J Neurol (2012) 259:20192030
DOI 10.1007/s00415-012-6494-6
REVIEW
Seizures and epilepsy in herpes simplex virus encephalitis: current
concepts and future directions of pathogenesis and management
Johann Sellner Eugen Trinka
Received: 29 December 2011 / Revised: 21 March 2012 / Accepted: 22 March 2012 / Published online: 18 April 2012
Springer-Verlag 2012
Abstract Mortality related to herpes simplex virus
encephalitis (HSE) dropped dramatically with the system-
atic initiation of antiviral treatment in encephalitic syn-
dromes. Further efforts need to be taken to reduce long-
term morbidity in the survivors. In this regard, the high rate
of postencephalitic epilepsy, which is frequently refractory
to medical treatment, contributes significantly to the
unfavorable clinical outcome of the disease. Seizures dur-
ing the acute phase of HSE are the main risk for the
development of postencephalitic epilepsy. Yet, there are no
randomized controlled trials for the management of acute
seizures, preventive measures or the ideal duration of
antiepileptic treatment. Hence, concepts for the medical
treatment of seizures during the acute phase of HSE and
postencephalitic epilepsy are eagerly awaited. Epilepsy
surgery is a potential treatment option for the latter, but
only promising in a subgroup of patients suffering from
unilateral mesio-temporal lobe epilepsy and congruent
neuropsychological impairment. Relapsing HSE and post-
infectious autoimmune conditions can lead to seizures in
the aftermath of acute HSE. These conditions need to be
kept in mind in order to promptly assure the initiation of
accurate diagnostic steps and respective treatment. The
J. Sellner  E. Trinka
Department of Neurology, Christian-Doppler-Klinik,
Paracelsus Medical University, Salzburg, Austria
J. Sellner
Department of Neurology, Klinikum rechts der Isar,
Technische Universitat Munchen, Munich, Germany
J. Sellner (&)
2nd Neurological Department, Krankenhaus Hietzing mit
Neurologischem Zentrum Rosenhugel, Riedelgasse 5,
1130 Vienna, Austria
e-mail: sellner@lrz.tum.de
purpose of this review is to summarize the current patho-
genetical understanding, clinical and diagnostic consider-
ations, and treatment options of seizures in acute HSE and
postencephalitic epilepsy.
Keywords Herpes encephalitis  Seizures  Epilepsy 
Intractable  Surgery
Introduction
Encephalitis is defined as evidence for brain dysfunction
due to an inflammatory process of the brain parenchyma.
The condition remains a life-threatening disease with
unacceptably high death rates even with improved medical
care [27, 52]. The commonly occurring neurological long-
term sequelae further complement the spectrum of the
burden that this disease takes on the life of the patients and
their caregivers.
Herpes simplex encephalitis (HSE), the most common
pathogen detected in sporadic encephalitis [27], frequently
leads to persistent neurological deficits in the survivors.
Outcomes of 52 patients who were treated with acyclovir
and survived HSE were studied [88]. A complete recovery
was only observed in four (8 %), whereas the remainder
was discharged with neurological dysfunction. Memory
disturbances, personality or behavioral abnormalities, and
postencephalitic epilepsy are the most common neurolog-
ical sequelae in adult patients [59]. Developmental delay,
behavioral impairment, language disturbance, focal motor
deficits and epilepsy are typical long-term disturbances in
children [16]. Postencephalitic epilepsy is a major issue in
survivors of adult HSE; afebrile unprovoked seizures are
frequently encountered in the postacute phase ([21 days
from onset of initial symptoms) and are commonly
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refractory to medical treatment [55, 94, 107]. In this regard,
McGrath [59] assessed long-term outcome in 34 survivors
6 months to 11 years after acute HSE. Epilepsy was
diagnosed in 24 %, and most of the patients had poorly
controlled seizures despite anticonvulsive treatment.
Epilepsy secondary to encephalitis poses a serious
medical issue. However, knowledge on the pathogenesis
is scarce, and impairs effective prevention and develop-
ment of comprehensive treatment strategies. Reportedly,
the occurrence of seizures during the acute phase of HSE
raises the chance for the development of postencephalitic
epilepsy [46], which in turn is associated with poor long-
term prognosis [62]. Importantly, studies in animal
models suggest that the adequate control of seizures
during the acute phase of HSE is an effective means to
reduce mortality and morbidity [74]. All rabbits suffering
from HSE and developing seizures died, whereas the
mortality rate in animals that did not seize was 39 %.
Importantly, treatment with the antiepileptic drug phe-
nobarbital significantly reduced seizures and increased
survival.
This manuscript aims at reviewing the most recent
knowledge on the pathogenesis, clinical features and
treatment of seizures in acute HSE and postencephalitic
epilepsy. Moreover, emerging causes of seizures in the
postacute phase including relapse and postencephalitic
autoimmune disease are covered. Eventually, we outline
concepts and future directions to improve the long-term
outcome of this otherwise devastating condition.
