Acute Symptomatic Seizures A Clinically Oriented Review: Pedro Beleza, MD

R
EVIEW
A
RTICLE
Acute Symptomatic Seizures A Clinically Oriented Review

Pedro Beleza, MD
symptomatic, because they occur in the context of an
evolving Background: Acute symptomatic seizures are seizures closely related to neurological or systemic insults and represent
about 40% of all first seizures. Diagnosis may be difficult to perform due to the subjectivity involved in recognizing the severity
of insult needed to provoke epileptic seizures or in determining a clear temporal relationship. Appro- priate therapeutic
management, risk of developing epilepsy, and mortality depend largely on the underlying disorder.
Review Summary: A general overview regarding definition, epidemiology, and causes of acute symptomatic seizures is
provided. Diagnosis, frequency, risk factors, pathophysiology, therapeutic management, and prognosis of acute symptomatic
seizures related to each insult individually are discussed. The insults considered are: acute stroke, traumatic brain injury, central
nervous system infections, medication, alcohol and illicit drugs, electrolytic and metabolic disorders, anoxic encephalopathy,
eclampsia, reversible posterior leukoencephal-
clinical condition.1 The definition of acute symptomatic seizure was created for use in epidemiologic studies.1 The concept
rests on an epileptic seizure being a symptom of an acute cerebral disorder, affecting the brain primarily or secondarily.3 A
seizure that meets the criteria for acute symptomatic should still be classified as such even if there is also a remote symptomatic
etiology or a preexisting epilepsy.1 Situation-related seizures, a translation from the German “gelegenheitsanfalle,” is a broader
term that includes not only acute symptomatic seizures but also febrile seizures and isolated provoked seizures related to
situations not usually accompanied by seizures (eg, sleep deprivation and stress).4 Accordingly, ILAE has recently recommended
using the term “acute symptomatic seizure” instead of situation-related seizure.1 It is meaningful opathy, and limbic encephalitis.
to differentiate acute symptomatic seizures, febrile seizures,
Conclusions: Operational diagnostic criteria have been recommended by the International League Against Epilepsy and are based
on temporal relationship, severity, and type of insult. Antiepileptic drug prophylaxis is recommended in severe head trauma,
preeclampsia, and possibly high-risk subarachnoid or intracranial hemorrhage. It is crucial to rapidly identify all insults possibly
involved, treat underlying
and the ill-defined gray area of isolated provoked seizures. Febrile seizures are symptoms of selected seizure disorders with
major genetic influences including: (1) febrile seizures of childhood, a benign entity defined as the occurrence of seizures
accompanied by fever without CNS infection, in a child aged 6 months to 5 years5 and (2) febrile seizures plus, a chronic
diseases, revert corrigible factors, and in case of central nervous system involvement, use antiepileptic drugs during the acute
period. Risk of epilepsy is increased in patients with neurological insults but not with metabolic disorders. Some refractory
epilepsies in adults, mostly epilepsy due to hippocampal sclerosis, are preceded by acute symptomatic seizures related to
selected insults occurring at a specific time. Mortality rate is globally increased.
epilepsy syndrome occurring when febrile seizures persist after the sixth year of life or in combination with afebrile seizures,
usually generalized tonic-clonic seizures.6 Isolated provoked seizures related to situations not usually accompanied by seizures
may possibly represent some especially mild genetic epilepsies with insufficient epileptogenic ability to induce unprovoked
seizures.4 Provoked seizure is a term derived from Key Words: acute symptomatic seizures, causes, risk factors,
the categorization of seizures based on the presence or
absence treatment
(unprovoked seizures) of a presumed acute precipitating (The
Neurologist 2012;18:109–119)
insult.2 The current diagnostic scheme for epilepsies proposed by ILAE does not mention the term “acute symptomatic seiz-
ures” but instead has included some examples, like alcohol withdrawal (AW) seizures, drug or other chemically induced
seizures, and posttraumatic seizures, under the category of “seizures DEFINITION OF ACUTE SYMPTOMATIC SEIZURE An
acute symptomatic seizure was defined in a recent recommendation from the International League Against Epi- lepsy (ILAE) as a
clinical seizure occurring in close temporal
not necessarily requiring a diagnosis of epilepsy.”7 Defining acute symptomatic seizures on clinical grounds may be difficult, as
it implies recognizing the severity of insult required to provoke seizures and the determination of a temporal relationship.
relationship with an acute central nervous system (CNS) insult, which may be metabolic, toxic, structural, infectious, or in-
flammatory.1 Seizures related to tumors, formerly considered as acute symptomatic2 are now considered progressive
SEVERITY OF INSULT REQUIRED TO PROVOKE SEIZURES The severity of insult needed to provoke a seizure can be
From the Department of Neurology, EEG Unit, Espirito Santo Saude Hospitals, Arrabida Hospital and Clipovoa, Po ́voa de
Varzim, Portugal. The author declares no conflict of interest. Reprints: Pedro Beleza, MD, Department of Neurology, EEG Unit,
Espirito Santo Saude Hospitals, Arrabida Hospital and Clipovoa, Rua Dom
understood considering 4 conceptual models: (1) acute disease model (eg, progressive organic dysfunction) in which multiple
insults are needed to provoke a seizure; (2) chronic disease model (eg, stroke, chronic renal failure) in which seizures Manuel I,
183, 4490-592 Povoa de Varzim, Portugal. E-mail: beleza.76 @gmail.com. Copyright r 2012 by Lippincott Williams & Wilkins
ISSN: 1074-7931/12/1803-0109 DOI: 10.1097/NRL.0b013e318251e6c3
occur after a single insult in the context of chronic disease; (3) unique insult model (eg, eclampsia) in which seizures happen after
a high-magnitude insult; and (4) genetic predisposition in which seizures occur after an insult of relatively low intensity.8
The Neurologist Volume 18, Number 3, May 2012 www.theneurologist.org |
109

Beleza The Neurologist Volume 18, Number 3, May 2012
DELAY BETWEEN INSULT AND SEIZURE REQUIRED TO BE CONSIDERED AS AN ACUTE
which may lead to diagnosis of structural lesions and may have some value in predicting the risk of seizure recurrence.15 In the
SYMPTOMATIC SEIZURE With regard to the temporal relationship needed for an event to be considered an acute symptomatic
seizure, it theo- retically consists of the period until clinical stabilization of disease, which is a subjective concept in clinical
practice. ILAE has conventionally considered: (1) the period of 1 week in stroke, head trauma, or anoxic encephalopathy; (2) the
ac- tive phase in CNS infection or inflammatory disease, based on persistent clinical, laboratorial, or imaging findings; (3) within
24 hours in documented severe selected metabolic derange- ments; and (4) within 7 to 48 hours of the last drink in AW.1
emergency department, CT is usually the procedure of choice because of relative speed and its effectiveness in excluding
catastrophic problems that may require immediate attention. MRI in the first seizure needs more exploration, although in selected
cases and in nonemergent situations, MRI could be more sensitive than a CT scan to detect abnormalities in patients with single
seizures.16 Routine EEG has a yield of about 29% of EEGs showing epileptiform activity, which predicts the risk of seizure
recurrence and allows an initial classification of seizures.15 EEG may also suggest the presence (continuous δ slowing),
localization, and nature (eg, periodic lateralized epileptiform discharges in acute stroke or herpes simplex ence- REMOTE
SYMPTOMATIC SEIZURES AND EPILEPSY Acute symptomatic seizures must be differentiated from seizures occurring after
the acute insult, the so-called remote symptomatic seizures,2 because they differ in prognosis and
phalitis) of a brain lesion.17 A lumbar puncture is essential if the clinical presentation is suggestive of an acute brain infection.
