, and the absence of skin lesions.
Comment. This child presented with a picture of sepsis but, more specifically, a central nervous
system infection as evidenced by seizures, nuchal rigidity, and a bulging fontanel. At this juncture, it is
unclear whether the cause of the findings is bacterial or viral. Pathogens that must be included in the
differential diagnosis are late-onset group B streptococcal infection, Escherichia coli, and Listeria
monocytogenes. From a viral etiologic perspective, herpes simplex virus (HSV) and enterovirus sepsis can
present in this fashion. Importantly, the age of 2 weeks is the most probable time for neonatal HSV
encephalitis. Regardless, the clinical presentation represents an acute medical emergency and warrants
rapid diagnosis and institution of therapy.

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Diagnosis
Cultures for evidence of bacterial infec-
tion should be obtained from blood,
urine, and CSF. As with adult herpes
simplex encephalitis, the CSF must be
probed by PCR for evidence of HSV
DNA as well as detection of entero-
virus infection. In addition, blood should
be obtained to assess clotting parameters
and evidence of hepatic dysfunction.
Such data are invaluable for classifying
the child according to the extent of
disease and, ergo, the prognosis.
In the infant in Case 9-2, the PCR
for HSV DNA from the CSF was posi-
tive, thus confirming a diagnosis of neo-
natal herpes resulting in encephalitis.
Further, from the PCR preparation it was
possible to ascertain that the disease
was caused by HSV-2. In reviewing the
history, it is usual for mothers to be
totally unaware that they have HSV in-
fection of the genital tract because most
maternal infections are asymptomatic.
Further, this baby was born 3 weeks early,
which occurs frequently with this disease.
Once the diagnosis of neonatal HSV
infection is made, it is important to now
define the extent of disease. Table 9-1
identifies the three classifications of
neonatal HSV infection: skin, eye, and
KEY POINT
mouth; encephalitis; and multiorgan dis-
h In a child suspected of
seminated disease, accounting for 45%, having neonatal herpes
35%, and 20% of cases, respectively. Ap- simplex virus infection,
proximately three out of four babies with cultures for evidence of
disseminated infection will also have dis- bacterial infection
ease of the brain. Skin vesicles are the should be obtained
hallmark of disease and, when present, from blood, urine, and
allow for a prompt diagnosis; however, CSF. The CSF must be
these lesions are not always present. probed by polymerase
The most benign form of disease is that chain reaction for
which involves the skin.15,16 These chil- evidence of herpes
dren are born to women with estab- simplex virus DNA as
well as detection of
lished genital HSV infection who transmit
enterovirus infection.
significant antibodies to the virus across
the placenta to the fetus. Usually, a scalp
monitor or skin abrasion provides a
nidus for infection following contact
with infected maternal genital secre-
tions. These children present between
day 7 and 9 of life for care. For children
with encephalitis or disseminated dis-
ease, the diagnosis becomes more chal-
lenging. Babies with disseminated
disease are usually born to women who
experience a primary infection in the
third trimester of gestation and do not
provide significant transplacental anti-
bodies to protect the fetus. As would be
imagined, the potential viral load is sig-
nificantly greater in these women than

TABLE 9-1 Characteristics of Babies With Neonatal Herpes Simplex

Virus Infection

Disease Skin, Eye,

Characteristic Disseminated Classification CNS Mouth
Number of babies (%) 93 (32) 96 (33) 102 (35)
Number premature 33 (35) 20 (21) 24 (24)
[G36 weeks] (%)
Enrollment age, days 11.6 T 0.7 17.4 T 0.8 12.1 T 1.1
Clinical findings
Skin lesions (%) 72 (77) 60 (63) 86 (84)
Brain involvement (%) 69 (74) 96 (100) 0 (0)
Pneumonia (%) 46 (49) 0 (0) 0 (0)

CNS = central nervous system.

