REVIEW ARTICLE

Evaluation of Seizure
Etiology From Routine

C O N T I N UU M AUDIO
INTERVIEW AVAILABLE

Testing to Genetic
ONLINE

Evaluation
By Stephan U. Schuele, MD, MPH, FAAN

ABSTRACT
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PURPOSE OF REVIEW: Recognizing the cause of a first seizure and identifying

the etiology of epilepsy are essential for management. A systematic
approach to patients who present with a first seizure helps distinguish
between an acute symptomatic seizure, a provoked or unprovoked
CITE AS:
seizure, and potential mimickers. Routine testing with EEG and MRI may
CONTINUUM (MINNEAP MINN)
2019;25(2, EPILEPSY):322–342. reveal a predisposition for further seizures and help to establish the
underlying epilepsy syndrome. An acquired etiology can be identified in
Address correspondence to 30% of patients with established epilepsy. The remaining 70% of patients
Dr Stephan U. Schuele,
Northwestern University,
have a presumably genetic etiology. Particularly in patients with specific
Department of Neurology, epilepsy syndromes or suspicion for an autosomal dominant inheritance,
Abbott Hall #1425, 710 N Lake genetic testing and counseling should be considered.
Shore Dr, Chicago, IL 60611,
s-schuele@northwestern.edu.
RECENT FINDINGS: Neuroimaging, autoimmune antibodies, and genetic testing
RELATIONSHIP DISCLOSURE:
have revolutionized our ability to investigate the etiology of many
Dr Schuele has received personal
compensation for serving on the epilepsies. The new epilepsy classification distinguishes structural,
speaker’s bureau of Eisai Co, Ltd metabolic, genetic, infectious, and immune-mediated etiologies, which
and Sunovion Pharmaceuticals
Inc. Dr Schuele serves on the
often help determine prognosis and treatment.
board of directors of the
American Clinical SUMMARY: There is growing acceptance and demystification of the term
Neurophysiology Society and the
Epilepsy Foundation Greater
epilepsy as the most common cause for recurrent seizures. The new
Chicago, and on the editorial classification of epilepsy does not stop with the recognition of particular
board of Journal of Clinical epilepsy syndromes but aims to determine the underlying etiology.
Neurophysiology. Dr Schuele has
received research/grant support This can lead to earlier recognition of surgical candidates, a better
from the Danny Did Foundation understanding of many of the genetic epilepsies, and medical treatments
and the National Institutes of
aimed at the underlying mechanism causing the disease.
Health and has been asked to
provide expert medical
testimony in cases involving
sudden unexpected death in
INTRODUCTION
epilepsy.

UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Schuele reports no disclosure.
© 2019 American Academy
of Neurology.
E
valuating the cause of a seizure is essential to inform rational treatment
decisions and counseling,1 beginning with the question of whether a
spell is truly epileptic or instead may be related to some other
physiologic or psychogenic paroxysmal, transient phenomenon.2 At
the next level, we need to decide whether an epileptic seizure was
caused by an acute insult, provoked by other triggers, or related to a
predisposition for recurrent, unprovoked seizures, defined as epilepsy.

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 The term etiology is typically reserved for the cause of the underlying epilepsy KEY POINT
itself. Before deciding which tests are indicated in the evaluation of a patient’s
● Syncope is the most
epilepsy etiology, it is useful to classify the suspected seizure type(s) and to common mimicker of a
determine the type of epilepsy, either generalized or focal. Particularly when new-onset seizure. A
considering a genetic evaluation, it is helpful to recognize if the patient is situational trigger, an aura
presenting with a distinct epilepsy syndrome. of “going to faint,” and a
quick recovery often
The most recent classification of the epilepsies emphasizes the importance of
support a diagnosis of
searching for the underlying etiology which can be divided into structural, vasovagal syncope.
metabolic, genetic, infectious, immune, or unknown categories (FIGURE 2-1). For
a comprehensive evaluation of epilepsy, a number of comorbidities and
complications should be addressed (TABLE 2-1). Unfortunately, in many patients,
the steps to understand the cause of the seizure and the etiology of the epilepsy
are insufficient for specific categorization of the etiology, and patients end up
as yet another “seizure disorder.”
This article discusses the basic workup of patients presenting with a new-onset
seizure to determine the cause of the first seizure and whether the patient has
epilepsy. In patients with epilepsy, a comprehensive epilepsy evaluation is
needed to determine the underlying etiology. We will then discuss which
patients may benefit from advanced testing, including a genetic evaluation.

NEW-ONSET SEIZURE
The initial question when a patient presents with a first transient paroxysmal
episode is whether the event was likely epileptic or not, based on the patient’s
recollection and witnesses’ reports (FIGURE 2-2). Risk factors for provoked
seizures, such as sleep deprivation and alcohol or illicit drug exposure, need to be

FIGURE 2-1
Classifications of the epilepsies.
a
Denotes onset of seizure.
Reprinted with permission from Scheffer IE, et al. Epilepsia 2017.1 © 2017 John Wiley and Sons.

