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: [email protected]

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

2 |    NASCIMENTO et al.

1 | I N T RO DU CT ION
Key Points
The ILAE recommends a three-­ level framework upon 1. Focal seizures are divided into focal aware,
classifying epilepsies.1 First, one needs to identify the focal impaired awareness, and focal to bilateral
seizure type. Second, the epilepsy type needs to be de- tonic-­clonic seizures.
termined: focal, generalized, combined generalized and 2. Focal epilepsies account for most epilepsy cases
focal, or unknown. Third, the clinician should attempt both in children and adults.
to make a diagnosis of a specific epilepsy syndrome. An 3. Seizure semiology, neuroimaging, neurophysi-
etiologic diagnosis and potential comorbidities should be ology, and neuropathology are diagnostic cor-
sought at each step. The use of this framework aims to nerstones in the evaluation of patients with
improve the care of patients with epilepsy and advance focal epilepsies.
epilepsy research. 4. Patients with focal epilepsies who become drug-­
In this seminar in epileptology, we address the following resistant should promptly undergo assessment
learning objective of the ILAE's competency-­based curric- in an epilepsy center.
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- Current terms to define focal seizures are established1
rate on the diagnostic evaluation of focal epilepsies from and detailed instruction manual is available for opera-
neuroimaging, neurophysiology, and neuropathology tional classification.3 Focal seizures are subdivided into
standpoint. Lastly, we summarize the role of presurgical focal aware, focal impaired awareness (impaired aware-
evaluation in patients with drug-­resistant focal epilepsy. 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
2 | I L A E C LASSIFICAT ION OF of motor and non-­motor signs are added when they are
FOC A L S E I ZU R E S present at seizure onset (i.e., focal tonic seizures). Focal
seizures elicit a wide variety of symptoms and clinical be-
The role of the ILAE classification guidelines is to aid haviors that are highly diverse. Descriptors can be added
clinicians in defining and classifying seizures over the in free text form to enhance specificity. Focal seizures may
lifecycle. As a dynamic index used by treating clinicians, be age-­specific with self-­limited focal seizures accounting
seizure3 and epilepsy1 classification is a highly relevant for 25% of pediatric epilepsies.7 Clinical manifestations
tool to optimize patient management and advance re- of focal seizures evolve in a sequence of clinical features
search initiatives by providing a common vernacular in which may reflect a broadly distributed network over one
the form of a multinational language. Since first initiated hemisphere or remain discretely localized in brain region.
by the ILAE in 1981, revisions and modifications have Semiology provides information on the anatomical loca-
occurred over time. Modifications accommodate newly tion of the seizure onset zone and has important manage-
identified etiologies and incorporate advances in neuro- ment ramifications when focal seizures are drug-­resistant
imaging and electrophysiology and recent discoveries in- necessitating presurgical evaluation.8,9 Although seizure
volving genetics and immune-­mediated causes. Updating semiology is often similar in children and adults, epilepsy
prior classifications significantly influences management etiologies are typically distinct among the two patient
for all patients who experience focal seizures. populations.
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 3 | ETIOLOGIES OF FOC AL
hemisphere” are classified for medical or surgical treatment EPILEPSIES IN CHILDREN
using the earliest clinical feature (i.e., motor or non-­motor
descriptive signs). Then, they are sub-­classified, depending Focal epilepsy is the most common mode of onset for epi-
on the changes in the patients' awareness throughout the lepsy in childhood, accounting for about two-­thirds of all
seizure (i.e., aware or impaired awareness).3 Position pa- epilepsy cases. When thinking about etiology, there are
pers by the ILAE Task Force on Nosology and Definitions three main groups to consider. The most common etiolo-
in 2022 address current definitions and classifications in- gies of focal epilepsy syndromes in children are summa-
volving patients with focal seizures.4–­7 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 (SeLECTS) presents in school-­aged children with focal
seizures affecting the lower face with prominent drooling,
Specific self-­limited focal epilepsy syndromes have been re- dysarthria, and facial twitching. Seizures are usually seen
cently defined by the ILAE in both neonates and infants5 shortly after falling asleep or shortly before awakening
and children.7 The most common types are outlined below. and during sleep, when they may evolve to bilateral tonic–­
Self-­limited neonatal epilepsy usually begins in the 1st clonic seizures. EEG shows characteristic high-­amplitude
week of life with focal tonic or clonic seizures in an other- centrotemporal epileptiform discharges. The majority of
wise healthy baby. There may be a positive family history patients' seizures resolve by age 12 years, and nearly all pa-
of similarly affected neonates. Most of these babies will tients' seizures remit by age 16 years. Imaging and genetic
have a pathogenic variant in KCNQ2 (potassium voltage-­ studies are typically normal.
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 3.2 | Focal epilepsy of unknown cause
period but usually before 18 months of age. Focal seizures but which do not meet criteria for a self-­
consist of behavioral arrest, impaired awareness, versive, limited focal epilepsy syndrome
or focal clonic movements. These seizures often occur in
brief clusters where several seizures occur over a few days Approximately half of children with focal epilepsies that
and, rarely, they can evolve to bilateral tonic–­clonic sei- begin in childhood but do not meet criteria for one of the
zures. Infants have normal development and imaging and self-­limited syndromes will have no known cause found
nearly all cases resolve by 3 years of age. Several genetic despite careful evaluation including brain MRI. Overall,
variants have been found for this syndrome, mainly PRRT2 these patients have a very favorable prognosis with regard
(proline-­rich transmembrane protein 2) but also SCN2A to seizures, with one population-­based long-­term study
(sodium voltage-­ gated channel alpha subunit 2) and showing that 81% of patients achieve seizure freedom
SCN8A (sodium voltage-­gated channel alpha subunit 8). and 68% can be weaned off antiseizure medication(s).10
Self-­limited epilepsy with autonomic seizures (SeLEAS; Favorable outcome is particularly likely if the child
formerly known as Panayiotopoulos syndrome) most com- has a normal development and a normal neurologic
monly begins in preschool-­aged children. Seizures often examination.
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 3.3 | Focal epilepsy of known cause
can have prolonged seizures. Remission typically occurs
within 1–­2 years of onset. Imaging and genetic studies are Approximately half of focal epilepsies in childhood that do
typically normal. not fall into a specific self-­limited epilepsy syndrome will
4 |    NASCIMENTO et al.