In other circumstances, the test may be misleading, because a prolonged seizure itself can cause cerebrospinal fluid
pleocytosis.15
management. A recent study has shown that individuals whose first seizures were acute symptomatic seizures were 80% less
likely to experience a subsequent unprovoked seizure but had higher early mortality, compared with individuals with a first
remote symptomatic seizure when the etiology is stroke, traumatic brain injury (TBI), and CNS infection.9 These differences
support the argument against the inclusion of acute symptomatic seizures in the current definition of epilepsy. In 2005, ILAE
described epilepsy as “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures,” which
may include single seizures even if acute symptomatic.10 However, it is unclear when epilepsy should be considered as a first
acute symptomatic seizure, because the operational meaning of “enduring predisposition” to have seizures is still under
refinement. An operational def-
TREATMENT AND OUTCOME Efficacy of acute symptomatic seizure treatment is thought to depend on early determination
of all reversible insults and their rapid correction. Despite having biological plausibility, this hypothesis has not yet been
confirmed. Patients with acute symptomatic seizure do not need to be treated with antiepileptic drugs (AED) on a long-term
basis, although such treatment may be warranted on a short-term basis until the acute condition is resolved.18 As acute
symptomatic seizures reflect, at least partially, the severity of insult, it is un- derstandable that their occurrence is generally
associated with a poor outcome.19 However, the direct influence of acute symptomatic seizures on prognosis has not yet been
specifically addressed. inition of “probable epilepsy” was proposed as being after 1 provoked seizure and clinical,
electroencephalography (EEG), imaging, genetic, or other evidence indicating greater than a
EPIDEMIOLOGY OF ACUTE SYMPTOMATIC SEIZURES 50% chance of having an unprovoked seizure.11 The risk of a
Population-based studies showed that the cumulative
risk first unprovoked seizure at 10 years of follow-up after an acute
for acute symptomatic seizures from birth to 80 years of age
is symptomatic seizure is 17% for structural causes, 17% for
3.6%20 and age-adjusted incidence is 29 to 39/100,000
person- encephalopathic ones, and even higher after status epilepticus
years.20,21 Acute symptomatic seizures represent 40% of
total (SE) (41%), particularly if due to structural (45%) or ence-
seizures,20 40% of all first seizures,21 and 50% to 70% of
SE phalopathic causes (57%).12 Further studies should clarify
episodes.22 There is almost double the risk of acute
symptomatic whether postencephalopathic SE should be regarded as epi-
seizures in males (5% until 80y of age) over females
(2.7%).20 lepsy and managed accordingly. Also, the risk of subsequent
This seems to reflect sex-related differences in incidence of
un- unprovoked seizure in patients with repetitive acute symptom-
derlying conditions, such as head trauma, rather than any bio-
atic seizures needs assessment.
logical phenomenon.20 Acute symptomatic seizures are more commonly seen at age extremes, such as epilepsy with an in-
EVALUATION OF A FIRST SEIZURE The occurrence of a first seizure in an adult requires a detailed evaluation aimed mainly
at identifying provoking factors that may be involved and to evaluate the risk of de-
cidence of 253/100,000 newborns/y and of 123/100,000 elders/y, probably due to increased incidence of metabolic, infectious,
and encephalopathic disorders in the neonatal period and of stroke in the elderly.20 veloping epilepsy. The patient’s history as
well as physical and neurological examination may disclose a probable cause of
CAUSES OF ACUTE SYMPTOMATIC SEIZURES
seizure or an increased risk of seizure recurrence (if remote
The main causes of acute symptomatic seizures are
acute symptomatic seizure or family history of epilepsy is present).
stroke (16%), TBI (16%), CNS infection (15%), medication,
Routine testing for glucose, serum electrolytes, calcium, and
alcohol and illicit drugs (14%), electrolytic and metabolic
dis- full blood count has been recommended in the emergency
orders (9%), encephalopathy (5%), and eclampsia (2%).20
department setting by some centers.13,14 Toxicology screening
Causes of acute symptomatic seizures through life show the
may be helpful in specific clinical circumstances (recom-
same distribution as the CNS pathology found across
different mendation level U).15 Neuroimaging and routine EEG should
ages: (1) newborns—encephalitis, metabolic disorders, and
en- be considered as part of the neurodiagnostic evaluation (rec-
cephalopathy; (2) children—encephalitis and head trauma;
(3) ommendation level B).15 Brain computed tomography (CT) or
adults—head trauma, medication or AW, stroke, brain
tumors, magnetic resonance imaging (MRI) has a yield of about 10%,
and eclampsia; and (4) elderly—stroke.20 Neurological and
110
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The Neurologist Volume 18, Number 3, May 2012 Acute Symptomatic Seizures: A Review
systemic insults will be individually discussed according to the
hemorrhage (SAH) 8% and intracerebral hemorrhage (ICH)
following topics: (1) frequency, risk factors (Table 1), patho-
7.3%] compared with ischemic stroke (4.2%).42 A recent
work physiology, and treatment considerations of acute symptomatic
showed that hemorrhagic stroke and cortical lesion were in-
seizures; (2) significance of acute symptomatic seizures in
dependent predictors of acute symptomatic seizures.39 Acute
prognosis of underlying disease and risk for developing epilepsy.
