Published online: 2020-11-05

Acute Provoked Seizures—Work-Up and

Management in Adults
Rana Moosavi, MD, MS1 Christa B. Swisher, MD, FNCS, FACNS1

1 Department of Neurology, Duke University Medical Center, Durham, Address for correspondence Christa B. Swisher, MD, FNCS, FACNS,
North Carolina Department of Neurology, Duke University Medical Center, DUMC
3824, Durham, NC 27710 (e-mail: christa.swisher@gmail.com).
Semin Neurol

Abstract Acute provoked seizures, also known as acute symptomatic seizures, occur secondary
Keywords to a neurological or systemic precipitant, commonly presenting as a first-time seizure.
► acute provoked In this article, we will discuss etiology, emergent protocols, medical work-up, initial
seizures treatment, and management of these seizures. The definitions, classifications, and
► acute symptomatic management of convulsive status epilepticus and nonconvulsive status epilepticus in
seizures an acute setting will also be reviewed.
► nonconvulsive

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seizures
► convulsive status
epilepticus

Seizures can be categorized into two broad categories:
provoked and unprovoked. Provoked seizures are defined
as resulting from a precipitating insult. Multiple terminolo-
gies exist to describe a seizure that occurs secondary to an
underlying medical illness: provoked, acute symptomatic,
and remote symptomatic seizures. Some provoked seizures
may have little or no clinical correlate but are identified
electrographically and are referred to as nonconvulsive
seizures (NCSs). This review will discuss the definition,
etiology, recommended work-up, and general management,
including antiseizure drugs (ASDs), for an acute provoked
seizure in an acute care setting such as the intensive care unit
(ICU) or emergency department (ED).
Definitions and Classifications
Acute Symptomatic Seizure Definition
Originally defined by the International League Against Epi-
lepsy (ILAE), an acute symptomatic seizure is a “seizure
occurring in close temporal relationship with an acute CNS
insult, which may be metabolic, toxic, structural, infectious,
or inflammatory.”1
Acute symptomatic seizures can be referred to as provoked
seizures or reactive seizures, though the term “acute symp-
tomatic seizure” is recommended.2 This is differentiated from
remote symptomatic seizures, which occur >7 days after an
initial insult and, therefore, occur in the setting of a pre-
existing brain injury.3 A variety of clinical manifestations
may be seen based on seizure classification and terminology.4
Seizures can be focal onset with or without impaired aware-
ness, generalized onset, or focal to bilateral (previously
called secondarily generalized).
Nonconvulsive Seizure Definition
NCSs are defined as seizures lasting
10 seconds with either
no or only subtle clinical manifestations (facial or limb twitch-
ing, gaze deviation, nystagmus).5 Electroencephalography
(EEG) is necessary for the diagnosis of NCS. EEG criteria for
NCS are any pattern >10 seconds meeting any one of the
following three criteria: (1) repetitive generalized or focal
epileptiform discharges
3 Hz, or (2) repetitive generalized
or focal epileptiform discharges <3 Hz and the presence of
a secondary criterion (significant improvement in the clinical
state or appearance of previously absent normal EEG patterns
in response to acute administration of a rapidly acting ASD,
such as a benzodiazepine), or (3 sequential rhythmic, periodic,
or quasiperiodic waves
1 Hz and unequivocal evolution in
frequency, morphology, or spatial extent.6

