Herpes Simplex:

Encephalitis Children and Adolescents

Richard J. Whitley, MD, and David W. Kimberlin, MD

Herpes simplex encephalitis (HSE) remains one of the most devastating infections of the
central nervous system despite available antiviral therapy. Children and adolescents ac-
count for approximately one third of all cases of HSE. Clinical diagnosis is suggested in the
encephalopathic, febrile patient with focal neurologic signs. However, these clinical find-
ings are not pathognomonic because numerous other infections in the central nervous
system can mimic HSE. Support for the diagnosis from a neurodiagnostic perspective is
aided by the demonstration of disease of the temporal lobe by magnetic resonance image
scan and spike and slow-wave activity on electroencephalogram. In the current era, the
gold standard for establishing diagnosis is the detection of herpes simplex virus DNA in the
cerebrospinal fluid by polymerase chain reaction (PCR). Although PCR is an excellent test
and far more desirable than brain biopsy, false negatives can occur early after disease
onset. Current therapeutic management calls for the administration of acyclovir at 10 mg/kg
every 8 hours for 21 days. Even with early administration of therapy after the onset of
disease, nearly two thirds of survivors will have significant residual neurologic deficits.
Recent investigative efforts are assessing the value of PCR detection of viral DNA at the
completion of therapy and the value of prolonged antiviral therapy.
Semin Pediatr Infect Dis 16:17-23 © 2005 Elsevier Inc. All rights reserved.

S ince the first suggestions of herpes simplex encephalitis

(HSE) by the Mathewson Commission in 19261 and sub-
sequent description of the histopathologic changes,2 herpes
parent in the left temporal lobe, in which perivascular cuffs of
lymphocytes and numerous small hemorrhages were found.
This temporal lobe localization subsequently has been deter-
simplex virus (HSV) infection of the brain has become rec- mined to be characteristic of HSE in individuals older than 3
ognized as the most common cause of sporadic fatal enceph- months of age.
alitis in the United States.3 Intranuclear inclusion bodies con- In the mid-1960s, Nahmias and Dowdle5 demonstrated 2
sistent with HSV infection were demonstrated first in the antigenic types of HSV. Viral typing allowed the demonstra-
brain of a neonate with encephalitis by Smith and coworkers2 tion that HSV-1 was responsible primarily for infections
in 1941. Virus subsequently was isolated from this brain “above the belt” (including brain disease in adults), whereas
tissue.2 When the first case of HSE was reported in children HSV-2 was responsible primarily for infections “below the
or adolescents is unclear; however, clinicopathologic find- belt” and brain disease in neonates, although this epidemio-
ings are similar to that encountered in adults. The first adult logic paradigm is changing significantly in the 21st century of
case of HSE providing similar proof of viral disease (ie, in- genital herpes. Notably, recent studies indicate that either
tranuclear inclusions in brain tissue and virus isolation) was virus can infect the mouth or genital tract. However, essential
described in 1944 by Zarafonetis and coworkers4 The most to all observations is that HSE routinely is caused by HSV-1 in
striking pathologic findings in this patient’s brain were ap- virtually all patients. Indeed, frank encephalitis attributed to
HSV-2 has been reported only in a few cases in the world’s
literature.6
Departments of Pediatrics, Microbiology, Medicine and Neurosurgery, The
University of Alabama at Birmingham, Birmingham, AL.
Funded in whole or in part with Federal funds from the National Institute of
Allergy and Infectious Diseases, National Institutes of Health, Depart- Pathology and Pathogenesis
ment of Health and Human Services, under Contract (NO1-AI-30025, The pathologic changes induced by replicating HSV include
NO1-AI -65306, NO1-AI -15113, NO1-AI-62554, N01-AI-30025), the
General Clinical Research Unit (RR-032), and the State of Alabama. ballooning of infected cells and the appearance of chromatin
Address reprint requests to Richard J. Whitley, MD, 303 CHB, 1600-Sixth within the nuclei of cells followed by degeneration of the
Avenue South, Birmingham, AL 35233. E-mail: [email protected] cellular nuclei. Cells lose intact plasma membranes and form

