INVITED REVIEW
Seizures and Epileptiform Patterns in SAH and Their
Relation to Outcomes
Carolina B. Maciel and Emily J. Gilmore
Summary: In subarachnoid hemorrhage (SAH), seizures are frequent and
occur at different time points, likely reflecting heterogeneous pathophysiol-
ogy. Young patients, those with more severe SAH (by clot burden or presence
of severe mental status changes at onset or focal neurologic deficits at any
time), those with associated increased cortical irritation (by infarction or
presence of underlying hematoma), and patients undergoing craniotomy are at
higher risk. Advanced neurophysiologic monitoring allows for seizure burden
quantification, identification of subclinical seizures, and interictal patterns as
well as neurovascular complications that may have an independent impact on
the outcome in this population. Practice regarding seizure prophylaxis varies
widely; its institution is often guided by the risk–benefit ratio of seizures and
medication side effects. Newer anticonvulsants seem to be equally effective
and may have a more favorable profile. However, questions regarding the
association of seizures and vasospasm, the therapeutic dosing, timing, and
duration of antiepileptic treatment and the impact of seizures and antiepi-
leptics on the outcome remain unanswered. In this review, we provide a broad
overview of the work in this area and offer a diagnostic and therapeutic
approach based on our own expert opinion.
Key Words: Seizures, Periodic patterns, Subarachnoid hemorrhage, Con-
vulsions, Status epilepticus.
(J Clin Neurophysiol 2016;33: 183–195)
S pontaneous subarachnoid hemorrhage (SAH) from aneurysmal
rupture has an overall estimated annual incidence rate of 9 per
100.000 persons (Becker, 1998; de Rooij et al., 2007; Linn et al.,
1996; Rincon et al., 2013) and is the main cause of sudden death
from stroke (Arnaout et al., 2015). Certain geographic locations may
have higher incidences, such as Finland and Japan, with 22.7 per
100.000 and 19.7 per 100.000 persons-years, respectively (de Rooij
et al., 2007). Despite stable rates of hospital admissions because of
SAH in the United States (Linn et al., 1996; Rincon et al., 2013),
mortality rates have decreased 1.2% per year over the last three
decades (Rincon et al., 2013). Improved mortality rates likely reflect
the timing of neurosurgical and endovascular interventions, the
routine use of nimodipine, and advances in neurocritical care and
rehabilitative medicine. Survivors also face physical (Connolly et al.,
2012), cognitive (Al-Khindi et al., 2010; Quinn et al., 2014; Storey,
1967), and psychological (Quinn et al., 2014; Storey, 1967)
From the Department of Neurology, Yale New Haven Hospital, Yale School of
Medicine, New Haven, Connecticut, U.S.A.
E.J.G. is supported by Yale’s Center for Clinical Investigation CTSA Grant
(ULTR000142), Yale’s Claude D. Pepper Older Americans Independence
Center (P30AG021342 NIH/NIA), American Brain Foundation, and the
National Institute of Health.
Address correspondence and reprint requests to Carolina B. Maciel, MD,
Department of Neurology, Yale New Haven Hospital, Yale School of
Medicine, 15 York St, Building LCI, 10th floor, Room 912, New Haven,
CT 06520, U.S.A.; e-mail: carolina.maciel@yale.edu.
Copyright Ó 2016 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/16/3303-0183
Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016
challenges during recovery. Their loss to society is significant
considering the young age of onset (mean of 55 years [Rincon et al.,
2013]) and the inability to resume previous activities, including
work, that plagues more than half of the survivors (Passier et al.,
2011; Quinn et al., 2014).
Once the aneurysm is secured, management priorities transi-
tion to strategies for preventing secondary brain injury (Nogueira
et al., 2014) and medical complications. Over the past decade,
evidence indicates that several mechanisms beyond vasospasm as
quantified by transcranial Doppler ultrasound (TCD) or angiography
impact SAH outcomes. One of the leading culprits is relative
hypoperfusion leading to a demand–supply mismatch (Chen et al.,
2014). Changes in cerebral blood flow such as profound hyperemia
followed by persistent oligemia during seizures and cortical
spreading depression (CSD) exemplify the potential for secondary
brain injury mediated by pathologic neurovascular coupling (Con-
nolly et al., 2015). Seizures, which are also metabolically demand-
ing, may through similar dynamics lead to higher morbidity, longer
hospital stays, and increased hospitalization costs (Claassen et al.,
2007; Little et al., 2007).
Continuous electroencephalography (cEEG) has become an
increasingly popular tool for evaluating brain function and monitor-
ing for potential complications after acute neurologic injury. As
a window into brain function, cEEG assesses for subclinical seizures,
provides prognostic information, and, more recently, helps predict
delayed cerebral ischemia (DCI) in patients with SAH.
This review focuses on the most recent literature on seizures
in patients with SAH, including the pathophysiology of neuronal
hyperexcitability, risk factors and incidence of seizures, the clinical
impact of seizures, and the role of primary seizure prophylaxis (PSP)
and secondary seizure prophylaxis.
PATHOPHYSIOLOGY
The presence of blood in the subarachnoid space triggers
mechanical and direct and indirect chemical effects, all having the
potential for lowering the seizure threshold at different time points.
The association of seizures with SAH ictus and rebleeding suggests
that seizures correlate with blood extravasation into the subarachnoid
space and that rehemorrhage may be a trigger for seizure activity
(Butzkueven et al., 2000; Hart et al., 1981; Hasan et al., 1993; Pinto
et al., 1996; Robertson, 1949; Sundaram and Chow, 1986; Taylor
and Waitfield, 1936). Clinically, ictal bleeding episodes often have
a prominent tonic component (with either opisthotonos or empros-
thotonos), longer duration (measured in minutes versus seconds), are
preceded by intense headache and vasomotor phenomena (facial
rubor) and may reflect a more ominous progression (e.g., intracranial
hypertension) (Gastaut et al., 1963).
Clinical seizures in patients with SAH are usually generalized,
particularly early on when associated with ictal bleeding (Cabral
183
C. B. Maciel and E. J. Gilmore Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016
et al., 1976; Choi et al., 2009; Fung et al., 2015; Hart et al., 1981; Lin
et al., 2003; Rose and Sarner, 1965). Focal seizures or “fits,” with or
without secondary generalization, although less common, predom-
inate in the convalescence period after aneurysm obliteration
(Butzkueven et al., 2000; Keranen et al., 1985; Lin et al., 2003;
Pinto et al., 1996; Sundt et al., 1982). The etiology of the tonic
phenomenon is controversial; it is unclear whether it is a result of
brainstem epileptic discharges or a nonepileptic manifestation
secondary to transient midbrain dysfunction causing disinhibition
of pontobulbar centers (Gastaut et al., 1963; Hart et al., 1981;
Lundberg, 1960; Sundaram and Chow, 1986). The observation of
tonic posturing shortly before death (Robertson, 1949; Timberlake
and Kubik, 1952) in addition to concurrent electroencephalographic
flattening (Gastaut et al., 1963; Lundberg, 1960) could support the
theory of intracranial hypertension (Hart et al., 1981; Taylor and
Waitfield, 1936) as an etiology of such fits.
Nevertheless, the strong association of seizures with focal
pathologies, as evidenced by their higher incidence in patients with
focal contusion, infarction, hematoma, or subdural hematoma
supports the idea that diffuse injury from hemorrhage or intracranial
pressure (ICP) are not solely responsible for the development of
recurrent seizures (Claassen et al., 2003; Lin et al., 2003). In fact, the
mechanisms whereby early and late epileptic phenomena develop
may differ substantially (Bladin et al., 2000; Lin et al., 2003, 2008).
Mechanical effects of blood and glutamatergic toxicity may be
important underlying mechanisms for onset seizures (OS) (Bladin
et al., 2000; Lee and Hablitz, 1991; Pinto et al., 1996). Oxygen free
radical reactions that generate lipid peroxide in the presence of blood
and increased availability of iron, as a catalytic agent in the
subarachnoid space, may play a role in edema formation and brain
injury and may trigger late seizures (Macdonald and Weir, 1991;
Pinto et al., 1996; Rahme et al., 2011). The systemic proinflamma-
tory state promoted by SAH may also have implications in the
development of nonconvulsive seizures (NCSz) during the acute
posthemorrhage period (Claassen et al., 2014). Corticomeningeal
scarring from structural damage caused by either the hemorrhage
itself or other complications (including those secondary to treatment)
may underlie the pathogenesis of delayed seizures (DS) (Bladin
et al., 2000; Claassen et al., 2003; Hasan et al., 1993; Jennett, 1979;
Lin et al., 2008).
Cellular mechanisms by which seizure activity transitions to
status epilepticus and then to a postictal state are multifactorial.
Extracellular increases in potassium, acidification of surrounding
tissue, and mediating substances such as adenosine, neuropeptide-Y,
and substance P are all described culprits (Kohling, 2014). However,
the exact pathophysiology behind the failure in crossing the
boundary from an ictal to postictal state remains poorly understood.
It is unlikely that any single mechanism is the sole factor
leading to epilepsy as a chronic condition because many studies
describe a large number of divergent mechanisms implicated in
seizure chronification (Kohling, 2014).
EPIDEMIOLOGY
Seizures can be convulsive or nonconvulsive, and may occur at
any time during the clinical course of SAH. Ascertaining the true
incidence of seizures over time is challenging as different studies have
discrepant definitions and include heterogeneous patient populations.
For consistency, seizure occurrence based on time elapsed from SAH
ictus will be referred to as ictal seizures, OS, late seizures, and DS as
described in Table 1. According to one population-based study, the
184
cumulative incidence of epilepsy (using the definition of the
International League Against Epilepsy) (Fisher et al., 2014) in SAH
survivors was 4% at 6 months, 10% at 2 years, and 12% at 5 years
(Huttunen et al., 2015). Generalized convulsive status epilepticus is
much less common, occurring in up to 0.2% of patients with
spontaneous SAH (aneurysmal or not) (Claassen et al., 2007).
Table 2 summarizes the incidence of clinical seizures through
different studies. Table 3 summarizes the available evidence
regarding factors influencing seizure occurrence. The striking
diversity in results across studies reflects the differences in patient
selection, use of prophylaxis, modality of aneurysm treatment, length
of follow-up, and variability in seizure definitions.
The incidence of NCSz is 11% to 18% in critically ill patients
(Claassen et al., 2004b, 2014). The presence of coma, convulsive
seizures before monitoring, and history of epilepsy are reported risk
factors (Claassen et al., 2004b). In a cohort of patients with poor-
grade SAH undergoing cEEG and multimodal monitoring with
intracortical minidepth electrodes, NCSz were present in 8% of
patients, whereas intracortical seizures were seen in 38% of patients
(Claassen et al., 2013). Nineteen percent of patients having intra-
cortical seizures had concurrent scalp EEG patterns on the ictal–
interictal continuum (Claassen et al., 2013), thus it is possible that
ictal–interictal continuum is a reflection of intracortical seizures that
could not be captured by scalp electrodes.
Furthermore, 10% to 18% of neurocritically ill patients may
experience nonconvulsive status epilepticus (Claassen et al., 2004b;
Pandian et al., 2004). Similarly, nonconvulsive status epilepticus was
identified in 2.8% to 14% of monitored patients with SAH (Claassen
et al., 2004a; Claassen et al., 2003, 2004b; Dennis et al., 2002;
Lindgren et al., 2012; Little et al., 2007) with onset between 2 and 20
days from initial hemorrhage (Little et al., 2007). Prolonged
monitoring beyond 24 hours increases the yield of capturing NCSz,
particularly in comatose critically ill patients (Claassen et al., 2004b).
Importantly, the reported incidence of subclinical events is influ-
enced by selection bias because patients are more likely to be
monitored if they have a poor examination (often a reflection of the
severity of brain injury) or if there is an increased suspicion for
subclinical seizures.
Timing
Because ictal seizures are often witnessed and reported by lay
bystanders, it is virtually impossible to be certain whether or not
such events were truly epileptic in nature (Hart et al., 1981;
Sundaram and Chow, 1986). Some studies even excluded such
events when reporting OS incidences (Keranen et al., 1985;
Sundaram and Chow, 1986). Regardless, seizure activity seems to
have a higher incidence in the acute period, reaching up to 26%
(Butzkueven et al., 2000; Byrne et al., 2003; Dekaban and Mc, 1952;
Hart et al., 1981; Lin et al., 2003; Rhoney et al., 2000; Sundaram and
Chow, 1986), particularly within 48 hours of SAH onset (Byrne
et al., 2003; Fabinyi and Artiola-Fortuny, 1980; Fung et al., 2015;
Lin et al., 2003; Olafsson et al., 2000; Pinto et al., 1996).
In longitudinal studies, DS incidence reached up to 25% with
prolonged follow-up (Cabral et al., 1976; Olafsson et al., 2000; Rose
and Sarner, 1965) from the reported 4% to 10% in the initial 4 weeks
after SAH (Hart et al., 1981; Hasan et al., 1993; Rose and Sarner,
1965; Sundaram and Chow, 1986). A recent meta-analysis showed
overall incidences of 2.3% for in-hospital seizures and 5.5% for DS
with a mean onset latency of 7.45 months (Raper et al., 2013).
Of note, the latency time from aneurysm treatment to
development of DS seems to vary according to neurosurgical
Copyright Ó 2016 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016 Seizures and Epileptiform Patterns