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 Herpes Simplex Virus Infections
KEY POINTS
h Aggressive diagnostic
procedures need to be
implemented as soon as
a child suspected of
having neonatal herpes
simplex virus infection
reaches the emergency
department. The use of
polymerase chain reaction
for diagnosis and MRI to
identify the extent of
central nervous system
disease in all patients
is indicated.
h Acyclovir remains the
only licensed therapeutic
medication for neonatal
herpes simplex virus
infections; however,
disease classification
influences the duration
of therapy.
h End-of-therapy evaluation
of the CSF for evidence
of viral DNA by polymerase
chain reaction has
become the standard of
care in neonatal herpes
simplex virus infection.
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those with established infection. These
children have a blood-borne infection
that involves multiple organs, especially
the liver and lung. These children can
present from the first few days of life to
up to 10 days. Often they present in
shock, and therapy is of little value.
Those babies with encephalitis war-
rant special consideration. First, as in
Case 9-2, presentation is at about
2 weeks of life. Second, skin vesicles, the
hallmark of neonatal herpes, are only
present in less than half of these babies.
The CSF findings for these chil-
dren resemble adult herpes simplex
encephalitis but with a higher lymphocyte
count and protein level. It is important to
remember that CSF protein levels are
routinely higher in the otherwise normal
newborn than in older individuals.
Additional comments are in order
about the use of PCR for diagnosis. All
babies with neonatal HSV infection, re-
gardless of classification, warrant a CSF
examination for detection of viral DNA.17
This recommendation is predicated upon
data indicating that even some children
classified as having localized skin dis-
ease went on to develop neurologic im-
pairment. When their CSF was examined
in retrospect, they were found to be HSV-
DNA positive, indicating asymptomatic
infection of the CNS. As noted later in
the article, this finding has important
implications for the duration of therapy.
A brain CT scan, or preferably MRI, is
indicated for all babies with neonatal HSV
infection. Because neurologic findings
can be atypical, an image is indicated even
in the mildest presentations of disease,
namely that of skin, eye, and mouth.
In summary, aggressive diagnostic
procedures need to be implemented as
soon as the child suspected of having
neonatal herpes simplex virus infection
reaches the emergency department. The
use of PCR for diagnosis and MRI for
extent of CNS disease in all patients is
indicated.17 Physicians caring for these
children must be sensitive to parents’
feelings of guilt. They will question the
fidelity of the relationship and are
often accusatory of one another. The
recurrence of cutaneous lesions in the
child is a continual reminder of the orig-
inal onset of disease. Involvement of
social workers and psychologists will be
of value in supporting the family.
Treatment
Acyclovir remains the only FDA-approved
medication for neonatal HSV infections;
however, disease classification influences
the duration of therapy. For babies with
disease localized to the skin, only 14 days
of therapy is required. For babies with
either encephalitis or disseminated dis-
ease, the duration of therapy is 21 days.
The dosage for therapy is 20 mg/kg IV
every 8 hours. Outcome at this dosage
is significantly better than original con-
trolled studies.15 Mortality for skin, en-
cephalitis, and disseminated disease is
0%, 5%, and 30%, respectively, 24 months
after treatment.
As would be anticipated, neurologic
outcome is a function of disease clas-
sification. In the most recent studies,
babies with disease localized to the skin
(PCR negative in the CSF), all developed
normally through 2 years of life.18 Of
those with encephalitis, 45% had no or
mild impairment as compared with dis-
seminated disease, whereby 80% who
survived developed normally.12 With early
therapy, babies with disseminated dis-
ease, even if the CNS is involved, appear
to do well on follow-up.
Virus type did influence outcome for
babies with encephalitis. Specifically, ther-
apy of HSV-1 infections of the brain led
to a normal neurologic outcome in ap-
proximately 70% of babies. In contrast,
HSV-2 infections of the brain with ther-
apy led to normal development in about
35% of babies. This observation has rele-
vance for long-term suppressive therapy.19
Three other aspects regarding treat-
ment are important. First, end-of-therapy
evaluation of the CSF for evidence of viral
December 2015