Herpes simplex encephalitis
Herpes simplex encephalitis (HSE) is one of the most
severe clinical manifestations of herpes simplex virus
(HSV) infection. The incidence of HSE is estimated at *1
case per 250500,000 persons per year, with one-third of
the cases concerning children [5]. The symptoms and signs
of HSE reflect virus replication and inflammation within
the temporal lobe and orbital surface of the frontal lobe
[25]. Fever, headache, lethargy, irritability, confusion,
focal deficits, aphasia and seizures are among the most
common presenting clinical features.
In the majority of the cases, HSE is caused by HSV-1, a
double-stranded DNA virus with a genome size of 152 kb
encoding for at least 84 different polypeptides [73]. HSV-2
accounts only for 26 % of the cases, but clinical and
radiological features can be similar to encephalitis caused
by HSV-1 [90]. Before the introduction of acyclovir, most
patients with HSE died. Following the successful imple-
mentation of acyclovir in the management of viral
encephalitis, a broad spectrum of sequelae and outcomes
can be observed in the survivors.
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J Neurol (2012) 259:20192030
Pathogenesis of HSE
Infection with HSV-1 is transmitted through direct contact
or respiratory droplets [102]. HSV has the ability to enter
the central nervous system (CNS), and replicate in neurons
and glia cells. The inflammatory process of HSE is char-
acterized by hemorrhagic-necrotizing features and local-
ized in the predilection sites within the fronto-temporal
brain regions, albeit extratemporal manifestations can be
observed on occasion [60, 101].
The first confirmed case of HSE dates back to a report
by Smith in 1941, when HSV was isolated on autopsy from
the brain tissue of an infant with acute necrotizing
encephalitis [84]. Susceptibility to the disease in adults
remains unclear, since HSV-1 infections in the general
population are widespread. Seropositivity rates for HSV-1
exceed 65 % in middle adulthood [106], but only a small
subgroup develops HSE during lifetime. Studies from the
1980s suggested that HSE is related to primary infection in
one-third of the cases and to reactivation of latent virus in
the remaining [65, 103]. No differences in clinical features
have been observed between HSE because of primary
infection or reactivation [90]. Virus entry via the olfactory
mucosa and subsequently the olfactory bulbs, and the
cribriform plate of the ethmoid bone into the anterior fossa
is implicated in primary infection. For the reactivation
hypothesis, the virus may enter the oral mucosa and sen-
sory nerve endings. HSV is then transported to the regional
ganglia, e.g., the trigeminal, nodose, vagal and ciliary
ganglia, where latency is established [25]. Indeed, studies
in animal models revealed that HSV-1 is transported via
retrograde transport to the cell nucleus of sensory ganglia
within the first 24 h following infection and eventually
enters the CNS within 72 h post infection [79]. Conditions
that have been shown to support reactivation include
ultraviolet (UV) light stimulation, hyperthermia and stress.
The immune system is involved in the suppression of
reactivation from the latent state. This is maintained by the
secretion of non-cytolytic granules by CD8? T-cells [40].
In detail, granzyme B was shown to degrade HSV-1
immediate early protein (ICP) 4, which is essential for gene
expression required for reactivation.
Pathophysiology of neuronal injury
The lytic cycle of HSV-1 infection evokes an intricate
immune response within the CNS. Subsequently, inflam-
matory responses consisting of activation of brain-resident
cells, immigration of peripheral-blood mononuclear cells
and bloodbrain barrier disruption are detected in human
and experimental HSE [2, 3, 56, 76, 77, 82]. Hemorrhagic
necrosis and liquefaction develop after approximately
2 weeks [102]. Early initiation of antiviral therapy was
J Neurol (2012) 259:20192030
shown to limit the extent of neuronal damage and alter the
catastrophic natural disease course. Recent studies revealed,
however, that the host immune response is involved in the
neuronal injury and outcome, even more than direct viral
cytotoxicity [12, 50]. A retrospective analysis of 45 patients
with HSE found that usage of corticosteroids was an inde-
pendent predictor of good outcome [36]. Notably, high levels
of the pro-inflammatory cytokines IFN-c and IL-6 values were
associated with poor outcome [37]. Hence, reduction of col-
lateral neuronal injury by modulation of the immune response
might be an emerging option to change the unsatisfactory
prognosis of HSE.
Seizures during the acute course of HSE
Demographics and clinical characteristics
Up to 50 % of adult patients with HSE present with sei-
zures, and additional patients develop seizures during the
acute and subacute course [59, 104]. Indeed, 75 % of
patients with HSE were reported to have seizures during
the acute stage of the disease [62]. In children, seizure rates
are even higher than in adult patients [31, 42]. Studies by
Whitley [103, 104] revealed that in HSE seizures on pre-
sentation were most frequently focal (65 %), followed by
generalized (23 %) and a combination of both (12 %).
