Received: 9 January 2023

| Accepted: 3 March 2023

DOI: 10.1002/epd2.20045

SEMINAR IN EPILEPTOLOGY

Focal epilepsies: Update on diagnosis and classification

Fábio A. Nascimento1 | Daniel Friedman2 | Jurriaan M. Peters3 |

Meriem K. Bensalem-­Owen4 | Fernando Cendes5 | Stefan Rampp6,7 |
Elaine Wirrell8
| Ingmar Blümcke 9
| William Tatum 10
| Sándor Beniczky11,12,13
1
Department of Neurology, Washington
University School of Medicine, Abstract
St. Louis, Missouri, USA Correctly diagnosing and classifying seizures and epilepsies is paramount to en-
2
Department of Neurology, NYU sure the delivery of optimal care to patients with epilepsy. Focal seizures, defined
Grossman School of Medicine,
New York, New York, USA
as those that originate within networks limited to one hemisphere, are primar-
3
Department of Neurology, Boston ily subdivided into focal aware, focal impaired awareness, and focal to bilateral
Children's Hospital, Harvard Medical tonic–­clonic seizures. Focal epilepsies account for most epilepsy cases both in
School, Boston, Massachusetts, USA
children and adults. In children, focal epilepsies are typically subdivided in three
4
Department of Neurology, University
groups: self-­limited focal epilepsy syndromes (e.g., self-­limited epilepsy with
of Kentucky College of Medicine,
Lexington, Kentucky, USA centrotemporal spikes), focal epilepsy of unknown cause but which do not meet
5
Department of Neurology, criteria for a self-­limited focal epilepsy syndrome, and focal epilepsy of known
Universidade Estadual de Campinas cause (e.g., structural lesions—­developmental or acquired). In adults, focal epi-
(UNICAMP), Campinas, Brazil
6
lepsies are often acquired and may be caused by a structural lesion such as stroke,
Department of Neurosurgery,
University Hospital Erlangen, infection and traumatic brain injury, or brain tumors, vascular malformations,
Erlangen, Germany metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure
7
Department of Neurosurgery, semiology, neuroimaging, neurophysiology, and neuropathology constitute the
University Hospital Halle (Saale), Halle,
Germany
cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become
8
Department of Neurology, Mayo drug-­resistant should promptly undergo assessment in an epilepsy center. After
Clinic, Rochester, Minnesota, USA excluding pseudo-­resistance, these patients should be considered for presurgical
9
Insitute of Neuropathology, University evaluation as a means to identify the location and extent of the epileptogenic
Hospital Erlangen, Erlangen, Germany
10
zone and assess their candidacy for a surgical procedure. The goal of this semi-
Department of Neurology, Mayo
Clinic, Jacksonville, Florida, USA
nar in epileptology is to summarize clinically relevant information concerning
11
Department of Clinical focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide
Neurophysiology, Danish Epilepsy healthcare professionals, patients, and caregivers continue to have access to high-­
Center, Dianalund, Denmark
quality educational resources concerning epilepsy.
12
Aarhus University Hospital, Aarhus,
Denmark KEYWORDS
13
Department of Clinical Medicine, education, electroencephalography, epilepsy, focal epilepsy, MRI, neuroimaging,
Aarhus University, Aarhus, Denmark
neuropathology

Correspondence
Fábio Augusto Nascimento e Silva,
Department of Neurology, Washington
University School of Medicine, Campus
Box 8111, 660 South Euclid Avenue, St.
Louis, MO 63110, USA.
Email: fabion@wustl.edu

Epileptic Disorders. 2023;00:1–17. wileyonlinelibrary.com/journal/epd2 © 2023 International League Against Epilepsy. | 1

2 |   
1 | I N T RO DU CT ION
The ILAE recommends a three-­ level framework upon
classifying epilepsies.1 First, one needs to identify the
seizure type. Second, the epilepsy type needs to be de-
termined: focal, generalized, combined generalized and
focal, or unknown. Third, the clinician should attempt
to make a diagnosis of a specific epilepsy syndrome. An
etiologic diagnosis and potential comorbidities should be
sought at each step. The use of this framework aims to
improve the care of patients with epilepsy and advance
epilepsy research.
In this seminar in epileptology, we address the following
learning objective of the ILAE's competency-­based curric-
ulum2: “1.7.3 –­Correctly diagnose and classify focal epilep-
sies.” We start by detailing the ILAE classification of focal
seizures before exploring the most common etiologies of
focal epilepsies in children and adults. We then elabo-
rate on the diagnostic evaluation of focal epilepsies from
neuroimaging, neurophysiology, and neuropathology
standpoint. Lastly, we summarize the role of presurgical
evaluation in patients with drug-­resistant focal epilepsy.
2 | I L A E C LASSIFICAT ION OF
FOC A L S E I ZU R E S
The role of the ILAE classification guidelines is to aid
clinicians in defining and classifying seizures over the
lifecycle. As a dynamic index used by treating clinicians,
seizure3 and epilepsy1 classification is a highly relevant
tool to optimize patient management and advance re-
search initiatives by providing a common vernacular in
the form of a multinational language. Since first initiated
by the ILAE in 1981, revisions and modifications have
occurred over time. Modifications accommodate newly
identified etiologies and incorporate advances in neuro-
imaging and electrophysiology and recent discoveries in-
volving genetics and immune-­mediated causes. Updating
prior classifications significantly influences management
for all patients who experience focal seizures.
Epilepsies that are focal, combined focal and general-
ized, and have unknown onsets may occur.1 By definition,
focal seizures “originating within networks limited to one
hemisphere” are classified for medical or surgical treatment
using the earliest clinical feature (i.e., motor or non-­motor
descriptive signs). Then, they are sub-­classified, depending
on the changes in the patients' awareness throughout the
seizure (i.e., aware or impaired awareness).3 Position pa-
pers by the ILAE Task Force on Nosology and Definitions
in 2022 address current definitions and classifications in-
volving patients with focal seizures.4–­7
NASCIMENTO et al.
Key Points
1. Focal seizures are divided into focal aware,
focal impaired awareness, and focal to bilateral
tonic-­clonic seizures.
2. Focal epilepsies account for most epilepsy cases
both in children and adults.
3. Seizure semiology, neuroimaging, neurophysi-
ology, and neuropathology are diagnostic cor-
nerstones in the evaluation of patients with
focal epilepsies.
4. Patients with focal epilepsies who become drug-­
resistant should promptly undergo assessment
in an epilepsy center.
Current terms to define focal seizures are established1
and detailed instruction manual is available for opera-
tional classification.3 Focal seizures are subdivided into
focal aware, focal impaired awareness (impaired aware-
ness occurring at any point during the seizure), and focal
to bilateral tonic–­clonic seizures (previously known as sec-
ondarily generalized tonic–­clonic seizures). Specific forms
of motor and non-­motor signs are added when they are
present at seizure onset (i.e., focal tonic seizures). Focal
seizures elicit a wide variety of symptoms and clinical be-
haviors that are highly diverse. Descriptors can be added
in free text form to enhance specificity. Focal seizures may
be age-­specific with self-­limited focal seizures accounting
for 25% of pediatric epilepsies.7 Clinical manifestations
of focal seizures evolve in a sequence of clinical features
which may reflect a broadly distributed network over one
hemisphere or remain discretely localized in brain region.
Semiology provides information on the anatomical loca-
tion of the seizure onset zone and has important manage-
ment ramifications when focal seizures are drug-­resistant
necessitating presurgical evaluation.8,9 Although seizure
semiology is often similar in children and adults, epilepsy
etiologies are typically distinct among the two patient
populations.
3 | ETIOLOGIES OF FOC AL
EPILEPSIES IN CHILDREN
Focal epilepsy is the most common mode of onset for epi-
lepsy in childhood, accounting for about two-­thirds of all
epilepsy cases. When thinking about etiology, there are
three main groups to consider. The most common etiolo-
gies of focal epilepsy syndromes in children are summa-
rized in Table 1.
NASCIMENTO et al.    | 3

TABLE 1 Most common etiologies of focal epilepsy syndromes in children.