symptomatic seizures were found in 16.2% patients with ICH and in 4.2% patients with ischemic stroke.39
Acute Stroke
NEUROLOGICAL INSULTS
SAH
Acute symptomatic seizures correlate independently with
Acute symptomatic seizures after stroke occur in 2.4% to 6.3% of patients.38,39 Most seizures occur within 2 days, and almost
half (43%) within 24 hours after stroke.25 Seizures are
high blood volume in basal cisterns on initial brain CT43 [odds ratio (OR)=1.1, P=0.05] but not with duration of loss of
consciousness, Glasgow Coma Scale (GCS), presence of mostly focal.23,40 Some generalized tonic-clonic seizures have
aneurysm, or previous history of hypertension.19 Seizures
been reported, although they most probably represent a sec-
possibly arise due to blood in cisterns that may have an
irritant ondary generalization.40 Accordingly, in animal models, the seizure onset zone corresponds to ischemic penumbra.41 A
pro-
effect in the brain cortex44 and after early ischemic brain lesions caused by arterial vasospasm.45 Most patients present
spective study revealed that the frequency of acute symptomatic
generalized seizures,19 suggesting a large seizure onset zone,
seizures is almost twice in hemorrhagic stroke [subarachnoid
most probably mesial and possibly involving the temporal and/ or frontal lobe with a fast spread to the remaining cortex.46 AEDs
are recommended after first acute symptomatic seizures and during the acute phase. Although there are no strict TABLE 1. Risk
Factors for Acute Symptomatic Seizures According
guidelines, some centers suggest AED for 1 to 2 weeks for to
Different Insults
patients who have had a single seizure and AED for 4 to 6
Insults Risk Factors Subarachnoid
hemorrhage
r 2012 Lippincott Williams & Wilkins www.theneurologist.org |
Study
High blood volume in basal cisterns Butzkueven
et al19 Intracerebral
hemorrhage
weeks for the selected group of patients with recurrent seizures or SE during hospital treatment.47
The routine long-term use of anticonvulsants is not recommended (class III, level of evidence B) but may be considered
for patients with risk factors such as prior seizure, parenchymal hematoma, infarct, or middle cerebral artery aneurysms (class
IIb, level of evidence 3B).48 The administration of prophylactic AED may be considered in the immediate posthemorrhagic
period (class IIb, level of evidence B),48 mostly in the presence of high blood volume in basal cisterns.19 Some concerns exist
regarding phenytoin use in seizure prophylaxis, because it has been associated with a worsened cognitive and neurological
outcome.49 Acute symptomatic seizures represent an independent risk factor for late seizures (seizures occurring between 24h
and 6wk) (OR = 27, P<0.01) and are predictive of an unfavorable functional recovery (GCS) at 6 weeks (OR=7.8, P= 0.04),
possibly being surrogate markers for severity of brain insult.19 Late seizures occur in 2/3 of patients within the first 4 weeks and
correlate with rebleeding and high blood volume on initial CT scan.50 Patients with SAH have a 34-fold increase risk of
developing epilepsy compared with the general population.51
ICH
Acute symptomatic seizures correlate with temporal or parietal cortical involvement23,52 and to selected etiologies such as
aneurysm, angioma, or neoplasm.24 Seizures possibly occur due to the presence of blood metabolism products, namely
hemosiderin that seems to have epileptogenic activity similarly to that observed in rat models in whom focal epilepsies are
produced after iron injections into the brain cortex.53 AEDs are recommended after a first acute symptomatic seizure and
should be taken during the acute phase (1 to 2 wk).47 A brief period of prophylactic AED soon after ICH onset may be
considered, as it may reduce the risk of early seizures in patients with lobar hemorrhage (class IIb, level of evidence C).54 The
occurrence of acute symptomatic seizures in patients with ICH does not influence functional or vital outcome at 6 months.52
Risk of developing epilepsy after an acute symptomatic seizure is 27% within 5 years.55 Temporal or parietal cortex;
Faught aneurysm, angioma, or neoplasm
et al23 Weisberg et al24 Ischemic stroke Clinically severe strokes, cortical
involvement
Bladin et al25 Cerebral vein thrombosis
Aphasia or motor deficit; superior
Ferro sagittal sinus and cortical vein;
et al26,27 parenchymal lesions CNS infections Encephalitis; herpes simplex or
neurocysticercosis; impairment of consciousness (GCS r12 at admission)
Kim et al28
Traumatic brain
injury
Children, loss of consciousness or
Bruns and amnesia >30 min, acute
Hauser29 intracerebral hematomas or subdural hemorrhages Medication Chlorpromazine,
clozapine,
maprotiline, clomipramine, bupropion, meperidine, flumazenil, cyclic antidepressants, theophylline, isoniazid, alkylating
antineoplastic agents, and cyclosporine; overdose of medication, intravenous administration; brain lesions; and renal or hepatic
dysfunction
Starkey and Lawson30 Devinsky et al31 Delanty et al8
Illicit drugs Amphetamine-like agents overdose;
cocaine, mostly in women, if smoked
Pascual- Leone et al32 Dhuna et al33 Alldredge et al34 Metabolic and electrolyte disorders
Natremia <115 mg/dL; magnesemia
Boggs35 <0.8 mg/dL; calcemia <5 mg/dL;
Whang glycemia <36 mg/dL; glycemia
et al36 >450 mg/dL associated with
Gao et al37 ketoacidosis
CNS indicates central nervous system; GCS, Glasgow Coma Scale.
