REVIEW

CURRENT
OPINION Treatment options for posttraumatic epilepsy
Lara L. Zimmermann, Ryan M. Martin, and Fady Girgis

Purpose of review
Posttraumatic seizures (PTS) and posttraumatic epilepsy (PTE) are common and debilitating consequences of
traumatic brain injury (TBI). Early PTS result in secondary brain injury by raising intracranial pressure and
worsening cerebral edema and metabolic crisis. PTE is a localization-related epilepsy strongly associated
with TBI severity, but risk factors for PTE and epileptogenesis are incompletely understood and are active
areas of research. Medical management of PTS in adults and children is reviewed. Surgical options for
posttraumatic drug-resistant epilepsy are also discussed.
Recent findings
Continuous electroencephalography is indicated for children and adults with TBI and coma because of the
high incidence of nonconvulsive seizures, periodic discharges, and associated secondary brain injury in
this population. Neuroinflammation is a central component of secondary brain injury and appears to play
a key role in epileptogenesis. Levetiracetam is increasingly used for seizure prophylaxis in adults and
children, but variability remains.
Summary
PTS occur commonly after TBI and are associated with secondary brain injury and worse outcomes in
adults and children. Current medical and surgical management options for PTS and PTE are reviewed.
Keywords
continuous electroencephalography, ictal–interictal continuum, metabolic crisis, nonconvulsive seizure, trau-
matic brain injury

INTRODUCTION EARLY POSTTRAUMATIC SEIZURES AND

Posttraumatic seizures (PTS) and posttraumatic epi-
lepsy (PTE) are a common and debilitating conse-
quence of traumatic brain injury (TBI). Early PTS
result in secondary brain injury at a time when the
injured brain is extremely vulnerable because of
impaired cerebral autoregulation and neuroinflam-
mation. This article reviews the current literature
on mechanisms of secondary brain injury after
TBI including the ictal–interictal continuum, the
role of neuroinflammation in epileptogenesis, med-
ical treatments for PTE, and surgical options for
posttraumatic drug-resistant epilepsy. The latest lit-
erature on management of PTS in children is also
reviewed.
SECONDARY BRAIN INJURY
Seizures are common in neuroscience ICU patients
&&
with acute brain injury [1–4,5 ], occur in 22–33%
&&
of patients with moderate–severe TBI [1,4,5 ] and
&
are associated with increased ICU length of stay [6 ].
Risk factors include severity of head injury, younger
age, acute parenchymal hematoma, acute subdural
hematoma, diffuse cerebral edema, and penetrating
brain injury [7]. A growing body of literature indi-
cates that early PTS are not benign, but instead result
in secondary brain injury, brain atrophy [8], and
worse clinical outcomes via a variety of mechanisms
including alterations in cerebral blood flow (CBF)
with associated increased intracranial pressure [9],

DEFINITIONS
PTS are classified as:
(1) Immediate, occurring within 24 h after injury;
(2) Early seizures, occurring within 7 days after
injury;
(3) Late seizures, occurring more than 7 days after
injury; when recurrent, defining PTE.
Department of Neurological Surgery, UC Davis Medical Center, Univer-
sity of California, Sacramento, California, USA
Correspondence to Lara L. Zimmermann, MD, Department of Neuro-
surgery, UC Davis Medical Center, University of California, 4860 Y
Street, Suite 3740, Sacramento 95817, CA, USA. Tel: +1 916 734
3658; e-mail: LLZimmermann@ucdavis.edu
Curr Opin Neurol 2017, 30:580–586
DOI:10.1097/WCO.0000000000000505

www.co-neurology.com Volume 30  Number 6  December 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

 Treatment options for posttraumatic epilepsy Zimmermann et al.
KEY POINTS
 Early posttraumatic seizures are common after TBI and
are associated with secondary brain injury.
 Seizure prophylaxis is recommended to decrease the
incidence of early posttraumatic seizures, but does not
prevent PTE.
 Continuous electroencephalography is indicated for
children and adults with moderate–severe TBI and
coma because of the high incidence of nonconvulsive
seizures in this population.
 The ictal–interictal continuum describes EEG patterns
that fall on the spectrum between definite seizures and
benign patterns and periodic discharges may be
associated with secondary brain injury.
 Surgical options for posttraumatic drug-resistant
epilepsy exist, including lesionectomy, hippocampal
transection, and neuromodulation.
progressive cerebral edema [10], metabolic crisis
&& &&
[11,12,13 ], and brain tissue hypoxia [14 ].