TABLE 1. Definitions of Epileptic Events Based on Timing of Its Occurrence During the Clinical Course of a Ruptured Aneurysm
Proposed Term Timing of Occurrence Possible Clinical Significance
Ictal seizure (IS) First minutes of SAH Aneurysmal rupture and initial bleeding event
Onset seizure (OS) Early clinical course including ictal bleeding event Rebleeding, hematoma, residual cortical irritation
and IS. Usually include the initial hours preceding
aneurysmal treatment
Late seizure (LS) Hospital course, from surgical treatment to Surgical or treatment complication, infarction,
discharge. Usually includes initial 7–14 days residual cortical irritation
following aneurysmal treatment
Delayed seizures (DS) or epilepsy* Late clinical course after discharge, remote (more Residual cortical irritation, structural cortical lesion,
than 14 days) from aneurysmal rupture and its delayed ischemic complications
treatment
Note that some studies do not report all the events making such distinction, and those terms were adapted based on different studies published to date.
*Epilepsy as recently defined by the International League Against Epilepsy encompasses any of the following conditions relevant to a patient population with SAH: two or more
unprovoked seizures occurring .24 hours apart or 1 unprovoked seizure and a probability of at least 60% of recurrent seizures over a 10-year period (Fisher et al., 2014). Thus, if this
definition were to be taken into consideration and seizures during hospitalization were believed to be unprovoked, any patient with SAH who experienced a second seizure during the
index hospitalization would have been considered having epilepsy. That is not the case in the majority of the studies presented here, when the term epilepsy or delayed seizures refer to
seizures occurring remotely from the initial hospitalization, at times regardless of the number of unprovoked events.