be due to a known underlying cause. Such children have a acute symptomatic seizures, especially when concurrent
higher risk of developing drug-­resistant epilepsy and a lower movement disorders are present. Infectious causes such as
likelihood of epilepsy remission. The vast majority of known neurocysticercosis should be considered especially when
causes of focal epilepsy in childhood are structural causes, the MRI is concordant with the clinical diagnosis.
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 4 | ETIOLOGIES OF FOC AL
Structural causes can be divided into two groups: de- EPILEPSIES IN ADULTS
velopmental, where brain development is abnormal, and
acquired. More extensive malformations of cortical (e.g., The population of adults with epilepsy consists of people
hemimegalencephaly) development present at an earlier who have had epilepsy for many years and in some cases
stage in life with developmental delay and epilepsy which disease onset in childhood or adolescence. There are oth-
is often drug resistant. Some of these infants can present ers who develop epilepsy de novo in adulthood. While the
initially with infantile spasms with or without focal sei- causes of focal epilepsy are heterogenous and epilepsy can
zures but then evolve to focal or multifocal epilepsy over start at all ages, there are some etiologies that are more fre-
time. Less extensive forms of developmental structural quently encountered in adulthood. The ILAE published a
abnormalities such as focal cortical dysplasia (FCD) may position paper in 2017 with a revised classification of the
present later in childhood or even in adulthood where epilepsies.1 This paper incorporated etiologies as these can
drug-­resistant epilepsy is common. inform long-­term outcome and direct management. This
Among acquired causes, one of the most common etiolo- section will review the etiologies of epilepsy manifesting
gies is perinatal brain injury associated with intraventricular primarily in adulthood. Most common etiologies of focal
hemorrhage and subsequent periventricular leukomalacia epilepsy syndromes in adults are summarized in Table 2.
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- 4.1 | Structural etiologies
ther as focal seizures or as epileptic spasms. Other types of
structural changes can be seen at any age and include stroke, Most adult epilepsies are focal and are frequently the result
trauma, tumors, for example, low-­grade epilepsy-­associated of acquired structural brain abnormalities such as stroke,
tumors including gangliogliomas and dysembryoplastic brain trauma, or infections, or due to neoplasms, vascular
neuroepithelial tumors (DNETs), post-­infectious brain in- malformations, or a genetic condition. Some patients with
jury after meningitis or encephalitis, or other brain injury. epilepsy may have a combination of both acquired struc-
In children who have had a prior prolonged febrile seizure tural brain abnormality and a genetic disorder.
within the first years of life, hippocampal edema can be seen The prevalence of epilepsy increases with age and
acutely which, over time, can evolve to mesial temporal scle- peaks in the elderly. The association is explained by a
rosis. This is an important etiology as it is often drug resistant higher frequency of cerebrovascular disease, neurode-
and amenable to epilepsy surgery.13 generative conditions, and neoplasms in this age group.14
For some patients with developmental structural abnor- Cerebrovascular disease accounts for 50%–­70% of epilepsy
malities of the brain, an underlying genetic cause can be in adults. A cutoff of 7 days is used to determine whether
found such as variants with a second brain somatic hit or a post-­stroke seizure is considered early (acute symptom-
postzygotic somatic mosaicism only. These include condi- atic) or late.15 Dementia, particularly Alzheimer's disease,
tions such as Sturge–­Weber syndrome, tuberous sclerosis and neurodegenerative disorders account for 10%–­20% of
complex, DEPDC5 (DEP domain containing 5, GATOR1 late-­onset cases of epilepsy.16
subcomplex subunit) and other genes affecting the mTOR Seizures are among the most common manifestations
(mammalian target of rapamycin) pathway, or the galactose of cerebral neoplasms.17 Seizures can be the presenting
transporter SLC35A2 (solute carrier family 35 member A2). symptom in about 30%–­50% of individuals or start during
These children can be considered for epilepsy surgery if it is the course of the disease in 10%–­30% of patients. Tumor
deemed that seizures are arising from a specific focus. location and histology influence the risk for epilepsy.18
Metabolic derangements are most commonly associ- Additionally, several other factors can lead to epilepto-
ated with generalized seizures as opposed to focal seizures genesis in brain tumors such as genetic predisposition,
although very young infants can present with focal seizures integrity of the blood–­ brain barrier, and changes in
due to metabolic disorders. Immune-­mediated epilepsies the concentration of neurotransmitters (glutamate and
are relatively rare in children although autoimmune eti- GABA) and microenvironment. In neuroglial tumors,
ologies, especially anti-­NMDA, are often associated with the RAS–­RAF-­MAP-­Kinase pathway seems to influence
NASCIMENTO et al.    | 5