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EVALUATION OF SEIZURE ETIOLOGY

explored. In approximately 20% of cases, patients may already reveal a history

of absence, myoclonic, or subtle focal aware seizures that were previously
unrecognized as signifying a new-onset epilepsy syndrome. CASE 2-1 exemplifies
the different aspects of a seizure history and the common pitfalls, such as missing
a history of prior auras or overlooking a subtle lesion on brain MRI.
The extended history and examination should determine whether the patient
has evidence of an acute symptomatic seizure (eg, a persistent focal deficit,
prolonged altered consciousness or fever) requiring urgent workup including
brain imaging, blood work, and lumbar puncture to look for infectious causes.
The examination should assess potential injuries from a convulsive seizure, such
as tongue bites, lacerations, back pain from a compression fracture, or shoulder
pain from a subluxation.
Recent developments in the definition and classification of epilepsy align the
diagnosis of epilepsy with the indication for treatment.3,4 Patients with a first
seizure, who have an epileptogenic structural abnormality on brain imaging
and/or interictal epileptiform activity on EEG, have a greater than 60% risk of
recurrence after a first unprovoked seizure and are considered as having

TABLE 2-1 Epilepsy Evaluation

Epilepsy Type: Focal or Generalized

◆ Presence of a specific epilepsy syndrome
◆ Focal: determine if frontal, temporal, or parietooccipital onset; laterality
Seizure Type
◆ Seizure description (patient and witness reports; descriptive seizure classification)
◆ EEG findings (interictal, ictal)
◆ International League Against Epilepsy seizure type (basic, advanced classification)
◆ Frequency, triggers, timing, awareness of events, risk factors
Etiology
◆ Structural
◆ Metabolic
◆ Genetic
◆ Infectious
◆ Immune
◆ Unknown
Comorbidities
◆ Nonepileptic seizures
◆ Depression, anxiety, attention deficit hyperactivity disorder
◆ Migraine
◆ Cognitive impairment
◆ Mortality, sudden unexpected death in epilepsy (SUDEP)

EEG = electroencephalogram.

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 KEY POINTS

● Laboratory testing after

a first seizure should include
a complete blood cell
count; blood chemistry,
including calcium,
magnesium, and phosphate;
thyroid-stimulating
hormone; and urine
toxicology. A 12-lead ECG
should also be considered.

● Acute brain insults can

have a risk of leading to late
seizures in up to 20% of
patients and do not warrant
prolonged seizure
prophylaxis, even if the
injury was associated with
early seizures or status.
Exceptions are possibly a
penetrating head trauma
and herpes encephalitis,
which are associated
with a 50% risk of
developing epilepsy.

FIGURE 2-2
Systematic approach to patients with new-onset seizure.
CT = computed tomography; EEG = electroencephalogram; MRI = magnetic resonance imaging.
Modified with permission from Gavvala JR, Schuele SU, JAMA.2 © 2016 American Medical Association.

epilepsy. Those patients typically benefit from antiepileptic medication, which

is also considered for patients after a first nocturnal convulsion.5
Patients with a provoked seizure are typically not treated but are counseled
about lifestyle modifications and, if necessary, referred for drug and/or alcohol
rehabilitation. Acute symptomatic seizures are often treated with temporary
antiepileptic coverage for a variable amount of time, depending on how quickly
the underlying process resolves or the acute trigger can be corrected. Acute brain
insults can have a risk of leading to late seizures in up to 20% of patients and do
not warrant prolonged long-term seizure prophylaxis, even if the injury was
associated with early seizures or status. Exceptions are possibly a penetrating
head trauma and herpes encephalitis, which are associated with a 50% risk of
developing epilepsy.

Brain Imaging
Patients with a first seizure should undergo neuroimaging. Urgent imaging should
be performed in any patients with a new neurologic deficit, persistent altered
mental status, recent trauma, or prolonged headache. CT scan is often used as the
first imaging modality because of its ease of access and should be considered for

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EVALUATION OF SEIZURE ETIOLOGY

CASE 2-1 A 41-year-old right-handed woman presented for evaluation at an

epilepsy center. Three weeks earlier she had collapsed and convulsed on
a soccer field during a hot summer day. She remembered being at the
field watching her son play, walking toward the other side of the field,
and then losing consciousness. She was unaware of what happened when
she arrived in the emergency department. There was no witness
report, and she was thought to have had a syncopal event given the
circumstances as well as the results of the normal EEG and brain CT in the
emergency department.
During follow-up in an epilepsy center, it was revealed that the patient
had asked a witness who had seen the event, who described how the
patient collapsed to the ground, became rigid, and then started
convulsing for more than a minute. Afterward, the patient appeared
confused and incoherent.
The patient remembered on further questioning that she had a really
weird feeling of sudden, strong fear for about 10 seconds right before she
passed out. The patient had this sudden, distinct fear sensation a few
times before, 1 to 2 times per year, over the last 4 years. She was typically
able to calm herself down with a few deep breaths, usually lasting for a
minute or less. During some of these episodes, she had told her husband
that she felt weird, and when he checked on her, she seemed to always
be able to respond. This had happened while running but also when
resting.
Brain MRI had been done in the interim and was initially interpreted as
normal. On further review, her brain MRI was found to demonstrate a
6-mm ovoid signal abnormality in the right middle temporal gyrus
(FIGURE 2-3). Within the subcortical white matter of the right middle
temporal gyrus there was a region of T2/fluid-attenuated inversion
recovery (FLAIR) hyperintense signal that had a smaller cystic component
with a hypointense rim. This likely represented a focal cortical dysplasia
or glioneuronal tumor. Subsequent 36-hour ambulatory EEG was read
as normal.
The patient’s epilepsy was classified as right temporal lobe epilepsy
with the symptomatology of psychic aura preceding a bilateral tonic-
clonic seizure. According to the International League Against Epilepsy,
this would be classified as a focal aware emotional seizure progressing to
a bilateral tonic-clonic seizure. The frequency was one to two auras per
year with an isolated convulsion. The etiology was identified as right
middle temporal focal cortical dysplasia versus low-grade tumor, and
there were no comorbidities.
There were no further events, and the seizures were controlled with
levetiracetam. The patient underwent resective surgery to confirm the
etiology and ensure the underlying lesion was not a malignant tumor.
Intraoperative electrocorticography found spikes anterior to the lesion.
Surgical pathology demonstrated a ganglioglioma with surrounding tissue
showing focal cortical dysplasia type IIIb. The patient remained
seizure free on medication.