treatment (shorter latency in craniotomies when compared with
carotid ligation and longer when craniotomies are compared with
endovascular treatment) and aneurysmal location (shortest latency in
middle cerebral artery when compared with both anterior and
posterior cerebral arteries) (Cabral et al., 1976; Raper et al., 2013).
Prolonged latencies reaching 5 to 8 years are reported (Hart et al.,
2011; Olafsson et al., 2000), but the majority of DS have reported
onset within the initial 12 months from insult (Bidzinski et al., 1992;
Choi et al., 2009; Chumnanvej et al., 2007; Hart et al., 2011; Hasan
et al., 1993; Huttunen et al., 2015; Keranen et al., 1985; Lin et al.,
2003, 2008; Ohman, 1990; Rhoney et al., 2000; Ukkola and
Heikkinen, 1990).
Sex and Age
Associations with the patient’s sex are not robust. Data
favoring a higher incidence in men come from a small study
(Rhoney et al., 2000) and another cohort in which men with middle
cerebral artery aneurysms were treated surgically whereas women
were randomized to conservative treatment or surgery (Storey,
1967). In the latter study, the data might have been skewed by
selection bias, because it was believed at that time that women with
middle cerebral artery aneurysms would fare worse with surgery than
men. Young patients may have a higher tendency for exhibiting
seizures (Choi et al., 2009; Hart et al., 2011; Huttunen et al., 2015;
Lin et al., 2003); however, the evidence supporting this association
requires further validation.
Premorbid Conditions
Hypertension has been linked to a higher seizure risk in the
posthemorrhagic period (Ohman, 1990). This relationship could
reflect an indirect effect because patients with hypertension are
more likely to have cerebral infarction and consequent epilepsy.
History of epilepsy may increase the risk of seizures after SAH
(Byrne et al., 2003; Claassen et al., 2004b); however, this remains
debatable (Butzkueven et al., 2000) because this patient population
has been excluded in the majority of studies (Baker et al., 1995;
Huttunen et al., 2015; Keranen et al., 1985; Lin et al., 2008;
Rhoney et al., 2000), thereby making it challenging to address this
issue.
Location and Number of Aneurysms
Despite conflicting reports stating otherwise (Buczacki et al.,
2004; Choi et al., 2009; Claassen et al., 2003; Hart et al., 1981;
Hasan et al., 1993; Ibrahim et al., 2013; Lin et al., 2003; Pinto et al.,
1996; Rhoney et al., 2000; Sundaram and Chow, 1986), middle
cerebral artery aneurysm location seems to be the location most
commonly associated with seizures in patients with SAH (Baker
et al., 1995; Bidzinski et al., 1992; Byrne et al., 2003; Cabral et al.,
1976; Hart et al., 2011; Jeffreys, 1981; Ohman, 1990; Rose and
Sarner, 1965; Storey, 1967; Ukkola and Heikkinen, 1990), although
rigorous statistical methods controlling for confounders were not
applied in the majority of these studies. However, in a recent meta-
analysis, there were no significant differences in the location or grade
of aneurysms in patients experiencing postoperative seizures (Raper
et al., 2013). The presence of multiple aneurysms has not been
associated with higher seizure rates (Claassen et al., 2003; Lin et al.,
2003).
Aneurysm Treatment Modality and Other
Neurosurgical Procedures
Different neurosurgical methods of aneurysm obliteration
may influence the incidence of postoperative seizures (Cabral
et al., 1976; Raper et al., 2013; Ukkola and Heikkinen, 1990).
Craniotomies were associated with higher rates of seizures (Chang
et al., 2015; Hart et al., 2011; Huttunen et al., 2015; Raper et al.,
2013), with incidences ranging from 15%–27.5% (Cabral et al.,
1976; Rose and Sarner, 1965) to ,10% more recently (Bidzinski
et al., 1992; Choi et al., 2009; Hasan et al., 1993; Ohman, 1990;
Raper et al., 2013; Ukkola and Heikkinen, 1990). Additionally,
subsequent craniotomies may increase the seizure risk (Hart et al.,
2011); temporary clipping intraoperatively and wrapping techniques
may also be associated with an increased risk (Ukkola and
Heikkinen, 1990).
Timing of surgery did not seem to be important for the
development of seizures (Bidzinski et al., 1992; Butzkueven et al.,
2000; Keranen et al., 1985; Ohman, 1990). However, earlier surgery
may decrease rebleeding events, which may lead to less seizures
associated with aneurysm rerupture.
Vascular modalities have evolved from common carotid
ligation to endovascular coiling obliteration and are associated with

Copyright Ó 2016 by the American Clinical Neurophysiology Society 185

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C. B. Maciel and E. J. Gilmore

TABLE 2. Summary of Studies Including Ruptured Aneurysmal Subarachnoid Hemorrhage Reporting Incidence of Different Clinical Seizures According to the
Timing of Their Occurrence
Aneurysm Mean Time
Author and Type of Sample Size Treatment Onset Late Delayed From SAH to
Year Study (No. Patients) Modality Prophylaxis Seizures Seizures Seizures Delayed Seizure
Cabral et al., 1976 Retrospective 152 (116 CT; CT versus No primary prophylaxis NA 22%a overall: 27.5% CT; 17 months-CT;
36 CCAL) CCAL 5% CCAL 58 months-CCAL
Hart et al., 1981 Retrospective 100 NA Variable, no loading dose 19%b 12%c NA NA
Keranen et al., 1985 Retrospective 177 CT Non–weight-based load 1 NA 1%d 14%e 8.4 months
maintenance
Sundaram and Retrospective 131 NA Variable, no loading dose 19%f 16%g NA
Chow, 1986
Ohman 1990 Prospective 307 CT No primary prophylaxis NA 9.4%h 6.7 months
Ukkola and Retrospective 183 CT Variable regimen NA 8%h 10 months
Heikkinen, 1990
Bidzinski Prospective 121 CT No secondary prophylaxis 6.6%i 6.6%j 6 months
et al., 1992 unless recurrent event
Hasan et al., 1993 Prospective 381 (214 CT; CT, NT No primary prophylaxis NA 9%k 18 days
167 NT)
Pinto et al., 1996 Prospective 253* CT, NT No primary prophylaxis 6.3%b NA NA NA
Rhoney et al., 2000 Retrospective 95 (84 CT; CT, EV, NT Non–weight-based load 1 17.9%l 4.1%m 14%n 362 days
3 EV; 8 NT) maintenance
Butzkueven Retrospective 412* CT Variable regimen 7.8%o 4.1%p NA

Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016

et al., 2000
Claassen et al., 2003 Prospective 247** (176 CT; CT, EV, NT Weight-based load 1 7%q 7%r NA
39 EV; 4 NT) maintenance
Copyright Ó 2016 by the American Clinical Neurophysiology Society