Issue Theme Seizures and Status Copyright © by Thieme Medical DOI https://doi.org/
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Acute Provoked Seizures Moosavi, Swisher
Status Epilepticus Definition
Patients with acute symptomatic seizures may present with or
subsequently develop status epilepticus (SE). SE is categorized
as SE with prominent motor symptoms (i.e., convulsive SE
[CSE]) or SE without prominent motor symptoms (i.e., non-
convulsive SE [NCSE]).7,8 The definition of SE, as per the
Neurocritical Care Society, is
5 minutes of (1) continuous
clinical and/or electrographic seizure activity or (2) recurrent
seizure activity without clinical recovery in between.7 The
definition of SE per the ILAE is described as a condition
resulting from either the failure of the mechanisms responsi-
ble for seizure termination or from the initiation of mecha-
nisms, which lead to abnormally prolonged seizures (after
time point t1) resulting in long-term consequences (after time
point t2).7 Treatment initiation should occur by time point t1.
For CSE, t1 is defined as 5 minutes and t2 is defined as
30 minutes.7 Definitions of t1 and t2 for NCSE have not yet
been described.
EEG Criteria for Nonconvulsive Status Epilepticus
The electrographic definition of NCSE has varied over time. The
EEG criteria for NCSE proposed in 2013, also known as the
“Salzburg criteria,” defined it for patients without known
epileptic encephalopathy as: (1) epileptic discharges > 2.5 Hz,
or (2) epileptic discharges 2.5 Hz or rhythmic delta/theta
activity >0.5 Hz and one of the following: (a) clinical and EEG
improvement after intravenous (IV) ASD, or (b) subtle clinical
ictal phenomena during the EEG pattern mentioned above, or
(c) typical spatiotemporal evolution. In patients with epileptic
encephalopathy, there should be an increase in EEG findings
compared with baseline or improvement in clinical symptoms
and EEG after administration of an IV ASD.9,10
Prevalence
Population-based studies have determined that the cumula-
tive risk of developing acute seizures is 3.6%.11 Up until the age
of 80, women have a 2.7% risk and men have double the risk at
5%. Both have a bimodal distribution with higher incidence in
newborns (253/100,000) and the elderly (123/100,000).11 An
age-adjusted incidence of 35/100,000 was calculated across a
50-year timeframe.11 Across all age groups, the most common
causes were trauma, stroke, drug withdrawal, and infection. In
patients aged 15 to 34 years, drug withdrawal and brain
trauma were the most common causes. From age 35 to
64 years, the most common cause was drug withdrawal. For
patients >65 years old, stroke accounted for more than half of
all causes for acute symptomatic seizures.11
Mortality
There is an estimated 20% mortality risk within the first
30 days following an acute seizure, regardless of gender.12
The risk is higher for individuals >65 years of age. Among
patient deaths within the first 30 days, cerebrovascular disease
and anoxic brain injury predominated.12 One large retrospec-
tive study discovered that patients with acute symptomatic
seizures had a 1-month mortality risk that was 8.9 times
Seminars in Neurology
higher than those with first-time unprovoked seizures.13 Ten-
year mortality risks were similar in both groups. This study
also demonstrated a higher early mortality if the acute symp-
tomatic seizures were due to stroke, traumatic brain injury
(TBI), or central nervous system (CNS) infection.13
Demographics
Patients presenting with acute symptomatic seizures to the
ED are usually subsequently admitted. However, many acute
symptomatic seizures occur in patients who are initially
hospitalized for nonseizure reasons. In 2005, the Agency
for Healthcare Research and Quality identified seizures or
epilepsy in approximately 1.4 million out of 39.2 million
(3.6%) total hospitalized patients.14 One study compared
patients with a prior seizure history to those without, and
determined that patients with no prior seizure history were
more likely to develop symptomatic seizures than those with
a prior history (43 vs. 32%, respectively).15 Additionally,
patients without a prior seizure history were more likely
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to be discharged to hospice or die.15
Critically ill patients may present with, or subsequently
develop, neurological insults. Additionally, ICU patients have
a propensity for toxic or metabolic derangements, thus
placing them at a higher risk of acute symptomatic seizures.
Patients in the ICU with nonneurological conditions such as
sepsis, metabolic abnormalities, drug intoxication, or with-
drawal have acute seizure rates up to 10%.16
Clinical Presentation
Acute provoked seizures may result in obvious clinical
seizure activity, subtle manifestations (i.e., gaze deviation,
nystagmus, subtle twitching, altered mental status), or may
not be associated with any clinical signs (i.e., nonconvulsive).
Seizures are often seen in critically ill patients, particularly
those in the neuro-ICU due to their underlying neurological
injuries including TBI, intracranial hemorrhages, brain
tumors, ischemic strokes, and CNS infections, to name a
few.17 Numerous studies have revealed that approximately
20% of critical care patients have nonconvulsive electro-
graphic seizures.17,18 The majority of seizures (92%) in ICU
patients are nonconvulsive.17
In patients who present with altered mentation, NCSs
represent 8 to 30% of the underlying cause.19 In elderly
patients presenting with delirium, 28% were found to have
EEG patterns that were confirmatory for NCSE.20
Having a high index of suspicion of NCS and NCSE is
essential, as the diagnosis can only be made with continuous
EEG (cEEG) monitoring. It has been demonstrated that the
first seizure occurs within 60 minutes in approximately 50%
of patients, and within 24 hours in 80% of patients, thereby
necessitating cEEG monitoring.21,22
Patients may develop refractory and superrefractory SE.
Refractory SE (RSE) occurs in approximately 9 to 43% of all SE
cases, and is defined as continuous seizure activity despite
first- and second-line antiseizure medications.9 Superrefrac-
tory SE is continuous seizure activity for 24 hours that is
 Acute Provoked Seizures Moosavi, Swisher

Table 1 Common etiologies of acute symptomatic seizures craniotomy, Glasgow Coma Scale (GCS) <8 within 24 hours
after evacuation, and delay in surgical intervention >24 hours.
Common etiologies of acute symptomatic seizures The degradation products from SAH blood are thought to be an
Cardiovascular disease Anoxic brain injury epileptogenic trigger.25,30
Ischemic stroke Neoplasm
Hemorrhagic stroke Primary versus metastatic
Hypoxic-ischemic Injury
Subarachnoid Solid versus leptomeningeal
hemorrhage Inflammatory/autoimmune High seizure rates are noted in patients with postanoxic en-
Cerebral venous sinus Autoimmune encephalitis cephalopathy. Seizure activity is seen in approximately 35% of
thrombosis Multiple sclerosis patients who undergo EEG monitoring after cardiac arrest.22 In
Trauma Acute disseminated
this setting, seizures are often nonconvulsive, though myoclonic
Subdural hematoma encephalomyelitis
Epidural hematoma Sarcoidosis SE is common in this patient population as well.
Traumatic brain injury Cerebral vasculitis
Medication/substance Systemic lupus erythematosus Substance-Related
related Hashimoto encephalopathy
Alcohol withdrawal Electrolyte disturbances Alcohol withdrawal and intoxication account for one-third of
Illicit (cocaine, Hyponatremia, hypernatremia hospital admissions for seizures.25,31 Signs and symptoms of
phencyclidine, etc.) Hypocalcemia alcohol withdrawal include tremors, diaphoresis, tachycardia,
Prescribed medications Hypoglycemia, hyperglycemia and agitation. Seizures are often focal or generalized motor.
(antibiotics, Miscellaneous
antidepressants, etc.) Eclampsia Chronic alcohol use has been linked to the development of
Infection Posterior reversible white matter atrophy and decreased density of Purkinje cells in
Bacterial meningitis encephalopathy the cerebellum. It is unknown if this resultant atrophy increases
Viral meningitis syndrome