While seizures during the acute phase of encephalitis were
not shown to be associated with higher mortality, they are
significantly related to poor 3-month outcome [62]. Hsieh
reported complementary prognostic relevance of seizures
on admission and abnormal EEG findings in children with
HSE [31]. The course of HSE can be complicated by status
epilepticus [35], which is more refractory in HSE than for
other etiologies [30, 58]. Misra [63] reported 4 cases
(29 %) of status epilepticus among 14 patients with HSE.
Of note, the chance to die from encephalitis is higher with
Fig. 1 Typical MRI and EEG findings in acute HSE. a Axial FLAIR
MRI showing abnormal signal and edema within the left juxtainsular
formation (arrowhead). b Periodic lateralized epileptiform discharges
2021
the occurrence of status epilepticus [62]. It is likely that
seizures in acute HSE are under-diagnosed; particularly
non-convulsive seizures may be missed. Epileptic nystag-
mus as the only symptom of non-convulsive status epi-
lepticus was reported in the setting of HSE [45].
With the occurrence of seizures or neurological deteri-
oration, EEG monitoring is required. Recurrent or intrac-
table seizures lead to raised intracranial pressure, increased
metabolic activity, acidosis and vasodilatation, which in
turn further elevates intracranial pressure [86]. Several case
series confirmed that decompressive craniectomy is a
potential life-saving measure for the treatment of severe
encephalitis-associated increased intracranial pressure.
However, whether survival is associated with unacceptably
high morbidity rates including postencephalitic epilepsy
remains to be determined [41].
EEG findings in acute HSE
The increased rate of seizures in HSE has been attributed to
injury of the highly epileptogenic limbic system. Typical
EEG findings are shown in Fig. 1. During the first 57 days
of illness, changes in the EEG are characterized by spike
and slow wave activity, often arising from the temporal
lobe. In the absence of antiviral therapy, the encephalitic
process spreads to the contralateral temporal lobe over a
period of 10 days. Later, paroxysmal sharp waves or tri-
phasic complexes with temporal predominance can be
observed [96]. This pattern was initially described in viral
encephalitis by Radermecker [69]. Some patients develop
periodic lateralizing epileptiform discharges (PLEDs) at a
rate of 23 Hz originating from the temporal lobe [83].
PLEDs may be absent very early in the course of the dis-
ease and are not specific for HSE but support the diagnosis.
Importantly, the resolution of EEG abnormalities in
patients with HSE does not correlate well with clinical
recovery [61].
(PLED) over the left temporal lobe. c Generalized theta-delta activity
over the temporal regions
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Molecular pathogenesis of seizures in acute HSE
Virus
The virus itself is capable of inducing neuronal hyperex-
citability. Studies with hippocampal cultures revealed that
HSV-1 infection causes a long-lasting reduction in the
depolarizing membrane potential, thus resulting in a
hyperexcitable neuronal state [10, 105]. Furthermore, there
was a correlation between the extent of HSV-1 copies and
neuronal hyperexcitability. Lesions within the limbic cir-
cuit [8] and hyperexcitability in the hippocampal CA3
region [10, 105] were identified as potential morphological
and functional correlates of seizures in animal models of
HSE. Dynorphin is an inhibitory transmitter present in
mossy fiber afferents to CA3 principal neurons and is
proposed to play a central role in the events that sustain
hyperexcitability and transition to an epileptic phenotype.
Indeed, collapse of dynorphin homeostasis has been
reported in the hippocampal dentate gyrus of animals
infected with HSV-1, indicating selective and persistent
vulnerability of this region [85]. Notably, Schlitt et al. [74]
found evidence that the ability of different HSV-1 strains to
replicate in nervous tissue (neurovirulence) corresponds
to the occurrence of seizures and subsequent mortality.
Fever/immune response
Host-derived febrile responses can trigger seizures, espe-
cially in patients with structural brain abnormalities, such
as encephalitis, and in newborns and children [48]. Indeed,
in these patients seizures can be induced or facilitated
directly by high body temperature, typically in the range of
3840 C. Calcium influx, decreased inhibition in the
hippocampus through reduction of GABA release and
transient increase in excitatory synaptic transmission are
potential mechanisms involved [7]. Moreover, hyperther-
mia-induced hyperventilation and alkalosis may addition-
ally contribute to febrile seizure generation [71].