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FIGURE 2-3
Right middle temporal gyrus lesion in the patient in CASE 2-1. A, Coronal T2-weighted turbo
spin echo. B, Coronal fluid-attenuated inversion recovery (FLAIR). C, Axial T2-weighted
turbo spin echo. D, Axial FLAIR. See case text for details.

This case illustrates the different aspects of a seizure history and common COMMENT
pitfalls, such as missing a history of prior auras or overlooking a subtle lesion
on brain MRI and the option for early surgery to understand the etiology and
distinguish benign versus potentially malignant underlying pathology in
selected candidates.

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EVALUATION OF SEIZURE ETIOLOGY

patients with new-onset seizures seen in the emergency department to assess

for an acute brain insult, such as a stroke, bleed, or traumatic injury, often
followed by a more accurate brain MRI performed with and without contrast.6,7
CT scans and standard MRI protocols often fail to detect the lesions associated
with chronic epilepsy; for this reason, an MRI should be performed using an
epilepsy-specific protocol. These lesions typically do not require acute
interventions and are arguably better evaluated during subsequent follow-up.
The use of an epilepsy-protocol MRI, with communication to the reader of the
suspected seizure focus before reading of the study, and review of the imaging
results by an expert neuroradiologist doubles the sensitivity in detecting the
often subtle abnormalities that may be amenable to epilepsy surgery.8,9

Electroencephalogram
Emergency EEG is indicated for patients who do not have a timely recovery after
a seizure, have fluctuating mental status changes, or show a neurologic deficit
that is not explained by the imaging findings. A routine EEG is insufficient to

CASE 2-2 A 36-year-old right-handed woman found to have an incidental

hypophyseal brain aneurysm underwent elective clipping via left pterional
craniotomy. She was awake and alert postoperatively, and the next day,
she was witnessed to have staring episodes and confusion. Her brain CT
demonstrated a small parenchymal hemorrhage in the posterior inferior
left frontal lobe and a small amount of subarachnoid blood. The patient
was started on levetiracetam. Video-EEG was initiated, which showed
evidence of left hemispheric dysfunction and moderate encephalopathy
during the first 2 recording days. On the third day, four electrographic
seizures arising from the left temporal area were seen without a clear
clinical correlate. Lacosamide was added, the seizure activity subsided,
and the patient improved quickly. Left temporal sharp waves were noted,
often in a semiperiodic pattern (FIGURE 2-4). The left temporal sharp wave
activity persisted during the subsequent 3 recording days, although with
diminishing frequency, and the patient was discharged.
The patient was seen in the epilepsy clinic 4 weeks later; she was
seizure free and still taking both medications. An EEG was performed at
that time, which showed resolution of the epileptiform activity. Both
seizure medications were sequentially tapered over a period of 2 months,
first by withdrawing levetiracetam, then lacosamide. The patient was
seen in follow-up 7 months postoperatively and has remained
seizure free.
The patient’s condition was classified as acute symptomatic seizures
with the symptomatology of an altered awareness/responsiveness
seizure. According to the International League Against Epilepsy, this would
be classified as a focal impaired awareness seizure. The frequency was
several per day, but after postoperative day 3, the patient was seizure
free. The etiology was identified as post–left pterional craniotomy for
aneurysm clipping and a small left inferior frontal hemorrhage with
subarachnoid blood, and there were no comorbidities.

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detect subclinical seizure activity, which is captured within the first 30 minutes
in only one-fourth of patients found to have subclinical seizures on long-term
monitoring and in the first 2 hours in one-half of those patients. The yield
increases to greater than 90% with 24- to 36-hour continuous recordings.
CASE 2-2 illustrates the need for prolonged monitoring to capture subclinical
seizures in a patient with an acute symptomatic seizure after brain surgery,
but also emphasizes that the initial EEG may not be appropriate to assess the
long-term risk for subsequent development of epilepsy.
EEG recording after a new-onset seizure can show interictal epileptiform
activity and help determine the potential seizure type and recurrence risk after
a first event. Of patients with new-onset seizures, 29% will have epileptiform
abnormalities on EEG.6 An initial EEG is particularly valuable for patients with
a predisposition for generalized seizures. Those patients tend to have a higher
frequency of epileptiform discharges compared with focal epilepsies and a
typical response to activation with hyperventilation and photic stimulation. The
EEG in generalized epilepsies may normalize with appropriate treatment, and it

FIGURE 2-4
EEGs of the patient in CASE 2-2. A, EEG on postoperative day 4 with prominent left temporal
sharp waves and spikes, often in semiperiodic runs, during stage II sleep. B, EEG 1 month
after surgery. Asymmetry and continuous slow over the left temporal region as sequelae of
the surgery during stage I sleep; no epileptiform abnormalities are seen.

This case illustrates the need for prolonged monitoring to capture COMMENT
subclinical seizures in a patient with an acute symptomatic seizure after
brain surgery. It also emphasizes that EEGs in the early phase may not be
appropriate to assess the long-term risk of epilepsy. The patient remained
seizure free after discontinuing medication despite periodic focal sharp
waves in the acute seizure setting.

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EVALUATION OF SEIZURE ETIOLOGY

is important to obtain a pretreatment study. There does appear to be a slightly

higher yield of epileptiform abnormalities on EEGs performed in patients within
24 to 48 hours of a new-onset seizure. However, acute EEG changes may reflect
the sequelae of the acute insult to the brain or aftermath of the seizure and may
not necessarily be predictive of the risk of late seizure recurrence (CASE 2-2).
Patients presenting with a provoked seizure should get at least an EEG and a
brain imaging study because not infrequently they are found to have a remote
structural abnormality or an EEG indicating a predisposition for generalized
seizures.