Focal epilepsy of
Self-­limited focal epilepsy syndromes Focal epilepsy of known cause unknown causea
• Self-­limited neonatal epilepsy (KCNQ2) Structural, developmental (malformations of cortical
• Self-­limited infantile epilepsy (PRRT2, development; possible genetic origin: e.g., DEPDC5 and
SCN2A, SCN8A) TSC1/TSC2)
• Self-­limited epilepsy with autonomic Structural and/or acquired
seizures • Perinatal brain injury
• Self-­limited epilepsy with centrotemporal • Hypoxic–­ischemic injury
spikes • Stroke
• Trauma
• Tumor
• Vascular malformation
• Post-­infectious
• Hippocampal injury/FS
• Immune-­mediated (anti-­NMDAR)
Abbreviation: FS, febrile seizure(s).
a
Not meeting criteria for a self-­limited focal epilepsy syndrome.

3.1 | Self-­limited focal Self-­limited epilepsy with centrotemporal spikes

epilepsy syndromes
Specific self-­limited focal epilepsy syndromes have been re-
cently defined by the ILAE in both neonates and infants5
and children.7 The most common types are outlined below.
Self-­limited neonatal epilepsy usually begins in the 1st
week of life with focal tonic or clonic seizures in an other-
wise healthy baby. There may be a positive family history
of similarly affected neonates. Most of these babies will
have a pathogenic variant in KCNQ2 (potassium voltage-­
gated channel subfamily Q member 2). This epilepsy syn-
drome typically resolves by 6 weeks of age.
Self-­limited infantile epilepsy begins after the neonatal
period but usually before 18 months of age. Focal seizures
consist of behavioral arrest, impaired awareness, versive,
or focal clonic movements. These seizures often occur in
brief clusters where several seizures occur over a few days
and, rarely, they can evolve to bilateral tonic–­clonic sei-
zures. Infants have normal development and imaging and
nearly all cases resolve by 3 years of age. Several genetic
variants have been found for this syndrome, mainly PRRT2
(proline-­rich transmembrane protein 2) but also SCN2A
(sodium voltage-­ gated channel alpha subunit 2) and
SCN8A (sodium voltage-­gated channel alpha subunit 8).
Self-­limited epilepsy with autonomic seizures (SeLEAS;
formerly known as Panayiotopoulos syndrome) most com-
monly begins in preschool-­aged children. Seizures often
occur shortly after falling asleep and have prominent au-
tonomic features, in particular recurrent retching. The
seizure frequency is low but about a quarter of patients
can have prolonged seizures. Remission typically occurs
within 1–­2 years of onset. Imaging and genetic studies are
typically normal.
(SeLECTS) presents in school-­aged children with focal
seizures affecting the lower face with prominent drooling,
dysarthria, and facial twitching. Seizures are usually seen
shortly after falling asleep or shortly before awakening
and during sleep, when they may evolve to bilateral tonic–­
clonic seizures. EEG shows characteristic high-­amplitude
centrotemporal epileptiform discharges. The majority of
patients' seizures resolve by age 12 years, and nearly all pa-
tients' seizures remit by age 16 years. Imaging and genetic
studies are typically normal.
3.2 | Focal epilepsy of unknown cause
but which do not meet criteria for a self-­
limited focal epilepsy syndrome
Approximately half of children with focal epilepsies that
begin in childhood but do not meet criteria for one of the
self-­limited syndromes will have no known cause found
despite careful evaluation including brain MRI. Overall,
these patients have a very favorable prognosis with regard
to seizures, with one population-­based long-­term study
showing that 81% of patients achieve seizure freedom
and 68% can be weaned off antiseizure medication(s).10
Favorable outcome is particularly likely if the child
has a normal development and a normal neurologic
examination.
3.3 | Focal epilepsy of known cause
Approximately half of focal epilepsies in childhood that do
not fall into a specific self-­limited epilepsy syndrome will
4 |   
be due to a known underlying cause. Such children have a
higher risk of developing drug-­resistant epilepsy and a lower
likelihood of epilepsy remission. The vast majority of known
causes of focal epilepsy in childhood are structural causes,
and thus high-­quality, epilepsy protocol brain MRI is man-
datory for all cases of focal epilepsy, excepting those meeting
criteria for a clear self-­limited epilepsy syndrome.11,12
Structural causes can be divided into two groups: de-
velopmental, where brain development is abnormal, and
acquired. More extensive malformations of cortical (e.g.,
hemimegalencephaly) development present at an earlier
stage in life with developmental delay and epilepsy which
is often drug resistant. Some of these infants can present
initially with infantile spasms with or without focal sei-
zures but then evolve to focal or multifocal epilepsy over
time. Less extensive forms of developmental structural
abnormalities such as focal cortical dysplasia (FCD) may
present later in childhood or even in adulthood where
drug-­resistant epilepsy is common.
Among acquired causes, one of the most common etiolo-
gies is perinatal brain injury associated with intraventricular
hemorrhage and subsequent periventricular leukomalacia
in premature infants, and hypoxic–­ischemic injury as the
major injury in term infants. These infants often present
with neonatal seizures which then may settle and recur ei-
ther as focal seizures or as epileptic spasms. Other types of
structural changes can be seen at any age and include stroke,
trauma, tumors, for example, low-­grade epilepsy-­associated
tumors including gangliogliomas and dysembryoplastic
neuroepithelial tumors (DNETs), post-­infectious brain in-
jury after meningitis or encephalitis, or other brain injury.
In children who have had a prior prolonged febrile seizure
within the first years of life, hippocampal edema can be seen
acutely which, over time, can evolve to mesial temporal scle-
rosis. This is an important etiology as it is often drug resistant
and amenable to epilepsy surgery.13
For some patients with developmental structural abnor-
malities of the brain, an underlying genetic cause can be
found such as variants with a second brain somatic hit or
postzygotic somatic mosaicism only. These include condi-
tions such as Sturge–­Weber syndrome, tuberous sclerosis
complex, DEPDC5 (DEP domain containing 5, GATOR1
subcomplex subunit) and other genes affecting the mTOR
(mammalian target of rapamycin) pathway, or the galactose
transporter SLC35A2 (solute carrier family 35 member A2).
These children can be considered for epilepsy surgery if it is
deemed that seizures are arising from a specific focus.
Metabolic derangements are most commonly associ-
ated with generalized seizures as opposed to focal seizures
although very young infants can present with focal seizures
due to metabolic disorders. Immune-­mediated epilepsies
are relatively rare in children although autoimmune eti-
ologies, especially anti-­NMDA, are often associated with
NASCIMENTO et al.
acute symptomatic seizures, especially when concurrent
movement disorders are present. Infectious causes such as
neurocysticercosis should be considered especially when
the MRI is concordant with the clinical diagnosis.
4 | ETIOLOGIES OF FOC AL
EPILEPSIES IN ADULTS
The population of adults with epilepsy consists of people
who have had epilepsy for many years and in some cases
disease onset in childhood or adolescence. There are oth-
ers who develop epilepsy de novo in adulthood. While the
causes of focal epilepsy are heterogenous and epilepsy can
start at all ages, there are some etiologies that are more fre-
quently encountered in adulthood. The ILAE published a
position paper in 2017 with a revised classification of the
epilepsies.1 This paper incorporated etiologies as these can
inform long-­term outcome and direct management. This
section will review the etiologies of epilepsy manifesting
primarily in adulthood. Most common etiologies of focal
epilepsy syndromes in adults are summarized in Table 2.
4.1 | Structural etiologies
Most adult epilepsies are focal and are frequently the result