1045-1870/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. 17

doi:10.1053/j.spid.2004.09.007
18 R.J. Whitley and D.W. Kimberlin

multinucleated giant cells. As host defenses are mounted, an lication can lead to severe CNS infection; however, more
influx of mononuclear cells can be detected in infected tissue. often a host-virus interaction results in latency. After latency
HSE results in acute inflammation, congestion, and/or hem- is established, reactivation can occur, with virus proliferation
orrhage, most prominently in the temporal lobes and usually and shedding at mucocutaneous sites appearing as skin ves-
asymmetrically in adults7 and more diffusely in the newborn. icles or mucosal ulcers. Occasionally, primary infection can
Adjacent limbic areas also show involvement. The meninges become systemic, affecting other organ systems besides the
overlying the temporal lobes may appear clouded or con- central and peripheral nervous systems. Such circumstances
gested. After approximately 2 weeks, these changes proceed include disseminated neonatal HSV infection with multior-
to frank necrosis and liquefaction of the involved brain tissue. gan involvement (as defined in Kimberlin and Whitley, “Neo-
Microscopically, involvement extends beyond areas that natal Herpes: What Have We Learned?” in this issue), multi-
appear grossly abnormal. At the earliest stage, the histologic organ disease of pregnancy, and infrequently dissemination
changes are not dramatic and may be nonspecific. Conges- in patients undergoing immunosuppressive therapy. Multi-
tion of capillaries and other small vessels in the cortex and organ disease likely is the consequence of viremia in a host
subcortical white matter is evident; other changes, including not capable of limiting replication to mucosal surfaces.
petechiae, also are evident. Vascular changes that have been Infection with HSV-1 is transmitted by respiratory drop-
reported in the area of infection include areas of hemorrhagic lets or through direct contact (to a susceptible individual)
necrosis and perivascular cuffing. The perivascular cuffing with infectious secretions (such as virus contained in orola-
becomes prominent in the second and third weeks of infec- bial vesicular fluid). Acquisition of HSV-2 infection usually is
tion. Glial nodules are common findings after the second the consequence of transmission via genital routes. Under
week.8,9 The microscopic appearance becomes dominated by these circumstances, virus replicates in the vaginal tract or on
evidence of necrosis and, eventually, inflammation; the latter penile skin sites, with seeding of the sacral ganglia.
is characterized by a diffuse perivascular subarachnoid
mononuclear cell infiltrate, gliosis, and satellitosis-neu-
ronophagia.7,10 In such cases, widespread areas of hemor-
Pathogenesis of Encephalitis
rhagic necrosis, mirroring the area of infection, become most The pathogenesis of HSE in older children (⬎3 months of
prominent. Oligodendrocytic involvement and gliosis (as age), adolescents, and adults is understood only partly but
well as astrocytosis) are common findings, but these changes likely is similar for all age groups. Both primary and recurrent
develop very late in the disease. Although found in only HSV infections can cause disease of the CNS. Studies per-
approximately 50 percent of patients, the presence of in- formed by the National Institute of Allergy and Infectious
tranuclear inclusions supports the diagnosis of viral infec- Diseases (NIAID) Collaborative Antiviral Study Group
tion, and these inclusions most often are visible in the first (CASG) revealed that approximately one-third of the cases of
week of infection. Intranuclear inclusions (Cowdry type A HSE are the consequence of primary infection. For the most
inclusions) are characterized by an eosinophilic homoge- part, the patients with primary infection are younger than 18
neous appearance and often are surrounded by a clear, un- years of age. The remaining two-thirds of cases occur in the
stained zone beyond which lies a rim of marginated chroma- presence of preexisting antibodies, but only approximately
tin. 10 percent of patients have a history of recurrent herpes
labialis. Patients with preexisting antibodies are considered
to have HSE as a consequence of reactivation of HSV.13 When
General Observations on the DNA from the peripheral (labial) and CNS isolates are
the Pathogenesis of Human Disease compared by restriction endonuclease analysis, the isolates
Fundamental to the development of HSE is the source of usually are identical; however, such is not always the case.
virus that causes disease in the central nervous system (CNS). The virus isolated from the peripheral site can be different
Indeed, access of virus to the brain or, alternatively, reactiva- from that retrieved from the CNS.14 Thus, the issue of reac-
tion of virus in the temporal lobe is not a well-understood tivation of virus directly within the CNS, the potential for
phenomenon. However, more is known about human dis- enhanced neurotropism of certain viruses, and the selective
ease and its pathogenesis. The pathogenesis of human dis- reactivation and access of one virus by the trigeminal route or
ease, particularly primary infections (as defined in Kimberlin other routes to the CNS require further elucidation.
and Whitley, “Neonatal Herpes: What Have We Learned” in The route of access of virus to the CNS in primary infec-
this issue) depends on intimate, personal contact of a suscep- tion, especially in humans, is a subject of debate. Classic
tible individual (namely, one who is seronegative) with studies defined pathways for access of HSV to the brain in
someone excreting HSV. The virus must come in contact with animals and include both the olfactory and trigeminal nerves
mucosal surfaces or abraded skin for infection to occur. With among others.15 However, which of these nerve tracts uni-
viral replication occurring at the site of infection, the de- formly leads to HSV infection in the CNS of humans is not
enveloped capsid is transported by neurons to the dorsal root clear. The anatomic distribution of nerves from the olfactory
ganglia, where, after another round of viral replication, la- tract into the limbic system, along with the recovery of virus
tency is established. These events have been demonstrated in from the temporal lobe (the site of apparent onset of HSE in
a variety of animal models, as reviewed.11 Transport of the the human brain), suggests that viral access to the CNS via
virion is by retrograde axonal flow.12 In some instances, rep- this route is a tenable hypothesis. Reports in the literature
Herpes simplex encephalitis 19