EPILEPSY EVALUATION
The evaluation in a patient with established epilepsy differs in many aspects from
that of a first seizure. In particular, chances to have a reliable witness report for
the events are higher, and the yield of EEG to capture interictal epileptiform
abnormalities increases. In patients with frequent events, video-EEG recording
can be considered, and brain imaging needs to focus on structural abnormalities
amenable to surgery.

Seizure Evaluation
Patients with established epilepsy may have several seizure types. The interview
should provide guidance for the patient to describe the seizures in his or her
own words, to characterize different seizure types associated with specific
epilepsy syndromes, or recognize that focal seizures often evolve from an aura to
loss of awareness and sometimes convulsions. A variety of sources for witness
reports may be available, and the patient or family may have already recorded an
event on video. It may also become apparent when speaking to family members
and other witnesses that the patient is not aware of some seizures. For patients
with epilepsy who continue to have seizures, we want to know if the seizure was
caused by some trigger or nonadherence to medication or is indicative of an
incomplete medication response requiring medication adjustment. Seizures may
be seen mostly during certain times of the day or triggered by specific situations,
suggesting a form of rare reflex epilepsy.
The physician should use a systematic descriptive vocabulary to capture the
essential components of the clinical seizure and its evolution (FIGURE 2-5).10
Many epilepsy centers use this vocabulary to create a seizure classification based
purely on the clinical symptoms and observed behavioral signs, which is helpful
to localize the seizure onset and to capture all essential components of a seizure
and its evolution. This independence from other tests allows a seizure description
without having to know the EEG onset pattern, which is often more practical.11
CASES 2-1 and 2-2 demonstrate the use of a systematic descriptive classification in
parallel with the International League Against Epilepsy (ILAE) classification.
The ILAE seizure classification was revised in 2017.12,13 The terms for each
seizure type indicate the suspected or confirmed EEG onset (focal versus
generalized) followed by a brief descriptor of the patient’s symptoms, creating
an electroclinical entity. The basic version divides focal aware seizures and
focal impaired awareness seizures (FIGURE 2-6). Focal and generalized seizures
can be classified as motor and nonmotor. A more extended version allows
additional descriptors.
Approximately 70% to 80% of patients with chronic focal epilepsies
eventually develop interictal epileptiform discharges. The yield is noticeably

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 KEY POINTS

● Typical MRI lesions

associated with surgically
amenable epilepsy, such as
glioneuronal tumors,
low-grade gliomas,
hippocampal sclerosis,
small cavernous
malformations, and subtle
malformations of cortical
development (eg, cortical
dysplasia or isolated
periventricular nodular
heterotopia), are not seen
on brain CT scans and often
missed on standard MRIs.

● An epilepsy-protocol
FIGURE 2-5
brain MRI differs from a
Glossary of descriptive terminology for ictal symptomatology.
a
Autonomic symptoms can be verifiable for the observer (eg, tachycardia, goosebumps).
typical MRI in that it includes
Data from Blume WT, et al, Epilepsia.10 thin 1- to 3-mm slices
without interslice gap and
coronal fluid–attenuated
inversion recovery
higher in long-standing focal epilepsies compared with first-time seizures. The sequences, which offer
yield to capture the presence of discharges depends on the duration of the additional sensitivity over
recording. Today, most patients and physicians prefer the convenience of an standard-protocol MRIs.
ambulatory EEG and the ability to request interpretation by an expert reader
● A brain CT and an EEG
over repeat routine EEGs. In a study by Faulkner and colleagues,14 in patients
should be considered even
with epilepsy found to have interictal epileptiform abnormalities during 4 days in the presence of an
of EEG recordings, interictal epileptiform discharges were recorded in 44% alternative etiology for a
of patients within 4 hours, 58% within 8 hours, 85% within 24 hours, and 95% provoked seizure.
within 48 hours of recording. Recording for the full 96-hour period revealed
only 5% new interictal epileptiform discharges. The median latency to the
first discharge was significantly shorter in patients with generalized epilepsies
(43 minutes) compared with focal epilepsies (512 minutes for extratemporal
and 590 minutes for temporal lobe epilepsies), indicating a 2-day recording
length as most adequate for looking for interictal epileptiform activity
and a potentially shorter recording length in suspected generalized epilepsies.

FIGURE 2-6
International League Against Epilepsy classification of seizure types.
Reprinted with permission from Fisher RS, et al, Epilepsia.12 © 2017 John Wiley and Sons.

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EVALUATION OF SEIZURE ETIOLOGY

TABLE 2-2 Electroclinical Syndromes Arranged by Age at Onseta

Neonatal Period
◆ Benign familial neonatal epilepsy
◆ Early myoclonic encephalopathy
◆ Ohtahara syndrome
Infancy
◆ Epilepsy of infancy with migrating focal seizures
◆ West syndrome
◆ Myoclonic epilepsy in infancy
◆ Benign infantile epilepsy
◆ Benign familial infantile epilepsy
◆ Dravet syndrome
◆ Myoclonic encephalopathy in nonprogressive disorders
Childhood
◆ Febrile seizures plus (can start in infancy)
◆ Panayiotopoulos syndrome
◆ Epilepsy with myoclonic atonic (previously “astatic”) seizures
◆ Self-limiting epilepsy with centrotemporal spikes
◆ Autosomal dominant nocturnal frontal lobe epilepsy
◆ Late-onset childhood occipital epilepsy (Gastaut type)
◆ Epilepsy with myoclonic absences
◆ Lennox-Gastaut syndrome
◆ Epileptic encephalopathy with continuous spike-and-wave during sleep
◆ Landau-Kleffner syndrome
◆ Childhood absence epilepsy
Adolescence to Adulthood
◆ Juvenile absence epilepsy
◆ Juvenile myoclonic epilepsy
◆ Epilepsy with generalized tonic-clonic seizures alone
◆ Progressive myoclonic epilepsies
◆ Autosomal dominant epilepsy with auditory features
◆ Other familial temporal lobe epilepsies
Less Specific Age Relationship
◆ Familial focal epilepsy with variable foci (childhood to adult)
◆ Reflex epilepsies

a
Modified with permission from Berg AT, et al, Epilepsia.16 © 2010 John Wiley and Sons.