of acquired structural brain abnormalities such as stroke,
brain trauma, or infections, or due to neoplasms, vascular
malformations, or a genetic condition. Some patients with
epilepsy may have a combination of both acquired struc-
tural brain abnormality and a genetic disorder.
The prevalence of epilepsy increases with age and
peaks in the elderly. The association is explained by a
higher frequency of cerebrovascular disease, neurode-
generative conditions, and neoplasms in this age group.14
Cerebrovascular disease accounts for 50%–­70% of epilepsy
in adults. A cutoff of 7 days is used to determine whether
a post-­stroke seizure is considered early (acute symptom-
atic) or late.15 Dementia, particularly Alzheimer's disease,
and neurodegenerative disorders account for 10%–­20% of
late-­onset cases of epilepsy.16
Seizures are among the most common manifestations
of cerebral neoplasms.17 Seizures can be the presenting
symptom in about 30%–­50% of individuals or start during
the course of the disease in 10%–­30% of patients. Tumor
location and histology influence the risk for epilepsy.18
Additionally, several other factors can lead to epilepto-
genesis in brain tumors such as genetic predisposition,
integrity of the blood–­ brain barrier, and changes in
the concentration of neurotransmitters (glutamate and
GABA) and microenvironment. In neuroglial tumors,
the RAS–­RAF-­MAP-­Kinase pathway seems to influence
NASCIMENTO et al.
TABLE 2 Most common etiologies of focal epilepsy syndromes in adults.
Structural Genetic Infectious
Stroke Familial temporal lobe Viral encephalitis
Hippocampal sclerosis epilepsy Parasitic infections
Hypoxic–­ischemic injury Autosomal dominant (malaria,
Neurodegeneration sleep-­related neurocysticercosis)
(Alzheimer's disease) hypermotor epilepsy Bacterial meningitis,
Tumors (primary –­ (CHRNA4, CHRNB2, encephalitis, e.g.,
high-­grade glioma, CHRNA2) brain abscess or
meningioma –­or meningoencephalitis
metastatic) Fungal infections
Brain trauma (candida, aspergillus,
Malformation of cortical cryptococcus)
development (HME,
PMG, FCD, MOGHE)
Vascular malformations
(cavernoma, meningeal
angiomatosis)
Abbreviations: FCD, focal cortical dysplasia; HME, hemimegalencephaly; MOGHE, malformation of cortical development with oligodendroglial hyperplasia in
epilepsy; PMG, polymicrogyria.
tumor growth and epileptogenesis.19 It is worth noting
that brain metastases have a less infiltrative growth pat-
tern and do not seem to modulate neuronal excitability
when compared to primary brain tumors. When feasible,
identification of molecular biomarkers may guide further
treatment, for example, IDH1 (isocitrate dehydrogenase
(NADP(+)) 1), co-­deletion of chromosomes 1p and 19q,
BRAF (v-­RAF murine sarcoma viral oncogene homolog
B1) V600E or MGMT promoter methylation.
Low-­grade gliomas, IDH1 mutant, WHO CNS grade
2, for example, oligodendrogliomas and astrocytomas,
occur commonly in the 3rd and 4th decades of life.20 The
mean age of patients with high-­ grade gliomas (WHO
CNS grade 3 and 4), such as anaplastic astrocytomas and
glioblastomas, is around 60 years. Approximately 35% of
patients with metastases have seizures and these can be
the initial manifestation while the primary tumor is di-
agnosed at a later time. The mean age of patients with
metastases is around 70 years. Most meningiomas are be-
nign, frequently asymptomatic, more frequent in females,
and the most common age at diagnosis is about 50 years.
Supratentorial meningiomas with peritumoral edema are
associated with the greatest risk of seizures. The incidence
of seizures in patients with meningiomas is about 30%.
Dysembryoplastic neuroepithelial tumors and gangliogli-
omas are low-­grade developmental brain tumors (WHO CNS
grade 1) and occur most often in the temporal lobe of young
adults and teenagers. Postsurgical long-­term seizure control
>5 years is highest among all surgically amenable etiologies.13
Focal cortical dysplasias are highly epileptogenic mal-
formations of cortical development. In 2022, the ILAE
published an updated international consensus classifica-
tions scheme of FCD including a multi-­layered integration
   | 5
Immune-­
Metabolic mediated Unknown
Mitochondrial Anti-­LGI1
Acute intermittent Anti-­NMDAR
porphyria Anti-­GABA-­B
Adrenoleukodystrophy Anti-­Caspr2
Wilson's disease
of histopathology, neurogenetic, and neuroimaging.21 In
surgical cohorts, FCDs were the most common disease
condition in children and the third most common dis-
ease condition in adults, manifesting more commonly in
the frontal lobe.22 Another common focal lesion in adults
were cavernomas with a mean disease onset in the 2nd de-
cade of life, predominant localization in the temporal lobe
and high probability of postsurgical seizure control.13,22
Cerebral vascular malformations associated with epi-
lepsy are a heterogeneous group of vascular disorders with
various presentations and clinical course. The most com-
mon cerebral vascular malformations in adults are arte-
riovenous malformations (AVMs) and cavernomas. Most
AVMs are sporadic and present as a solitary lesion, while
about 5% of AVMs occur in individuals with a genetic syn-
drome such hereditary hemorrhagic telangiectasia. The ge-
netic contributions to AVMs are multi-­factorial and include
germline and somatic variants.23 Arteriovenous malforma-
tions usually become symptomatic after the age of 20 years.
Besides hemorrhage, seizures are the second most common
presenting symptom of cerebral AVMs and can be seen in
up to 45% of patients.24 Cavernomas, also known as cavern-
ous angiomas or cavernous malformations (CMs), can pres-
ent in sporadic or familiar forms (autosomal dominant with
variable penetrance). Familial cases, and a portion of spo-
radic cases, are caused by variants in the following genes:
CCM1/KRIT1 (cerebral cavernous malformation gene 1)
(most frequent type), CCM2/MGC4607 (cerebral cavern-
ous malformation gene 2), and CCM3/PDCD10 (cerebral
cavernous malformation gene 3). They most often become
symptomatic from the 2nd to the 5th decades of life. Seizures
are the most common clinical manifestations of CMs and
are seen in half of patients.25 The anatomic location of CMs
6 |   
tend to affect the symptomatology. In one study, 86% of
patients with seizures on presentation had lobar lesions.26
Seizures associated with cavernomas frequently originate in
the temporal lobe and have a high likelihood of postsurgical
seizure control.13,22 Early diagnosis, timely treatment, and
systemic surveillance are now possible in individuals with
cerebral vascular malformations thanks to the advance-
ments in neuroimaging and genetic testing.
Traumatic brain injury (TBI) is the cause of epilepsy in
almost 30% of individuals who develop epilepsy between
the ages of 15 and 34 years.27 Late symptomatic seizures,
associated with post-­ traumatic epilepsy (PTE), manifest
more than 7 days after the injury. The risk of developing
PTE appears to be directly related to the severity of the TBI.
Epilepsy resulting from brain trauma tends to be drug resis-
tant. Since the latency to first seizure can be decades after
the trauma, many research efforts are put into understand-
ing the neural networks and molecular pathologies involved
in epileptogenesis in order to prevent its development.
4.2 | Genetic etiologies
Genetic etiologies in focal epilepsy are increasingly being
diagnosed and this will eventually drive management from
an empirical approach to that of precision medicine.28,29
However, genetic testing is not yet routinely integrated in
the evaluation of adults with epilepsy. Over the past two dec-
ades, numerous genetic variants associated with various epi-
lepsies have been identified. Familial temporal lobe epilepsy
and autosomal dominant sleep-­related hypermotor epilepsy
(ADSHE), previously referred to as autosomal dominant
nocturnal frontal lobe epilepsy (ADNFLE), can manifest ei-
ther in adolescence or in adult years. Multiple genes have
been implicated in these two genetic epilepsies. For instance,
ADSHE can be caused by variants in CHRNA4 (cholinergic