The immune response to HSV-1 is involved in the ini-
tiation of seizures and epileptogenesis [21, 24, 39]. The
secretion of pro- and anti-inflammatory cytokines and
chemokines, and upregulation of cell surface receptors
within the CNS are observed in patients and animal models
of HSE [32, 76]. HSV-1 is recognized by toll-like receptor
(TLR)2 and TLR3, and microglia was identified as the
major source of HSV-1-induced cytokines such as TNF-a,
IL-1b, CCL5 and CXCL10 [49]. These responses were
shown to be type I interferon dependent and mediated by
transcription factors such as nuclear factor kappa light-
chain-enhancer of activated B-cells (NF-kB), a p38 mito-
gen-activated protein kinase (MAPK) and c-Jun NH2-ter-
minal kinase (Jnk). The pro-inflammatory cytokine
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J Neurol (2012) 259:20192030
interleukin-1b, which is not only increased by fever but
also inflammation, has pro-epileptogenic properties [72,
100]. The critical role of TNF-a and IL-1b in generating a
protective immune response against the virus was also
highlighted in studies with transgenic animals lacking
either one of the cytokines [78]. Indeed, a concerted action
of the innate and adaptive immune response is required to
restrict virus expansion and eliminate the pathogen. The
innate immune response with infiltration of macrophages
and activation of microglia is followed by a delayed host
adaptive immune response with priming and clonal
expansion of HSV-1-specific T-cells [12]. This cellular
immune response is critically involved in the pathophysi-
ology of temporal lobe seizures and subsequent epilepto-
genesis [70, 108]. CD8? T-cells were shown to secrete
cytotoxic granules to lyse virus-infected cells. Malipiero
et al. [53] demonstrated that the subsequent overexcitation
of NMDA receptors results in neuronal degeneration.
Indeed, in animal models of HSE, this delayed immune
response was also shown to be a cause of CNS pathology
and related to outcome in humans [37, 50]. Whether a
global suppression of immune responses by additional
steroid therapy during the acute phase of HSE will also
alter seizure frequency and subsequent sequelae continues
to be a matter of research [57].
Medical treatment of seizures occurring during acute
HSE
Clinical studies reported consistently that the occurrence of
seizures during acute encephalitis is linked to the devel-
opment of postencephalitic epilepsy and poor outcome.
Hence, the adequate control of epileptic activity during
acute encephalitis is of key importance. However, there are
no randomized controlled trials testing prophylactic anti-
convulsive therapy in acute viral encephalitis. Currently, a
prophylactic treatment of HSE patients in general or with a
history of a single, uncomplicated seizure during the acute
course is not recommended [89]. This concept may change
if early identification of patients at risk of seizures or
epilepsy is possible.
A proactive treatment and diagnostic approach are
required for the treatment of recurrent seizures or status
epilepticus. Here, rapid administration of intravenous
benzodiazepines and anticonvulsants is indicated [81, 93].
There are no trials evaluating the efficacy of different first
and second line antiepileptic drugs in HSE. The treatment
approach to seizures in HSE is similar to that of any focal
or secondarily generalized epilepsy due to acquired causes
[80]. If seizures are not easily controlled by standard iv
therapy, patients may require intubation and mechanical
ventilation, so that higher doses of sedating anticonvulsive
drugs can be used [86]. Development of seizures or clinical
J Neurol (2012) 259:20192030
deterioration in the course of acute HSE may be related to
intracerebral complications including brain edema, herni-
ation, hydrocephalus, hemorrhage or ischemia. Hence,
evaluation with brain MRI is then required.
Following adequate seizure control, the antiepileptic
treatment is continued with oral preparations. There are no
data concerning potential first or second line drugs in viral
encephalitis and the optimal duration of antiepileptic
therapy. Commonly, oral anticonvulsant treatment is
maintained for 612 months and is tapered thereafter.
Situations in which phenytoin or valproate cannot be given
because of contraindications such as concurrent pregnancy
can be expected. Newer intravenous anticonvulsants like
lamotrigin, levetiracetam or lacosamide may be used in this
context, but their efficacy and safety have not been spe-
cifically studied in HSE [29, 92]. Favorable seizure control
with lamotrigine and low-dose benzodiazepines has been
reported in a case of maternal HSE during pregnancy [75].
Drug interactions should be closely monitored. The low-
ering of phenytoin and valproate to subclinical levels by
concomitant administration of acyclovir has been reported
[67] but could not be confirmed in an animal model [98].
General measures
Repeated control of body temperature is required. Fever
can be lowered by giving acetaminophen or ibuprofen.
Electrolyte disturbances should be checked. Attention
should be paid to sufficient oxygenation, fluid balance and
hydration. Compression stockings should be fitted in
patients with reduced mobility in order to reduce the risk of
deep vein thrombosis and pulmonary embolism. Prophy-
lactic antithrombotic treatment with heparin can be started
after ruling out a major hemorrhagic component of the
encephalitic lesion on neuroimaging.
Postacute seizures: relapse, postinfectious autoimmune
disease and unprovoked, afebrile seizures
(postinfectious epilepsy)
Demographic and clinical characteristics
Annegers [1] evaluated the risk of unprovoked seizures in a
population-based cohort of 714 survivors of encephalitis or
meningitis. Individuals with a previous CNS infection had
a sevenfold increase in the risk for developing unprovoked
seizures. The 20-year risk for developing seizures was
22 % for persons with viral encephalitis and early seizures.
In contrast, the risk for postacute seizures was only 10 %
without seizures during the acute course.