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 In most patients, particularly if they respond to medical therapy and KEY POINT
remain seizure free, a confirmation of the seizure and epilepsy type through
● According to national
symptomatology and interictal EEG is sufficient for management. However, guidelines, patients who
in patients whose seizures remain resistant to medication after 1 year, an continue to have seizures
evaluation in the epilepsy monitoring unit is recommended to understand the after 1 year on medical
actual cause of the seizures. Approximately 25% of patients considered therapy should be referred
to an epilepsy center.
intractable are found to have nonepileptic seizures, and 10% to 20% of patients
with epilepsy also have nonepileptic events. Some patients with generalized
epilepsies will not be recognized unless they are monitored off medication for
several days. Last but not least, there is the considerable number of patients
with focal epilepsy who are candidates for epilepsy surgery who benefit from
a presurgical evaluation in the epilepsy-monitoring unit.15

Epilepsy Type
The next step in the evaluation is to determine the type of epilepsy: focal,
generalized, or unknown. In the ILAE classification, the seizure type and
epilepsy type largely overlap with each other; however, there is recognition of a
subgroup of patients (eg, those with Lennox-Gastaut syndrome or Dravet
syndrome) who can have focal and generalized onset seizures and present
with a combined generalized and focal epilepsy. In focal epilepsies, the epilepsy
type should be further divided into the anatomic region of suspected seizure
origin based on seizure description, imaging, and interictal EEG investigations or
confirmed by ictal video-EEG–recorded seizures and accordingly classified as left
or right, temporal, frontal, or parietooccipital lobe epilepsy.

Epilepsy Syndrome
A variety of distinct epilepsy syndromes have been described, many with onset
in childhood or adolescence (TABLE 2-2).16 The recognition of these syndromes
is not only important for treatment and prognosis, it also guides genetic
evaluations because many of the established epilepsy syndromes have a likely
genetic etiology.

Etiology of Epilepsy
The etiology of epilepsy can be divided into six different categories: structural,
metabolic, genetic, infectious, immune, and unknown.1,16 The etiologies are not
mutually exclusive, allowing a structural-genetic cause for patients with tuberous
sclerosis or a metabolic-genetic cause for patients with epilepsy associated with
inborn errors of metabolism. Genetic generalized epilepsies include four epilepsy
syndromes still referred to as idiopathic generalized epilepsies: childhood
absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and
sporadic generalized tonic-clonic seizures alone. Genetic generalized epilepsies
also include the group of patients with epileptic encephalopathies, which are
often due to a specific genetic cause.

STRUCTURAL. Most patients with epilepsy require a high-resolution epilepsy-

protocol brain MRI to assess the possibility of a structural etiology. An exception
can be made in patients with a convincing history and classical EEG findings
of an idiopathic generalized epilepsy. The presence of a resectable, epileptogenic
lesion should trigger a surgical evaluation in patients with medication-resistant

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EVALUATION OF SEIZURE ETIOLOGY

epilepsy. In patients with intractable focal epilepsy and a normal MRI, a

fludeoxyglucose positron emission tomography (FDG-PET) scan is useful in
looking for a hypometabolic region.

METABOLIC. Epilepsy associated with inborn errors of metabolism usually has

the features of an epileptic encephalopathy with seizures arising at an early age,
often refractory to antiepileptic drugs, and associated with severe cognitive,
sensory, and/or motor impairment.17 Most metabolic epilepsies have a presumed
genetic basis.1 They are typically categorized according to the biochemical
pathway involved and the age of onset. The presence of other neurologic
abnormalities, such as movement disorders and ataxia, systemic involvement,
parental consanguinity, and a positive family history of a similar illness, can be
clues.18 The general examination should look for dysmorphic features and an
abnormal head circumference. Skin and hair abnormalities can point toward
Menkes syndrome or a biotinidase deficiency. A formal ophthalmologic
evaluation is essential in identifying signs of pigmentary retinopathy (neuronal
ceroid lipofuscinosis, mitochondrial disorders), macular cherry-red spots
(gangliosidosis, Niemann-Pick disease), lens dislocation (sulfite oxidase
deficiency), and cataracts (serine biosynthesis defects). A selected number of
inborn errors of metabolism can present in adolescence and adulthood
(TABLE 2-3) and require a systematic evaluation for biochemical abnormalities
and genetic causes (FIGURE 2-7).

TABLE 2-3 Metabolic Epilepsies Presenting in Adolescence or Adulthood

Progressive Myoclonic Epilepsies

◆ Ceroid lipofuscinosis
◆ Sialidosis type 1
◆ Gaucher disease type III
◆ Mitochondrial cytopathies
◆ Lafora disease
◆ Unverricht-Lundborg disease
With Intellectual Disability
◆ Disorders of creatine metabolism
◆ Mitochondrial disorders
◆ Glucose transporter type 1 deficiency
◆ Urea cycle defects
◆ Organic acidemias
◆ Succinic semialdehyde dehydrogenase deficiency
◆ Lysosomal storage disorders (juvenile Niemann-Pick disease type C)
Without Intellectual Impairment
◆ Wilson disease
◆ Porphyria

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FIGURE 2-7
Epilepsy associated with inborn errors of metabolism.
EEG = electroencephalogram; MRI = magnetic resonance imaging; MRS = magnetic resonance
spectroscopy; 5-MTHF = L-methyltetrahydrofolate.
Reprinted with permission from Sharma S, Prasad AN, Int J Mol Sci.18 © 2017 MDPI AG, Basel, Switzerland.