Lin et al., 2003 Retrospective 217 CT Variable regimen 7.8%b 2.3%c 6.9%s 8.3 months
Byrne et al., 2003 Prospective 233 EV (15 had CT Variable regimen, but no 11%t 0% 3%u NA
before EV) prolonged primary prophylaxis
Buczacki et al., 2004 Retrospective 472*** CT No primary prophylaxis NA NA 4.9%v NA
Lin et al., 2008 Retrospective 137 (80 CT; 50 EV; CT, EV Secondary prophylaxis 3.6%w 5.8%x 5.8%y 102 days
7 CT 1 EV) discontinued on discharge
unless repeated event
Choi et al., 2009 Retrospective 547 CT Variable regimen 7.9%b 2.5%z 3.1%s 3.5 months
Hart et al., 2011 Prospective 2,143 (1,070 CT; CT, EV Variable regimen NA 10.9% overall: NA
1,073 EV) 13.6% CT;
8.3% EV
Ibrahim et al., 2013 Retrospective 413 NA Variable regimen 13.8% overall NA
Fung et al., 2015 Retrospective 425 NA Variable regimen 10.5%o 2.5%aa NA NA
Chang et al., 2015 Retrospective 1,134 (900 CT; CT, EV, NT Variable regimen but all with NA 7.1%bb 11.2%cc NA
150 EV; 84 NT) primary prophylaxis
Huttunen Retrospective 876 (544 CT; CT, EV, NT NA 15%dd 12.8%ee 8 months
et al., 2015 311 EV; 21 NT)
*All types of SAH, not only aneurysmal SAH. Total sample of aneurysmal SAH is 331 patients in the study by Butzkueven; a total number of patients with aneurysmal SAH is not provided in the study by Pinto.
**Patients with aneurysmal and spontaneous nonaneurysmal SAH included.
***All aneurysmal SAH surgically treated within 21 days with the following additional exclusions: space occupying hematoma needing urgent evacuation, WFNS grade V, poor examination with worse than flexor motor
response to noxious, infratentorial aneurysm, rebleed before surgery, death during hospital stay or in the year after surgery.
a
Postoperative epilepsy defined as any fit occurring in postoperative period up to 7 years follow-up. The definition in the original article was adapted here and included LS 1 DS.
b
Onset seizures defined as fits within 12 hours of initial hemorrhage.
c
Delayed seizures defined as those occurring anytime from 12 hours after hemorrhage but before neurosurgical treatment.
d
Early seizures defined as those occurring in initial 7 days of surgical treatment of aneurysm. The “early epilepsy” definition in the original article was adapted here in late seizures.
e
Delayed seizures defined as 2 spontaneous seizures occurring after the first week of surgery and separated by minimal interval of 24 hours. The original article used the term “late epilepsy” for this.
f
Early seizures defined as those occurring in initial 14 days of hemorrhage. The definition in the original article was adapted here and included OS 1 LS.
g
Delayed seizures defined as those occurring after initial 2 weeks of hospitalization. The original article used the term “late seizure” for this.
h
Overall seizure incidence. The original article does not specify timing of its occurrence.
 i
Early seizures defined as those occurring in the perioperative period (during SAH, between SAH and operation or after operation before discharge). The original article does not specify a term for this.
Copyright Ó 2016 by the American Clinical Neurophysiology Society

Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016

Delayed seizures defined as two or more seizures occurred after discharge. The original article used the term “epilepsy” for this.
j

Late seizures defined as epileptic events excluding those that occurred within 12 hours of bleed/rebleed/surgical treatment or in the setting of hyponatremia. The original article uses the term “epileptic seizure” for this.
k
l
Onset seizures defined as those occurring in the prehospital setting only. The original article used the term “pre-hospital seizures” for this.
m
Late seizures defined as those occurring anytime during the hospitalization. The original article used the term “in-hospital seizures” for this.
n
Delayed seizures defined as those occurring after discharge in survivors on follow-up. The original article used the term “outpatient seizure” for this.
o
Onset seizures defined as those occurring within 24 hours of onset of SAH.
p
Late seizures defined as those occurring between 24 hours of onset of headache and 6 weeks after SAH. The definition in the original article was adapted here and included LS 1 DS.
q
Early seizures defined as those occurring during the hospital stay. The original article used the term “in-hospital seizure” which was adapted here to include OS 1 LS.
r
Delayed seizure defined as two or more unprovoked seizures after hospital discharge. The original article used the term “epilepsy” for this. If any unprovoked seizure (less than 2 episodes) definition was used the incidence of
seizure after discharge in this patient population was 11%.
s
Delayed seizure defined as two or more unprovoked seizures 1 week after hospital discharge and occurring more than 24 hours apart. The original article used the term “late epilepsy” for this. If any unprovoked seizure (less than
2 episodes) definition was used, the incidence of seizure after discharge in this patient population was 9.7% in Lin’ study and 5.1% in Choi’s study.
t
Onset seizure defined as those occurring within 24 hours of SAH onset. This incidence reflects 26 of 243 patients in this cohort. Ten patients were then removed from analysis of subsequent seizure types and risk factors as they
were not treated with EV (9 had CT and 1 treated conservatively). The original article uses the term “ictal seizures” for this.
u
Delayed seizure defined as seizures occurring after 24 hours of SAH onset. The original article uses the term “late seizures” for this and has been adapted because none of the patients experienced a seizure during the hospital
stay, and the first seizure occurred more than 30 days from SAH onset.
v
Delayed seizure defined as seizures occurring from 2 weeks after surgical treatment of aneurysm up to 12 months. The original article uses the term “late epilepsy for this.”
w
Onset seizures defined as those occurring within 24 hours of SAH onset.
x
Late seizures defined as those occurring between 24 hours of SAH onset and 2 weeks. The original article uses the term “early seizures” for this.
y
Delayed seizures defined as those occurring after 2 weeks of SAH onset. The original article uses the term “late seizures” for this.
z
Late seizures defined as those occurring after 12 hours of SAH onset up to 1 week after treatment. The original article uses the terms “preoperative” and “postoperative seizures up to 1 week” for this and was adapted here.
aa
Late seizures defined as those occurring from aneurysm treatment and discharge.
bb
Late seizures defined as those occurring during the hospital stay up to aneurysm treatment. The original article uses the term “early seizure” for this.
cc
Delayed seizures defined as those occurring during the hospital stay after the aneurysm treatment. The authors do not provide the length of follow-up.
dd
Early seizures defined as those occurring within 1 week of SAH onset. The original article uses the term “acute seizures” for this.
ee
Delayed seizures following the definition of the International League Against Epilepsy. The original article uses the term “epilepsy” for this.
CCAL, common carotid artery ligation; CT, craniotomy with clipping or gauze wrapping of aneurysm; DS, delayed seizures; EV, endovascular treatment of aneurysm; LS, late seizures; NA, either nonapplicable or data not
available from original article; NT, no neurosurgical treatment/expectant management; OS, onset seizures; SAH, subarachnoid hemorrhage; WFNS, world federation of neurosurgical societies clinical preoperative grading.
Heikkinen, 1990).
Rhoney et al., 2000; Sundaram and Chow, 1986; Ukkola and
1993; Ibrahim et al., 2013; Keranen et al., 1985; Pinto et al., 1996;
others do not (Cabral et al., 1976; Claassen et al., 2003; Hasan et al.,
association (Ohman, 1990; Rose and Sarner, 1965; Storey, 1967) but
(ICH) has been more controversial and some studies point toward an
et al., 2003; Ibrahim et al., 2013), whereas intracerebral hematoma
hematoma was independently associated with seizures (Claassen
cause structural damage and subsequent epileptogenicity. Subdural
other nonepileptic complications in patients with SAH that may
thickness of subarachnoid blood has a strong causal association with
et al., 2003; Ohman, 1990; Pinto et al., 1996). However, quantity and
Butzkueven et al., 2000; Choi et al., 2009; Ibrahim et al., 2013; Lin
associated with higher seizure frequency (Bidzinski et al., 1992;

Bleeding Pattern

users (Chang et al., 2015).

increased glutamate activity through cocaine kindling in chronic
and increase in serotonergic neurotransmission and through
neurotransmission through an acute decrease in GABAergic activity
2015). The proposed mechanisms include increased excitatory
2014) independently from aneurysmal rerupture events (Chang et al.,
seizures in patients with SAH (Chang et al., 2015; Murthy et al.,

controversial (Hart et al., 1981; Hasan et al., 1993).

chloride influx (Lecker et al., 2012). However, this remains
mediated by the reversible inhibition of glycine receptor-mediated
(Feffer et al., 1978; Makhija et al., 2013), an effect that could be

through unclear mechanisms.