have demonstrated that electron microscopic evidence has, of patients who have received either no therapy or an inef-
in fact, confirmed that this route has been the case in some fective antiviral medication, such as idoxuridine or cytosine
individuals with HSE.16-19 Animal model data support the arabinoside. In such situations, the mortality rate is in excess
contention that the olfactory tract provides one neurologic of 70 percent; only approximately 2.5 percent of all patients
avenue for viral access to the CNS and causes localization of with confirmed disease (9.1% of survivors) returned to nor-
the infection in brain regions analogous to medial temporal mal function after recovering from their illness.31-35 Because
structures in humans.20,21 Definitive proof for such progres- brain biopsy with isolation of HSV from brain tissue was the
sion in humans is lacking. method of diagnosis in these early studies, a far broader spec-
Reactivation of HSV, leading to focal HSE, is a similarly trum of HSV infections of the CNS actually was thought to
confusing problem from the standpoint of pathogenesis. exist. However, with the more recent use of PCR for diagnosis
Evidence of latent virus within infected brain tissue ex- of HSE, virtually all patients have a focal neurologic disease,
ists22; however, virus reactivation at that site remains suggesting a limited spectrum of disease.36
purely hypothetical. Reactivation of virus peripherally
(namely, in the olfactory bulb or the trigeminal ganglion)
with subsequent neuronal transmission to the CNS has
Diagnosis
been suggested.15,21,23,24 Nonetheless, a relevant observa- Several aspects relating to the diagnosis of HSE merit discus-
tion is that with recurrent herpes labialis, whereby reacti- sion particularly in relation to disease: (1) the clinical presen-
vation of virus from the trigeminal ganglia occurs, HSE is tation with regard to the sensitivity and specificity of various
a very uncommon event. Furthermore, HSE does not oc- clinical characteristics of children and adolescents; (2) the
cur more frequently in immunocompromised patients. historical use of brain biopsy to establish the diagnosis; (3)
Host immunity plays an important, but as yet undefined, conditions that mimic HSE; and (4) noninvasive means of
role in the pathogenesis of HSE. Possibly, the CNS is partic- diagnosis. Data from the NIAID CASG compare presentation
ularly prone to HSV infection because intraneuronal spread and outcome for patients with positive brain biopsies and
may shelter virus from host defense mechanisms. HSE occurs those with negative brain biopsies.6 These data provide the
no more frequently in the immunosuppressed host than in only definitive comparisons of patients with confirmed dis-
the normal host; however, when it does occur, the presenta- ease versus other clinical entitles that mimic HSE. Of 432
tion is atypical, with a subacute but progressively deteriorat- patients who were evaluated for HSE because of focal neuro-
ing course.25 logic findings, HSV was isolated from brain tissue of only 193
(45%). Only three of the remaining patients (nonbiopsy-
proven patients) had combinations of serologic and clinical
Clinical Presentation of HSE findings that were suggestive of HSE. These patients subse-
quently were shown by PCR to have HSV DNA in their cere-
Background brospinal fluid (CSF). Approximately one-third of these pa-
HSV infections of the CNS are among the most severe of all tients were children and adolescents (⬍18 years of age).
viral infections of the human brain. Currently, HSE is esti- Thus, in this series, focal neurologic findings predicted HSE
mated to occur in approximately 1 in 250,000 to 1 in and did so irrespective of age.
500,000 individuals per year. At the University of Alabama at As shown in Table 1, most patients with HSE confirmed by
Birmingham, the diagnosis of HSE was confirmed by brain biopsy presented with a focal encephalopathic process, in-
biopsy in an average of 10 patients per year for an incidence cluding (1) altered mentation and decreasing levels of con-
of approximately 1 in 300,000 individuals, an incidence sim- sciousness with focal neurologic findings, (2) CSF pleocyto-
ilar to those in Sweden and England.26,27 In the United States, sis and proteinosis, (3) the absence of bacterial and fungal
HSE is thought to account for as many as 10 percent to 20 pathogens in the CSF, and (4) focal electroencephalographic
percent of all encephalitic viral infections of the CNS,28 be- (EEG), computed tomographic (CT), and/or technetium
fore the occurrence of West Nile Virus encephalitis. brain scan findings.6 Although magnetic resonance imaging
The economic cost of HSE is considerable, being estimated (MRI) is a more sensitive diagnostic tool and has, for the most
in 1983 for hospitalization alone of adolescents and adults to part, replaced CT scans, definitive studies have not been
be more than $500 million.29,30 The total medical cost is reported.37-40
considerably higher because of the long-term care and sup- The frequency of headache and CSF pleocytosis is higher
port services required for many of the survivors, resulting in in patients with confirmed HSE than in patients with diseases
estimates in excess of $1 billion. that mimic HSE. With near uniformity, and irrespective of
HSE occurs throughout the year and in patients of all ages, age, patients with HSE present with fever and changes in
with approximately one-third of cases occurring in patients personality. Seizures, whether focal or generalized, occur in
younger than age 20 years but older than 6 months of age and only approximately two-thirds of all patients with confirmed
approximately one-half in patients older than 50 years.6 Cau- disease. Thus, the clinical findings of HSE are nonspecific
casians account for 95 percent of patients with diseases con- and do not allow for empiric diagnosis of disease predicated
firmed by either biopsy or polymerase chain reaction (PCR). solely on clinical presentation. Although clinical evidence of
Both sexes are affected equally. a localized temporal lobe lesion often is thought to indicate
The severity of disease is determined best by the outcome HSE, a variety of other diseases can mimic this condition.
20 R.J. Whitley and D.W. Kimberlin