receptor nicotinic alpha 4 subunit), CHRNB2 (cholinergic
receptor nicotinic beta 2 subunit), and CHRNA2 (cholinergic
receptor nicotinic alpha 2 subunit), which are genes encod-
ing subunits of the neuronal nicotinic acetylcholine recep-
tor (nAChR). A more severe form of ADSHE has been noted
with variants of the sodium-­activated potassium channel
encoded by KCNT1 (potassium sodium-­activated channel
subfamily T member 1).30 Loss-­of-­function germline vari-
ants in the GATOR complex 1 gene DEPDC5 have also been
described but recent research suggested an association with
FCD ILAE Type 2 due to second hit somatic variants acquired
in neuroglial precursor cells during neurodevelopment.31
4.3 | Infectious etiologies
Like children, adults with central nervous system in-
fections can develop seizures in the acute state and/or
NASCIMENTO et al.
later develop epilepsy. In developed countries, the risk
of post-­infectious epilepsy is around 8% but up to 26%
in resource-­poor countries.32,33 Epileptogenesis depends
on the pathogen, degree of cortical involvement, and the
resulting inflammatory response. There is evidence that
delays in treatment may influence epileptogenesis. Viral
encephalitis, parasitic infections such as malaria, and
neurocysticercosis increase the risk of developing epi-
lepsy, while bacterial meningitis may result infrequently
in long-­term epilepsy.34
4.4 | Metabolic etiologies
Metabolic disorders associated with epilepsy can have a
genetic (inborn) substrate and may be a result of enzyme
deficiencies that affect biochemical pathways. The fre-
quency of metabolic epilepsies may have been underes-
timated as approximately 600 metabolic epilepsies have
been identified thus far.35
The most frequent metabolic disorders comprise pri-
mary mitochondrial disorders—­ which can present at
any age.36 Mitochondrial disorders that can present with
focal seizures in adults include the DNA polymerase sub-
unit gamma (POLG) related disorders; mitochondrial
encephalopathy, lactic acidosis, and stroke-­like episodes
(MELAS); and myoclonic epilepsy with ragged red fibers
(MERRF).37 POLG mutations represent the most common
cause of mitochondrial epilepsy in all ages. POLG-­related
phenotypes with adult-­onset typically feature multiple mi-
tochondrial DNA deletions. Occipital lobe seizures have
been noted and, in certain cases, seizures may progress to
status epilepticus.38 MELAS is caused by mutations in the
mitochondrial DNA in the MT-­TL1 (mitochondrially en-
coded tRNA leucine 1) gene. Status epilepticus can occur
in the context of stroke-­ like symptoms. The proposed
mechanism leading to seizures in this syndrome include
neurotransmitter, ion mechanisms, and oxidative stress.39
MERRF can occur in early adulthood. The majority of
MERRF cases bear m.8344A > G mutations. Myoclonic
seizures are a hallmark of this syndrome; however, there
are reports of focal seizures as well.40
Among treatable metabolic epilepsies, acute intermit-
tent porphyria, adrenoleukodystrophy, and Wilson disease
have different modes of inheritance and can present in
adulthood. Acute intermittent porphyria is an autosomal
dominant disease involving defects in heme metabolism
while adrenoleukodystrophy follows an X-­linked inheri-
tance pattern. Wilson disease is inherited in an autosomal
recessive fashion and caused by variants in the ATP7B
(ATPase Copper transporting beta) gene that result in
excessive amounts of copper accumulation in several or-
gans. Timely diagnosis of these disorders is critical as they
are amenable to specific treatment interventions.41
NASCIMENTO et al.
4.5 | Immune etiologies
Despite substantial discoveries over the past couple of
decades, autoimmune epilepsy remains an underrecog-
nized cause of seizures.42 Neural autoantibodies targeting
cell surface or intracellular antigens have been impli-
cated. The diagnoses can be confirmed by antibody test-
ing, either in spinal fluid or in serum. Cancer screening
should be undertaken in circumstances where there is a
high association with a specific antibody. Anti-­N-­methyl
D-­aspartate receptor (NMDAR) and gamma aminobutyric
acid B (GABA-­B) receptor antibodies are associated with
50% risk of ovarian cancer and small cell lung cancer,
respectively.43 The average age of patients with NMDAR
antibodies is about 20 years, while the average age of the
other major antibodies LGI1, GABA-­ B, and Caspr2 is
around 60 years. Leucine-­rich glioma-­inactivated 1 (LG1)
antibodies are rarely associated with cancer. NMDAR an-
tibodies and LGI1 antibodies are significantly more com-
mon than the other antibodies.
4.6 | Unknown etiology
In some instances, and despite significant advances in
testing and refined imaging techniques, the etiology of ep-
ilepsy cannot be determined. Several factors influence di-
agnosis and management. Some patients are not referred
in a timely manner to an epilepsy specialist for evaluation.
Also, differences in healthcare systems and limitations of
resources such as brain MRI in certain countries may pre-
clude adequate testing (i.e., long-­term video-­EEG moni-
toring). Determining the etiology of focal epilepsy across
the lifespan can offer a unique opportunity for counseling
and etiology-­driven seizure management, especially in the
current era of precision medicine.
TABLE 3 Summary of auxiliary workup modalities in the management of focal epilepsies.
Neuroimaging Neurophysiology
• CT (emergency patients with • Routine EEG
first seizure, widely available) • Routine EEG, sleep-­deprived
• MRI (recommended for all • Ambulatory EEG
patients with epilepsy; ideally • Inpatient long-­term video-­EEG monitoring
HARNESS protocol with or (LTM/EMU)
without MRI post-­processing) • ESI/MSI
• Interictal PET
• Ictal SPECT
• Functional imaging (spatial
distribution of functional
cortex; MRI and/or MEG)
Abbreviations: CT, computed tomography; EEG, electroencephalogram; EMU, epilepsy monitoring unit; ESI, EEG source imaging; LTM, long-­term EEG
monitoring; MEG, magnetoencephalography; MRI, magnetic resonance imaging; MSI, magnetic source imaging; PET, positron emission tomography; SPECT,
single photon emission computed tomography.
   | 7
5 | DIAGNOSTIC WORKUP OF
FOC AL EPILEPSIES
The following sections will address the diagnostic workup
of focal epilepsies including neuroimaging, neurophysi-
ology, and neuropathology. Table 3 summarizes the aux-
iliary workup modalities in the management of patients
with focal epilepsies.
6 | DIAGNOSTIC WORKUP
OF FOCAL EPILEPSIES,
NEUROIMAGING
6.1 | Significance and indications
Neuroimaging in epilepsy serves different purposes.11,44
Early neuroimaging is crucial in emergencies, when a
seizure may occur as a secondary manifestation accompa-
nying, for example, focal neurological deficits, cognitive al-
terations, headache, or fever. Seizures may also occur as a
first manifestation of intracranial tumors, steering the pa-
tient toward oncological rather than a primarily epilepto-
logical diagnostic pathway and treatment. Neuroimaging
is performed in the early stage of the diagnostic evaluation
of epilepsy to establish a syndromic diagnosis and deter-
mine the underlying etiology of recurrent seizures.44
Overall, however, imaging reveals an epileptogenic le-
sion in only around 20% of patients with new-­onset sei-
zures. In patients with focal onset seizures, this percentage
reaches ~50%45 but depends on the level of technological
sophistication and neuroimaging technique. In general,
patients with epilepsy without an identifiable lesion on
MRI (i.e., with causes other than structural lesions) have a
better prognosis for seizure control with antiseizure med-
ication.46 In patients with drug-­resistant focal epilepsies,
Neuropathology
• Standardized operational procedure (SOP)
for inspection, distribution, processing of
epileptogenic brain tissue
• Routine light microscopic assessment with
hematoxylin–­eosin or cresyl violet or luxol-­
fast-­blue stainings
• Antibodies to identify aberrant
immunoreactivity patterns of disease-­specific
protein epitopes
8 |    NASCIMENTO et al.