1997; Tsurushima et al., 2000; Westhout and Nwagwu, 2007)
et al., 2010; Firlik et al., 1999; Marks et al., 1993; Numaguchi et al.,
seizures (Carhuapoma et al., 2001; Clouston et al., 1995; Enomoto
however, infrequent reports of intra-arterial vasodilators inducing
incidence (Ohman, 1990; Ukkola and Heikkinen, 1990). There are,
purpose, exposure to nimodipine does not seem to impact seizure
larly, although not tested in a randomized clinical trial for this
patients with refractory epilepsy (Chaisewikul et al., 2001). Simi-
sequent studies did not support a robust effect as add-on therapy in
antiepileptic properties (Ba

Drug Exposure

et al., 2011).
studies have failed to confirm this association (Choi et al., 2009; Hart
seizure risk in 1 study (Byrne et al., 2003); however, subsequent

and Sarner, 1965; Sbeih et al., 1986; Storey, 1967).

negligible given the low overall numbers (Raper et al., 2013; Rose
neous and some studies suggested that this dissimilarity was
incidence according to different treatment modality is not homoge-
(Molyneux et al., 2005). Nevertheless, the difference in seizure
confidence interval, 0.37–0.074) with an endovascular approach
absolute risk reduction in seizures was 0.52 (1.5% vs. 3.1%,
showed that in patients suited for both clipping and coiling, the
Raper et al., 2013). The International Subarachnoid Aneurysm Trial
5% to 0%–3%, respectively (Byrne et al., 2003; Cabral et al., 1976;
lower rates of postoperative seizures with incidences ranging from
Having a more severe bleeding pattern at onset has been

Cocaine has been recently associated with OS and late

Exposure to fibrinogenic agents has been linked to seizures

Preclinical data suggested that calcium channel blockers have

Cerebrospinal fluid diversion was associated with higher

girici, 2006; Sills et al., 1994). Sub-

Seizures and Epileptiform Patterns

187
 188

C. B. Maciel and E. J. Gilmore

TABLE 3. Summary of Studies in Ruptured Aneurysmal Subarachnoid Hemorrhage Reporting Most Common Risk Factors With Development of Clinical Seizures
Stroke
Author Examination or
and RF Bleed Amount of at Onset ICH or Clinical Location of Drug
Year Analysis Age Sex Events HTN SAH Onset* Seizure** SDH Hydro Deficit Aneurysm VSP Effect
Rose and Univariate 1a NA NA NA NA 2 2 ICH 1; SDH NA 1 MCA 1 NA NA
Sarner, 1965 ¼ NA
Cabral et al., Univariate NA NA NA NA NA 2b NA ICH ¼ NSc; NA 1 MCA 1 2 NA
1976 SDH ¼ NA
Hart et al., Univariate 2 NA 1 NA NA NA 2 NA NA NA NSd NA 2e
1981
Keranen Univariate 2 2 NA NA NA 1f NA ICH ¼ NSc; 1 1 NSg 1 NA
et al., 1985 SDH ¼ NA
Sundaram Univariate NA NA 1 2 NA NA 2 NA NA NA 2 NA NA
and Chow,
1986
Ohman 1990 Stepwise 2 2 NA 1 1h 1i NA ICH 1; SDH NA 1 MCA 1 2 2j
Logistic ¼ NA
Regression
Ukkola and Univariate 2 2 NA NA NA 2 NA ICH ¼ NSc; NA NA MCA 1 1 2j
Heikkinen, SDH ¼ NA
1990
Bidzinski Univariate 1a 2 NA NA NA 1f 2 NA NA NA MCA 1 NA NA
et al., 1992

Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016

Hasan et al., Multivariate*** 2 2 1 2 1k 2 2 2 NA 2 2 NA 2l
1993
Pinto et al., Univariate 2 2 1 2 1k,m 1f 2 ICH ¼ NSc; 2 1 2 NA NA
1996 SDH ¼ NA
Copyright Ó 2016 by the American Clinical Neurophysiology Society

Rhoney et al., Univariate 2 1_ NA 2 NSn 2 2 ICH ¼ NSc; 2 NA NSo 2 2p

2000 SDH ¼ NA
Butzkueven Conditional and 1a 2 1 2 1k 2 1 NA NA NA NA 2 NA
et al., 2000 ordered logistic
regression
Claassen Backward- 2 2 NA 2 2q 2q 2 ICH ¼ 2q; 2 1 2 2q NA
et al., 2003 stepwise logistic SDH ¼ 1
regression
Lin et al., Univariate 1a 2 2 2 1m 1i 2 NA 2 1 2 2 NA
2003
Byrne et al., Logistic 2 2 2 NA 2 1b 2 NA 2 2 MCA 1 for 2 NA
2003 regression OS
Buczacki Multivariate NA 2 NA NA NA 1f NA NA NA NA 2 NA NA
et al., 2004
Lin et al., Multivariate*** 2 2 NA 2 2 1f 2 ICH ¼ 2q; 2 2 2 2 NA
2008 SDH ¼ NA
Choi et al., Multivariate 1a 2 1 2 1m 1f 2 NA 1 1 2 2 NA
2009
Hart et al., Multivariate*** 1a 2 NA NA 2 2 NA NA NA 1 MCA 1 2 NA
2011
Ibrahim et al., Binary logistic NA 2 NA 2 1k 2q 2 ICH ¼ 2; NA NA 2 NA NA
2013 regression SDH ¼ 1
Chang et al., Multiple logistic 1a 2 NA 2 2 1f for early NA ICH 1 for 2 NA MCA 1 NA 1r
2015 regression seizure early seizure;
SDH ¼ NA
Huttunen Multivariate*** 1a 2 NA NA 2 1f 1 (acute ICH 1s; 2 NA 2 NA NA
et al., 2015 seizures) SDH ¼ NA
*Examination at onset in this table represents loss of consciousness, alteration of consciousness, Glasgow Coma Scale, and clinical subarachnoid hemorrhage grades.
Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016 Seizures and Epileptiform Patterns

Clinical Presentation

ICH, intracerebral hemorrhage; MCA, middle cerebral artery; NA, variable not assessed in the study; NS, difference not significant; RF, risk factors; SAH, subarachnoid hemorrhage; SDH, subdural hematoma; VSP, vasospasm.
Whether examination features at presentation represent an
independent predictor of increased risk for subsequent seizures
remains controversial because they may reflect the severity of the
clinical picture and risk for further cerebral injury. Rigorous
statistical methods to control for confounders were not applied in
the majority of the studies linking the level of arousal or coma at
onset and focal neurologic deficits to seizures (Bidzinski et al., 1992;
Choi et al., 2009; Keranen et al., 1985; Lin et al., 2003; Ohman,
1990; Pinto et al., 1996).