111

Ischemic Stroke
2 weeks of the insult.72 Risk factors for seizures at presentation
Predictors for acute symptomatic seizures are clinically
of CVT are focal signs (aphasia, motor deficit), localization
of severe infarcts (risk 2.10 times higher, applying Canadian
CVT (superior sagittal sinus and cortical vein), and paren-
neurological score) and cortical involvement. Also, an asso-
chymal lesion, mainly if supratentorial.26,27 Most important
ciation between extensive and hemorrhagic infarcts was
predictors for seizures occurring within 2 weeks are supra-
found.25,39 Although rare, acute seizures may occur during
tentorial lesions as seen on CT/MRI at admission and
seizures a transient ischemic attack (TIA).56 The differential diagnosis
at the presentation of CVT. Some studies suggest that AEDs
between TIA and seizures may be difficult to perform, for
should be used for 2 weeks in patients with CVT and supra-
example in shaking TIA57 and special seizures and in aphasic
tentorial lesions who present seizures.72 A Cochrane Review
or akinetic subtypes.58 In lacunar stroke, 2.6% of patients have
failed to find any evidence supporting the use of AEDs for
the seizures40 probably related to concurrent cortical involvement
primary prevention of seizures related to CVT.73 Acute and
not directly induced by lacunar stroke. Accordingly,
symptomatic seizures may lead to neurological and systemic
a population-based study showed that in 11 out of 13 patients
deterioration, SE, and death, although seizures have not been
with seizures after lacunar stroke (diagnosed on CT scan
shown to be an independent predictor of death and/or without
apparent cortical ischemic lesion) MRI revealed as-
dependency.26 There is a moderate risk of developing
epilepsy sociated ipsilateral posterofrontal or anterotemporal cortical
within 1 year after acute CVT seizures but later than that it is
ischemic lesion. In addition, single-photon emission CT
rare.27 showed hypoperfusion in the ipsilateral frontal area in
all patients.59 Regarding the etiology of stroke, contrary to what was
TBI previously thought, the risk for acute symptomatic
seizures is
Acute symptomatic seizures occur in 6% of patients74
not increased in cardioembolic strokes.60 Acute brain ischemia
who experience a TBI. Risk factors for occurrence include
age leads to a high concentration of extracellular glutamate that has
(children), markers of severe lesion such as loss of con- been
shown to have the ability to produce recurrent epilepti-
sciousness or amnesia for >30 minutes, and acute ICH or
form discharges in cultural hippocampal neurons.61 The Eu-
subdural hematomas.29 A large randomized double-blind
study ropean Stroke Organization recommends AED to prevent
has shown that phenytoin exerts a beneficial effect by
reducing recurrence of seizures after stroke (class I, level A).62 A recent
seizures only during the first week after severe head injury.75
study revealed that patients with early seizures (<2wk) had
This clinical trial has largely contributed to the American low
seizure recurrence rates (3%), which suggests that after an
Academy of Neurology recommendation for acute symptom-
acute symptomatic seizure a patient should be treated ex-
atic seizure prophylaxis with phenytoin for 7 days after
severe clusively during the first 2 weeks.63 Others argue that the de-
TBI (level A).76,77 Carbamazepine has been evaluated in
an- cision to treat after a first acute symptomatic seizure should be
other study, with results similar to those for phenytoin—a re-
individualized and be based on the functional consequences of
duction in early seizures but no effect on epilepsy even
during first seizure and the preferences of patient.64 The coadministra-
the period of treatment.78 VPA has been evaluated in only 1
tion of recombinant tissue plasminogen activator and the drugs
study, and the comparator was 1 week of phenytoin, making
levetiracetam, valproic acid (VPA), phenytoin, and phenobarbi-
the effect on early seizures difficult to interpret. The early tal
seems to be safe and viable.65 Furthermore, seizures emerging
seizure rate was higher on VPA than on phenytoin, although
during thrombolysis are considered a good sign of restoration of
with the small numbers of early seizures, the difference is not
blood flow.66 Most of the first-generation AEDs, particularly
statistically significant. VPA showed no positive effect in re-
phenytoin, may not be the appropriate choice for these patients
lation to late seizures.79 Independent risk factors for
develop- based on its potential negative effect on functional recovery and
ing posttraumatic epilepsy are acute symptomatic seizures,
>65 interaction with warfarin and salicylates.49 Also, salicylates
years of age, loss of consciousness or amnesia for >24 hours,
displace benzodiazepine and VPA from their plasma protein-
acute intracerebral hematomas, subdural hematomas, and
brain binding sites, which may lead to some decline in their total
contusions.29 Severe TBI increases the risk of epilepsy by
plasma level.67 In contrast, the more recently developed AEDs,
about 17-fold, which translates into >15% of people with se-
including lamotrigine, gabapentin, pregabalin, oxcarbazepine,
vere TBI developing epilepsy.80 Adults with moderate to se-
topiramate, levetiracetam, zonisamide, and lacosamide do not
vere TBI presented 9 times higher risk of epilepsy when
acute demonstrate significant interaction with anticoagulants or anti-
symptomatic seizures are associated. Differently, in children,
platelet agents. In elderly adults with focal onset seizures, la-
acute symptomatic seizures were not associated with an in-
motrigine and gabapentin are recommended (level of evidence
creased risk of epilepsy.81 Mesial temporal lobe epilepsy
(TLE) A) as first-line monotherapy.68 Gabapentin remains the only
may result from TBI in adolescents and adults and not ex-
drug that has been specifically evaluated in stroke patients,
clusively in children. It is frequently bilateral and includes
demonstrating a high rate of long-term seizure freedom (81% at
multifocal lesions.82 Posttraumatic epilepsy begins in most
pa- 30 mo).69 Acute symptomatic seizures are possibly harmful for
tients within the first year, although in severe TBI it may
happen ischemic penumbra due to additional metabolic stress involving
up to 20 years later.80 What occurs in the brain during those
that vulnerable zone.70 Studies in animals showed that repeated
months or years is of great interest, because this period repre-
seizures in the context of brain ischemia increase infarct size and
sents an opportunity for intervention with antiepileptogenic
may harm functional recovery.71 In humans, acute symptomatic
therapies. As clinical trials show that treatment with conven-
seizures correlated on univariate analysis with worse functional
tional AEDs (phenytoin, phenobarbital, carbamazepine,
VPA, or prognosis at admission and follow-up (median of 9mo) and
magnesium) after TBI does not protect against later
development an increased mortality rate at 30 days and 1 year,25 although
of epilepsy,83 the identification of the cellular and molecular
severity of stroke was not a controlled variable.