structural imaging plays an essential role in the planning
of invasive recordings and epilepsy surgery.47,48 Presence
of an epileptogenic lesion is a significant predictor of
successful epilepsy surgery,47,49 although complete lesio-
nectomy of the structural lesion alone is not always suffi-
cient to achieve long-­term seizure freedom.50 In contrast,
non-­lesional patients represent an especially challenging
subgroup with comparably limited postsurgical seizure
outcomes.48
6.2 | Structural imaging: MRI And CT
CT is recommended in emergency patients with a first sei-
zure51 and is widely available worldwide.44 It is sensitive
to bleedings, but also small calcified and bone lesions as
well as skull defects (e.g., in patients with encephalocele).
However, due to better differentiation of brain tissues,
all patients with focal epilepsy should undergo at least a
1.5 T MRI using a protocol optimized for the evaluation of
epilepsy, while the application of CT is limited to special
situations.11,44 Patients should undergo repeated MRI if
previous imaging did not follow an optimized protocol.11
Furthermore, children with focal seizures and unreveal-
ing MRI performed below the age of 1 year should un-
dergo repeated MRI.
6.3 | MRI: The HARNESS protocol
The ILAE Neuroimaging Task Force has recently recom-
mended the “HARNESS” MRI protocol (“Harmonized
Neuroimaging of Epilepsy Structural Sequences”), which
allows detection of the complete range of epileptogenic
lesions, while limiting the required scanning time.11 This
protocol includes three mandatory and two optional se-
quences (Table 4). HARNESS leverages the advantages
of isotropic 3D MRI acquisition without interslice gap to
allow flexible re-­slicing. A high resolution of 1 mm or bet-
ter is suggested to reduce partial volume effects. In com-
bination, this eliminates the need for pathology-­specific
sequences and angulations. For inspection of the hip-
pocampus, a 2D T2-­weighted series angulated perpendic-
ularly to the long axis of the hippocampus with increased
intra-­slice resolution is suggested. Two optional series pro-
vide additional sensitivity in specific cases: gadolinium-­
enhanced 3D T1 to assess tumors, vascular malformations,
and infectious processes, and susceptibility-­ weighted
SWI/T2*, which is sensitive to iron deposits, blood prod-
ucts, and calcifications. The protocol is recommended for
field strengths of 3 T however the sequences can also be
obtained with 1.5 T.11 Even when acquired with an opti-
mal HARNESS protocol, the MRI interpretation should
consider the context of the EEG findings, semiology, and