Late unprovoked seizures occur in 4065 % of adult
patients after an episode of HSE [11, 18]. The risk of
2023
seizures following HSE is greatest in those who had sei-
zures during the acute period. Seven (10 %) of the 71
children with acute encephalitis (pathogen identified in
52 %), which were followed by Fowler, developed epi-
lepsy [22]. In detail, children who presented with seizures
during the acute phase had an eightfold increased risk of
later developing epilepsy (95 % CI 1.0464.6; P \ 0.05).
Interestingly, girls had an almost five-fold higher risk of
developing encephalitis compared to boys (95 % CI
1.0223.4; P \ 0.05). Of the 330 children with a history of
encephalitis studied by Lee and co-workers, 54 (16 %)
developed epilepsy [46]. The diagnosis of epilepsy was
made in 80 % of these children within 6 months from acute
encephalitis. Twelve percent of the 74 children assessed by
Baek and coworkers developed postencephalitic epilepsy
[4]. A significantly higher rate of postencephalitic epilepsy
was reported for patients with seizures during the acute
stage (P = 0.0005), vomiting (P = 0.03) and abnormal
EEG findings (P = 0.007). With a high rate of failure to
respond to anticonvulsive therapy, outcome from posten-
cephalitic epilepsy is usually poor [11, 64, 94].
Different pathogenetical processes can be the substrate
for seizures in the postacute phase of HSE, as shown in
Fig. 2. These include (1) classical postencephalitic epi-
lepsy, (2) relapse as the correlate for resumption of intra-
cerebral viral replication and inflammation and (3)
postencephalitic autoimmune disease in terms of a chronic
inflammatory CNS disorder. Treatment and outcome
among the options differ, and a diligent search for the
underlying pathology is essential. The frequencies of the
different processes leading to seizures in the postacute
Fig. 2 Current understanding of the development of seizures in acute
HSE and thereafter. Seizures and epilepsy in the postacute phase of
HSE can be related to a relapse, postinfectious autoimmune disease or
classical afebrile unprovoked seizures (= postencephalitic epilepsy).
Relapses usually develop within days to weeks from discontinuation
of antiviral therapy because of insufficient elimination of virus and
can become symptomatic with seizures (black). Immune responses of
potential autoimmune origin may develop after HSE, particularly in
children, and lead to seizures several weeks to months after HSE
(blue). Eventually, postencephalitic epilepsy develops years after
HSE (mostly mesial temporal lobe epilepsy) and is usually related to
changes of neuronal excitability in the hippocampus following injury
during acute HSE (red)
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phase as well as the exact pathomechanisms are unclear.
Currently, it can only be speculated that classical posten-
cephalitic epilepsy is more frequent than seizures in the
postacute phase because of relapse or postencephalitic
autoimmune disease. Going by reports in the literature,
higher rates of postencephalitic autoimmune disease can be
assumed in pediatric than in adult HSE. In addition, whe-
ther there is an overlap between relapse and postinfectious
autoimmune disease, and genetic background and the virus
strain plays a role need to be evaluated in further studies
[13, 15].
Relapse
There is no general consensus on the definition of a relapse.
The most recent definition suggested by De Tiege [16] is
shown in Table 1. Negative PCR examinations need to be
taken with caution since there are cases with negative PCR
and favorable response to acyclovir [20]. Such cases are
likely to be rated as relapse, but final confirmation with
brain biopsy will only rarely be possible.
Relapses are reported in up to 26 % of acyclovir-treated
pediatric HSE patients [33, 38]. There are also reports of
children with two relapses [15]. Among the six pediatric
patients with HSE relapse reported by de Tiege, seizures
were part of the neurological deterioration in five [15].
Two relapse cases that presented with seizures were also
positive for HSV-1 PCR in the CSF investigation [33, 97].
The relapse rate in adults and older children is less clear
but appears to be at the lower end of the range reported in
children [96]. Accordingly, Stahl [88] reported on only 1
relapsing patient among 53 survivors of HSE (2 %) and
Skoldenberg [82] 3 in 26 patients (12 %). There are no
details provided about whether seizures occurred during
the relapses in the patients of these two studies.
Early relapses due to the resurgence of viral replication
are known to occur a few days after cessation of antiviral
treatment. Patients experience initial improvement and
then develop symptoms or progressive deterioration
1 week to 3 months from completion of acyclovir therapy.
It is believed that inadequate duration and/or dosage of
acyclovir is the underlying cause of this process [33, 38]. In
all of the seven patients reported by Ito, acyclovir re-
Table 1 Diagnostic criteria for a HSE relapse, from [16]
1 Presence of new necrotic-hemorrhagic lesions distant from the
initial site of encephalitis
2 Positive HSV PCR and/or increased alpha interferon level in the
CSF
3 Reappearance of intrathecal synthesis of HSV IgG
4 Isolation of HSV from brain biopsy and/or clinical improvement
under a new course of acyclovir treatment
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J Neurol (2012) 259:20192030
treatment lead to a reduction of new signs and symptoms
[33]. Prolonged antiviral treatment may reduce the relapse
rate by more effective elimination of the remaining viral
load. In this regard a double-blind phase III study evalu-
ating a regimen with oral valacyclovir over a period of
90 days after HSE was completed recently in the US, and
results are eagerly awaited (http://clinicaltrials.gov/ct2/
show/NCT00031486). It is assumed that immune defects
raising susceptibility for HSE and reactivation may be
involved in the pathogenesis of a relapse. The failure of
adequate interferon production has been shown just
recently in a case of an early relapse [51].