Role of Seizure Prophylaxis

Variable antiseizure medication regimens used in different
studies challenge the interpretation of their impact on incidence of
seizures (Awad, 2013; Raper et al., 2013; Rosengart et al., 2007).
Studies supporting a decrease in postoperative seizures with routine
PSP lacked rigorous methodology to control for confounders
(Keranen et al., 1985; Rhoney et al., 2000; Ukkola and Heikkinen,
1990). Moreover, in up to two-thirds of patients, late and DS may
occur even with prophylaxis (Choi et al., 2009; Claassen et al., 2003;
Keranen et al., 1985; Rhoney et al., 2000; Sbeih et al., 1986). Not
surprisingly, subtherapeutic levels of antiseizure medication may
increase the risk for seizure recurrence at any time, but especially in
the early postoperative period (Baker et al., 1995; Kvam et al., 1983;
Rhoney et al., 2000; Rose and Sarner, 1965). Strikingly, the
Severe bleeding was associated with higher incidence of seizures; thickness of subarachnoid clot was not predictive of seizures.

incidence of DS and late seizures has not differed significantly with

anticonvulsant exposure (Raper et al., 2013).
Coma duration of 1 to 8 hours was associated with higher incidence of seizures; preoperative clinical grade was not.

Neurologic Deficits and Ischemic Complications

***Multivariate analysis with Cox proportional hazards model including fixed and time-dependent covariates.

It is challenging to ascertain whether neurologic deficits

**Onset seizure as a risk factor for recurrent seizures at any time: late, postoperative, or delayed epilepsy.

present in SAH are a result of thromboembolic complications,

DCI, vasospasm or even hematoma, particularly in retrospective
analyses. Several studies have found an association of stroke and/or
clinical deficits with increased seizure risk in patients with SAH
(Choi et al., 2009; Claassen et al., 2003; Hart et al., 2011; Kotila and
The presence and the volume of ICH were associated with higher incidence of seizures.
Cocaine was independently associated with higher incidence of early and late seizures.

Waltimo, 1992; Ohman, 1990). However, pinning down the

Those variables did reach significance on univariate, but not on multivariate analysis.

underlying mechanism in each case remains challenging. The

ischemic brain has increased excitotoxic release secondary to local
A high cisternal blood score was associated with higher incidence of seizures.
High preoperative clinical grade associated with higher incidence of seizures.
Trend in favor of vertebrobasilar circulation for higher incidence of seizures.

Trend in favor of the middle cerebral artery for higher incidence of seizures.

metabolic dysfunction (Heiss et al., 1992), which may lower the

Trend in favor of intracerebral hematoma for higher incidence of seizures.

A higher Fisher’s grade was associated with higher incidence of seizures.

Trend in favor of anterior cerebral artery for higher incidence of seizures.

seizure threshold (Bladin et al., 2000). Roberston first inquired

Trend in favor of higher Fisher’s grade for higher incidence of seizures.

whether vasospasm would represent an etiology of seizures in SAH

Aminocaproic acid exposure had no impact in seizure incidence.

(Robertson, 1949); however, an independent causal association has

Younger age noted as a risk factor for development of seizures.

Tranexamic acid exposure had no impact on seizure incidence.

not been borne out in subsequent studies (Hart et al., 1981; Ukkola
Nimodipine exposure had no impact in seizure incidence.

and Heikkinen, 1990).

Cocaine exposure had no impact in seizure incidence.

NEUROTELEMETRY
Akin to continuous cardiac telemetry, cEEG has become an
important monitoring tool for neurocritically ill patients. For over
Unconsciousness at onset of SAH.

a decade, EEG has been used in SAH to assist with identification of

bleeding lateralization and of focal damage when imaging modalities
were not readily available (Walton, 1953). More recently, cEEG has
proven helpful in detecting DCI even before being clinically evident,
in identifying NCSz (Kondziella et al., 2015) and in prognostication
for poor clinical grade patients (Claassen et al., 2006).
The latest standardized nomenclature for intensive care unit
EEG patterns (Hirsch et al., 2005, 2013) allowed for a unified
language that can facilitate communication between providers with
good interrater reliability, especially for seizure detection (Gaspard
m
b