TABLE 4 Mandatory and optional sequences of the HARNESS MRI-­protocol.11

Name Weighting Resolution Advantages

Mandatory sequences
Magnetization-­prepared rapid
gradient echo (MPRAGE,
Siemens), Spoiled gradient
echo (SPGR, GE), Turbo field
echo (TFE, Phillips)
3D fluid attenuation inversion
recovery (FLAIR)
Coronal spin echo (acquisition
plane perpendicular to long
axis of the hippocampus)
Optional sequences
Gadolinium-­enhanced MRI
Susceptibility-­weighted imaging
T1 3D 1 × 1 × 1 mm, no interslice gap Allows for reformatting to different
angulations and view planes,
visualization of brain anatomy and
morphology
T2-­FLAIR 3D 1 × 1 × 1 mm, no interslice gap Allows for reformatting to different
angulations and view planes, fluid
attenuation enhances visibility of
lesions such as FCD, hippocampal
sclerosis, and tubers
T2 2D 0.4 × 0.4 × 2 mm High in-­plane resolution and coronal
view plane provides optimal
visualization of hippocampal
internal structure
T1 3D Contrast agent improves assessment of
tumors, vascular malformations, or
infectious processes
T2*/SWI 3D Sensitive to iron deposits, blood
products and calcifications, e.g., for
assessment of cavernomas
NASCIMENTO et al.
other clinical information.12 Experience of the examiner is
also fundamental, and an MRI reported as normal might
really harbor a subtle structural abnormality not initially
identified by the interpreter,52 in particular FCDs.53
The visual inspection of digitally stored 3D MRIs
(usually in DICOM format), acquired with the smaller
isotropic voxel size as possible,11 should be done using a
platform that allows multiplanar reformatting. There are
several options of user-­friendly DICOM viewers that run
on most desktop computers and can be incorporated into
the routine of epileptologists.
6.4 | MRI post-­processing
In patients with subtle lesions, visual analysis of MRI may
not be sufficient. Post-­processing techniques may offer so-
lutions by computationally analyzing morphological MRI
features, such as sulcal depth, contrast of the gray-­white
matter junction, volumes, and cortical thickness, among
others. A comparison to healthy controls then provides
objective metrics of structural alterations potentially pro-
viding evidence for a subtle lesion.54 The use of artificial
intelligence approaches in parallel to the visual analyses
may enhance further the detection of very subtle FCDs in
previously negative MRIs.55
6.5 | PET and SPECT
Positron emission tomography (PET) and single photon
emission computed tomography (SPECT), imaging meth-
ods that are mainly used in the presurgical evaluation
context, provide additional localizing information espe-
cially in selected (e.g., non-­lesional) cases.56–­59 Interictal
PET, currently largely fluorodeoxyglucose (FDG)-­ PET,
can reveal decreased glucose metabolism, which may be
observed in the seizure onset zone. SPECT evaluates re-
gional cerebral blood flow, which is increased during a
seizure. If the radioactive SPECT tracer is injected at sei-
zure onset or shortly thereafter, an ictal SPECT may local-
ize the seizure onset zone. Subtraction of ictal-­interictal
SPECT co-­ registered with MRI (SISCOM) has shown
increased specificity58 relative to interictal SPECT alone
and is less informative especially in extratemporal lobe
epilepsy.59
6.6 | Functional imaging
Functional imaging with fMRI or magnetoencephalogra-
phy (MEG), also primarily used in the presurgical evalu-
ation context, provides information about the spatial
   | 9
distribution of functional cortex (e.g., motor and sensory
cortex) as well as language-­related areas.60,61 The aim of
epilepsy surgery is to ultimately achieve improvement in
one's quality of life. Consequently, permanent functional
deterioration from the effect of recurrent seizures must
be avoided. However, individual functional anatomy is
variable and epileptogenic lesions may lead to consider-
able reorganization, especially when they occur early in
life. Functional imaging thus contributes to evaluating
the viability of surgical therapy and aids planning of re-
section extents. Additional information from functional
multimodal imaging improves MRI detection of subtle
lesions.44
7 | DIAGNOSTIC WORKUP
OF FOCAL EPILEPSIES,
NEUROPHYSIOLOGY
7.1 | Confirmation of focal epilepsy
Once a diagnosis of focal epilepsy is considered, EEG can
be used to confirm or refute clinical suspicions, and in
some cases establish an electroclinical diagnosis: a clini-
cal diagnosis supported by EEG. Several factors, however,
limit the use of EEG as an auxiliary test in the diagnosis
of focal epilepsy.
First, EEG is a low-­amplitude, continuous and dynamic
biosignal that requires considerable expertise for interpre-
tation. The EEG signal recorded at the scalp reflects the
summed potentials generated in a relatively large area (≥6–­
10 cm2) of the cortex at the cerebral convexity and, there-
fore, represents only a small portion of brain activity of
clinical interest. Multiple non-­brain sources further lower
the signal to noise ratio (SNR). This low SNR is partly re-
sponsible for high inter-­observer variability. Furthermore,
there is a risk of over-­or under-­reading EEG findings. The
former constitutes misinterpreting normal variants, arti-
facts, or other clinically irrelevant transients as epilepti-
form. The latter constitutes dismissing a subtle but true
epileptiform abnormality. Even experienced EEG readers
may still have a practice style of interpreting with “high
sensitivity” or with “high specificity.”62,63 “Conservative”
EEG reading has been recommended to achieve high
specificity and avoid over-­reading with resultant epilepsy
misdiagnosis.64
Second, epileptiform abnormalities can occur in the
EEG of up to 4% of school-­aged children in the absence of
epilepsy, that is, on average 1 child in every classroom of
30 children if everyone were to undergo an EEG without
indication. This fraction increases in children with comor-
bid learning disabilities, attention deficit hyperactivity
disorder, and autism spectrum disorder.65,66
10 |    NASCIMENTO et al.

In clinical practice, therefore, the diagnostic yield
of an EEG depends on the prior (or pre-­test) probability.
According to Bayes' theorem for calculating conditional
probabilities, a clinician should update prior information
(e.g., is focal epilepsy present in this patient?) whenever
new and relevant information is provided (e.g., the EEG is
abnormal and contains temporal epileptiform discharges).67
In clinical practice, evidence and information are presented
sequentially, not all at once. For example, a neurologically
healthy toddler with a spell of brief unresponsiveness and
an EEG with one focal epileptiform discharge may still not
have epilepsy. The same EEG, however, could be support-
ive of an epilepsy diagnosis when the pre-­test probability
is higher: a new event occurs, or a more detailed history is
provided by an eyewitness in the same patient. The EEG has
important limitations, and the results should be interpreted
within the appropriate clinical context of the patient.68
The diagnostic yield of EEG can be improved in various
ways. If the first routine EEG is normal, consider obtain-
ing a repeat routine EEG that captures sleep and, ideally,
is recorded following sleep deprivation.69 Ambulatory EEG
is a good tool to capture major “spells,” but it can be unre-
vealing when brief subtle events occur.70 In addition, the
quality of ambulatory EEG recordings may deteriorate over
time which can prevent assessment of interictal findings.
Children, uncooperative patients, and prolonged record-
ings may be susceptible to artifact obscuring meaningful
interpretation. Inpatient long-­term video-­EEG monitoring
in a dedicated epilepsy monitoring unit is the gold-­standard
to diagnose, classify, quantify, and characterize patients re-
ferred for uncontrolled seizures when the event of interest
is captured. Prolonged high-­ quality assessment of both
background and interictal patterns provide supportive in-
formation in conjunction with ictal EEG.
Interictal EEG also has an important role in the diagno-
sis of epilepsy.71 When seizures are highly suspicious from a
clinical standpoint, the diagnosis of epilepsy is a clinical one
that can be made irrespective of the presence or absence of an
epileptiform EEG. In these cases, however, EEG can be help-
ful in classifying epilepsy—­focal, generalized, or combined
generalized and focal, or unknown—­with respective treat-
ment implications. If spells are of moderate clinical suspicion
for epileptic seizures, the presence of interictal epileptiform
abnormalities on EEG establishes the diagnosis of epilepsy.71
The absence of interictal epileptiform abnormalities on EEG
though does not rule out the diagnosis of epilepsy. When
spells are of low clinical suspicion, the presence of interictal
epileptiform abnormalities on EEG may increase the likeli-
hood of epilepsy. A proposed algorithm is shown on Figure 1.
7.2 | Utility in classification and guiding
(workup and) therapy
In addition to confirming the diagnosis of focal epilepsy,
EEG is used in classification of epilepsy syndromes,