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Fungal meningitis
Neurocysticercosis
Cerebral abscess
Sepsis
resistant to third-line agents or anesthetics. The incidence of
superrefractory status is currently unknown.9
Etiology and Pathophysiology
There are many etiologies resulting in the development of acute
symptomatic seizures. Common categories include cerebro-
vascular, infection, trauma, toxins, metabolic derangements,
autoimmune/inflammatory, and neoplastic (►Table 1).
Cerebrovascular Disease
A prospective multicenter study found that the earlier the
seizure developed after an acute ischemic stroke, the worse the
prognosis.23,24 Larger infarct size and cortical location were
associated with a higher risk of acute symptomatic seizures.
About 8.9% of patients with ischemic stroke were noted to
develop seizures.23,25,26 It has been proposed that seizures
poststroke are due to biochemical changes caused by hypoxia
and the release of excitotoxic neurotransmitters.27
The risk of developing acute symptomatic seizures is higher
in lobar intracerebral hemorrhage (ICH), vascular malforma-
tions, and from aneurysmal rupture.24,28,29 A prospective trial
noted that 14% of ICH patients developed acute symptomatic
seizures within 7 days of ICH onset.24 Patients with subarach-
noid hemorrhage (SAH) have a 4 to 16% risk of seizures.28
Trauma
In traumatic subdural hematoma (SDH) there is a 24% risk of
seizure development, particularly 7 days or more after the
insult.30 For patients with TBI, the presence of SDH increases
the risk of seizure development. Risk factors for the develop-
ment of acute symptomatic seizures include the need for a
the propensity of seizures.25,31 In terms of recreational drug
use, amphetamines, 3,4-methylenedioxy methamphetamine
(MDMA), heroin, and cocaine can result in seizures.26
Infections
Acute symptomatic seizures can be the presenting symptom of
systemic or CNS infections.16 In developing countries, infec-
tions are the leading cause of acute symptomatic seizures in
both adults and children.25,32 Common infections resulting in
seizures are bacterial meningitis, viral encephalitis, cerebral
abscesses, and endocarditis. In patients with bacterial menin-
gitis, seizures occur in 5 to 27% of patients and tend to occur
early in the disease. Patient with Streptococcus pneumoniae
infections, low GCS score, and focal neurological deficits are
more likely to experience early-onset seizures.26,33–35 Due to
its predilection for the temporal lobes, viral encephalitis as a
result of herpes simplex virus infection has a high incidence of
seizures, approximately 25%.26,36
Cerebral abscesses are a common cause of seizures in
developing countries. Neurocysticercosis causes 30% of epi-
leptic seizures in Central and South America.37 The parasite
causes inflammation and edema, which are thought to lower
the seizure threshold.25,26,37
Inflammatory/Autoimmune
Inflammatory conditions such as autoimmune encephalitis,
multiple sclerosis, acute disseminated encephalomyelitis,
sarcoidosis, and systemic and cerebral vasculitis have been
linked to provoked seizures. These disease states have vary-
ing risks of seizure development, the least of which is
multiple sclerosis and the highest being N-methyl-D-aspar-
tate (NMDA)-receptor encephalitis (up to 75%).26,38,39
Electrolyte Disturbances
Disturbances in metabolic homeostasis may result in acute
seizures. Management requires identifying the culprit and
treating the underlying disorder. In most cases, the neurologi-
cal symptoms are reversible. Both hypo- and hypernatremia

Seminars in Neurology
Acute Provoked Seizures Moosavi, Swisher

can cause neurological manifestations due to the brain having Table 2 Diagnostic evaluation of acute seizures
limited adaptability to changes in sodium concentration.40
Neurological symptoms are more common in acute hypona- Initial laboratory and diagnostic evaluation of underlying
tremia rather than chronic. Convulsive seizures typically occur causes and complications of seizures
with sodium concentrations <115 mEq/L. This is considered a Telemetry Fingerstick glucose
medical emergency and has a reported mortality as high as Tachycardia, Hypoglycemia or hyperglycemia
arrhythmias Urine and serum toxicology
50% due to cerebral edema.40 Hypernatremia, particularly
Blood pressure Alcohol, cocaine,
sodium levels >160 mEq/L, may result in altered mental status. Hypotension or methamphetamines, etc.
Seizures are relatively uncommon with hypernatremia. hypertension Thyroid panel
Pulse oximetry Hyperthyroidism
Hypoxia Imaging: CT and/or MRI
Evaluation, Work-Up, and Medical Temperature Intracranial hemorrhage,
Management Hyperthermia neoplasms, hypoxic injury, etc.
Arterial blood gas Chest X-ray
Patients may present with a multitude of symptoms after an Acidosis, hypoxia, Pneumonia
acute symptomatic seizure. Symptoms range from subtle (i.e., hypercarbia Lumbar puncture
transient confusion) to obvious (generalized tonic-clonic [GTC] Serum creatine kinase Infectious, autoimmune,
Rhabdomyolysis paraneoplastic
convulsions). In stable patients, a detailed history of the event
Serum troponin
should be acquired. A witnessed account is particularly useful Cardiac ischemia
in describing the event if the patient is unresponsive, confused, Electrocardiogram
or has amnesia. Associated neurological symptoms that should Cardiac ischemia,