changes involved in the cascade of events leading up to epilepsy might reveal new therapeutic targets. Multiple experimental
Cerebral Venous Thrombosis (CVT)
models are revealing that there may be stepwise changes that In
CVT, 40% of patients show seizures at presentation
occur in the neuronal network over days to weeks, or even of
disease and a further 6.9% of patients have seizures within
months and years, after an epileptogenic insult. Early changes
112

include the induction of immediate early genes and post-
campus is more resistant to lesions, requiring more severe
translational modifications of neurotransmitter receptor and ion
insults to produce an epileptogenic zone. Other studies have
channel/transporter proteins.84–86 Within days, neuronal death,
shown that a previous history of meningitis or encephalitis at
initiation of an inflammatory cascade, and new gene transcription
an early age (r4 y of age) is a predictor of excellent surgical
has been reported to occur.87,88 Later changes occurring over days
outcome after anterior temporal lobectomy, independently of
to weeks include anatomic changes including axonal sprouting
the presence of HS on preoperative MRI.100 Some reports
have and dendritic modifications, such as the mossy fiber sprouting that
shown that nonfulminant herpetic encephalitis may be a
cause is commonly observed as a hallmark of the chronic epileptic
of HS.101 Recently, the association between human herpes
brain.89 Treatment trials with varying degrees of success have
virus (HHV)-6 infection, complex febrile seizures, and devel-
included compounds that block glutamate receptors or calcium
opment of TLE has been under investigation. Occurrence of
channels, caspase inhibitors and antiapoptotic agents, and neu-
HHV-6 infection coincides with the incidence peak of
complex rotrophic factors, as well as stem cell transplantation.90 Although
febrile seizures. Some studies have shown that 2/3 of patients
there have been some positive results, these treatments have not
with HS who underwent temporal lobectomies present ac- yet
been translated to humans. An important reason for this dis-
tive replication of HHV-6B, which does not occur in other
connect is (1) the lack of available biomarkers in clinical use to
causes of epilepsy.102 This working hypothesis has yet to be
indicate underlying pathogenesis and (2) the unclear alignment
confirmed. between animal models and human patients with
respect to the time-dependent mechanisms within the epileptogenic cascade.91
DISEASES WITH SYSTEMIC INVOLVEMENT
CNS Infection
Acute symptomatic seizures occur in 5% of patients with
Medication, Alcohol, and Illicit Drugs acute CNS
infection.81 Risk factors for occurrence include
Medication encephalitis (14 times more than meningitis),
etiology (eg,
Acute symptomatic seizures may occur after use or
herpes simplex, neurocysticercosis), age (>42y of age) and
withdrawal of medication.2 Risk of medication-related
seizures GCS r12 at admission.28 In herpes simplex encephalitis,
depends on medication type (intrinsic epileptogenicity), and
on acute symptomatic seizures occur in 40% to 60% of patients,
dose and factors intrinsic to the patient (brain lesions and
renal reflecting virus tropism to the mesial temporal lobe.92 Neuro-
or hepatic dysfunction).35 Concrete knowledge of the risk of
cysticercosis presents as acute symptomatic seizures when
seizures related to different medications is based on level 4
imaging identifies at least 1 parasite in the transitional or de-
evidence. Medications related to a moderate risk of seizures
generative phase.93 Although new-onset seizures may occur
are chlorpromazine, clozapine,31 maprotiline, clomipramine,
during calcified cystic stage, chronic epilepsy is generally at-
bupropion, meperidine, and flumazenil.35 A particularly high
tributed to this cyst stage.94 Seizures may occur in acute CNS
risk of seizures is seen in overdose of cyclic antidepressants
infection setting mediated by proinflammatory cytokines such
(up to 20% of patients)30 (especially amoxapine and
maproti- as IL-1 and tumoral necrosis factor87 that, in a culture of
line), theophylline, isoniazid, alkylating antineoplastic
agents, hippocampal neurons, inhibit γ-aminobutyric acid (GABA)
and cyclosporine.35 Factors involved in serum and brain
levels receptors and lower seizure threshold.95 AEDs are commonly
of medication include high dosage, intravenous (IV) admin-
used after first acute symptomatic seizures during the acute
istration, and intrinsic properties of medication affecting de-
phase. Risk factors for developing epilepsy depend on the
gree of penetration into CNS, such as lipid solubility,
molecular existence of acute symptomatic seizures, type of CNS in-
weight, ionization, and protein binding.35 Mechanisms re-
fection, and imaging findings. The risk for epilepsy is 22% for
sponsible for medication-related seizures are well understood
patients with viral encephalitis and acute symptomatic seiz-
for antibiotics, which represent an intermediate risk of seiz-
ures, 10% for patients with viral encephalitis without acute
ures.35 Penicillin, which has been used to create animal
models symptomatic seizures, 13% for patients with bacterial meningitis and acute symptomatic seizures, 2.4% for patients with
of receptor.104 epilepsy,103 Cephalosporins, prevents GABA imipenem, from binding and fluoroquinolones
to the GABA
A
bacterial meningitis without acute symptomatic seizures, and 2.1% for patients with aseptic meningitis.81 Persistent neuro-
antagonize GABA
A
cysticercosis abnormalities on brain CT, namely persistent cysts and calcified cysts, show a 56% and 52% risk of recurrent
seizures, respectively.96 That is the reason why some authors recommend monitoring cyst activity with CT scanning and
continuation of AEDs until resolution of the acute lesion.96 Epilepsy usually begins within 5 years, although it can occur 20
years after CNS infection. Neurocysticercosis is the most common cause of epilepsy in developing countries, where it accounts
for up to 30% of all seizures.97 Refractory epilepsies developed after CNS infections are predominantly multifocal98 and
temporal lobe epilepsies. Multifocal epilepsies usually occur after severe encephalitis with diffuse brain lesions. TLE may
develop if CNS infection occurs at young ages or if the etiologic agent involved presents tropism for this lobe. Acute meningitis
or encephalitis occurring before 4 years of age are more commonly related to hippocampal sclerosis (HS), and when occurring
after this age, they are more frequently associated with extrahippocampal neocortical epilepsy, rarely with abnormalities on
brain MRI.99 In elderly subjects, the hippo-
receptors. Isoniazid competes with pyridoxine, which is usually transformed into pyridoxal phosphate, a
cofactor for GABA synthesis, thus leading to a decrease in GABA levels.105 Treatment of seizures related to neuroleptics and