Table 1 Comparison of Findings in “Brain-Positive” and “Brain- the temporal lobe.42-46 Early in the disease, the abnormal
Negative” Patients With Herpes Simplex Encephalitis6 electric activity usually involves one temporal lobe and then
Number (%) of Patients spreads to the contralateral temporal lobe as the disease
evolves, usually during a period of 7 to 10 days. The sensi-
Brain- Brain
Positive* Negative* tivity of the EEG is approximately 84 percent, but the speci-
ficity is only 32.5 percent. CT scans initially show low-den-
Historical findings
sity areas with mass effect localized to the temporal lobe,
Alteration of 109/112 (97) 82/84 (98)
which can progress to radiolucent and/or hemorrhagic le-
consciousness
CSF pleocytosis 107/110 (97) 71/82 (87) sions.47,48 Bitemporal disease occurs commonly in the ab-
Fever 101/112 (90) 66/85 (78) sence of therapy, particularly late in the course of the disease.
Headache 89/110 (81) 56/73 (77) When these neurodiagnostic tests are used in combination,
Personality change 62/87 (71) 44/65 (68) the sensitivity is enhanced; however, the specificity remains
Seizures 73/109 (67) 48/81 (59) inadequate. None of these neurodiagnostic tests is uniformly
Vomiting 51/111 (46) 38/82 (46) satisfactory for diagnosing HSE. MRI detects evidence of HSE
Hemiparesis 33/100 (33) 19/71 (26) before CT demonstration.38
Memory loss 14/59 (24) 9/47 (19) A sensitive and specific means of diagnosis is the isolation
Clinical findings at of HSV from tissue obtained at brain biopsy. However, PCR
presentation
detection of HSV DNA in the CSF replaces routine brain
Fever 101/110 (92) 64/79 (81)
Personality change 69/81 (85) 43/58 (74)
biopsy for diagnostic purposes (see below). Brain biopsy is of
Dysphasia 58/76 (76) 36/54 (67) value in clinical presentations that are confusing; complica-
Autonomic dysfunction 53/88 (60) 40/71 (56) tions, either acute or chronic in nature, occur in approxi-
Ataxia 22/55 (40) 18/45 (40) mately 3 percent of patients. Fears of potentiating acute ill-
Hemiparesis 41/107 (38) 24/81 (30) ness (by incising the brain in a diseased area) or of causing
Seizures 43/112 (38) 40/85 (47) chronic seizure disorders have not been substantiated by fol-
Focal 28 13 low-up studies performed by NIAID CASG.
Generalized 10 14
Both 5 13
Cranial nerve defects 34/105 (32) 27/81 (33) Serologic Evaluation
Visual field loss 8/58 (14) 4/33 (12) Several strategies utilizing antibody production as a means of
Papilledemia 16/111 (14) 9/84 (11) diagnosing HSE have been utilized.49 Because most enceph-
*Of 432 patients assessed. alitic patients are HSV-seropositive at presentation, serocon-
version per se usually is not helpful as fever alone can reac-
tivate labial herpes, resulting in antibody elevations. A
fourfold rise in serum antibody was neither sensitive nor
Examination of the CSF is indicated in patients with al-
specific enough to be useful. A fourfold or greater rise in CSF
tered mentation, provided it is not contraindicated because
antibody occurred significantly more often within a month
of increased intracranial pressure. It is essential to assess both
after onset of disease in patients with biopsy-proven HSE: 85
biochemical parameters, as well as to obtain a specimen for
percent versus 29 percent. By 10 days after clinical presenta-
PCR. In patients with HSE, CSF findings are nondiagnostic,
tion, however, only 50 percent of brain-biopsy-positive pa-
being similar in patients with confirmed disease and those
tients had a fourfold rise in CSF antibody. Thus, this test is
with diseases that mimic HSE.41 Both the CSF white blood
useful only for retrospective diagnosis. The use of a ratio of
cell count (lymphocytes predominance) and CSF protein be-
serum to CSF antibody of 20 or less did not improve sensi-
come elevated as the disease progresses. The average CSF
tivity during the first 10 days of disease.
white blood cell count is 100 cells/␮L; the protein averages
approximately 100 mg/dL. Sequential evaluation of CSF
specimens from patients with HSE indicates increasing cell PCR Detection of Viral DNA
counts and levels of protein. The presence of CSF red blood PCR detection of HSV DNA in the CSF has become the diag-
cells is not diagnostic for HSE. Approximately 5 to 10 percent nostic method of choice.50-58 Data from the NIAID CASG
of patients have a normal CSF formula on first evaluation. defined the sensitivity and specificity as 94 percent and 98
This later observation is especially the case in children, in percent, respectively. These CSF specimens were obtained
whom presentation includes fever, encephalopathy, altered from patients with biopsy-confirmed or negative disease. No-
mentation, and an initially normal CSF examination. How- tably, the specificity would have been higher except that
ever, repeating the CSF examination even within 24 hours some tissue specimens were fixed in formalin, which killed
will, in most cases, reveal abnormalities. infectious virus, before attempts at isolation in cell culture
Noninvasive neurodiagnostic studies support a presump- were made. HSV DNA persists in 80 percent of tested speci-
tive diagnosis of HSE. These studies have included EEG, CT, mens for 1 week or more despite antiviral therapy.
technetium brain scans, and MRI scans. Focal changes of the More recently, real-time PCR has been applied to evalua-
EEG are characterized by spike and slow-wave activity and tion of CSF specimens from patients with HSE. Virus load in
periodic lateralized epileptiform discharges, which arise from the CSF appears to correlate directly with clinical outcome.
Herpes simplex encephalitis 21