DNA by PCR has become the standard
of care. Approximately 5% of babies with
CNS disease remain PCR positive in the
CSF and require an additional week of
therapy or longer until PCR is negative.
If the CSF is PCR positive at the com-
pletion of standard IV therapy, a poor
outcome can be anticipated. Unfortu-
nately, no randomized controlled stud-
ies have documented the outcome of
children requiring longer than 21 days
of therapy, prospectively. Second, some
experts recommend a reevaluation of
the brain by CT or MRI since damage
can be progressive. Such studies pro-
vide a baseline for future evaluations.
Third, the value of long-term suppres-
sive therapy with oral acyclovir has re-
cently been demonstrated. Specifically,
a randomized placebo-controlled trial of
acyclovir (300 mg/m2 orally every 8 hours)
demonstrated improved neurologic
outcome for the active treatment re-
cipients. Bayley Scale of Infant Develop-
ment scores greater than 80 (normal)
were found in 69% of therapy recipients
but only 33% of placebo recipients.20
From a pathogenesis perspective, this
observation implies persistent low-level
replication of HSV in the brain. This
finding is in direct contrast to studies in
adults, as noted earlier in the article.
The sample size was too small to de-
termine the impact on recurrent skin
lesions, although there was a trend toward
decreased cutaneous recurrences, which
is a concern for the parents of these chil-
dren, especially if the child is in day care.
In summary, following IV acyclovir
therapy, oral acyclovir should be ad-
ministered for a minimum of 6 months.
Clearly, the dosage requires adjustment
as the child grows. Administration of
medication 3 times a day can lead to
noncompliance. As a consequence, some
physicians compound valacyclovir for
once daily or 2 times a day administration.
Other Considerations
Several other points warrant consider-
ation. First, the natural history of genital
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KEY POINTS
HSV infections is changing, with an in- h Some experts recommend
creasing proportion of primary infec- a reevaluation of the
tions, over 50%, being caused by HSV-1. brain by CT or MRI after
This may well increase the proportion treatment for neonatal
of babies with HSV-1 infections. Second, herpes simplex virus
sporadic case reports indicate the de- infections, since damage
velopment of resistance to acyclovir. can be progressive.
Extremely high viral loads (genome copy h The value of long-term
of 105 or greater) in the CSF appear to suppressive therapy with
result in selective pressure for the de- oral acyclovir for neonatal
velopment of resistance. Under such herpes simplex virus
circumstances, an alternative therapeu- infections has recently
tic would be foscarnet. Third, very few been demonstrated.
babies with encephalitis will have a h Following IV acyclovir
recurrent episode. Under such circum- therapy for neonatal
stances, an interferon pathway genetic herpes simplex virus
defect has been identified.21 Likely, infection, oral acyclovir
these children will require suppressive should be administered
therapy for life. In children, mutations for a minimum
in toll-like receptor 3 (TLR3) and its of 6 months.
pathway have been associated with
herpes encephalitis.22
Finally, and ideally, prevention of neo-
natal HSV infection would be the goal.
Unfortunately, recent vaccine trials have
not provided protection from the dis-
ease, perhaps owing to the incorrect
antigens utilized, given the changing
epidemiology of maternal genital her-
pes.23 In the absence of an efficacious
vaccine, the American Academy of Pe-
diatrics17 has set forth guidelines for
prevention with antiviral therapy. If the
mother has a proven primary infection
in the third trimester, prophylactic treat-
ment should be administered for 14 days.
On the other hand, if the mother has a
history of genital herpes, surface cultures
are recommended within 24 hours of
delivery and if positive, treatment ad-
ministered for 14 days if only skin is
involved and 21 days if evaluation in-
dicates organ involvement.17
Summary
Neonatal HSV infections represent an
interface between modern medicine
(acyclovir therapy with long-term sup-
pression) and sociologic factors of our
society, namely the guilt associated with
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 Herpes Simplex Virus Infections
genital infection of the parents that
harms a newborn child. As a conse-
quence, care providers must be physi-
cians in the true sense of the word.
Not only is it necessary to attend to the
details of medical management but
also to the support of the family as well.
CONCLUSION
HSV infections of the CNS are devas-
tating and require prompt diagnosis
and institution of therapy. Heightened
awareness of the disease is essential
regardless of whether in a newborn or
in an adult.
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