antidepressants consists primarily of reducing dosage or changing to an alternative medication with a lower risk of seizures such
as haloperidol, risperidone, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors.106 Seiz- ures can be a
feature of withdrawal from barbiturates, benzodiazepines, and other sedatives including meprobamate, chloral hydrate,107 and
zolpidem.108 Downregulation of GABA receptors is probably the mechanism involved.109 Either with barbiturates or
benzodiazepines, withdrawal seizures are dose related and are unlikely in patients taking recommended therapeutic
doses.109,110 Short-acting barbiturates (eg, pentobarbital, secobarbital, amobarbital, and butalbital) are most likely to produce
seizures between day 1 and day 5 after intake discontinuation; full-blown delirium tremens sometimes follows.111 Seizures
during benzodiazepine withdrawal usually occur within 24 hours of stopping a short-acting agent and within several days of
stopping a long-acting agent.112 A Cochrane review concluded that gradual
113

tapering (over 10wk) of benzodiazepines was preferable to abrupt
levels than if inhaled), and not necessarily with concomitant
discontinuation. Switching from short half-life benzodiazepine to
overdose signs.32 Amphetamine-like–related seizures are
often long half-life benzodiazepine before gradual taper withdrawal did
accompanied with other signs of overdose (fever,
hypertension, not receive much support from this study. Carbamazepine might
cardiac arrhythmias, delirium, or coma).34 There is fair prob-
have promise as an adjunctive medication for benzodiazepine
ability of seizure occurrence after hallucinogens.93 In North
withdrawal, particularly in patients receiving benzodiazepines in
America and Europe, the most popular hallucinogens are
daily dosages of 20mg/d or more of diazepam (or equivalent).113
peyote cactus containing mescaline, mushrooms containing
Furthermore, withdrawal of any anticonvulsant and narcotic drugs
psilocybin and psilocin, and the synthetic ergot derivative
(eg, morphine, propoxyphene, midazolam, meperidine) can give
D
-lysergic acid diethylamide. The visual illusions and halluci-
rise to seizures.114
nations produced by these agents are not considered epileptiform,126 but true seizures can follow very high doses.127 Heroin
Alcohol
overdose, with coma, pinpoint pupils, and respiratory depres-
Acute symptomatic seizures may occur after AW or acute
sion, is sometimes associated with seizures, but their occur-
intoxication and represent 1/3 of total hospital admissions due
rence in this setting is so unusual that other possible causes to
seizures.115 A study showed that of all patients (n = 140) at
such as concomitant cocaine use, ethanol withdrawal, or CNS
first considered as presenting alcohol-related seizures, 54% had
infection should be sought.107 Drug-related seizures are
mostly seizures of other etiologies: head injury (26%), idiopathic
generalized but if focal may represent a cocaine-related
(16%), cerebrovascular accident (6%), lesion (4%), and tox-
stroke.128 Current or previous heroin abuse carries a 2.6
times icity (3%).116 Indicators of AW seizures include: history of
higher risk for developing epilepsy.129 chronic alcohol
abuse, history of current alcohol use with recent reduction in consumption, and generalized tonic-clonic
Electrolytic and Metabolic Disorders seizure with other
symptoms of withdrawal such as tremors,
Electrolytic disorders are frequently found in clinical
sweats, or tachycardia (generally beginning within 5 to 10 h of
practice though are rarely associated with seizures. The more
decreasing ethanol intake); the seizure must occur within 7 to
rapid the disturbance develops the more likely it is to induce
48 hours of the last drink.93 AW seizures usually occur either
seizures.130 Finding an electrolytic disorder in a patient with
as an isolated event or in brief clusters, although in <10% of
a first seizure should not preclude the investigation of other
patients they may present as SE. Seizures are more commonly
possible causes. Acute symptomatic seizures are
operationally generalized and characteristically show normal interictal
defined based on the blood sample obtained within 24 hours
of EEG.117 Acute alcohol ingestion has an inhibitory effect on
the seizure, when it is logical to assume that the findings are
N-methyl-
D
-aspartate (NMDA) receptors, reducing excitatory
similar to those at the time of the seizure.93 In a literature
glutamatergic transmission, and has an agonistic effect on
search of studies of electrolytic disorders and seizures, only
GABA are leading upregulated A
to receptors. tolerance. and In The chronic GABA
roles A
alcohol are receptors reversed abuse, are during NMDA downregulated, abstinence, receptors
case studies were found, and in these, the biochemical abnormalities were mostly reported as group means with standard
deviations. Cutoffs at the extreme end of abnormalities fa- with enhanced NMDA receptor function and reduced GA-
voring specificity over sensitivity have been provided by the
BAergic transmission, leading to many of the symptoms and
subcommission on definitions for acute symptomatic
seizure.93 signs of acute withdrawal syndrome, including seizures.118
Accordingly, seizures may occur in hyponatremia (<115mg/
Studies in animals revealed that the seizure onset zone is lo-
dL), especially when a rapid decrease of serum sodium cated
in the brainstem probably in the inferior colliculus119 and
occurs.35 Hypernatremia may cause seizures specially during
also involves the amygdale120 but not the neocortex. AW
rehydration, and it is recommended that sodium
concentration seizures must be promptly treated, because the risk of re-
is reduced at a rate below 0.5 mmol/L/ h to prevent
seizures.131 currence within the same withdrawal episode is about 13% to
Hypomagnesemia (< 0.8 mg/dL) and hypocalcemia (< 5.0
mg/ 24%.121 The only known factor associated with lower seizure
dL) predispose patients to seizures.36 Hypoglycemia (< 36
mg/ recurrence is serum ethanol levels >100 mg/dL.122 In primary
dL) causes seizures by mechanisms similar to those of
cerebral prevention of seizures in AW and for treatment of the AW
hypoxemia. Damage is greatest at the same levels of the cer-
syndrome, benzodiazepines (lorazepam or diazepam) should
ebral cortex, hippocampus, striatum, and cerebellum that are
be chosen (level A recommendation).123 They have a phar-
most vulnerable to hypoxia.35 Nonketotic hyperosmolar
coma macological profile similar to ethanol, enhancing GABAergic
more commonly results in seizures than does diabetic ketoa-
transmission in the CNS. Benzodiazepines (diazepam or lor-
cidosis (glycemia >450mg/dL associated with ketoacidosis),
azepam) are also recommended after the first seizure, including