TABLE 2 Most common etiologies of focal epilepsy syndromes in adults.

Immune-­
Structural Genetic Infectious Metabolic mediated Unknown
Stroke Familial temporal lobe Viral encephalitis Mitochondrial Anti-­LGI1
Hippocampal sclerosis epilepsy Parasitic infections Acute intermittent Anti-­NMDAR
Hypoxic–­ischemic injury Autosomal dominant (malaria, porphyria Anti-­GABA-­B
Neurodegeneration sleep-­related neurocysticercosis) Adrenoleukodystrophy Anti-­Caspr2
(Alzheimer's disease) hypermotor epilepsy Bacterial meningitis, Wilson's disease
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 of histopathology, neurogenetic, and neuroimaging.21 In
that brain metastases have a less infiltrative growth pat- surgical cohorts, FCDs were the most common disease
tern and do not seem to modulate neuronal excitability condition in children and the third most common dis-
when compared to primary brain tumors. When feasible, ease condition in adults, manifesting more commonly in
identification of molecular biomarkers may guide further the frontal lobe.22 Another common focal lesion in adults
treatment, for example, IDH1 (isocitrate dehydrogenase were cavernomas with a mean disease onset in the 2nd de-
(NADP(+)) 1), co-­deletion of chromosomes 1p and 19q, cade of life, predominant localization in the temporal lobe
BRAF (v-­RAF murine sarcoma viral oncogene homolog and high probability of postsurgical seizure control.13,22
B1) V600E or MGMT promoter methylation. Cerebral vascular malformations associated with epi-
Low-­grade gliomas, IDH1 mutant, WHO CNS grade lepsy are a heterogeneous group of vascular disorders with
2, for example, oligodendrogliomas and astrocytomas, various presentations and clinical course. The most com-
occur commonly in the 3rd and 4th decades of life.20 The mon cerebral vascular malformations in adults are arte-
mean age of patients with high-­ grade gliomas (WHO riovenous malformations (AVMs) and cavernomas. Most
CNS grade 3 and 4), such as anaplastic astrocytomas and AVMs are sporadic and present as a solitary lesion, while
glioblastomas, is around 60 years. Approximately 35% of about 5% of AVMs occur in individuals with a genetic syn-
patients with metastases have seizures and these can be drome such hereditary hemorrhagic telangiectasia. The ge-
the initial manifestation while the primary tumor is di- netic contributions to AVMs are multi-­factorial and include
agnosed at a later time. The mean age of patients with germline and somatic variants.23 Arteriovenous malforma-
metastases is around 70 years. Most meningiomas are be- tions usually become symptomatic after the age of 20 years.
nign, frequently asymptomatic, more frequent in females, Besides hemorrhage, seizures are the second most common
and the most common age at diagnosis is about 50 years. presenting symptom of cerebral AVMs and can be seen in
Supratentorial meningiomas with peritumoral edema are up to 45% of patients.24 Cavernomas, also known as cavern-
associated with the greatest risk of seizures. The incidence ous angiomas or cavernous malformations (CMs), can pres-
of seizures in patients with meningiomas is about 30%. ent in sporadic or familiar forms (autosomal dominant with
Dysembryoplastic neuroepithelial tumors and gangliogli- variable penetrance). Familial cases, and a portion of spo-
omas are low-­grade developmental brain tumors (WHO CNS radic cases, are caused by variants in the following genes:
grade 1) and occur most often in the temporal lobe of young CCM1/KRIT1 (cerebral cavernous malformation gene 1)
adults and teenagers. Postsurgical long-­term seizure control (most frequent type), CCM2/MGC4607 (cerebral cavern-
>5 years is highest among all surgically amenable etiologies.13 ous malformation gene 2), and CCM3/PDCD10 (cerebral
Focal cortical dysplasias are highly epileptogenic mal- cavernous malformation gene 3). They most often become
formations of cortical development. In 2022, the ILAE symptomatic from the 2nd to the 5th decades of life. Seizures
published an updated international consensus classifica- are the most common clinical manifestations of CMs and
tions scheme of FCD including a multi-­layered integration are seen in half of patients.25 The anatomic location of CMs
6 |    NASCIMENTO et al.