Relapses can also occur months to years after the acute
course of HSE [14, 54, 87]. For these late relapses, it is
hypothesized that the local immune response was insuffi-
cient to control latency and reactivation of virus became
possible. HSE reactivation can also be a potential com-
plication of epilepsy surgery. In this regard, Gong et al.
[26] reported a case of a toddler who experienced a relapse
after subtotal hemispherectomy 16 months from acute
HSE.
Postencephalitic autoimmune disease
Early neurological deterioration in survivors of HSE usu-
ally starting within 1 month from acute disease and of
suspected autoimmune origin has been reported recently. In
the literature more infant and child than adult cases have
been reported [34]. Extra-pyramidal disturbances, particu-
larly with choreoathetoid movements, are most frequently
the leading symptom [15]. Seizures can be observed but are
less frequent than in relapsing patients, but exact rates are
unclear [16].
Usually new hemorrhagic-necrotic lesions are absent,
but new diffuse white matter lesions are detected on MRI.
For this entity, secondary autoimmune mechanisms fol-
lowing HSV infection are discussed, but continue to be a
matter of debate, and diagnostic criteria have not been
established to date. CSF PCR for HSV should be negative,
but rare cases with positive PCR have been reported. CSF
levels of alpha interferon are within the normal range [16].
Antiviral treatment does not prevent further neurological
deterioration or improve the disease course. Efficacy of
corticosteroids is variable, and prognosis of these patients
is generally poor. Further studies are eagerly awaited for
this disease entity.
Lellouch-Tubiana [47] reported the neuropathological
biopsy findings of three children who contracted HSE
before the age of 2 years and developed intractable focal
epilepsy after a symptom-free period. The main observa-
tion was persistent immune activation in all sections as
evidenced by the presence of mononuclear cells with a
similar pattern as found in acute HSE. HSV DNA could
J Neurol (2012) 259:20192030
only be detected in one patient. Interestingly, there are
asymptomatic patients who develop progressive chronic
white matter lesions months to years after HSE [16].
Notably, the rare condition of chronic HSE, which is
characterized by intractable seizures, progressive neuro-
logical deficits and viral replication, needs to be distin-
guished from postencephalitic autoimmune disease [16].
Postencephalitic epilepsy (afebrile, unprovoked
seizures)
Postencephalitic epilepsy is characterized by various clin-
ical seizure patterns and ill-defined seizure-onset zones.
CSF and MRI investigations are required in the workup in
order to rule out relapse and postinfectious autoimmune
disease. Hjalmarsson [28] evaluated 236 Swedish HSE
patients that suffered from the condition between 1990 and
2001 and found that these patients had a 60- to 90-fold
higher risk to be admitted to hospital due to epilepsy than
the general population. Indeed, while 3 patients (1 %) had
epilepsy prior to HSE, 49 patients (21 %) had epilepsy
following CNS infection with HSV-1. The largest number
of patients with intractable post-HSE epilepsy (n = 10)
was among the patients of the Montreal patient series with
intractable postencephalitic epilepsy (n = 42). The
majority (72 %) had complex partial seizures with or
without generalization [94]. The predominant seizure pat-
terns were unilateral temporal (19 %), bilateral temporal
(20 %) and extratemporal/multifocal or generalized
(52 %). Thirty-six (86 %) patients reported an aura, with
limbic-mesial temporal (epigastric, deja vu, fear, olfactory)
being the most frequent (64 %), followed by neocortical
(auditory, vertiginous) and extratemporal auras (visual,
somatosensory) in 12 and 21 %, respectively. A non-
localizing aura (cephalic, dizziness, strange feeling) was
present in 26 %.
Donaire evaluated seizure semiology in seven patients
with postencephalitic epilepsy and presence of mesio-
temporal sclerosis [17]. Automotor seizures were found in
four patients, dialeptic seizures in two and hypermotor
seizures in one. Epileptic auras were present in five and
were classified as abdominal (n = 2), psychic (n = 2) and
cephalic (n = 1). In the lack of mesiotemporal epilepsy,
EEG identified diffuse disease, such as generalized, lateral
and posterior temporal interictal epileptiform discharges or
bi-temporal, independent seizure onsets [17, 55].