INFECTIOUS. Infections trigger not only acute symptomatic seizures during the
initial infection but may also lead to late seizures remote from the initial infection
onset and its resolution that are instead consistent with epilepsy. Infectious
etiologies include neurocysticercosis, viral encephalitis, bacterial meningitis,
fungal infection, tuberculosis, toxoplasmosis, malaria, and HIV.
Neurocysticercosis is more prevalent in developing countries and is often the
leading cause of epilepsy in those countries. Seizures can occur in any stage of
the cyst formation. Seizures in the acute phase of a bacterial meningitis are an
ominous sign and associated with increased mortality. Late epilepsy is seen
in approximately 5% to 10% of survivors after bacterial meningitis.19 Viral
encephalitis–related epilepsy is most commonly seen with herpes simplex type 1,
which develops in 50% of patients. Acute seizures are a presenting symptom
of herpes simplex type 1 in a similar proportion. Cytomegalovirus is the most
common fetal viral infection and can cause malformations of cortical
development and calcifications, with seizures typically presenting in the first
month of life. Subacute sclerosing panencephalitis is a chronic, progressive
disorder associated with an initial measles infection before the age of 2 years.
Acute symptomatic seizures are seen in influenza B, varicella, measles, mumps,
rubella, and West Nile virus, but there is limited information about how often the
acute viral encephalitis leads to late seizures.20 Approximately 50% of congenital
Zika virus cases are associated with epilepsy, typically presenting in the first

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EVALUATION OF SEIZURE ETIOLOGY

months of life.21 Tuberculous vasculitis and also cortical tuberculomas can lead to
epilepsy. Seizures in cerebral toxoplasmosis are typically associated with the
reactivation of a latent infection in immunocompromised individuals.

INFLAMMATORY. Increasingly, autoimmune antibody syndromes are recognized

as a cause of epilepsy.22 The majority of these antibodies are directed against
neuronal cell surface antigens, including synaptic neurotransmitter receptors,
ion channels, or related proteins (TABLE 2-4). A second group has antibodies
specific for intraneuronal nuclear or cytoplasmic antigens. Both groups have
an association with cancer risk, which is as high as 90% in the patients with
nuclear or cytoplasmic antibodies. Thyroid antibodies seen in patients with
steroid-responsive encephalopathy and patients with high levels of glutamic
acid decarboxylase 65 antibodies can present with immune-mediated epilepsy.
Patients with autoimmune epilepsy often present with a high frequency of
seizures and/or treatment-refractory status epilepticus, which is discussed in
“Epilepsy Emergencies: Status Epilepticus, Acute Repetitive Seizures, and
Autoimmune Encephalitis” by Stephen VanHaerents, MD, and Elizabeth E.
Gerard, MD, in this issue of Continuum.23 Aside from high seizure frequency and
treatment resistance, patients often show progressive mental status change,
neuropsychiatric symptoms, autonomic dysfunction, a viral prodrome, and

TABLE 2-4 Autoimmune Antibodies Associated With Epilepsy

Antinuclear and Cytoplasmic Antibodies

◆ Antineuronal nuclear antibody type 1 (ANNA-1) (anti-Hu)
◆ Antineuronal nuclear antibody type 2 (ANNA-2) (anti-Ri)
◆ Antineuronal nuclear antibody type 3 (ANNA-3)
◆ Antiglial neuronal antibody type 1 (AGNA) (SOX1)
◆ Purkinje cell antigen type 1 (PCA-1) (anti-Yo)
◆ Purkinje cell antigen type 2 (PCA-2)
◆ Purkinje cell antigen type Tr (PCA-Tr)
◆ Collapsin response mediator protein-5 (CRMP-5) (anti-CV2)
◆ Amphiphysin
◆ Glutamic acid decarboxylase 65 (GAD65)
Plasma Membrane Antibodies
◆ N-methyl-D-aspartate (NMDA) receptor
◆ Voltage-gated potassium channel (VGKC) complex
◆ Leucine-rich glioma inactivated 1 (LGI1)
◆ Contactin-associated protein-like 2 (Caspr2)
◆ α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor
◆ γ-Aminobutyric acid (GABA)-B receptor
◆ P/Q and N-type calcium channel
◆ Neuronal ganglionic AChR
◆ IgLON5 neuronal cell surface protein

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sometimes facial or faciobrachial dyskinesias. Testing may show CSF findings KEY POINT
consistent with inflammation, increased signal in the mesial temporal lobe on
● Genetic testing should be
T2-weighted images, and associated malignancies on screening.24 In patients considered in all patients
with longer-standing epilepsy who may not have initially presented as an with an autosomal dominant
emergency, the yield of a positive antibody test result can be predicted through familial epilepsy, epileptic
an Antibody Prevalence in Epilepsy (APE) score of greater than 4, which has a encephalopathies, and
progressive myoclonic
sensitivity of 82.6% and a specificity of 82.0%.24 The score was validated in a
epilepsy and patients with
large cohort of patients with epilepsy and had a sensitivity of 97.7% in patients clinical findings suggestive
with epilepsy of unknown etiology to predict the presence of an autoimmune of a genetic etiology.
antibody, which was seen in 43 of 87 patients.25