Multimodal neuromonitoring data indicates
that cerebral hemodynamic changes including alter-
ations in CBF and cerebral oxygen start early,
preceding electrographic seizure onset [15–18].
Convulsive and nonconvulsive seizures increase
cerebral metabolic rate and CBF and result in sec-
ondary brain injury by raising intracranial pressure
and worsening cerebral metabolic crisis [9]. Meta-
bolic crisis is defined as a state of reduced oxidative
metabolism, increased glucose consumption, and
an impaired redox state of the brain, and occurs
in 74% of patients after TBI [19]. It occurs despite
adequate hemodynamic resuscitation after trauma
and its duration is a strong independent predictor of
poor outcome at 6 months [19]. Furthermore, acute
glucose and lactate metabolism predict frontal-
temporal cognitive recovery between 6 and 12-
& Due to the high incidence of nonconvulsive
months post-TBI [20 ].
The ictal–interictal continuum and secondary
brain injury
The incidence of acute seizures after moderate–
severe TBI is approximately 22% and more than half
are nonconvulsive [1]. Periodic discharges that do
not meet criteria for seizures are even more pervasive
after an acute brain injury, but their neurological
repercussions remain incompletely understood. The
term ictal–interictal continuum describes electroen-
cephalography (EEG) patterns that fall on the spec-
trum between definite electrographic seizures and
benign interictal patterns that are potentially
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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
harmful and may result in progressive neuronal
&&
injury [21 ]. A definite electrographic seizure is
defined as generalized spike-wave discharges at
3 Hz (3/s) or faster. Epileptiform discharges at 1 Hz
(1/s) or slower without evolution or clinical corre-
late are likely benign. Lateralized or generalized
periodic discharges occurring with intermediate fre-
quency fall on the ictal–interictal continuum.
A critical and unanswered question is how
aggressively should we treat electrographic patterns
that fall within the ictal–interictal continuum?
Recent studies indicate that activity on the ictal–
interictal continuum is not necessarily benign
&& && &&
[13 ,14 ]. Vespa et al. [13 ] studied 34 patients
with severe TBI who underwent multimodal neuro-
monitoring with scalp and intracortical depth EEG
as well as cerebral microdialysis and found that
metabolic crisis occurred during both seizures and
periodic discharges, but not during electrically quiet
&&
periods. Witsch et al. (2017) [14 ] prospectively
studied 90 comatose patients with high-grade spon-
taneous subarachnoid hemorrhage who underwent
multimodal neuromonitoring with continuous
scalp EEG, intracortical depth EEG, brain tissue
oxygenation (Pbt02), and regional CBF monitoring.
They found 36% had periodic discharges on scalp
EEG and 23% had periodic discharges on depth
EEG with frequencies spanning the ictal–interictal
continuum (0.5–2.5 Hz). Increasing frequency of
periodic discharges was associated with increased
regional CBF, increased global cerebral perfusion
pressure, and reductions in brain tissue oxygen
&&
indicating secondary brain injury [14 ]. This sug-
gests that EEG patterns that fall on the ictal–inter-
ictal continuum may warrant aggressive treatment.
When feasible, it is recommended to correlate the
ictal–interictal continuum pattern with other
markers of neuronal injury such as intracranial pres-
sure, Pbt02, cerebral microdialysis, or depth elec-
&&
trode recordings [21 ].
seizures and secondary brain injury in patients with
acute brain injury, the Neurocritical Care Society
International Multidisciplinary Consensus Confer-
ence on Multimodality Monitoring recommends
that ‘EEG should be considered in all patients with
acute brain injury and unexplained and persistent
altered consciousness and in comatose ICU patients
without an acute primary brain condition who have
an unexplained impairment of mental status’ [22].