tend to affect the symptomatology. In one study, 86% of later develop epilepsy. In developed countries, the risk
patients with seizures on presentation had lobar lesions.26 of post-­infectious epilepsy is around 8% but up to 26%
Seizures associated with cavernomas frequently originate in in resource-­poor countries.32,33 Epileptogenesis depends
the temporal lobe and have a high likelihood of postsurgical on the pathogen, degree of cortical involvement, and the
seizure control.13,22 Early diagnosis, timely treatment, and resulting inflammatory response. There is evidence that
systemic surveillance are now possible in individuals with delays in treatment may influence epileptogenesis. Viral
cerebral vascular malformations thanks to the advance- encephalitis, parasitic infections such as malaria, and
ments in neuroimaging and genetic testing. neurocysticercosis increase the risk of developing epi-
Traumatic brain injury (TBI) is the cause of epilepsy in lepsy, while bacterial meningitis may result infrequently
almost 30% of individuals who develop epilepsy between in long-­term epilepsy.34
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 4.4 | Metabolic etiologies
PTE appears to be directly related to the severity of the TBI.
Epilepsy resulting from brain trauma tends to be drug resis- Metabolic disorders associated with epilepsy can have a
tant. Since the latency to first seizure can be decades after genetic (inborn) substrate and may be a result of enzyme
the trauma, many research efforts are put into understand- deficiencies that affect biochemical pathways. The fre-
ing the neural networks and molecular pathologies involved quency of metabolic epilepsies may have been underes-
in epileptogenesis in order to prevent its development. timated as approximately 600 metabolic epilepsies have
been identified thus far.35
The most frequent metabolic disorders comprise pri-
4.2 | Genetic etiologies mary mitochondrial disorders—­ which can present at
any age.36 Mitochondrial disorders that can present with
Genetic etiologies in focal epilepsy are increasingly being focal seizures in adults include the DNA polymerase sub-
diagnosed and this will eventually drive management from unit gamma (POLG) related disorders; mitochondrial
an empirical approach to that of precision medicine.28,29 encephalopathy, lactic acidosis, and stroke-­like episodes
However, genetic testing is not yet routinely integrated in (MELAS); and myoclonic epilepsy with ragged red fibers
the evaluation of adults with epilepsy. Over the past two dec- (MERRF).37 POLG mutations represent the most common
ades, numerous genetic variants associated with various epi- cause of mitochondrial epilepsy in all ages. POLG-­related
lepsies have been identified. Familial temporal lobe epilepsy phenotypes with adult-­onset typically feature multiple mi-
and autosomal dominant sleep-­related hypermotor epilepsy tochondrial DNA deletions. Occipital lobe seizures have
(ADSHE), previously referred to as autosomal dominant been noted and, in certain cases, seizures may progress to
nocturnal frontal lobe epilepsy (ADNFLE), can manifest ei- status epilepticus.38 MELAS is caused by mutations in the
ther in adolescence or in adult years. Multiple genes have mitochondrial DNA in the MT-­TL1 (mitochondrially en-
been implicated in these two genetic epilepsies. For instance, coded tRNA leucine 1) gene. Status epilepticus can occur
ADSHE can be caused by variants in CHRNA4 (cholinergic in the context of stroke-­ like symptoms. The proposed
receptor nicotinic alpha 4 subunit), CHRNB2 (cholinergic mechanism leading to seizures in this syndrome include
receptor nicotinic beta 2 subunit), and CHRNA2 (cholinergic neurotransmitter, ion mechanisms, and oxidative stress.39
receptor nicotinic alpha 2 subunit), which are genes encod- MERRF can occur in early adulthood. The majority of
ing subunits of the neuronal nicotinic acetylcholine recep- MERRF cases bear m.8344A > G mutations. Myoclonic
tor (nAChR). A more severe form of ADSHE has been noted seizures are a hallmark of this syndrome; however, there