Table 2 Diseases That Mimic Herpes Simplex Encephalitis62

Treatable Diseases (n ⴝ 46)* Nontreatable Diseases (n ⴝ 49)*
Abscess/subdural empyema Vascular disease 11
Bacterial 5 Toxic encephalopathy 5
Listeria 1 Reye syndrome 1
Fungal 2 Viral (n ⴝ 40)
Mycoplasma 2 Arbovirus infection
Tuberculosis 6 St. Louis encephalitis 7
Cryptococcal 3 Western equine encephalitis 3
Rickettsial 2 California encephalitis 4
Toxoplasmosis 1 Eastern equine encephalitis 2
Mucormycosis 1 Other herpesviruses
Meningococcal meningitis 1 Epstein–Barr virus 8
Other viruses Others viruses
Cytomegalovirus 1 Mumps virus 3
Influenza A 4 Adenovirus 1
Echovirus infection† 3 Progressive multifocal leukoencephalopathy (JC virus) 1
Tumor 5 Lymphocytic choriomeningitis 1
Subdural hematoma 2 Subacute sclerosing panencephalitis 2
Systemic lupus erythematosus 1
Adrenal leukodystrophy 6
*Of 432 patients assessed.
†Drug therapy under investigation.

In an initial study, the quantity of virus (copies of viral DNA/ Urinary and fecal incontinence have been reported in a few
mL) correlated statistically with decreased level of conscious- patients. An aseptic meningitis syndrome also is a common
ness, the presence of a lesion detected by either CT or MRI, finding, frequently being associated with a Mollaret syn-
and a poor neurologic outcome.59-61 drome, and not without complications.36 These findings have
not been limited solely to adults, as reports in children have
occurred.36
Differential Diagnosis Guillain-Barré syndrome and localized dermatomal rashes
Diseases That Mimic HSE associated with acute neuritis also have been attributed to
In a compilation of the NIAID CASG data, 193 of 432 (45%) HSV infections. Similarly, benign recurrent lymphocytic
patients undergoing brain biopsy for a focal encephalopathic meningitis or Mollaret syndrome has been associated with
process had HSE.41 As shown in Table 2, the remaining pa- both HSV-1 and HSV-2 infection.63,64 Acute retinal necrosis
tients were evaluated for diseases that mimic HSE.62 Thirty- has been reported as a long-term complication of HSE.65
eight patients had disease amenable to other forms of ther-
apy, including brain abscess, tuberculosis, cryptococcal
infection, and brain tumor. An additional 19 patients had Therapy
diseases that were indirectly treatable, and another 38 pa- The first antiviral drug reported as efficacious therapy of HSE
tients had an alternative diagnosis established for which there was idoxuridine; however, it proved to be both ineffective
was no current therapy, usually other viral infections. Thus, and toxic.31 Subsequent therapeutic trials defined vidarabine
those diseases that mimic HSV infection of the CNS and that as a useful medication for the management of biopsy-proven
require immediate medical intervention should be consid- HSE34,35; however, it has been replaced by acyclovir in the
ered if the PCR is negative for HSV DNA. physician’s armamentarium. During these studies, the vari-
Importantly, the diagnoses of other types of encephalitis, ables of age, duration of disease, and level of consciousness at
particularly enterovirus and Epstein-Barr virus, CNS disease the onset of therapy proved to be major determinants of
were established more commonly in children and adoles- clinical outcome. Patients younger than 30 years of age and
cents than in older individuals. In addition, adrenal leuko- with a more normal level of consciousness (lethargic as op-
dystrophy occurred only in children. posed to comatose) were more likely to return to normal
function than were older patients, especially those who were
Associated Neurologic Syndromes semicomatose or comatose. An important note to recognize is
HSV obviously involves areas of the nervous system other that 90 percent of individuals younger than 30 years of age
than the brain. Primary and recurrent genital herpes have were children and adolescents. From these data, older pa-
been associated with neuritis localized to one extremity or tients (older than 30 years of age), whether comatose or semi-
even transverse myelitis. Neuritis evident in such patients can comatose, had mortality rates that approached 70 percent—a
be associated with altered sensation of the lower extremities, figure very similar to that encountered in the placebo recip-
as can dysesthesias, shooting pain, and motor impairment. ients of the previously cited studies. If therapy is to be effec-
22 R.J. Whitley and D.W. Kimberlin