EPILEPTOGENESIS AFTER TRAUMATIC
BRAIN INJURY
Neuroinflammation is a central component of sec-
ondary brain injury after TBI and plays a key role in
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Trauma and rehabilitation
the development of PTE. Epileptogenesis, the neuro-
biological process by which epilepsy develops after
TBI, occurs in three phases: primary brain injury,
latency period (active neuroinflammation and
neurobiological alterations leading to increased pro-
pensity for seizures), and establishment of recurrent
&&
spontaneous seizures, or PTE [23 ]. Neuroinflam-
mation after TBI is characterized by breakdown of
the blood–brain barrier, microglial and astrocyte
activation and migration, release of inflammatory
cytokines, and progressive cerebral edema and brain
dysfunction. Through key inflammatory signaling
&&
factors (interleukin-1b and HMGB1) [23 ], neuro-
inflammation begets seizures, and seizures beget
neuroinflammation. A specific single-nucleotide
polymorphism of the interleukin-1b appears to be
protective against developing PTE [24], indicating
that genetics may influence epileptogenesis by
modulating neuroinflammatory cascades. Unfortu-
nately, no immune modulatory therapy has yet
proven effective to reduce acute PTS, PTE, or
improve neurological outcomes after TBI.
POSTTRAUMATIC EPILEPSY
PTE is generally a localization-related epilepsy aris-
ing from the temporal or frontal lobe [25]. The risk
of developing PTE is highest in the first 2 years after
injury and strongly associated with TBI severity
(relative risk ¼ 1.5, 4, and 29 for mild, moderate,
and severe TBI, respectively). Other risk factors
include cortical contusions, subdural hematomas,
penetrating brain injury, and neurosurgical hema-
toma evacuation [26–28]. Using the TBI Model Sys-
tems National Databank, Ritter et al. [29] recently
published a prognostic model for predicting PTE,
identifying subdural hematoma, cortical contusion
burden, craniotomy, and acute PTS as significant
predictors of PTE at 2 years. Genetics likely play
an important role in epileptogenesis as discussed
above [30].
MANAGEMENT OF POSTTRAUMATIC
SEIZURES
Seizure prophylaxis and treatment of early
posttraumatic seizures
The Brain Trauma Foundation Guidelines, 4th Edi-
tion, continues to recommend the use of seizure
prophylaxis to decrease the incidence of early PTS
within 7 days of severe TBI. There is insufficient
evidence to recommend levetiracetam (UCB Inc;
Smyrna, Georgia) compared with phenytoin (Pfizer;
New York, New York) regarding efficacy in prevent-
&&
ing early PTS and toxicity [31 ]. The benefit of
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phenytoin to reduce the risk of early, but not late,
PTS was established a landmark trial conducted by
Temkin et al. [32]. However, levetiracetam is increas-
ingly used for seizure prophylaxis after TBI because
of ease of use and favorable safety profile. Recent
meta-analyses reveal no significant difference in the
rate of early PTS with levetiracetam compared with
& &
phenytoin [33 ,34 ] and a low dose may be sufficient
[35]. Unfortunately, no drug has proven effective to
reduce the risk of PTE. Patients who develop early
PTS, despite appropriate seizure prophylaxis, should
be treated to terminate electrographic seizures and
minimize secondary brain injury. The typical dura-
tion of antiepileptic drug treatment after an early
posttraumatic seizure is 3–6 months.
Treatment of posttraumatic epilepsy
Individuals who experience a late posttraumatic sei-
zure should be started on an antiseizure medication
immediately because the risk of recurrent seizures
approaches 90% within 2 years [36]. First-line agents
for treatment of PTE are agents with efficacy in focal
epilepsy, such as levetiracetam or oxcarbazepine
(Novartis Pharmaceutical Corp; East Hanover, New
Jersey). Duration of treatment is typically 2 years, but
the optimal timing of antiseizure medication with-
drawal after achieving complete seizure control is
unknown. Despite various medication options,
toxicity or intolerable adverse effects can interfere
with successful treatment. Independent of seizure
control, the adverse effects of antiseizure medications
strongly predicts impaired health-related quality of
life in epilepsy [37,38]. Functional cognitive deficits
that occur with epilepsy, or as a consequence of
antiepileptic drugs, including impaired attention,
executive function, and memory, are inherently del-
eterious and may also lead to medication noncom-
pliance. In other cases, PTS are refractory to medical
management. Confirmed PTE accounts for 5% of all
referrals to specialized epilepsy centers [39] to evalu-
ate surgical options.