with variants of the sodium-­activated potassium channel are reports of focal seizures as well.40
encoded by KCNT1 (potassium sodium-­activated channel Among treatable metabolic epilepsies, acute intermit-
subfamily T member 1).30 Loss-­of-­function germline vari- tent porphyria, adrenoleukodystrophy, and Wilson disease
ants in the GATOR complex 1 gene DEPDC5 have also been have different modes of inheritance and can present in
described but recent research suggested an association with adulthood. Acute intermittent porphyria is an autosomal
FCD ILAE Type 2 due to second hit somatic variants acquired dominant disease involving defects in heme metabolism
in neuroglial precursor cells during neurodevelopment.31 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
4.3 | Infectious etiologies (ATPase Copper transporting beta) gene that result in
excessive amounts of copper accumulation in several or-
Like children, adults with central nervous system in- gans. Timely diagnosis of these disorders is critical as they
fections can develop seizures in the acute state and/or are amenable to specific treatment interventions.41
NASCIMENTO et al.    | 7

4.5 | Immune etiologies 5 | DIAGNOSTIC WORKUP OF

FOC AL EPILEPSIES
Despite substantial discoveries over the past couple of
decades, autoimmune epilepsy remains an underrecog- The following sections will address the diagnostic workup
nized cause of seizures.42 Neural autoantibodies targeting of focal epilepsies including neuroimaging, neurophysi-
cell surface or intracellular antigens have been impli- ology, and neuropathology. Table 3 summarizes the aux-
cated. The diagnoses can be confirmed by antibody test- iliary workup modalities in the management of patients
ing, either in spinal fluid or in serum. Cancer screening with focal epilepsies.
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 6 | DIAGNOSTIC WORKUP
acid B (GABA-­B) receptor antibodies are associated with OF FOCAL EPILEPSIES,
50% risk of ovarian cancer and small cell lung cancer, NEUROIMAGING
respectively.43 The average age of patients with NMDAR
antibodies is about 20 years, while the average age of the 6.1 | Significance and indications
other major antibodies LGI1, GABA-­ B, and Caspr2 is
around 60 years. Leucine-­rich glioma-­inactivated 1 (LG1) Neuroimaging in epilepsy serves different purposes.11,44
antibodies are rarely associated with cancer. NMDAR an- Early neuroimaging is crucial in emergencies, when a
tibodies and LGI1 antibodies are significantly more com- seizure may occur as a secondary manifestation accompa-
mon than the other antibodies. 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-
4.6 | Unknown etiology tient toward oncological rather than a primarily epilepto-
logical diagnostic pathway and treatment. Neuroimaging
In some instances, and despite significant advances in is performed in the early stage of the diagnostic evaluation
testing and refined imaging techniques, the etiology of ep- of epilepsy to establish a syndromic diagnosis and deter-
ilepsy cannot be determined. Several factors influence di- mine the underlying etiology of recurrent seizures.44
agnosis and management. Some patients are not referred Overall, however, imaging reveals an epileptogenic le-
in a timely manner to an epilepsy specialist for evaluation. sion in only around 20% of patients with new-­onset sei-
Also, differences in healthcare systems and limitations of zures. In patients with focal onset seizures, this percentage
resources such as brain MRI in certain countries may pre- reaches ~50%45 but depends on the level of technological
clude adequate testing (i.e., long-­term video-­EEG moni- sophistication and neuroimaging technique. In general,
toring). Determining the etiology of focal epilepsy across patients with epilepsy without an identifiable lesion on
the lifespan can offer a unique opportunity for counseling MRI (i.e., with causes other than structural lesions) have a
and etiology-­driven seizure management, especially in the better prognosis for seizure control with antiseizure med-
current era of precision medicine. ication.46 In patients with drug-­resistant focal epilepsies,