tive, it must be instituted before the onset of hemorrhagic remain lacking. Second, no controlled clinical trial to date
necrosis of a dominant temporal lobe and of significant dete- has relied solely on PCR confirmation of disease to under-
rioration of consciousness. stand either the natural history of disease or the neurologic
Acyclovir is superior to vidarabine for the treatment of outcome independent of brain biopsy. Currently, the NIAID
HSE.66 The design and mechanism of action of acyclovir have CASG is performing a clinical trial to assess these outcome
been discussed at length.67 Acyclovir decreases the mortality events as well as the contribution of viral load and quantita-
rate to 19 percent 6 months after therapy. Importantly, 38 tive MRI extent of involvement to long-term prognosis.
percent of patients, irrespective of age, return to normal func- Lastly, the role of long-term therapy of HSE with orally bio-
tion. However, conversely, most patients are left with signif- available therapeutics after intravenous therapy remains to be
icant neurologic impairment. seen, and it currently is being studied to determine its con-
The NIAID CASG study defined a mortality rate of 55 tribution to overall morbidity.
percent at 6 and 18 months after the onset of treatment for
vidarabine recipients versus 19 percent and 28 percent, re-
spectively, for the acyclovir-treated group. Late deaths were
References
1. Mathewson Commission: Epidemic encephalitis: etiology, epidemiol-
not a consequence of either persistent or reactivated HSV ogy, treatment. Report of a Survey by the Mathewson Commission.
infection but occurred in patients who were severely im- New York: Columbia University Press, 1929
paired as a consequence of their disease. The mortality rate is 2. Smith MG, Lennette EH, Reames HR: Isolation of the virus of herpes
somewhat lower in children and adolescents but not statisti- simplex and the demonstration of intranuclear inclusions in a case of
cally different than older individuals. acute encephalitis. Am J Pathol 17:55-68, 1941
3. Meyer MH, Jr, Johnson RT, Crawford IP, et al: Central nervous system
As noted above, previous studies indicated that age and syndromes of “viral” etiology. Am J Med 29:334-347, 1960
level of consciousness influenced long-term outcome. A 4. Zarafonetis CJD, Smodel MC, Adams JW, et al: Fatal herpes simplex
more objective reflection of level of consciousness is the Glas- encephalitis in man. Am J Pathol 20:429-445, 1944
gow coma score (GCS). Scores that approached normal pre- 5. Nahmias AJ, Dowdle WR: Antigenic and biologic differences in herpes-
dicted enhanced survival. When GCS and age were assessed virus hominis. Prog Med Virol 10:110-159, 1968
6. Whitley RJ, Soong S-J, Linneman C Jr, et al: Herpes simplex encepha-
simultaneously, a GCS of 6 or less predicted a poor therapeu- litis: clinical assessment. JAMA 247:317-320, 1982
tic outcome, irrespective of the agent administered or of the 7. Boos J, Esiri MM. Sporadic Encephalitis I. Viral Encephalitis Pathology,
age of the patient.66 Diagnosis and Management. Boston: Blackwell Scientific Publishers,
Regarding morbidity, the vidarabine studies indicated that 1986:55-93
approximately 15 to 20 percent of patients overall would 8. Boos J, Kim JH: Biopsy histopathology in herpes simplex encephalitis and
in encephalitis of undefined etiology. Yale J Biol Med 57:751-755, 1984
develop normally after receiving therapy for HSE on long-
9. Kapur N, Barker S, Burrows EH, et al: Herpes simplex encephalitis:
term follow-up. The only comparative trial indicated that 13 long term magnetic resonance imaging and neuropsychological profile.
percent of vidarabine recipients were left with no or minor J Neurol Neurosurg Psychiatry 57:1334-1342, 1994
sequelae, whereas 22 percent had moderate or severe se- 10. Garcia JH, Colon LE, Whitley RJ, et al: Diagnosis of viral encephalitis by
quelae and 65 percent died during follow-up. For acyclovir brain biopsy. Semin Diagn Pathol 1:71-80, 1984
11. Hill TJ. Herpes simplex virus latency, in Roizman B (eds): The Herpes
recipients, 38 percent of patients were normal or had minor
viruses. Vol 3. New York, Plenum Publishing, 1985, pp 175-240
impairment, 9 percent of patients had moderate sequelae, 12. Cook ML, Stevens JG: Pathogenesis of herpetic neuritis and ganglionitis
and 53 percent of patients were left with severe impairment in mice: Evidence of intra-axonal transport of infection. Infect Immun
or died. No patient entered into the NIAID trials suffered a 7:272-288, 1973
relapse after completion of therapy. Relapse of HSE has been 13. Nahmias AJ, Whitley RJ, Visintine AN, et al: Herpes simplex encepha-
litis: laboratory evaluations and their diagnostic significance. J Infect
reported, although not well documented, in a few patients
Dis 145:829-836, 1982
after receiving vidarabine68,69 and acyclovir.69,70 Many pa- 14. Whitley RJ, Lakeman AD, Nahmias AJ, et al: DNA restriction-enzyme
tients were not afebrile at the conclusion of treatment, sug- analysis of herpes simplex virus isolates obtained from patients with
gesting that a longer duration of therapy to a minimum of encephalitis. N Engl J Med 307:1060-1062, 1982
14 to 21 days may be desirable. These findings indicate that 15. Johnson RT, Olson LC, Buescher EL, Herpes simplex virus infections of
the nervous system: problems in laboratory diagnosis. Arch Neurol
the current therapy of choice for the management of HSE is
18:260-264, 1968
acyclovir rather than vidarabine. Acyclovir is administered at 16. Dinn JJ. Transolfactory spread of virus in herpes simplex encephalitis.
a dosage of 10 mg/kg every 8 hours (30 mg/kg/d) for a period Br Med J 281:1392, 1980
of only 14 to 21 days. 17. Ojeda VJ, Archer M, Robertson TA, et al: Necropsy study of olfactory
portal of entry in herpes simplex encephalitis. Med J Aust 1:79-81,
1983
Future Considerations 18. Twomey JA, Barker CM, Robinson G, et al: Olfactory mucosa in herpes
simplex encephalitis. J Neurol Neurosurg Psych 42:983-987, 1979
Several considerations are in order. First, in the management 19. Whitley RJ. Therapeutic advances for severe and life-threatening herpes
of HSE in children, adolescents, and adults, we do not have simplex virus infections, in Lopez C, Roizman B, editors. Human Her-
PCR evidence of disease persistence as occurs in the new- pesvirus Infections. New York, Raven Press, 1986, pp 153-164
20. Schlitt M, Lakeman FD, Wilson ER, et al: A rabbit model of focal herpes
born. Stated more simply, these studies have not been per-
simplex encephalitis. J Infect Dis 153:732-735, 1986
formed. Such information may be important in gauging du- 21. Stroop WG, Schaefer DC: Production of encephalitis restricted to the
ration of therapy, as appears to be the case in the temporal lobes by experimental reactivation of herpes simplex virus.
management of neonatal disease. However, definitive data J Infect Dis 153:721-731, 1986
Herpes simplex encephalitis 23