The MRI of patients with intractable postencephalitic
epilepsy frequently demonstrates T2-signal alterations or
regional atrophy. Roughly 50 % of the children with
postencephalitic epilepsy evaluated by Chen [11] had
abnormal neuroimages, and even 73 % in the series eval-
uated by Donaire [17]. In the Montreal series of posten-
cephalitic epilepsy, temporo-mesial or neocortical atrophy
2025
was found in 31 % [94]. Interestingly, bilateral hippo-
campal volume loss is found more frequently in the after-
math of encephalitis than of bacterial meningitis [23]. The
lesion demonstrated by MRI, however, is frequently
widespread or largely discordant to the seizure onset and
symptomatogenic zone. This is particularly the case for
patients with temporal and additional extratemporal MRI
abnormalities [94].
The time from acute HSE to the onset of unprovoked
postencephalitic seizures seems to be defined by the ana-
tomic localization and volume of the lesion, as well as the
age at encephalitis. The latency in the initial Montreal
patient series was shorter in patients with extratemporal/
multifocal or generalized epilepsy (median 0.1 year)
compared to uni- or bilateral temporal lobe epilepsy
(median 2.6 and 0.9 years, respectively) [94]. In general,
the latency periods were longer in patient series comprising
only one or no HSE patient. A median of 3.4 years were
reported in the Mayo series (n = 18; HSE n = 1) [66] and
3.8 years in the Yale series (n = 22, no HSE) [55]. There
was a significant difference in the latency based on epi-
lepsy type in the Cleveland clinic series [43]. Time from
acute encephalitis to unilateral mesial temporal lobe epi-
lepsy was a mean of 8.7 years, whereas latency to bilateral
mesial temporal lobe epilepsy (2.7) and neocortical epi-
lepsy (3.7) was shorter. Two independent studies stressed
that the age at time of encephalitis is critical for the
development of the seizure focus [44, 55]. The authors
report that the development of CNS infection at an early
age, before the age of 46 years, is more likely to cause
hippocampal injury and subsequent mesio-temporal lobe
epilepsy. This principle may not be the case in patients
with extensive lesions. Based on the longer latency for this
seizure type, it can be speculated that the transition of the
injured hippocampus into an epileptogenic network
requires time [44, 99]. In contrast, in neocortical epilepsy
direct damage to cortical neurons by the virus itself and the
collateral damage by the immune system may explain the
shorter latency period.
Medical treatment of postencephalitic epilepsy
There are no randomized controlled trials on the efficacy of
antiepileptic drugs and their combinations for seizure
control in postencephalitic epilepsy, and recommendations
are based on expert opinion. At the time of early seizure
recurrence, many of the patients will be on phenytoin,
valproate or levetiracetam if seizures presented during the
acute phase of HSE. In addition to the three anticonvul-
sants mentioned above, the repertoire of standard anti-
convulsants includes carbamazepine and phenobarbital.
Among the newer drugs are gabapentin, lamotrigine, ox-
carbazepine, zonisamide, lacosamide or topiramate. The
123
2026
selection of antiepileptics needs to be adjusted to the
patient0 s age, sex, childbearing potential, co-morbidities
and concomitant medications [68]. Hence, if seizures
continued under consequent drug intake and sufficient drug
levels, the switch to another antiepileptic medication
should be carried out. Combination therapy should be
considered when treatment with two first line drugs failed
or when the first well-tolerated drug substantially improved
seizure control but failed to sustain seizure freedom at
maximal dosage.
In general, epilepsy following HSE is refractory to
treatment with antiepileptic drugs. Of note, Chen and co-
workers reported that 10 out of 11 children with posten-
cephalitic epilepsy due to HSE who were treated for
3 years or more had poor outcome of epilepsy [11]. Poor
outcome was defined by no significant change in seizure
frequency following anticonvulsive therapy. It may take a
year to gain sufficient seizure control, and epilepsy surgery
needs to be considered early in the course.
Surgery for refractory afebrile seizures following HSE
Surgical approaches are determined by the localization of
the focus and neuroimaging findings. Potential procedures
include anterior temporal lobe resection, neocortical
resections, frontal resections and anterior callosotomy, and
combinations of these methods. In addition to the risk of
perioperative mortality, major procedural complications
include the development of new neurological deficits,
postoperative infections, and cognitive and behavioral
changes [19].
The patients reported in the literature who underwent
epilepsy surgery always had intractable epilepsy with a
catastrophic disease course in which no significant sei- virus and active inflammation be detected in biopsy spec-
zure reduction could be accomplished by medical treat-
ment. These patients also frequently suffer from moderate
to severe neuropsychological impairment. Indeed, neuro-
psychological testing in patients from the Montreal cohort
determined widespread intellectual impairment in 55 % of
the patients [94]. It is conceivable that the success of epi-
lepsy surgery was limited in these patient series [91]. This
outcome from epilepsy surgery stands in contrast to the
results in temporal lobe resection for epilepsy due to other
causes, where up to two-thirds of patients become seizure
free after anterior temporal lobectomy [19]. The following
predictors for an unfavorable outcome from surgery were
identified: lack of a focal lesion on MRI, a short latency
period between acute encephalitis and seizure onset, older
age at the time of CNS infection and neocortical origin of
seizures. Severely affected patients with a widespread
functional deficit zone, with evidence of bilateral and dif-
fuse disease, and extratemporal clinical features were also
shown to have limited benefit from surgery. Accordingly,
123
J Neurol (2012) 259:20192030
only one out of four operated HSE patients had a favorable
outcome [94]. Surgical outcome was shown to be linked to
the severity of acute encephalitis, e.g., performance on the
Glasgow Outcome Scale (GOS) [95].