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be inquired about include a history of headache, fever, photo-
phobia, nausea, vomiting, neck stiffness, altered conscious-
ness, head trauma, abnormal movements such as myoclonus
or rhythmic shaking, timing of onset, recent travel, sick con-
tacts, history of alcohol or drug abuse, medications, and
relevant past medical history.
For clinical management, the first step is to check ABCs
(airway, breathing, and circulation). Ensure that the patient
is not in acute distress, particularly with regard to their
respiratory status. Vitals signs, pulse oximetry, temperature,
GCS determination, and finger-stick glucose should be
obtained immediately. IV access, ideally with two large
bore IVs, should be obtained. If this is not possible, an
intraosseous line should be obtained for medication admin-
istration. An electrocardiogram should also be performed.
Next, a thorough general and neurological exam should be
completed. The provider should look for signs of meningitis
such as neck stiffness, photophobia, and Kernig’s and Brud-
zinski’s signs. Signs of increased intracranial pressure may be
present, such as pupil dilation, sixth nerve palsy, or papil-
ledema (particularly if subacute or chronic). Observation of
forced gaze deviation, myoclonus, facial twitching, altered
consciousness, loss of bowel or bladder control, and nystag-
mus may be related to ongoing seizure activity.
Patients who have not returned to baseline should receive
supplemental oxygen and monitored for cardiac and pulmo-
nary stability. If the patient’s airway is compromised or if the
patient becomes hypoxemic despite supplemental oxygen,
then the patient should undergo intubation. Rapid sequence
intubation with a nondepolarizing neuromuscular blocking
agent, such as cisatracurium or rocuronium, is preferred.
Succinylcholine is not recommended due to the risk of
hyperkalemia. Additionally, succinylcholine may result in
worsening of elevated intracranial pressures. Vasopressors,
such as phenylephrine or norepinephrine, may be needed if
the patient becomes hypotensive. IV fluids should also be
considered in hypotensive patients, especially those present-
ing in GCSE (risk of rhabdomyolysis).
arrhythmia
Lactate level
Lactic acidosis
Basic metabolic panel
Electrolyte
abnormalities
Echocardiogram
Heart failure
Abbreviations: CT, computed tomography; MRI, magnetic resonance
imaging.
Once seizure activity has resolved and the patient is stabi-
lized, a laboratory work-up should include the following:
complete blood cell count, basic metabolic panel, calcium,
magnesium, creatine kinase, serum toxicology panel, urine
toxicology panel, liver function tests, cardiac enzymes, urinal-
ysis, blood cultures, and urine culture. Some of these tests
(►Table 2) are used to evaluate for underlying causes of the
acute symptomatic seizures (i.e., urine toxicology screen),
while others evaluate for potential seizure complications (i.e.,
cardiac and other muscle enzymes). Fever may be present as a
sign of underlying infection or as a symptom of the convulsive
seizures. If an underlying infectious etiology is suspected,
immediate initiation of broad-spectrum IV antibiotics and IV
acyclovir should be provided to empirically treat meningitis/
encephalitis, and a lumbar puncture should be performed. A
lumbar puncture is also indicated if there is a concern for an
autoimmune or paraneoplastic process. Some common infec-
tions such as upper respiratory infections or urinary tract
infections may lower the seizure threshold and be the inciting
event for the clinical presentation. Therefore, a portable chest
X-ray and infectious work-up are appropriate.
Consideration of diagnostic imaging should be done in
conjunction with the initial laboratory work-up. In an acute
setting, a noncontrast computed tomography (CT) of the
brain is a quick and easily accessible tool when evaluating for
a stroke, ICH, SAH, SDH, epidural hematoma, TBI, neoplasm,
or cerebral abscess. If the initial CT brain is unremarkable and
the underlying etiology of the seizures is unknown, a