GENETIC. Only approximately 30% of epilepsies are acquired, and the remaining
70% are likely caused by one or more genetic factors.26 The genetics of epilepsies
follow a complex pattern, and most genetically determined epilepsies have a
polygenic basis with several susceptibility genes contributing to the disease.27
Next-generation sequencing technology has revolutionized gene discovery in
epilepsy and many other disorders.28
Comparative genomic hybridization microarray (FIGURE 2-8) is typically
the first test for patients presenting with epilepsy and developmental delay,
intellectual impairment, and/or dysmorphic features. In patients with genetic
generalized epilepsy and intellectual disability, genomic hybridization
microarray is able to detect a copy number variant in 28%. Copy number variants
have been identified in approximately 1% of the idiopathic generalized epilepsies.
Phenotypic and genetic variability is seen in most genetic epilepsies, and
single-gene testing has been largely replaced by gene panels and whole exome

FIGURE 2-8
Genetic testing. Comparative genomic hybridization microarray is typically the first test for
patients presenting with epilepsy and developmental delay. Single-gene testing has been
largely replaced by gene panels and whole exome sequencing. Gene panels are either
targeted for a specific phenotype, eg, a progressive myoclonic epilepsy, or offered as a
comprehensive epilepsy gene panel. Whole exome sequencing and whole genome
sequencing are usually performed within the setting of a genetic clinic.
Courtesy Gemma Carvill, PhD, Northwestern University.

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EVALUATION OF SEIZURE ETIOLOGY

sequencing. Gene panels are either targeted for a specific phenotype, eg, a
progressive myoclonic epilepsy, or offered as a comprehensive epilepsy gene
panel. Whole exome sequencing and whole genome sequencing are usually
performed within the setting of a genetic clinic and research program with access
to genetic counseling and the ability to interpret variants of unknown significance.
Dravet syndrome is the best-known epileptic encephalopathy with a distinct
clinical presentation associated with a pathogenic variant in the SCN1A gene in
80% of patients. Dravet syndrome typically presents with early, prolonged
febrile seizures, which are often provoked by modest hyperthermia. Generalized
tonic-clonic, tonic, and hemiconvulsive seizures are most common. Myoclonic
seizures develop later in the course. Patients often show cognitive dysfunction,
ataxia, and psychomotor regression and demonstrate attention deficit
hyperactivity disorder–like behavior. However, variable penetrance and
phenotypic severity make clinical characterization challenging. Interestingly,
10% of families with generalized epilepsies with febrile seizures plus (GEFS+) are
positive for SCN1A, and family members are at risk of presenting with more
severe epilepsies, such as myoclonic-astatic seizures or Dravet syndrome. A
variety of other genes have been reported to cause Dravet syndrome–like
disorders, including SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1,
GABRG2, STXBP1, HCN1, CHD2, and KCNA2, requiring gene panel testing or
whole exome sequencing. Epileptic encephalopathies other than Dravet
syndrome have been associated with mutations in CDKL5, STXBP1, SCN2A,
SCN8A, KCNQ2 genes; most are de novo mutations. Recessive or mitochondrial
or more complex inheritance is rare and includes X-linked PCDH19
encephalopathy in girls with normal male carriers.
The clinical neurologist should be familiar with a small group of genetic
epilepsies that present with a rather distinct clinical phenotype and if clinically
indicated can be evaluated with commercially available gene panels. Notable
genetic epilepsies include the autosomal dominant focal epilepsies:

u Autosomal dominant temporal lobe epilepsy

u Autosomal dominant nocturnal frontal lobe epilepsy
u Familial focal epilepsy with variable foci

Autosomal dominant temporal lobe epilepsy is associated with mutations in

the LGI1 (30%) and RELN gene and has a 55% to 78% penetrance. Patients
present with distinct auditory auras or receptive aphasia that may progress to
tonic-clonic seizures. Onset is typically in adolescence or early adulthood, and
patients typically have normal intellect and good antiepileptic drug responses.
Autosomal dominant nocturnal frontal lobe epilepsy is associated with neuronal
nicotinic acetylcholine receptor mutations, which are seen in 20% of patients
with this disorder. A more severe form with intellectual disability is associated
with KCNT1 mutation. Penetrance is approximately 70%, and seizures typically
present in childhood to adolescence, characterized by clusters of nocturnal
seizures, which can be tonic, dystonic, or hypermotor, with 70% preceded by
nonspecific aura. The diagnosis is clinical, and the EEG often obscured or
normal. Patients respond well to carbamazepine and zonisamide, but 30% are
drug resistant. Familial focal epilepsy with variable foci is associated with
mutations in the DEPDC5, NPRL2, and NPRL3 genes, all part of the guanosine
triphosphatase (GTPase)–activating protein activity toward Rag (GATOR)