22. Rock DL, Frasher NW: Detection of HSV-1 genome in central nervous 48. Zimmerman RD, Russell EJ, Leeds NE, et al: CT in the early diagnosis of
system of latently infected mice. Nature 302:523-531, 1983 herpes simplex encephalitis. Am J Roentgenol 134:61-66, 1980
23. Davis LE, Johnson RT: An explanation for the localization of herpes 49. Cesario TC, Poland JD, Wulff H, et al: Six years experiences with herpes
simplex encephalitis. Ann Neurol 5:2-5, 1979 simplex virus in a children’s home. Am J Epidemiol 90:416-422, 1969
24. Griffith JR, Kibrick S, Dodge PR, et al: Experimental herpes simplex 50. Rowley A, Lakeman F, Whitley R, et al: Rapid detection of herpes
encephalitis: electroencephalographic, clinical, virologic, and patho- simplex virus DNA in cerebrospinal fluid of patients with herpes sim-
logic observations in the rabbit. Electroencephalogr Clin Neurophysiol plex encephalitis. Lancet 335:440-441, 190
23:263-267, 1967 51. Aurelius E, Johansson B, Skoldenberg B, et al: Rapid diagnosis of herpes
25. Barnes DW, Whitley RJ: CNS disease associated with varicella-zoster simplex encephalitis by nested polymerase chain reaction assay of ce-
virus and herpes simplex virus infection. Neurol Clin 4:265-283, 1986 rebrospinal fluid. Lancet 337:189-192, 1991
26. Longson M: The general nature of viral encephalitis in the United 52. Aurelius E, Johansson B, Skoldenberg B, et al: Encephalitis in immu-
Kingdom, in Ellis LS (eds): Viral Diseases of the Central Nervous Sys- nocompetent patients due to herpes simplex virus type 1 or 2 as deter-
tem. London, Bailliere Tindall, 1984, pp 19-31 mined by type-specific polymerase chain reaction and antibody assays
27. Skoldenberg B, Forsgren M, Alestig K, et al: Acyclovir versus vidarabine of cerebrospinal fluid. J Med Virol 39:179-186, 1993
in herpes simplex encephalitis: a randomized multicentre study in con- 53. Puchhammer-Stockl E, Heinz FX, Kundi M, et al: Evaluation of the
secutive Swedish patients. Lancet 2:707-711, 1984 polymerase chain reaction for diagnosis of herpes simplex virus en-
28. Corey L, Spear P: Infections with herpes simplex viruses. N Engl J Med cephalitis. J Clin Microbiol 31:146-148, 1993
314:749-757, 1986 54. Shoji H, Koga M, Kusuhara T, et al: Differentiation of herpes simplex
29. Straus S, Rooney JF, Sever JL, et al: Herpes simplex virus infection: biology, virus 1 and 2 in cerebrospinal fluid of patients with HSV encephalitis
treatment and prevention. Ann Intern Med 103:404-419, 1985 and meningitis by stringent hybridization of PCR-amplified DNAs.
30. Khetsuriani N, Holman RC, Anderson LJ: Burden of encephalitis-asso- J Neurol 241:526-530, 1994
ciated hospitalizations in the United States, 1988-1997. Clin Infect Dis 55. Sakrauski A, Weber B, Kessler HH, et al: Comparison of two hybrid-
35:175-182, 2002 ization assays for the rapid detection of PCR amplified HSV genome
31. Boston Interhospital Virus Study Group and the NIAID Sponsored sequences from cerebrospinal fluid. J Virol Methods 50:175-184, 1994
Cooperative Antiviral Clinical Study A, Chien, Whitley, et al: Failure of 56. Lakeman FD, Whitley RJ, for the National Institute of Allergy and
high dose 5-deoxyuridine in the therapy of herpes simplex virus en- Infectious Diseases Collaborative Antiviral Study Group: Diagnosis of
cephalitis: evidence of unacceptable toxicity. N Engl J Med 292:600- herpes simplex encephalitis: application of polymerase chain reaction
603, 1975
to cerebrospinal fluid from brain biopsied patients and correlation with
32. Longson M: Le defi des encephalitis herpetiques. Ann Microbiol (Paris)
disease. J Infect Dis 172:857-863, 1995
130:5, 1979
57. DeBiasi RL, Tyler KL: Polymerase chain reaction in the diagnosis and
33. Longson MM, Bailey AS, Klapper P. Herpes encephalitis, in Waterson
management of central nervous system infections. Arch Neurol 56:
AP (eds): Recent Advances in Clinical Virology. Vol 2. New York:
1215-1219, 1999
Churchill Livingston, 1980:147-157
58. Fodor PA, Levin MJ, Weinberg A, et al: Atypical herpes simplex virus
34. Whitley RJ, Soong S-J, Dolin R, et al: Adenine arabinoside therapy of