probably due to the anticonvulsant effect of ketosis.37 When
SE (level A recommendation).123 Some evidence exists that
there is suspicion that the seizure may be acute symptomatic
carbamazepine, oxcarbazepine, and topiramate may be as ef-
due to a metabolic derangement but the proposed cutoffs are
ficacious as benzodiazepines.124 A mortality rate of <3% has
not met, seizures should not be classified as acute
symptomatic been attributed to AW seizures.125
but instead be placed into an “unknown” category but excluded as epilepsy.93 Better cutoffs will require specific studies in the
Illicit Drugs
Seizures are considered as acute symptomatic based on
future. Regarding treatment, it is necessary to rectify the underlying disorder, and AED treatment is usually not needed.132 the
probability of seizure occurrence for specific drugs.93 There is high probability of cocaine involvement if metabolites are
Anoxic Encephalopathy found in urine or blood and for
amphetamine-like agents (eg,
Anoxic encephalopathy after cardiorespiratory arrest
may dextroamphetamine, methylphenidate, ephedrine, and meth-
cause early seizures in 36% of patients. Myoclonic and tonic-
amphetamine) if taken in excess.93 Cocaine-related seizures
clonic seizures are the predominate seizure types.133 Most
occur in 9.3% of subjects,32 mostly in women (3 times more
relevant studies on prognosis of postanoxia myoclonic status
frequent than men),33 immediately or within hours after drug
have defined myoclonic status based only on semiology
abuse, particularly if smoked (when it reaches higher serum
and not on EEG134,135 that, although it does not permit
114

confirmation of the epileptic nature of the myoclonus thereby
cytokines, endothelins, and tissue plasminogen activator that
allowing it be considered as an “acute symptomatic seizure,” it
stimulate excitatory neuronal receptors independently of vas-
also does not exclude it. According to those studies, myoclonic
cular effects.155 Magnesium sulfate is effective in
preventing status within 24 hours of the insult is regarded as a strong
eclampsia reducing by half the risk of seizures in patients
with predictor of poor vital and functional outcome, including
preeclampsia.156 In addition, magnesium sulfate is recom-
persistent vegetative state (recommendation level B),136 al-
mended in the treatment of eclampsia, as it has been shown
to though at least 8 patients did have a satisfactory outcome,
be more effective in decreasing seizure recurrence than dia-
being able to walk, interact, or even return to baseline.137–140
zepam or phenytoin.157 It acts through decreasing peripheral
All these patients had myoclonic SE after cardiorespiratory
vascular resistance, limits vasogenic edema, and centrally in-
arrest secondary to acute respiratory difficulties, rather than
hibits NMDA receptors, providing anticonvulsant activity by
primary cardiac events, raising the possibility that metabolic
increasing the seizure threshold.158 Prenatal exposure to pre-
changes before the arrest might limit anoxic brain damage and
eclampsia or eclampsia is a risk factor for epilepsy among
favor recovery.141 A recent work identified preserved brain-
children born at term.159 Furthermore, eclampsia may be a
risk stem reactions, somatosensory evoked potentials, and EEG
factor for TLE-HS. About 1/3 of women who underwent
reactivity as favorable predictors for awakening beyond veg-
temporal lobectomy due to TLE-HS and without other known
etative state in postanoxic SE provided that SE was treated
risk factors for HS started epilepsy 1 month to 2 years after
vigorously.142 Further studies are needed to evaluate the ben-
eclampsia. The possible mechanism involved is vaso- efit of
treating this subgroup of patients as SE. VPA, clona-
constriction of posterior circulation with subsequent hippo-
zepam, piracetam, and levetiracetam have proved efficacious
campal ischemia after acute hypertension.160 in the
treatment of cortical myoclonus.143 Continuous generalized periodic pattern (PP) is a common EEG endpoint of
Reversible Posterior Leukoencephalopathy (RPL) advanced
coma, particularly after cerebral hypoxia.144 PP is
RPL is characterized by imaging findings of subcortical
recognized as a nonconvulsive status epilepticus (NCSE) when
vasogenic edema (T2, DWI, and ADC hyperintensity) with
EEG or clinical improvement occurs after IV benzodiaze-
preferential parietooccipital involvement and subsequent res-
pines.145 PP is of less clear significance if no clinical or EEG
olution. Major etiologies involved are hypertensive emer-
regression happens after IV benzodiazepines; some authors
gency, eclampsia, and use of immunosuppressive or
cytotoxic regard PP as a sign of severe encephalopathy and others still
agents.161 Seizures are a frequent presentation of RPL
(87%), consider it as possibly epileptic.146 The prognosis of comatose
mostly isolated (63%), although SE may occur.161 Occipital
NCSE with regard to survival or regaining a meaningful life is
seizures are the predominant seizure type.162
Pathophysiology dismal in the overwhelming number of cases.147 A synergistic
involved is known for RPL of hypertensive etiology in
which, effect of ischemic brain injury and electrical SE on mortality
like eclampsia, rapidly increasing arterial tension beyond has
been suggested.148 All patients with comatose NCSE and
certain levels (160/100mm Hg in normotensives or 220/
coma-PP (PP without NCSE criteria) with mechanical ven-
110 mm Hg in hypertensives) leads to a loss of
autoregulation tilation are under generalized anesthesia that includes an an-
with subsequent vasodilatation and edema. Preferential in-
tiepileptic effect (none of these patients is left untreated). In
volvement of posterior circulation is hypothesized to occur
due comatose NCSE and coma-PP with sufficient spontaneous
to scarce sympathetic innervation.163 AED are used after the
respiration, a treatment trial with sufficient IV doses of an AED
first seizure and during acute episodes of RPL. Most patients
has been pragmatically proposed, although AEDs may increase
with acute symptomatic seizures do not progress to epi- the
risk of additional sedation and respiratory depression.146
lepsy.161 One study reported 3 patients with hypertensive
en- Positive results are rare as 1 study showed that only 2 of 33
cephalopathy of childhood onset who developed TLE-HS in
comatose NCSE patients improved with AEDs.149 If the re-
the following months to years.164 sponse leads to
electrographic and clinical improvement, the AED treatment should be continued.146 Less severe chronic
Limbic Encephalitis (LE) brain hypoxia like sleep apnea or
chronic obstructive pulmo-
Clinical features of LE include a recent onset (usually
nary disease is associated with an exacerbation of seizures in
within days or weeks) of seizures, anterograde amnesia, or
adults138 and may also predispose them toward seizures.