g
h

n
o
p
q
a

s
f

r
i
j

et al., 2014; Halford et al., 2015). Despite being first published in

Copyright Ó 2016 by the American Clinical Neurophysiology Society 189

C. B. Maciel and E. J. Gilmore Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016
2005, this revised terminology has only recently begun to be adopted
in published literature. Increased adoption of standardized nomen-
clature in the future is expected to facilitate collaborative research
leading to improved understanding of the clinical implications and
optimal management of pathologic EEG patterns (Halford et al.,
2015).
The increasing use of EEG in neurocritical care units allowed
for early identification of seizures. However, treating physicians are
frequently puzzled by the presence of rhythmic and periodic patterns.
Those, including the patterns that lie in the ictal–interictal contin-
uum, are often noted in monitored patients after SAH (Claassen
et al., 2006; Crepeau et al., 2013). Periodic discharges can be as
frequent as 23% (Claassen et al., 2005, 2006) to 48% (Crepeau et al.,
2013), and seem to be more common in older patients who
underwent coiling (Crepeau et al., 2013). Increased monitoring has
also led to increased detection of NCSz and nonconvulsive status
epilepticus, often leading to changes in management of patients.
However, the impact of cEEG monitoring on outcomes is yet to be
proven (Fitzpatrick and Lowry, 2007; Ney et al., 2013). The
Neurocritical Care Society (NCS) recommends cEEG to be consid-
ered in patients with SAH with a poor clinical grade or in those with
unexplained clinical deterioration (Diringer et al., 2011).
In patients with high-grade SAH in which case the clinical
examination is unreliable, quantitative EEG measures such as the
alpha/delta ratio have been shown to be helpful for detection of DCI
(Claassen et al., 2004a). Compressed spectral arrays can also display
long periods of raw EEG providing information on seizure burden
and sedation depth while remaining a reliable screening method for
seizure identification (Carlson, 2015; Moura et al., 2014).
More recently, Hartings et al. showed that it may be possible
to identify CSDs using time-compressed bipolar EEG recordings in
traumatic brain injury. This promising use of scalp monitoring may
allow for further advances in the understanding of the pathophys-
iologic effects of CSDs without invasive techniques (Hartings et al.,
2014).
CLINICAL SIGNIFICANCE
Conflicting data exist regarding seizure impact on outcomes
(Fung et al., 2015; Hart et al., 1981; Huttunen et al., 2015; Lin et al.,
2008; Pinto et al., 1996; Rhoney et al., 2000), and the available
evidence is confounded by a heterogeneous patient population, and
inconsistent seizure definitions. This is important because several
factors that increase seizure risk may also result in neurologic
sequelae. Moreover, the timing of outcome assessments is highly
variable, which may result in incongruent conclusions.
Convulsive seizures may cause a threefold increase in cerebral
blood flow because of decreased cerebrovascular resistance. This
change was independent of hypoxemia or changes in the arterial
pressure of carbon dioxide (Magnaes and Nornes, 1974). This
suggests that the driving force for decreased cerebrovascular
resistance is a response to an increased metabolic demand from
the ictal event (Magnaes and Nornes, 1974).
Intracranial pressure ICP changes after EEG bursts in burst-
suppressed patients suggests that potentially pathologic neurovas-
cular coupling occurs in acute brain injury (Connolly et al., 2015); an
effect that seems dependent on burst duration (Connolly et al., 2015).
Intracranial pressure is also increased during a convulsion (Gabor
et al., 1984; Magnaes and Nornes, 1974) despite neuromuscular
blockade (Gabor et al., 1984) and seems influenced by intracranial
compliance and the duration of seizures (Gabor et al., 1984; Solheim
190
et al., 2008). Importantly, even subclinical seizures can cause an
elevation in ICP (Gabor et al., 1984; Marienne et al., 1979) and
hemodynamic effects at systemic and local levels (Claassen et al.,
2013).
Two patterns of transient changes in mean arterial pressure
were identified during a convulsion: a transient increase in mean
arterial pressure, or a marked fall during the tonic phase of
a convulsion followed by an overshoot (Magnaes and Nornes,
1974). The mean arterial pressure increment may be a compensatory
mechanism to preserve cerebral perfusion pressure during a rise in
ICP after a seizure (Solheim et al., 2008).
Hemodynamic parameters, particularly blood pressure, have
direct clinical implications in patients with SAH. High mean arterial
pressures may influence aneurysm rerupture before treatment, and
hemodynamic augmentation is one of the pillars of diffuse
vasospasm management. At a local level, transient hyperemia and
increased membrane permeability (Cutler et al., 1968; Lorenzo et al.,
1972) followed by postictal hypoperfusion may lead to additional
neuronal death and cytotoxic edema (Chen et al., 2014; Kohling,
2014; Solheim et al., 2008). Moreover, the increased metabolic
demand coupled with excitotoxic and oxidative stresses are contrib-
utors to further cerebral damagedparticularly in an acutely injured
brain vulnerable to any further homeostatic imbalance (Gilmore
et al., 2010; Kohling, 2014).
It remains contentious whether structural brain damage is
caused by NCSz (Aminoff, 1998; Young and Jordan, 1998) because
the morbidity associated with them may be primarily a result of the
underlying etiology or seizure treatment rather than the seizures
themselves (i.e., seizures as a marker of disease severity). Moreover,
the pathophysiologic state of the acutely injured brain at the time of
seizure activity occurrence may have an impact on its vulnerability
to secondary brain injury (Claassen et al., 2014).
Nevertheless, it is clear that the cerebral dysfunction albeit
transient caused by NCSz can lead to catastrophic complications in
the neurocritically ill patient (Young and Jordan, 1998). Clinically
important consequences of NCSzs include increased cerebral edema
(Vespa et al., 2003), secondary brain injury (Bogousslavsky et al.,
1992; Holmes, 2002), and depressed level of consciousness, which
can increase the risk of aspiration and respiratory failure. Such
resulting effects of NCSz may translate into new or worsened
neurologic deficits, development of epilepsy, worsened seizures in
patients with epilepsy, and increased motality (Young and Jordan,
1998).
A wide range of psychological and cognitive deficits may
follow prolonged seizures and SE beyond those caused by medi-
cations, likely due to hippocampal injury (Holmes, 2002). In a recent
retrospective study, subclinical seizure burden directly correlated
with worse functional outcomes in SAH (De Marchis et al., 2016).
For each hour of NCSz, there was a 10% increase in the odds of
unfavorable outcome at 3 months.116 Overall, subclinical seizure
detection on cEEG (of any duration) was independently associated
with more than a threefold higher odds of disability or death.
Postictal pulmonary edema in generalized convulsions may also
contribute to in-hospital morbidity associated with prolonged
seizures (Kennedy et al., 2015). Moreover, prolonged seizures may
lead to aberrant neuroplasticity that may further lower the seizure
threshold (Holmes, 2002). Interestingly, abnormal neurogenesis
triggered by seizures is also generated by spreading depolarization
(Nogueira et al., 2014), thus providing potential insight regarding the
overlapping injury mechanisms from DCI and seizures in patients
with SAH. Mechanisms that lead to ictal discharges are also shared
with CSD and include a decline in extracellular magnesium and an
Copyright Ó 2016 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016
increase in extracellular potassium, blockade of the sodium pump
and increased membrane permeability, as well as inhibition of
GABA receptors (Dreier et al., 2012). A small study with patients
with highly selected high-grade SAH showed a strong association
between CSDs and DS, which was attributed to higher levels of brain
damage from DCI (Dreier et al., 2012). Perhaps blood–brain barrier
disruption in SAH from CSD is related to epileptogenesis in a certain
subset of patients.
In animals, interictal discharges have been implicated in
transient task-specific cognitive impairment that seems to have long-
term effects, likely related to reduced hippocampal output after
discharges (Holmes, 2014). It is possible that isolated intracortical
seizures may not be associated with profound tissue hypoxia or
metabolic crisis even when they are associated with worse outcome
(Claassen et al., 2013). However, this is a finding that needs further
confirmation.
The use of electroencephalographic patterns in outcome
prediction is relatively new with scarce evidence related to patients
with SAH. One study demonstrated that periodic discharge occurring
after 24 hours is an independent predictor of poor outcome,
particularly if lateralizing (Claassen et al., 2006). Crepeau et al.
did not find such prognostic impact (Crepeau et al., 2013). In
a heterogenous group of critically ill patients with coma, prolonged
periodic discharge was not associated with the outcome despite
a statistically significant association with electrographic seizures
(Ong et al., 2012). Similarly, the presence of lateralized periodic
discharges (LPD) was strongly associated with seizures in critically
ill patients (Fitzpatrick and Lowry, 2007; Pohlmann-Eden et al.,
1996; Punia et al., 2015). A quarter of patients with LPDs without
seizures may experience seizure recurrence on discharge (Punia
et al., 2015); and, this rate more than doubles when LPDs are
accompanied with NCSz (Punia et al., 2015). These findings could
potentially be extrapolated to patients with SAH, because periodic
discharge and LPDs are common in this patient population.
Recent literature suggests that a lack of sleep architecture may
be associated with poor outcomes in high-grade SAH, whereas lack
of reactivity or state changes may not be, although such conclusions
are limited by small study sizes (Claassen et al., 2006). Severe
background attenuation on intracortical monitoring was also found to
be an independent predictor of poor outcomes in patients with high-
grade SAH (Claassen et al., 2013).
Onset seizures often coincide with rebleeding (Butzkueven
et al., 2000; Hart et al., 1981; Sundaram and Chow, 1986), but do not
necessarily predict the risk for rebleeding (Pinto et al., 1996). They
may, however, be associated with pneumonia, which can indirectly
affect the clinical course of patients (De Marchis et al., 2013) and
cloud the clinical assessment of patients potentially impacting
management decisions (Fung et al., 2015).
Several studies have found an association between seizures
and worse functional outcome (Bidzinski et al., 1992; Buczacki
et al., 2004; Butzkueven et al., 2000; Claassen et al., 2003, 2014;
Keranen et al., 1985; Lin et al., 2003; Ohman, 1990; Pinto et al.,
1996) without an impact on overall mortality (Hart et al., 1981;
Rhoney et al., 2000; Sundaram and Chow, 1986). After excluding
patients with a history of epilepsy, Claassen et al. found a strong
relationship between in-hospital seizures and 12-month mortality
from SAH onset (Claassen et al., 2003). In addition, seizures were
also associated with worse quality of life and higher rates of anxiety
among survivorsdan effect that was not assessed independently from
the influence of prophylaxis itself (Claassen et al., 2003). As expected,
nonconvulsive status epilepticus in patients with SAH carries a high
mortality rate (Claassen et al., 2003; Dennis et al., 2002; Little et al.,
Copyright Ó 2016 by the American Clinical Neurophysiology Society
Seizures and Epileptiform Patterns
2007), and so does generalized convulsive status epilepticus (Claassen
et al., 2007). Lack of in-hospital seizures was identified as a possible
predictor of excellent functional recovery in SAH on univariate
analysis, but not when multivariate analysis was performed (Pegoli
et al., 2015). The length of hospital stay is also longer in patients who
experienced seizures (Claassen et al., 2003, 2007; Hoh et al., 2011;
Rhoney et al., 2000). There is insufficient data to conclude that OS are
predictive of delayed epilepsy (Baker et al., 1995; Bidzinski et al.,
1992; Butzkueven et al., 2000; Byrne et al., 2003; Choi et al., 2009;
Claassen et al., 2003; De Marchis et al., 2013; Hart et al., 1981; Hasan
et al., 1993; Huttunen et al., 2015; Lin et al., 2003; Pinto et al., 1996;
Rose and Sarner, 1965; Sundaram and Chow, 1986).
CLINICAL MANAGEMENT
The routine use of prophylaxis in SAH had been common
practice for decades, supported by extrapolated data from other acute
brain injuries (e.g., traumatic brain injury [TBI]). The studies
reporting seizures rates with and without the use of PSP are not
comparable, as important details on aneurysm and patient character-
istics differ significantly (Awad, 2013). Studies showing that the
incidence of postoperative seizures has declined with advances in
surgical techniques has triggered a re-evaluation of the indication for
prolonged anticonvulsants use (Bidzinski et al., 1992; Byrne et al.,
2003; Sbeih et al., 1986; Sundaram and Chow, 1986). Further
retrospective analysis shows that selecting low-risk patients for
a shorter PSP course is a safe approach (Baker et al., 1995) and some
authors propose an individualized approach using risk stratification
(Buczacki et al., 2004; Chang et al., 2015; Choudhari and
Kaliaperumal, 2007; Claassen et al., 2003; Connolly et al., 2012;
Keranen et al., 1985).
Despite the nonnegligible incidence of DS after more than
a year postbleed, continuing anticonvulsants is not supported by
available evidence (Connolly et al., 2012; Diringer et al., 2011; Steiner
et al., 2013), and its discontinuation after 3 to 6 months is reasonable
(Diringer et al., 2011). A study investigating the impact of phenytoin
on cognitive outcomes in patients with SAH led to abandonment of the
routine use of PSP in patients with SAH (Naidech et al., 2005). The
American Heart Association guidelines suggest using PSP in the
immediate posthemorrhagic period with a class IIb, level B recom-
mendation (Connolly et al., 2012). The Neurocritical Care Society
recommends limiting PSP to 3 to 7 days in addition to avoiding
phenytoin use (Diringer et al., 2011). Conversely, the European Stroke
Organization guidelines advise against PSP with a class IV, level C
recommendation (Steiner et al., 2013).
In the light of the potential morbidity associated with
rebleeding, we find it reasonable to continue PSP until the aneurysm
is secured even in patients without OS. Continued use once the
aneurysm is secured should be driven by clinical status and EEG
findings; we acknowledge the lack of high-quality data to guide this
decision. If the patient has clear risk factors for increased seizure
occurrence, it is reasonable to continue PSP during the hospitaliza-
tion (Connolly et al., 2012).
Despite the lack of adequate head-to-head comparisons in
patients with SAH (Marigold et al., 2013), the preferred drug for
prophylaxis seems to be levetiracetam because it seems noninferior
to phenytoin in acute brain injury (Chang et al., 2015; Karamchan-
dani et al., 2014; Murphy-Human et al., 2011; Szaflarski et al., 2010;
Zafar et al., 2012) and postcraniotomy patients (Weston et al., 2015),
is noninferior to valproate (Mink et al., 2011), does not interact with
nimodipine (Fleishaker et al., 1995; Tartara et al., 1991), seems more
191
C. B. Maciel and E. J. Gilmore Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016