Surgical options for posttraumatic
drug-resistant epilepsy
PTE can be amenable to surgical treatment once
drug resistance has been established or medication
side-effects are deemed intolerable. Prior to deciding
upon a surgical plan, a strong hypothesis must be
formulated as to the seizure onset zone. Grossly
abnormal or damaged brain tissue should always
raise high suspicion in epileptic patients, and
serves as a logical starting point when tailoring
investigations toward finding the seizure onset
zone. Localization methods include analysis of
Volume 30  Number 6  December 2017
 Treatment options for posttraumatic epilepsy Zimmermann et al.
seizure semiology, scalp EEG, neuroimaging, neuro-
psychological examination [40], and intracranial
monitoring in the form of subdural grids and depth
electrodes [41]. Patients who sustain high-velocity
acceleration–deceleration mechanisms with closed
head injury often have a predilection for temporal
lobe contusions, and surgical outcomes in these
patients can be similar to those of nontraumatic
temporal lobe epilepsy [42].
If a seizure focus is identified, several surgical
options exist. Focal seizures arising from nonelo-
quent or nonfunctional brain are amenable to resec-
tion in the form of a lesionectomy, lobectomy, or
topectomy [43–45]. When a large area of nonfunc-
tional cortex is considered epileptogenic, such as
hemispheric infarct, disconnection procedures such
as hemispherotomy can be curative [46]. When
seizures are localized to an area of the brain that
is still functional and clinically relevant, such as a
dominant hippocampus, transections offer an alter-
native to resection. By making transverse cuts along
the hippocampus, it is thought that the longitudinal
synchronization of seizure impulses along the struc-
ture is interrupted, whereas the memory output
fibers are preserved [47]. Responsive neurostimula-
tion is another option in this setting, where electro-
des are implanted either in or on the surface of
the functional epileptogenic tissue. Abnormal dis-
charges are relayed to a computer chip that responds
by delivering an electric stimulation pulse back to
the brain in an attempt to prevent the neural syn-
chronization that leads to a seizure. Although seem-
ingly an acute treatment, this technology is showing
promise as a long-term solution, in that improved
seizure outcomes tend to correlate with duration of
therapy [48].
When a distinct seizure focus is not identified,
several neuromodulation options and stimulation
targets exist [49]. Although not specifically studied
in PTE, deep brain stimulation of the anterior
nucleus of the thalamus is showing promise as it
results in 69% reduction in seizure frequency at
5 years for patients with drug-resistant partial epi-
&
lepsy [50 ]. This therapy is approved in Canada and
much of Europe, but has not yet received Food and
Drug Administration approval in the United States.
In contrast, vagal nerve stimulation is available, and
although it can decrease seizures by an average of
45%, it is rarely curative [51]. Although data in PTE
is scant, neuromodulation remains an option when
other modalities have failed [52].
Although the literature on surgical treatment of
PTE is sparse, literature on the surgical treatment of
nontraumatic epilepsy is often extrapolated to the
traumatic setting and can be used to guide investi-
gative and therapeutic decisions. The future of the
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field certainly holds promise for novel applications
and discoveries as the indications for neuromodu-
lation are expanding to the treatment of nonepilep-
tic TBI sequelae, such as motor and cognitive deficits
&
[53 ,54].
POSTTRAUMATIC SEIZURES IN CHILDREN
Epidemiology and risk factors for
posttraumatic seizures in children
TBI is the leading cause of death in children in
developed countries. The incidence of early PTS in
children is high (10–53%) [55], with most (78%)
occurring within 24 h after injury [55]. The overall
incidence of PTE in children with TBI is 0–12% with
onset 8 months to 5 years after injury. Children with
severe TBI are at significantly increased risk of PTS
compared with mild–moderate TBI [odds ratio
(OR) ¼ 13.7] and phenytoin prophylaxis is associ-
ated with a reduced risk of early PTS in children
(15 versus 53%) [55].
The incidence of early posttraumatic noncon-
vulsive seizures in children with TBI is higher than
the incidence of clinical seizures alone and, overall,
may be higher than the incidence of early PTS in
adults. Vespa et al. [1] reported an incidence of early
posttraumatic electrographic seizures of 22% in
adults, of which 52% were nonconvulsive seizures.
&&
O’Neill et al. [5 ] prospectively studied 144 children
with TBI who underwent continuous EEG monitor-
ing and identified seizures in 30% of cases. Of these,
94% were nonconvulsive and 53% met criteria for
nonconvulsive status epilepticus. Children less
than 2.4 year of age (OR ¼ 8.7) and children with
abusive head trauma (OR ¼ 6.0) were at significantly
&&
increased risk [5 ]. Subclinical seizures and convul-
sive and nonconvulsive status epilepticus are asso-
ciated with worse outcomes at hospital discharge
[56]. Similar to adults, this data suggests that non-
convulsive seizures and status epilepticus are asso-
&&
ciated with worsened outcomes in children [5 ,56].