affective disturbances with a prominent lability of mood and
Eclampsia
lack of inhibition. In addition, to establish the diagnosis, one of the following additional features must be observed: neoplasm,
Eclampsia is defined as the occurrence of seizures during
LE-associated autoantibodies, temporomedial fluid
attenuated gestational hypertension ( > 20 wk) with proteinuria ( > 300 mg/
inversion recovery/T2 signal hyperintensity on MRI that is
not 24 h),150 seen in 5% to 10% of pregnant whites.151 Seizures
otherwise explainable, or a chronic lymphocytic-microglial
LE may occur postpartum up to the sixth week (55% of patients),
demonstrated on histopathology. LE-associated antibodies
may prepartum (45% of patients), and during partum (5% of pa-
be directed against classic paraneoplastic antigens (Hu, Ma2,
tients).152 Seizures are usually preceded by visual disturbances
CV2/CRMP5, and amphiphysin) or cell membrane antigens
(50%), headache (19%) or epigastralgia (19%) and not nec-
(voltage-gated potassium channels, NMDA receptor, and oth-
essarily by signs of preeclampsia (arterial hypertension or
ers pending characterization).165 Whereas the disorders
related proteinuria) (38%).153 Seizures are usually attributed to brain
to the first category of antibodies are associated with cancer
edema secondary to brain vasodilatation after autoregulation
(lung, testis and other), prominent brain infiltrates of
cytotoxic loss provoked by a rapid increase in arterial hypertension. MRI
T cells, and limited response to treatment, the disorders
related typically shows vasogenic edema in parietooccipital areas.154
to the second category of antibodies associate less frequently
Some clinical findings, such as normal arterial tension or ab-
with cancer (thymoma, teratoma), seem to be antibody medi-
sence of papilledema, challenge the theory that the cited
ated, and respond significantly better to immunotherapy.166
mechanism is the only physiopathology involved. Accord-
Seizures occur in 90% of patients with LE with antibodies to
ingly, it has been proposed recently that uteroplacental ische-
cell membrane antigens, either voltage-gated potassium mia
causes the release of neurokinin B, inflammatory
channel or other cell membrane antigens167,168 and in 50% of
115

patients with paraneoplastic LE.169 Brain MRI shows a typical
8. Delanty N, Vaughan CJ, French JA. Medical causes of
seizures. evolution in all LE subtypes and is characterized by T2/fluid attenuated inversion recovery hyperintensity (representing
vasogenic edema) in the mesial temporal lobe within the first weeks and months of disease (occasionally it may persist for years),
followed by edema reversion associated with persistent hyperintensity and hippocampal atrophy, indistinguishable on imaging
from HS.170 It is unknown whether this imaging
Lancet. 1998;352:383–390. 9. Hesdorffer DC, Benn EK, Cascino GD, et al. Is a first acute symptomatic seizure epilepsy?
Mortality and risk for recurrent seizure. Epilepsia. 2009;50:1102–1108. 10. Fisher RS, van Emde Boas W, Blume W, et al.
Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International
Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470–472. evolution occurs in all patients with LE or it is specific to those
11. Fisher RS, Leppik I. Debate: when does a seizure imply
epilepsy? who present acute symptomatic seizures. According to some
Epilepsia. 2008;49(suppl 9):7–12. studies, LE is the
cause of 24% to 53% of TLE with HS (TLE- HS) of adult onset. HS after LE is more often bilateral than when related to other
causes.165 LE must be considered in the differential diagnosis of adults with recent TLE and amnesic disturbances171 and thus
should be investigated with brain MRI, cerebrospinal fluid, search for occult neoplasia, and autoantibodies related to LE. If the
diagnosis is confirmed, long-term
12. Hesdorffer DC, Logroscino G, Cascino G, et al. Risk of unprovoked seizure after acute symptomatic seizure: effect of status
epilepticus. Ann Neurol. 1998;44:908–912. 13. Tardy B, Lafond P, Convers P, et al. Adult first generalized seizure: etiology,
biological tests, EEG, CT scan, in an ED. Am J Emerg Med. 1995;13:1–5. 14. Dunn MJ, Breen DP, Davenport RJ, et al. Early
management of adults with an uncomplicated first generalised seizure. Emerg immunotherapy (corticosteroids, IVIg, plasma
exchange, cy-
Med J. 2005;22:237–242. clophosphamide, rituximab) is
recommended, and in paraneo-
15. Krumholz A, Wiebe S, Gronseth G, et al. Practice
parameter: plastic cases, treating tumor is the priority.166
evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Sub-
SUMMARY AND CONCLUSIONS Severe head trauma, preeclampsia and possibly high-risk
committee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2007;69:1996–2007. 16.
Wiebe S, Tellez-Zenteno JF, Shapiro M. An evidence-based SAH or ICH are so frequently related to seizures that pro-
approach to the first seizure. Epilepsia. 2008;49(suppl
1):50–57. phylaxis is recommended. A substantial proportion of in-
17. Luders HO, Noachtar S. Atlas and Classification of
Electro- augural seizures (40%) are acute symptomatic. In this setting, it is crucial to rapidly identify all insults possibly involved,
treat underlying diseases, reverse correctable factors, and, in the case of CNS involvement, use AEDs during the acute period.
Risk of developing epilepsy is increased in patients with neurological insults, mostly if accompanied with acute symptomatic
seizures, but not with metabolic disorders. Some
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Annegers JF, Hauser WA, Lee JR, et al. Incidence of acute refractory epilepsies in adults, mostly epilepsy due to HS, may
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1935-1984. be preceded by acute symptomatic seizures related to severe
Epilepsia. 1995;36:327–333. insults including CNS
infection, LE, head trauma, eclampsia, and rarely RPL. New studies are needed in patients with acute symptomatic seizures,
taking each specific insult into consid- eration separately, in order to better acknowledge risk factors including the genetic ones
involved in the development of epilepsy. Hopefully, in the future “true” AEDs may be used in this subgroup of patients to
prevent the subsequent develop-
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