Seminars in Neurology

magnetic resonance imaging (MRI) of the brain should be
performed. This should only be performed in a patient whose
clinical seizure activity has resolved and he/she has a stable
cardiopulmonary status. An MRI can assist in identification
of possible underlying etiologies, such as acute ischemic
stroke that may not be apparent on CT imaging.
Guideline-Based Treatment of Acute
Symptomatic Seizures
Two algorithms (►Fig. 1) have been proposed for the initial
treatment of CSE by the Neurocritical Care Society and Ameri-
can Epilepsy Society.7,41,42 The Neurocritical Care Society
states that the treatment recommendations also apply to
NCSE. Both guidelines recommend rapid and emergent ASD
administration with a benzodiazepine. The Neurocritical Care
Society recommends that benzodiazepines be administered
within 0 to 5 minutes, whereas the American Epilepsy Society
recommends between 5 and 20 minutes. Both recommend
administration of IV lorazepam, intramuscular (IM) midazo-
lam, or IV/rectal (PR) diazepam. The specifics of all benzodia-
zepines will be discussed in the following sections.7,41,42 As per
the Neurocritical Care Society guidelines, a repeat dose of the
chosen benzodiazepine within 5 to 10 minutes can be admin-
istered if seizures continue.42
A second-line ASD should be initiated for all patients with
SE 10 to 20 minutes post-benzodiazepine administration,
including the possible second dose. The goal is to either
obtain or maintain seizure control. Second-line medications
Fig. 1 Comparison of treatment algorithms for status epilepticus proposed by the American Epilepsy Society41 and Neurocritical Care Society.7,42
Acute Provoked Seizures Moosavi, Swisher
include fosphenytoin (fPHT), valproate sodium, phenobarbi-
tal (PHB), and levetiracetam (LEV).7,41,42 All are administered
as a weight-based IV loading dose. The Neurocritical Care
Society also recommends the option of a midazolam infusion
as a second-line medication.7
If seizures persist after administration of a second-line
ASD, they are considered at this point in RSE. Protocols from
the Neurocritical Care Society and American Epilepsy Society
differ in the proposed timing of each treatment phase. The
American Epilepsy Society notes that there are no clear data
available to guide therapy, and limited data regarding best
treatment options. Medications to be considered at this time
include IV anesthetics (i.e., infusions of midazolam, pento-
barbital, propofol, or thiopental) or administration of other
nonsedating ASDs.7,41,42 For patients in RSE, endotracheal
intubation may be performed to allow for the implementa-
tion of a medically induced coma.42
There are currently no specific guidelines for the treat-
ment of NCSs that do not meet the NCSE criteria. The
treatment of NCSs has reflected that of CSE and NCSE18;
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however, it is unclear if this is optimal practice. Additionally,
the ideal patient selection and optimal timing of treatment
escalation for initiation of IV anesthetic drugs (IVADs) is
unknown. It has been suggested that aggressive treatment
with IVADs is associated with an increased risk of death in the
elderly population.16,43 Furthermore, aggressive SE treat-
ment in the ICU with IVADs was found to prolong hospital
stay without improvement in outcomes,44 to be associated
with more infections,45 and to have a 2.9-fold relative risk of
Seminars in Neurology
Acute Provoked Seizures Moosavi, Swisher
Table 3 Benzodiazepines for status epilepticus
Medication Initial dose Available
formulation
Lorazepam 0.1 mg/kg IV IV, PO
(max: 4 mg per dose,
may in 5–10 minutes)
Diazepam 0.15–0.2 mg/kg IV IV, IM,
(max: 10 mg, PO, PR
may repeat in 5 minutes)
Midazolam 0.1–0.2 mg/kg IM IV, IM, IN
(max: 10 mg)
Abbreviations: IN, intranasal; IM, intramuscular; IV, intravenous; PO, oral; PR, rectal.
death.46 However, a subsequent large cohort study reported
that the use of IVADs for management of RSE did not increase
mortality.47
Benzodiazepines
Benzodiazepines are a class of medications that bind the
gamma-aminobutyric acid (GABA)-A receptor between α
subunits at the chloride ion channel. Binding causes an
increase in the frequency of channel opening, thus leading
to increased inhibitory effects on neuronal excitability. As
mentioned above, the Neurocritical Care Society and Ameri-
can Epilepsy Society SE guidelines recommend benzodiaze-
pines as the first-line therapy (also known as emergent initial
therapy) for SE (►Table 3).7,41 Overall, first-line treatment
will fail to terminate GCSE in 31 to 50% of patients.48
In a landmark study, the VA Cooperative Study on SE
compared four medications or combinations of medications
to evaluate efficacy of SE termination.49 Treatment arms
included (1) IV lorazepam, (2) IV PHB, (3) IV phenytoin
(PHT), and (4) IV diazepam followed by IV PHT. The study
demonstrated that lorazepam was superior to PHT for ter-
minating “overt” SE (65 vs. 44%) but was not more effective
than IV PHB or IV diazepam followed by IV PHT.49,50 Loraze-
pam has a rapid onset, and is the drug of choice for initial
treatment of SE for patients with IV access.49,50
Lorazepam
The initial dose of lorazepam used in the VA Cooperative
Study was 0.1 mg/kg IV. This is also the recommended dose
per the Neurocritical Care Society and American Epilepsy
Society guidelines, with a recommended maximum of 4 mg
per dose.7,41 The San Francisco Prehospital Treatment of
Status Epilepticus (PHTSE) study compared prehospital
treatment of CSE with lorazepam 2 mg IV versus diazepam
5 mg IV versus placebo. Upon arrival, CSE was more likely to
be terminated in patients treated with a benzodiazepine
(lorazepam 59%, diazepam 43%) compared with 21% of the
placebo arm.46,48 Cardiopulmonary complications were low-
er in the benzodiazepine groups compared with the placebo
Seminars in Neurology
Half-life Advantages Disadvantages
12–18 h Intermediate onset, Hypotension, respiratory
safe for hepatic depression
impairment,
longer duration
Parent drug: Rapid onset, Hypotension, respiratory
60–72 h may be depression, rapid redistribution
Metabolite: administered PR (shorter duration)
152–174 h
3h Rapid onset, Hypotension, respiratory
longer shelf-life, depression, rapid redistribution
most reliable (shorter duration)
IM absorption
group. The optimal dosing of lorazepam is unknown since no
randomized trials have been performed evaluating different
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dosing regimens. A retrospective study demonstrated that
adequate benzodiazepine dosing in SE was uncommon (only
31%), and that inadequate benzodiazepine dosing strategies
were associated with progression to RSE.51
Midazolam
In addition to an IV formulation, midazolam also has an IM
formulation that is popular among first responders due to its
convenience. Unlike lorazepam, it has a longer shelf life when
not refrigerated. The recommended IM dosing for midazolam
is 0.2 mg/kg, up to a maximum of 10 mg per dose.7 The 2012
multicenter, double-blind randomized noninferiority RAM-
PART trial compared prehospital administration of IV loraz-
epam versus IM midazolam for adults and children with SE.52
Success was defined as seizure cessation without the need for
additional rescue therapy at the time of arrival to the ED. In
adults, IM midazolam 10 mg was noninferior to IV lorazepam
4 mg for SE termination, and patients treated with IM mid-
azolam were more likely to have stopped seizing upon arrival
to the ED.52 The time to initiation of treatment was shorter in
the IM midazolam group due to the requirement to obtain
peripheral IV access to administer IV lorazepam.52 However,
after medication administration, the time to seizure cessa-
tion was shorter in the IV lorazepam group when compared
with IM midazolam.52 Overall, the study demonstrated that
IM midazolam is preferable in the prehospital setting,
whereas in hospitalized patients with established IV access,
lorazepam remains the preferred benzodiazepine.
Diazepam
In an acute setting, diazepam can be administered via IV or
PR. The recommended dose is 0.15 to 0.2mg/kg, with a
maximum of 10 mg given at one given time.7 The PHTSE
trial mentioned above demonstrated a lower efficacy rate
with IV diazepam compared with IV lorazepam.50 One of the
benefits of diazepam is that it can be administered PR and
therefore allows providers to prescribe it for breakthrough
seizures at home, particularly in children.
 Acute Provoked Seizures Moosavi, Swisher