F I G U R E 1 Decision tree for clinical events and EEG findings. Note that if spells are of high clinical suspicion for epileptic seizures, the
diagnosis of epilepsy can be made irrespective of the presence or absence of interictal epileptiform abnormalities on EEG. In these cases,
however, EEG may be helpful in classifying epilepsies—­focal, generalized, or combined generalized and focal—­with salient treatment
implications. EEG* represents routine EEG, repeated routine EEG, sleep-­deprived routine EEG, and ambulatory EEG. EEG* positive
represents EEG with epileptiform abnormalities; EEG* negative represents EEG without epileptiform abnormalities. EMU, epilepsy
monitoring unit; LTM, long-­term EEG monitoring.
NASCIMENTO et al.
understanding prognosis, and guiding further evaluation.
Self-­limited focal epilepsies of childhood, which account
for approximately 25% of pediatric epilepsies72 often have
characteristic EEG features that, in the correct clinical
context, can indicate benign course. Typically, children
with characteristic clinical and EEG features do not
need neuroimaging, which is important and relevant for
resource-­limited settings.7
Self-­
limited epilepsy with centrotemporal spikes
(SeLECTS) features, on EEG, high-­amplitude (≥200 μV),
bi/triphasic spike/sharp-­slow wave discharges with max-
imal negativity in the centrotemporal region and frontal
positivity that are activated in drowsiness.7,73 Discharges
are typically bilateral and independent but a single rou-
tine EEG may only identify discharges on one side. The
presence of interictal focal slowing, solely unilateral
discharges on multiple EEGs, and exclusively diurnal
discharges are atypical for self-­limited epilepsy with cen-
trotemporal spikes and should prompt consideration of an
alternative diagnosis, including an underlying structural
brain abnormality.7
Self-­
limited epilepsy with autonomic seizures
(SeLEAS) features, on EEG, multifocal, high-­amplitude
epileptiform discharges that are sleep-­activated. At ini-
tial presentation, discharges are most common in the
posterior head regions but can be seen throughout the
scalp in older ages.7
Childhood-­ onset visual epilepsy typically occurs in
children aged 8 to 9 years (range 1–­19 years) with brief
focal aware visual seizures and postictal headache.74 The
EEG is characterized by sleep-­predominant occipital dis-
charges but centrotemporal spikes can also be seen. Focal
slowing and unifocal discharges should prompt consider-
ation of an alternative diagnosis in both childhood-­onset
visual epilepsy and self-­limited epilepsy with autonomic
seizures (SeLEAS).7
Lastly, developmental and epileptic encephalopa-
thies (DEE) or epileptic encephalopathies (EE) with
spike-­and-­wave activation in sleep (EE-­SWAS and DEE-­
SWAS, respectively) may derive from focal epilepsy syn-
dromes such as SeLECTS, SeLEAS, or other structural
focal epilepsies. Clinically, (D)EE-­ SWAS consist of a
group of conditions characterized by a combination
of cognitive, language, behavioral, and motor regres-
sion.7 Electroencephalographically, (D)EE-­SWAS feature
marked activation of epileptiform abnormalities during
sleep with nearly continuous spike-­and-­wave complexes.
These cases are an example wherein EEG may be valuable
to guide treatment and monitor for therapy response.
Interictal EEG may also be an important tool to stratify
candidates for early epilepsy surgery (including neuro-
stimulation). Studies have shown that, at least in temporal
lobe epilepsy, surgery early in the course of epilepsy once
   | 11
a patient is identified as drug-­resistant is associated with
higher rates of seizure freedom and improved quality of
life compared to continued medical therapy.75 Therefore,
it is in the best interest of patients and health systems to
determine best candidates for early epilepsy surgery be-
fore they accumulate the negative medical and social
outcomes associated with intractability. Patients with uni-
lateral temporal lobe discharges on EEG and a concordant
MRI lesion have some of the best changes for postopera-
tive seizure freedom and would benefit most from early
surgical referrals.76,77
Another proposed role for EEG in the management
of patients with focal epilepsy is to identify patients who
can be withdrawn from antiseizure medication(s) after
prolonged seizure freedom. There is some controversy
as to whether an abnormal EEG, including epileptiform
discharges, indicates risk of relapse in weaning antisei-
zure medication(s).78 A meta-­analysis of available studies
on antiseizure medication withdrawal in seizure-­free pa-
tients suggests that the contribution of an abnormal EEG
to relapse risk is modest at best and the presence of ep-
ileptiform abnormalities in the absence of other clinical
risk factors for relapse like a structural lesion or develop-
mental delay.79 However, patients with focal seizures, in
the absence of a self-­limiting syndrome as above, are at a
higher risk for recurrence.
8 | DIAGNOSTIC WORKUP
OF FOCAL EPILEPSIES,
NEUROPATHOLOGY
The best outcome of histopathology examination of epi-
lepsy surgery brain tissue samples can be achieved in a
setting of collaborative interaction between epileptolo-
gists, neurosurgeons, and neuropathologists.80 The neu-
ropathology laboratory should be responsible, however,
for the standardized brain tissue procurement from any
neurosurgical intervention. Standardized operational pro-
cedures (SOP) for the neuropathology workup, including
inspection, distribution, and processing of epileptogenic
brain tissue, have been developed by the ILAE, as it will
reduce sampling errors in any pathology laboratory, en-
sure the best possible histological assessment, and support
research activities and brain banking initiatives.80
Long-­term tissue storage and archiving will become
more important in modern diagnosis as new molecular
tests are increasingly available (e.g., BRAF V600E and
IDH1 variant in the differential diagnosis of low-­grade
epilepsy-­
associated tumors (LEAT) and mTOR signal-
ing pathway genes or SLC35A2 variants in FCD).53,81
Clinicians may increasingly start requesting retrospec-
tive investigations or additional review of stored tissue
12 |    NASCIMENTO et al.
samples for patients who underwent epilepsy surgery in
the past.82,83 Advanced frozen storage facilities, adequate
record keeping, and protocols for microscopic review of
snap frozen samples will facilitate this process and im-
prove diagnostic accuracy. All histopathology reports
should refer to anatomical landmarks and orientation and
clearly state a histopathological diagnosis according to
current classification systems.
The concept of an integrated multi-­layer diagnostic
scheme has already been acknowledged in the 1st up-
date of the international FCD consensus classification.53
Herein, the histopathology diagnosis builds one layer
only and is amended by additional diagnostic findings
(i.e., MRI and genetics) to comprehensively describe the
genotype–­phenotype correlation of a given FCD subtype.
This will turn out to be more important in the near fu-
ture, when neurosurgical resections become less available
due to thermo-­coagulation or laser ablation procedures,
when a genetic mosaicism becomes a therapeutic target in
patients not being seizure-­free following surgery, or when
the available histopathology report is not concordant with
the clinical findings, for example, due to sampling errors
or unavailable accessory histochemical and/or immuno-
histochemical stainings. The integrated diagnosis should
then be assembled during a postsurgical patient manage-
ment conference led by the epileptologist in charge of the
patient following a comprehensive multidisciplinary re-
view of all available diagnostic reports.53
9 | RO L E O F PR E SU RG ICAL
E VA LUAT I O N IN DRU G -­R E SISTANT
FO C A L E P I LE PSIE S
For patients with epilepsy, lifelong seizure freedom with-
out adverse effects is the desired outcome of any interven-
tion.84 The ILAE defines drug resistance as failure of two
adequate trials of tolerated and appropriately used antisei-
zure medications to achieve sustained seizure freedom.85
After two failed antiseizure medications, a newly admin-
istered antiseizure medication is expected to result in
seizure-­free outcome in 11.8%, declining to 2.6% for more
than six drug failures.86 Epilepsy has a dynamic course,
and drug resistance applies only at the time of assessment
and does not imply a permanent condition.
Pseudo-­drug resistance is created by conditions mim-
icking drug failure with proper use. Functional seizures
misidentified as epileptic, antiseizure medication non-­
adherence, or adverse patient behavior, inadequate dos-
age, or inappropriate antiseizure medication selection are
reasons to explain why treatment fails to control seizures.87
It is estimated that one in five patients suspected of drug-­
resistant focal epilepsy are pseudo-­drug-­resistant.86
Surgery is a well-­accepted treatment for patients with
drug-­resistant epilepsy yet delays of up to 20 years may
occur.88 Three prospective longitudinal cohort studies
involving adults and children demonstrate high-­ level
evidence for the efficacy of epilepsy surgery (including
neurostimulation) in patients with drug-­ resistant focal
epilepsy.75,89,90 Nevertheless, only a small minority of pa-
tients are evaluated for surgery.
The goal of a presurgical evaluation is to identify the
location and extent of the epileptogenic zone approximat-
ing the minimum amount of brain required for seizure
freedom. Detailed interview of the patient and a witness
of their seizures lies at the cornerstone of a comprehen-
sive evaluation. Basic modalities include long-­term video-­
EEG, high-­resolution brain MRI, and neuropsychological
assessment. As complexity increases functional neuroim-
aging, electric/magnetic source imaging, functional MRI,
advanced MRI post-­ processing, and intracranial EEG
monitoring may further resolve discordant non-­invasive
evaluations.91 Each result has limitations. None should be
used in isolation. With multimodal concordance using a
multidisciplinary approach success is readily obtainable.
10 | CONCLUSION
Being able to correctly diagnose and classify focal epilep-
sies is essential for any clinician caring for people with
epilepsy. This seminar in epileptology summarizes up-­to-­
date, clinically relevant information concerning focal epi-
lepsies. We hope that this article contributes to the ILAE's
mission to ensure that worldwide healthcare profession-
als, patients, and caregivers continue to have high-­quality
resources that are crucial in understanding, diagnosing,
and treating epilepsy.
CONFLICT OF INTEREST STATEMENT
F. Nascimento is Associate Editor of Epileptic Disorders.
S. Beniczky is Editor-­ in-­
Chief of Epileptic Disorders.
D. Friedman receives salary support for consulting and
clinical trial-­related activities performed on behalf of The
Epilepsy Study Consortium, a non-­profit organization. D.
Friedman receives no personal income for these activities.
NYU receives a fixed amount from the Epilepsy Study
Consortium toward D. Friedman's salary. Within the past
two years, The Epilepsy Study Consortium received pay-
ments for research services performed by D. Friedman
from: BioXcell, Cerevel, Cerebral, Epilex, Equilibre,
Jannsen, Lundbeck, Praxis, Puretech, Neurocrine, SK Life
Science, Supernus, UCB, and Xenon. He has also served
as a paid consultant for Neurelis Pharmaceuticals. He has
received travel support from the Epilepsy Foundation.
He has received research support from NINDS, CDC,
NASCIMENTO et al.
Epitel, and Neuropace unrelated to this study. He holds
equity interests in Neuroview Technology. He received
royalty income from Oxford University Press. J. Peters,
M. Bensalem-­Owen, F. Cendes, S. Rampp, W. Tatum,
E. Wirrell, and I. Blümcke report no disclosures relevant
to the manuscript.
ORCID
Fábio A. Nascimento https://orcid.
org/0000-0002-7161-6385
Stefan Rampp https://orcid.org/0000-0002-4826-1520
Elaine Wirrell https://orcid.org/0000-0003-3015-8282
Ingmar Blümcke https://orcid.
org/0000-0001-8676-0788
William Tatum https://orcid.org/0000-0002-4536-3791
Sándor Beniczky https://orcid.
org/0000-0002-6035-6581
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SUPPORTING INFORMATION
Additional supporting information can be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Nascimento FA,
Friedman D, Peters JM, Bensalem-­Owen M,
Cendes F, Rampp S, et al. Focal epilepsies: Update
on diagnosis and classification. Epileptic Disord.
2023;00:1–17. https://doi.org/10.1002/epd2.20045
16 |    NASCIMENTO et al.