There is evidence, however, that a subgroup of patients
has a higher chance for better outcome from epilepsy
surgery. These are patients with clear unilateral temporal
lobe epilepsy. Their outcome is reported in a range com-
parable to mesial temporal lobe epilepsy of other causes
[17, 95]. Indeed, in the Montreal series six of the nine
patients with unilateral temporal seizure onset had favor-
able outcomes, whereas there was only one patient with
this seizure type in the group of patients with poor outcome
[95]. The pre-surgical evaluation by neuropsychological
assessment is of central importance. Donaire et al. [17]
selected patients with unilateral mesio-temporal posten-
cephalitic epilepsy and congruent memory deficits for
temporal lobe resection (n = 4). The outcome was excel-
lent; after a mean follow-up time of 4.1 years (range
17 years), patients were either seizure free or only expe-
rienced auras following surgery.
Hippocampal sclerosis and gliosis are frequently
encountered in the neuropathological workup of resected
tissue [95]. However, also perivascular lymphocytic infil-
trates and microglial activation can be found on occasion
[94]. This finding is consistent with a report by Cagnin who
evaluated patients up to 12 months after HSE using [11C]-
R-PK11195 PET, a tracer specific for activated microglia
[9]. Persistent microglia activation was detected not only in
the region affected during acute HSE, but also in areas
connected to the limbic system by neuronal pathways.
Rarely, HSV-1 can be detected in brain tissue even by
using different molecular diagnostic approaches. Should
imens of a patient with intractable postencephalitic epi-
lepsy, a course of acyclovir treatment should be undertaken
as this finding may be related to chronic encephalitis. In the
absence of inflammation the coincidental detection of
HSV-1 needs to be considered, given the high rate of
asymptomatic presence of this virus in human nervous
system tissue [6].
Taken together, there are several issues to consider in the
pre-surgical evaluation of potential candidates for epilepsy
surgery. A higher rate of success is likely to be obtained if
surgery is only performed in selected patients, the privi-
leged group defined by unilateral temporal lobe epilepsy and
only mild and congruent neuropsychological deficits.
Conclusion
Postencephalitic epilepsy is a major outcome-defining
long-term complication of HSE. The main risk factors are
J Neurol (2012) 259:20192030
seizures during the acute disease phase, but the efficacy of
prophylactic anticonvulsive treatment, acute seizure ther-
apy and the duration of treatment has not been studied in a
controlled fashion. The interplay of adaptive immune
responses and direct neuronal injury by the virus itself is
implicated in the development of epileptogenic lesions.
This calls for the design of efficient trials with sensitive
read-outs in order to improve the prognosis of posten-
cephalitic epilepsy. Postencephalitic epilepsy is frequently
refractory to medical treatment, even with newer anticon-
vulsants and add-on strategies. Whether certain anticon-
vulsants are more effective is unclear. The selection of
anticonvulsants needs to be matched to the patients seizure
type(s) and for combinations limited to two, or at most
three. Anterior temporal lobe resection is a feasible
approach in patients with postencephalitic unilateral tem-
poral lobe epilepsy. A precise pre-surgical evaluation with
special consideration of neuropsychological performance is
required to define this subgroup of patients with a chance
for favorable outcome. In contrast, the outcome from sur-
gery may be disappointing in severely affected patients
with a widespread functional deficit zone, evidence of
bilateral and diffuse disease, and particularly extratemporal
clinical features. Of note, therapeutic concepts for the
patients with intractable epilepsy but limited prospects to
benefit from surgery are eagerly awaited.
Seizures in the aftermath of HSE, however, may not
only be a consequence of epileptogenic foci due to cortical
injury formed in the acute phase of the disease. Relapses
and post-encephalitic autoimmune processes are additional
causes that need to be considered in the workup of patients
with new seizures in the aftermath of HSE.
More research is needed to further elucidate the patho-
logical disease mechanisms underlying HSE and posten-
cephalitic epilepsy.
Acknowledgments J. Sellner is supported by a scientific fellowship
from the European Federation of the Neurological Sciences (EFNS)
and the Technische Universitat Munchen, Germany.
Conflict of interest J. Sellner has no conflict of interest. E. Trinka
received personal compensation for activities with UCB Pharma,
Eisai Inc., Sunovion, Medtronic, Pfizer Inc., Ever-Neuropharma and
GlaxoSmithKline, Inc. as a consultant and/or speaker, and received
research support from UCB Pharma, Ever-Neuropharma, Medtronic
and GlaxoSmithKline, Inc.
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