Antiseizure Drugs
Most patients presenting in SE receive an additional IV ASD
for urgent control therapy, per the Neurocritical Care Society
guideline recommendations.7 The administration of an ASD
is referred to as second-line therapy for SE per the American
Epilepsy Society. Of note, if the patient has returned back to
baseline, no additional treatment beyond a benzodiazepine
is recommended per the American Epilepsy Society guide-
lines.41 The Neurocritical Care Society guidelines differ in
that ASDs are recommended in all patients presenting in SE
for urgent control therapy, unless the cause of SE is known
and corrected (i.e., hypoglycemia).7 These guidelines state
that the role of the IV ASD is to continue maintenance
therapy for patients who have stopped seizing or to stop
seizures for patients that have failed emergent initial
therapy.7
There are currently no guidelines for treatment of acute
provoked seizures (convulsive or nonconvulsive) that do not
meet the criteria of SE. In the ICU setting, NCSs are more
compared the efficacy of lacosamide (LCM) versus fPHT for
the treatment of NCS. In this trial, patients diagnosed with
NCS by EEG were randomized to either IV LCM 400 mg or IV
fPHT 20 mg PHT equivalents (PE)/kg. The primary endpoint
was cessation of electrographic seizures within 24 hours.
Seizures were controlled in 63.3% of subjects in the LCM arm
and 50% in the fPHT arm (p ¼ 0.02), demonstrating non-
inferiority of LCM in comparison to fPHT.53
It is recommended to load ASDs via IV to rapidly achieve
therapeutic serum concentrations. ►Table 4 details common
nonsedating ASDs that are utilized for seizure management
in the ED and ICU. Presently, there is a lack of high-quality,
evidence-based data to recommend the use of one ASD
preferentially for the treatment of benzodiazepine-resistant
SE.54 Currently, a variety of treatment options exist.
Phenytoin/Fosphenytoin
PHT and its prodrug, fPHT, are frequently used for acute
symptomatic seizures by inhibiting sodium channels in a
dose-dependent fashion, resulting in a block of the repetitive

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common than convulsive (92 vs. 8%, respectively).17 Given
the relative paucity of data, the treatment of convulsive
seizures and NCS that do not meet the criteria for SE
generally reflects the treatment of SE. However, the appro-
priate aggressiveness of treatment for isolated or recurrent
seizures is unknown. Only one multicenter, randomized
controlled trial has been performed in the critically ill
patient population with NCS (that do not meet the criteria
for NCSE). The TRENdS trial was a noninferiority trial that
firing of action potentials. PHT is available in oral (PO) and IV
formulations. The IV formulation of PHT contains propylene
glycol, which may be associated with side effects including a
risk of phlebitis with IV extravasation of PHT, which may be
severe given that PHT is highly caustic to veins. Purple glove
syndrome is a feared complication of IV PHT and presents
with a painful limb discoloration distal to this site of infu-
sion. This may occur with or without obvious IV extravasa-
tion. The SE loading dose of PHT is 20 mg/kg IV.41,42

Table 4 Antiseizure drugs

Medication Loading dose Maintenance dose Mechanism of action Adverse effects

Phenytoin 20 mg/kg IV 100 mg, Use-dependent inhibition Purple glove syndrome,
every 8 h IV of sodium channels nystagmus, diplopia, hirsutism,
ataxia cardiotoxicity, hypotension,
pancytopenia, ataxia, lupus-like
reaction, hepatotoxicity
Fosphenytoin 18–20 mg PE/kg IV 100 mg, Use-dependent inhibition Same as above. Reduced risk of
(maximum rate up to every 8 h IV of sodium channels phlebitis and hypotension
150 mg PE/min)
Valproic acid 20–30 mg/kg IV, 10–15 mg/kg/d IV, Exact mechanism unknown: Weight gain, hepatotoxicity,
infusion rate of divided every 8–12 h NMDA receptor antagonist, acute hemorrhage pancreatitis,
6 mg/kg/min histone deacetylase inhibitor, thrombocytopenia,
GABA potentiation hyperammonemia, hair loss,
and a dose-dependent tremor
Levetiracetam 20 mg/kg IV, <3000 mg/d, in two Exact mechanism unknown, Somnolence, dizziness,
infusion rate divided doses SV2A modulation irritability, behavioral
of 1.5 mg/kg/min problems, depression
Lacosamide 200–600 mg IV 200–300 mg, Selectively enhancement Dizziness, headache,
every 12 h of slow activation of voltage nausea, diplopia,
gated sodium channels PR prolongation
Perampanel 6–32a mg PO 8–12 mg/d Noncompetitive AMPA-type Somnolence, ataxia,
glutamine receptor blurred vision, aggression,
antagonist and hostility
Brivaracetam 100–200 mg IV 50–100 mg IV, SV2A modulation Dizziness and fatigue
every 12 h

Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, gamma-aminobutyric acid; IV, intravenous; NMDA, N-methyl-
D-aspartate; PE, phenytoin equivalents; PO, oral; SV2A, synaptic vesicle glycoprotein 2A.
a
Off -label loading dose.

Seminars in Neurology
Acute Provoked Seizures Moosavi, Swisher
fPHT is water soluble and therefore, the IV formulation does
not contain propylene glycol. With a lower risk of site irritation,
fPHT can be given more rapidly. Dosing is expressed as PE. The
SE loading dose of fPHT is 20 PE/kg IV.7,41,42 If seizures persist,
an additional IV fPHT 5 PE/kg dose or IV PHT 5 to 10 mg/kg dose
may be administered after 10 minutes. Given that PHT is highly
protein bound, total and free PHT serum levels should be
measured 1 hour after the loading dose. The reference range
for total PHT is 10 to 20 µg/mL and for free PHT is 1 to 2.5 µg/mL.
The maintenance dose of PHT/fPHT is 5 mg/kg/d divided
three times a day. Potential side effects include cardiotoxicity,
hypotension, pancytopenia, nystagmus, ataxia, lupus-like
reaction, hepatotoxicity, and hepatic enzyme induction.55
The risk of hypotension and arrhythmia is similar between
PHT and fPHT. Contraindications for both mediations
include second- or third-degree AV block, SA block, bradycar-
dia, and Adams–Stokes syndrome (syncopal episodes due to
intermittent heart block).18,55,56
The use of PHT/fPHT as first-line therapy for benzodiaze-
pine-resistant SE has recently been called into question.54,56 In
a network meta-analysis that included five randomized con-
trolled trials for the treatment of benzodiazepine-resistant SE,
PHT was found to be the least likely to reach SE cessation,
compared with other ASDs.54 It was speculated that this might
be related to the long infusion times needed for IV PHT infusion.
Another meta-analysis showed the overall efficacy of PHT for
CSE to be 50% lower than the efficacy of other ASDs.56
Quality data are notably limited for the efficacy of
PHT/fPHT for NCS and NCSE. Though it is commonly used
as first- or second-line therapy for NCS or NCSE, the TRENdS
study, a randomized controlled trial for patients with NCS,
demonstrated a 50% success rate for electrographic seizure
cessation at 24 hours.53
Valproic Acid
Valproic acid (VPA) has been shown to be effective in treating
multiple seizure subtypes for patients with epilepsy. Its
mechanism of action is unknown, but it is believed to be
an NMDA receptor antagonist, a histone deacetylase inhibi-
tor, and exert some GABA-related actions. It is available in PO
and IV formulations and is tolerated well at high doses (up to
100 mg/kg). The loading dose for VPA in SE is 20 to 40 mg/kg
IV.7,41,42 A total serum VPA level should be drawn within
1 hour after the loading dose. The maintenance dose of VPA is
10 to 15 mg/kg/d divided two to three times daily.41,42
Although typically well tolerated, side effects in the acute
setting include hepatotoxicity (particularly in children <2),
acute hemorrhage pancreatitis, thrombocytopenia, hyper-
ammonemia, and tremor. Additionally, there is a theoretical
bleeding risk due to effects on platelets.56 VPA is highly
protein bound and numerous drug–drug interactions are
possible. Main contraindications are liver disease, mitochon-
drial disorders, pregnancy (high risk of teratogenicity), and
urea cycle disorders.18,55,56
A meta-analysis of CSE patients found that the mean
efficacy of VPA lasting beyond the acute treatment phase
was 76%.56 A more recent meta-analysis of five randomized
controlled trials for patients with CSE demonstrated VPA
Seminars in Neurology
(and LCM) to have the best safety profiles with the lowest risk
of hypotension and respiratory depression.54 Studies evalu-
ating the efficacy of VPA in NCS and NCSE are lacking.
Levetiracetam
LEV is one of the most commonly used ASDs due to its lack of
drug–drug interactions, minimal side effects, and availability
in IV formulation. Though its mechanism of action is un-
known, it has been shown to have effects on calcium chan-
nels, GABA receptors, and potassium channels, and binds the
synaptic vesicle protein 2A. LEV is most useful if given early
in the course of SE.57 It can be administered as PO or IV.
A variety of loading doses have been recommended,
ranging from 20 to 60 mg/kg.54 The American Epilepsy
Society recommends a loading dose of 60 mg/kg with a
maximum dose of 4500 mg.41 Its main side effects are
somnolence, headache, irritability, depression, and psycho-
sis. It should be used with caution in patients with behavioral
concerns. Daily doses greater than 3,000 mg did not demon-
strate any added benefits.18,56,57
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A meta-analysis reported an efficacy of 69% for the use of
LEV in patients with benzodiazepine-resistant CSE, with
better efficacy than PHT but lower efficacy than PHB or
VPA.56 A more recent meta-analysis demonstrated that there
is a similar complication risk (respiratory depression and
hypotension) with LEV compared with other commonly used
ASDs in the treatment of CSE. VPA and LCM demonstrated a
lower complication risk.56 The efficacy of LEV to treat acute
provoked seizures presenting as NCS and NCSE in hospital-
ized patients is unknown.
Lacosamide
LCM has been approved by the U.S. Food and Drug Adminis-
tration (FDA) as an adjunct treatment for partial-onset
seizures, but it has been used off-label for the treatment of
CSE, NCS, and NCSE. LCM selectively enhances slow inactiva-
tion of voltage-gated sodium channels. In 2012 and 2016, at
the time of publication of the SE guidelines, there was limited
experience with LCM, and therefore it was not included as an
option for first- or second-line therapy for SE. Loading doses
of 200 to 600 mg have been used for SE, with maintenance
dosing of 100 to 200 mg every 12 hours, given PO or IV.18
Mild sedation, dizziness, headache, nausea, diplopia, and PR
interval prolongation are possible side effects.18,55,56 In the
ICU patient population, angioedema, allergic skin reactions,
hypotension, and pruritus have also been reported.
LCM has an overall efficacy of 56% for terminating CSE or
NCSE when administered as first-, second-, or third-line
therapy.58 The TRENdS trial compared the effectiveness of
LCM versus fPHT in critically ill patients who had electro-
graphic confirmation of NCSs. The primary endpoint was the
absence of electrographic seizures for 24 hours. It was con-
cluded that LCM was not inferior to fPHT and could be
considered an alternative for the treatment of NCSs.53
Phenobarbital
PHB has been in clinical use since the early 1900s. Initially
used as a sedative and sleep agent, it has been shown to be