Test yourself
1. How are focal seizures defined?
2. Is the following statement true or false?
Focal epilepsy is the most common mode of onset for epilepsy in childhood accounting for about two-­thirds of
all epilepsy cases.
3. Which of the following are considered self-­limited focal epilepsy syndromes?
A. Self-­limited focal neonatal epilepsy
B. Self-­limited infantile epilepsy
C. Self-­limited epilepsy with autonomic seizures
D. Self-­limited epilepsy with centrotemporal spikes
E. All the above
4. Is the following statement true or false?
Cerebrovascular disease accounts for 50%–­70% of epilepsy cases in adults.
5. Is the following statement true or false?
All patients with epilepsy should undergo at least a 1.5 T MRI using a protocol optimized for the evaluation of
epilepsy.
6. Which of the following MRI sequence is mandatory per the HARNESS MRI protocol?
A. Gadolinium enhanced, T1
B. Susceptibility-­weighted imaging, T2/SWI
C. Diffusion-­weighted (DWI)
D. 3D FLAIR, T2
E. None of the above
7. Which of the following epilepsy syndromes is most often associated with high-­amplitude bi/triphasic spike/
sharp-­slow wave discharges with maximal negativity in the centrotemporal region that are typically bilateral,
independent, and activated in drowsiness?
A. Self-­limited focal neonatal epilepsy
B. Self-­limited infantile epilepsy
C. Self-­limited epilepsy with autonomic seizures
D. Self-­limited epilepsy with centrotemporal spikes
E. Childhood-­onset visual epilepsy
8. Which of the following epilepsy syndromes is most often associated with multifocal, high-­amplitude epi-
leptiform discharges that are sleep activated and typically restricted to the posterior head regions at initial
presentation?
A. Self-­limited focal neonatal epilepsy
B. Self-­limited infantile epilepsy
C. Self-­limited epilepsy with autonomic seizures
D. Self-­limited epilepsy with centrotemporal spikes
E. Childhood-­onset visual epilepsy
9. Is the following statement true or false?
The standardized operational procedures for neuropathology workup recommend a systematic sampling of
5 mm interval tissue slabs along an anatomically defined plane of section for anatomical en bloc resections.
10. The ILAE defines drug resistance as failure of how many adequate trials of tolerated and appropriately used
antiseizure medications to achieve seizure freedom?
A. One
B. Two
C. Three
D. Four
E. Five
NASCIMENTO et al.    | 17

11. Which of the following is/are reason(s) for causing pseudo-­drug resistance?
A. Functional seizures
B. Antiseizure medication non-­adherence
C. Inadequate antiseizure medication dosage
D. Inappropriate antiseizure medication selection
E. All the above
Answers may be found in the supporting information.