encephalitis diagnosed by PCR amplification of viral DNA from CSF.
biopsy-proved herpes simplex encephalitis: National Institute of Al-
Neurology 51:554-559, 1998
lergy and Infectious Diseases Collaborative Antiviral Study. N Engl
59. Domingues RB, Fink MC, Tsanaclis SM, et al: Diagnosis of herpes simplex
J Med 297:289-294, 1977
encephalitis by magnetic resonance imaging and polymerase chain reac-
35. Whitley RJ, Soong S-J, Hirsch MS, et al: Herpes simplex encephalitis:
tion assay of cerebrospinal fluid. J Neurol Sci 157:148-153, 1998
vidarabine therapy and diagnostic problems. N Engl J Med 304:313-
60. Domingues RB, Lakeman FD, Mayo MS, et al: Application of compet-
318, 1981
itive PCR to cerebrospinal fluid samples from patients with herpes
36. Tyler KL: Herpes simplex virus infections of the central nervous system
Encephalitis and meningitis, including Mollaret’s. Herpes 11:57A-64A, simplex encephalitis. J Clin Microbiol 36:2229-2234, 1998
2004 (Suppl 2) 61. Domingues RB, Lakeman FD, Pannuti CS, et al: Advantage of polymer-
37. Zimmerman RA, Bilaniuk LT, Sze MG: Intracranial infection, in Brant- ase chain reaction in the diagnosis of herpes simplex encephalitis: pre-
Zawadski M, Norman D (eds): Magnetic Resonance Imaging of the sentation of 5 atypical cases. Scand J Infect Dis 29:229-231, 1997
Central Nervous System. New York, Raven Press, 1987, pp 235-257 62. Whitley RJ, Gnann JW, Viral encephalitis: familiar infections and
38. Schlesinger Y, Buller RS, Brunstrom JE, et al: Expanded spectrum of emerging pathogens. Lancet 359:507-513, 2002
herpes simplex encephalitis in childhood. J Pediatr 126:234-241, 1995 63. Picard FJ, Dekaban GA, Silva J, et al: Mollaret’s meningitis associated
39. Sener RN, Diffusion MRI in Rasmussen’s encephalitis, herpes simplex with herpes simplex type 2 infection. Neurology 43:1722-1727, 1993
encephalitis, and bacterial meningoencephalitis. Comput Med Imaging 64. Tedder DG, Ashley R, Tyler KL, et al: Herpes simplex virus infection as
Graph 26:327-332, 2002 a cause of benign recurrent lymphocytic meningitis. Ann Intern Med
40. Sener RN: Herpes simplex encephalitis: diffusion MR imaging findings. 121:334-338, 1994
Comput Med Imaging Graph 25:391-397, 2001 65. Kim C, Yoon YH: Unilateral acute retinal necrosis occurring 2 years
41. Whitley RJ, Cobbs CG, Alford CA, Jr et al: Diseases that mimic herpes after herpes simplex type 1 encephalitis. Ophthalmic Surg Lasers 33:
simplex encephalitis: diagnosis, presentation and outcome. JAMA 262: 250-252, 2002
234-239, 1989 66. Whitley RJ, Alford CA Jr, Hirsch MS, et al: Vidarabine versus acyclovir
42. Chien LT, Boehm RM, Robinson H, et al: Characteristic early electro- therapy in herpes simplex encephalitis. N Engl J Med 314:144-149,
encephalographic changes in herpes simplex encephalitis. Arch Neurol 1986
34:361-364, 1977 67. Gnann JW, Barton NH, Whitley RJ: Acyclovir— developmental aspects
43. Miller JHD, Coey A: The EEG in necrotizing encephalitis. Electroen- and clinical applications. Evaluations of new drugs. Pharmacotherapy
cephalogr Clin Neurophysiol 2:582-585, 1959 3:275-283, 1983
44. Radermecker J: Systematique its electrocencephalographic des encephali- 68. Davis LE, McLaren LE: Relapsing herpes simplex encephalitis following
tis it encephalopathies. Electroencephalography 5:1-243, 1956 (Suppl) antiviral therapy. Ann Neurol 13:192-195, 1983
45. Smith JB, Westmoreland BF, Reagan TJ, et al: A distinctive clinical EEG 69. Wang HS, Kuo MF, Huang SC, et al: Choreoathetosis as an initial sign
profile in herpes simplex encephalitis. Mayo Clin Proc 50:469-474, 1975 of relapsing of herpes simplex encephalitis. Pediatr Neurol 11:341-345,
46. Upton A, Grumpert J, Electroencephalography in diagnosis of herpes 1994
simplex encephalitis. Lancet 1:650-652, 1970 70. VanLandingham KE, Marsteller HB, Ross GW, et al: Relapse of herpes
47. Enzmann DR, Ransom B, Norman D, Computed tomography of herpes simplex encephalitis after conventional acyclovir therapy. JAMA 259:
simplex encephalitis. Radiology 129:419-425, 1978 1051-1053, 1988