effective against focal and GTC seizures, and its parenteral
form has been used in CSE.59 PHB binds to the GABA-A
receptor and prolongs the opening of chloride channels.59
It has a long half-life, good PO bioavailability, and lower
protein binding.59 However, it is a potent P450 enzyme
inducer, which means it will hasten the metabolism of other
medications that use the same enzyme system.59 It has fallen
out of favor due to its side-effect profile. which includes
prolonged sedation, decreased concentration, and concern
for compromise of cardiorespiratory function.59,60 The dos-
age for CSE recommended by the VA Cooperative Study49 and
the 2016 American Epilepsy Society guidelines is 15 mg/kg
IV.41 The Neurocritical Care Society, however, recommends
20 mg/kg IV.42
Other Antiseizure Drugs
Although more data are needed, three medications are showing
promise for the management of acute symptomatic seizures:
perampanel, brivaracetam, and clobazam. Perampanel works
as a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazo-
lepropionic acid (AMPA) receptor antagonist, causing a reduc-
tion in postsynaptic glutamate.18,61 Traditionally, it has been
used as monotherapy for focal seizures or as an adjunct for GTC
seizures. Although it has shown an effect on the termination of
SE in animal studies, there have been limited studies evaluating
its efficacy for acute symptomatic seizures and SE.61,62
Although data are sparse, there seems to be growing potential
for diversifying its use. One limitation is that it currently only
comes in an PO formulation. Adverse effects include somno-
lence, ataxia, blurred vision, aggression, and hostility, which
have resulted in a black box warning.18,59,61
Brivaracetam has a similar mechanism of action to LEV,
but with a 20-fold higher affinity and greater selectivity for
the SV2A protein. Additionally, it has higher CNS permeabil-
ity and bioavailability.59 It is FDA approved for treatment of
focal seizures, and comes in PO and IV formulations. The
most commonly reported side effects include somnolence,
dizziness, and fatigue.59 One study suggested that it has less
behavioral adverse effects in comparison to LEV. These two
medications are not effective when combined.59,63 Efficacy
and dosing in treating acute symptomatic seizures and SE are
unknown. Initial dosing ranges of 50 to 400 mg and mainte-
nance doses of 100 to 400 mg/d have been reported.64
Clobazam is a 1,5-benzodiazepine that has been approved
for the treatment of seizures associated with Lennox–Gas-
taut syndrome.65 It is available in 10 or 20 mg tablets, as well
as a 2.5 mg/mL PO suspension with good bioavailability and a
long half-life.59 Adverse effects include drowsiness, dizzi-
ness, poor coordination, and restlessness.59 Its main success
is as an adjunct in RSE,59,65 as there are currently limited data
on its use as monotherapy.
Conclusion
Acute symptomatic seizures are secondary to a systemic or
CNS insult. In an acute setting, a throughout work-up must be
completed and the underlying cause determined. If further
seizure activity ensues, there are a variety of antiseizure
Acute Provoked Seizures Moosavi, Swisher
medications that can be initiated. Choice will depend on
efficacy and side-effect profile. If the patient presents with
SE, or nonconvulsive status is suspected, then either algo-
rithm presented above can be initiated, as well as timely EEG
commencement for seizure localization and classification.
Conflict of Interest
R.M has received speaker’s honorarium from UCB and
speaker’s honorarium and advisory board honorarium
from Eisai. All the authors report no conflict of interest.
Acknowledgments
We would like to thank Safa Kaleem for her contribution in
manuscript editing.
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