tolerable (Karamchandani et al., 2014; Shah and Husain, 2009), and
may be associated with improved cognitive and functional outcomes
in subsets of patients with ICH (Taylor et al., 2011). Notably, the
bioavailability of levetiracetam may decrease by 30% when given in
oral formulation as compared with parenteral administration (Drust
et al., 2012; Mink et al., 2011). Additionally, critically ill patients
may exhibit increased clearance of levetiracetam (Drust et al., 2012;
Spencer et al., 2011), and elderly patients are more prone to delirium
with its use (Hommet et al., 2013; Hwang et al., 2014). Depending
on the patient, dose adjustments may be required.
Rates of adverse effects with pharmacoprophylaxis range
from 4.1% to 23.4% (Choi et al., 2009; Chumnanvej et al., 2007;
Deutschman and Haines, 1985; Manon-Espaillat et al., 1991;
Mattson et al., 1985; Raper et al., 2013; Rhoney et al., 2000; Sbeih
et al., 1986), and may decrease to 0.5% with short regimens
(Chumnanvej et al., 2007). Patients with SAH exposed to phenytoin
may have hyperthermia and increased vasospasm (Bleck and Chang,
2006). Moreover, some anticonvulsants may have a direct negative
impact on the outcomes of patients with acute brain injury (Gold-
stein, 1995; Rosengart et al., 2007) due to antineuroplasticity effects.
However, data confirming these findings are lacking (Nadeau et al.,
2014). Preclinical data show promising neuroprotecting effects of
felbamate (Germano et al., 2007), valproic acid (Tso et al., 2015),
topiramate (Seckin et al., 2009), and levetiracetam in SAH models
(Wang et al., 2006)dsome may display a CSD-supressant effect
(Ayata et al., 2006). Further studies in humans are needed to
compare the efficacy, impact on outcome, and tolerability.
Secondary seizure prophylaxis is a sensible decision and
recommended by available guidelines (Connolly et al., 2012;
Diringer et al., 2011; Steiner et al., 2013). Nevertheless, the duration
of secondary seizure prophylaxis remains debatable; the presences of
cortical injury, comorbidities, and side effects are all reasonable
factors to consider when discontinuing prophylaxis. See Fig. 1 for
a proposed algorithm of seizure prophylaxis in patients with SAH.
CONCLUSIONS
Seizures are frequent in patients with SAH and may occur at
different time points, which likely reflects mechanistic heterogeneity

FIG. 1. Algorithm for seizure prophylaxis after aneurysmal subarachnoid hemorrhage. *There is significant practice variability
regarding dosing of primary seizure prophylaxis and lack of large, randomized, double-blinded clinical trials to guide this decision.
Institutional guidelines should be followed when deciding whether or not to give a loading dose or to start maintenance dosing of
anticonvulsants. **Neurological deterioration of undetermined etiology and not explained by underlying infection, rebleeding,
hydrocephalus, medication effect, vasospasm, and delayed cerebral ischemia.

192 Copyright Ó 2016 by the American Clinical Neurophysiology Society

Journal of Clinical Neurophysiology
Volume 33, Number 3, June 2016
with varied clinical impact. Young patients, those with more severe
SAH or with associated cortical irritation and patients undergoing
craniotomy seem to be at higher risk. The use of seizure prophylaxis
needs to be guided by the risks associated with seizures and the
potential for adverse effects associated with the anticonvulsant used,
which include but are not limited to hyperthermia, mood disorders,
and worsened cognition.
Newer anticonvulsants seem to be equally effective and may
have a more favorable profile. Further studies confirming the
potential pleiotropic effects of selected anticonvulsants and pro-
spective head-to-head drug comparisons are needed to guide drug
selection in SAH. Continued use of prophylaxis beyond the acute
period should be assessed on a case-by-case basis.
Seizures may cause systemic complications, negatively influ-
ence initial neurologic assessment by clouding the examination, and
lead to secondary brain injury in this vulnerable patient population
with the potential for impacting long-term outcomes. The heteroge-
neity of data on frequency and timing of seizure occurrence may also
reflect the evolution of SAH management over time and further
prospective studies with rigorous methodology controlling for
confounders are greatly needed in this era of modern neurosurgical
and neurocritical care.
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