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complex, accounting for at least 10% of familial frontal lobe epilepsies. Patients KEY POINTS
show variable foci and a 50% to 80% penetrance. Onset is variable from 1 month
● Whole exome sequencing
to 51 years of age with an average of 12 years. Long periods of remission in the and whole genome
teen/adult years are noted. sequencing are usually
It is worthwhile to be familiar with glucose transporter type 1 (GLUT1) performed within the setting
deficiency syndromes associated with SLC2A1 gene mutation given the excellent of a genetic clinic and
research program with
response to dietary treatment and the recent discovery of milder, later-onset
access to genetic counseling
variants.29 The typical presentation is in the first months of life. Children often and the ability to interpret
present with seizure clusters and status epilepticus during fasting (eg, before variants of unknown
breakfast). Associated features are often severe psychomotor retardation, dystonia, significance.
ataxia, and acquired microcephaly. The syndrome can present as early-onset
● It is worthwhile to be
absence epilepsy and myoclonic-astatic epilepsy. A diagnostic clue is a low fasting familiar with glucose
CSF glucose level. Excellent responses to ketogenic diet are seen. transporter type 1 (GLUT1)
Periventricular nodular heterotopia associated with a filamin A mutation is deficiency syndromes
important to recognize given the implication for prenatal counseling in this associated with SLC2A1 gene
mutation given the excellent
X-linked dominant disorder. It affects female patients who typically show response to dietary
normal or borderline intelligence and presents with seizures in close to 90%. treatment and the recent
Forty-nine percent of classic bilateral periventricular nodular heterotopia cases discovery of milder,
are associated with X-linked filamen A mutations, which are perinatally lethal in later-onset variants.
affected males. As a consequence, half of male offspring perish, and half of
● Genetic counseling for a
female offspring are affected. specific epilepsy syndrome
Understanding the genetic etiology of an individual with epilepsy has a can be straightforward in
number of clinical implications. A genetic diagnosis provides closure and can patients with a 100%
penetrant syndrome but
avoid unnecessary testing or lead to important screening for known complications
complicated in situations of
or malignancies. There is the hereditary aspect for some genetic epilepsies, incomplete penetrance and
which affects prognosis and counseling. Mitochondrial disorders presenting de novo mutations (eg,
with epilepsy may not be recognized until adulthood and the diagnosis has Dravet syndrome) and
a direct impact on treatment and counseling of the patient and family members.30 should be performed
with the help of a
Discovering a specific gene abnormality can also open the door for precision genetic counselor.
medicine. A gene abnormality may not only cause the disease but also be
associated with a specific mechanism leading to seizures amenable to specific ● The high prevalence of
treatment. SCN1A-associated Dravet syndrome responds well to medications comorbidities associated
with epilepsy is best
such as clobazam and valproate and can worsen with sodium channel blockers, addressed within a
whereas SCN8A-associated Dravet syndrome may benefit from sodium channel comprehensive care
blockers and PCDH19-related Dravet syndrome may respond well to steroids.31 setting including a social
The mammalian target of rapamycin (mTOR) signaling pathways affect worker, psychologist,
psychiatrist,
regulation of cell growth and proliferation. Mutations in the mTOR pathway can
neuropsychologist,
lead to a spectrum of malformations of cortical development ranging from focal dietician, and
cortical dysplasia to hemimegalencephaly and megalencephaly, or can cause genetic counselor.
multisystem disorders such as tuberous sclerosis complex or hamartoma
syndromes including Cowden and Lhermitte-Duclos disease.32 Several mTOR
regulatory genes, DEPDC5, MTOR, NPRL3, PI3KCA, and PTEN, are associated
with hemimegalencephaly and lesional and nonlesional focal cortical dysplasia
and can present as germline or somatic mutations in the brain. In
polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome
(PMSE), an autosomal-recessive disorder associated with mutations in the
STRADA gene, treatment with the mTOR inhibitor rapamycin prevents the
occurrence of seizures. In tuberous sclerosis complex, seizure control with
everolimus, a synthetic mTOR inhibitor, has been more variable, suggesting that
treatment before seizure onset may be crucial for prevention of the epilepsy.32

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EVALUATION OF SEIZURE ETIOLOGY

Physicians treating patients with epilepsy are frequently asked about the
inheritance risk of epilepsy. In the absence of a family history or evidence of a
specific genetic syndrome, the epilepsy risk for the general population is estimated
at approximately 1%; for a child of a mother with epilepsy, 2.8% to 8.7%; for a
child of a father with epilepsy, 1.0% to 3.6%. It increases if the parent’s epilepsy
started before the age of 20 years.33 Genetic counseling for a specific epilepsy
syndrome can be straightforward in patients with a 100% penetrant syndrome but
complicated in situations of incomplete penetrance and de novo mutations (eg,
Dravet syndrome) and should be performed with the help of a genetic counselor.
COMORBIDITIES. Epilepsy presents with a bidirectional relationship with other
neurologic (eg, stroke, migraine, dementia, traumatic brain injury) and
psychiatric (eg, depression and anxiety) comorbidities.34 Several diseases,
including depression, anxiety, dementia, migraine, heart disease, peptic ulcers,
and arthritis, are up to 8 times more common in people with epilepsy than in the
general population.35 The prevalence of comorbidities persists even in patients in
seizure remission, and patients with inactive epilepsy remain at risk of
premature mortality, suggesting a systemic component involved in the etiology
of epilepsy. This component may be mediated by basic pathophysiologic
processes and/or genetic factors.36 To have a comprehensive understanding of
the etiology of epilepsy, these comorbidities and systemic vulnerability should be
taken into account and adequately treated.

CONCLUSION
Evaluating the etiology of seizures has noticeably changed over the past decade.
There is a greater emphasis to distinguish acute symptomatic and provoked
seizures (requiring treatment of the underlying condition) from an unprovoked
seizure, which may already represent epilepsy. There is growing acceptance and
demystification of the term epilepsy as the most common cause of recurrent
seizures. The new classification of epilepsy does not stop with the recognition of
particular epilepsy syndromes but aims to recognize the underlying etiology.
This can lead to earlier recognition of surgical candidates, a better understanding
of many of the epileptic encephalopathies, and with time, hopefully medical
treatments aimed at the underlying mechanism causing the disease.37

USEFUL WEBSITES
INTERNATIONAL LEAGUE AGAINST EPILEPSY
DIAGNOSTIC MANUAL
The website provides an excellent diagnostic
manual for epilepsy diagnosis in clinical practice.
Epilepsydiagnosis.org
GENE REVIEW
Peer-reviewed, regularly updated chapters
providing clinically relevant information on inherited
conditions, covering diagnosis, management, and
genetic counseling.
www.ncbi.nlm.nih.gov/books/NBK1116/

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