Seizure prophylaxis in children
The guidelines for the acute medical management of
severe TBI in infants, children, and adolescents
recommends prophylactic treatment with phenyt-
oin may be considered to reduce the incidence of
early posttraumatic seizure in pediatric patients
with severe TBI [57]. Mirroring the adult literature,
early seizure prophylaxis does not reduce the risk of
PTE in children [58]. However, practice variability
exists in the choice of seizure prophylaxis and use of
continuous electroencephalography (cEEG) moni-
&
toring [59]. Ostahowski et al. [60 ] examined the
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Trauma and rehabilitation
variability in seizure prophylaxis via a retrospective
multicenter study of five pediatric trauma centers
and 236 children and found only 79% of children
with severe TBI received seizure prophylaxis.
The most commonly used medications were fosphe-
nytoin (Pfizer; New York, New York) (47%) or phe-
nytoin (40%), followed by levetiracetam and
phenobarbital (West-Ward Pharmaceuticals Corp;
&
Eatontown, New Jersey) [60 ].
As in adults, levetiracetam is increasingly used
for seizure prophylaxis in children [59,61]. Chung
et al. (2016) [62] performed a prospective observa-
tion study of 34 children with moderate–severe TBI
at a single level one trauma center who received
levetiracetam for seizure prophylaxis and reported
an early PTS in 17% of children. The relative efficacy
of levetiracetam versus phenytoin for seizure pro-
phylaxis in children is not yet known.
Management of posttraumatic seizures in
children
Immediate PTS occur within 24 h of injury and often
en route to the hospital or in the emergency depart-
ment. Noncontrast head computed tomography (CT)
is indicated for children presenting with a PTS
because of the high rate of intracranial hemorrhage,
cerebral edema with brain shift, and recurrent seiz-
&
ures identified in this population. Badawy et al. [63 ]
found that of 536 children with mild TBI and an
immediate PTS, 15% had an abnormal head CT, and
22% of those experienced recurrent seizures. They
concluded children with mild TBI and an abnormal
head CT should be admitted to the hospital indepen-
dent of glasgow coma scale score given the risk of
recurrent seizure, hematoma expansion, and possible
need for neurosurgical intervention. However, inpa-
tient hospitalization may not be required for the
subset of children with mild TBI and immediate
PTS if head CT is normal as only 1% experienced
& There are no conflicts of interest.
recurrent seizures in the next 3 months [63 ].
PTE is typically a localization-related epilepsy,
but posttraumatic epileptic spasms with multifocal
epileptiform discharges responsive to vigabatrin
or adrenocorticotropic hormone has recently been
described in infants with nonaccidental head
trauma [64]. In children with focal epilepsy, a recent
meta-analysis suggests waiting at least 2 seizure-free
years before stopping antiseizure medications as
stopping earlier increases the risk of recurrent
&&
seizures by 34% [65 ]. It is important to consider
factors associated with increased risk for recurrent
seizures such as structural brain lesions, persistent
EEG abnormalities, high seizure frequency during
treatment and history of status epilepticus when
&&
considering stopping treatment [7,65 ].
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PATIENT COUNSELING
Imports topics to discuss with patients with PTE
include: [66]
(1) Not to drive for 3–6 months following complete
seizure control;
(2) Avoid activities during with a seizure could
result in serious injury;
(3) Women of reproductive age should be offered
preconception counseling;
(4) Epilepsy stigma and association with mental
health outcomes as recent data suggests that
PTE is associated with mental health outcomes
2 years after TBI [67 ].
&
CONCLUSION
Early PTS are common and result in secondary brain
injury after TBI because of increased intracranial
pressure, cerebral edema, and metabolic crisis, and
should be treated. Continuous EEG is indicated in
children and adults with moderate–severe TBI and
coma and society guidelines recommend the use of
seizure prophylaxis to decrease the incidence of
early PTS within 7 days of severe TBI in adults and
children. Unfortunately, no treatment currently
exists targeting epileptogenesis to reduce the risk
of PTE. Identification of risk factors for PTE and the
role of neuroinflammation in epileptogenesis are
exciting areas of research today.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
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The important study indicates that there is a relationship between PTE and mental
health outcomes 2 years after head injury and adds to a growing literature
describing the relationship between chronic epilepsy, antiepileptic drugs, and
health-related quality of life.
Volume 30  Number 6  December 2017