TABLE 3 Summary of auxiliary workup modalities in the management of focal epilepsies.

Neuroimaging Neurophysiology Neuropathology

• CT (emergency patients with • Routine EEG • Standardized operational procedure (SOP)
first seizure, widely available) • Routine EEG, sleep-­deprived for inspection, distribution, processing of
• MRI (recommended for all • Ambulatory EEG epileptogenic brain tissue
patients with epilepsy; ideally • Inpatient long-­term video-­EEG monitoring • Routine light microscopic assessment with
HARNESS protocol with or (LTM/EMU) hematoxylin–­eosin or cresyl violet or luxol-­
without MRI post-­processing) • ESI/MSI fast-­blue stainings
• Interictal PET • Antibodies to identify aberrant
• Ictal SPECT immunoreactivity patterns of disease-­specific
• Functional imaging (spatial protein epitopes
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.
8 |    NASCIMENTO et al.

structural imaging plays an essential role in the planning 6.3 | MRI: The HARNESS protocol
of invasive recordings and epilepsy surgery.47,48 Presence
of an epileptogenic lesion is a significant predictor of The ILAE Neuroimaging Task Force has recently recom-
successful epilepsy surgery,47,49 although complete lesio- mended the “HARNESS” MRI protocol (“Harmonized
nectomy of the structural lesion alone is not always suffi- Neuroimaging of Epilepsy Structural Sequences”), which
cient to achieve long-­term seizure freedom.50 In contrast, allows detection of the complete range of epileptogenic
non-­lesional patients represent an especially challenging lesions, while limiting the required scanning time.11 This
subgroup with comparably limited postsurgical seizure protocol includes three mandatory and two optional se-
outcomes.48 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-
6.2 | Structural imaging: MRI And CT ter is suggested to reduce partial volume effects. In com-
bination, this eliminates the need for pathology-­specific
CT is recommended in emergency patients with a first sei- sequences and angulations. For inspection of the hip-
zure51 and is widely available worldwide.44 It is sensitive pocampus, a 2D T2-­weighted series angulated perpendic-
to bleedings, but also small calcified and bone lesions as ularly to the long axis of the hippocampus with increased
well as skull defects (e.g., in patients with encephalocele). intra-­slice resolution is suggested. Two optional series pro-
However, due to better differentiation of brain tissues, vide additional sensitivity in specific cases: gadolinium-­
all patients with focal epilepsy should undergo at least a enhanced 3D T1 to assess tumors, vascular malformations,
1.5 T MRI using a protocol optimized for the evaluation of and infectious processes, and susceptibility-­ weighted
epilepsy, while the application of CT is limited to special SWI/T2*, which is sensitive to iron deposits, blood prod-
situations.11,44 Patients should undergo repeated MRI if ucts, and calcifications. The protocol is recommended for
previous imaging did not follow an optimized protocol.11 field strengths of 3 T however the sequences can also be
Furthermore, children with focal seizures and unreveal- obtained with 1.5 T.11 Even when acquired with an opti-
ing MRI performed below the age of 1 year should un- mal HARNESS protocol, the MRI interpretation should
dergo repeated MRI. 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 T1 3D 1 × 1 × 1 mm, no interslice gap Allows for reformatting to different
gradient echo (MPRAGE, angulations and view planes,
Siemens), Spoiled gradient visualization of brain anatomy and
echo (SPGR, GE), Turbo field morphology
echo (TFE, Phillips)
3D fluid attenuation inversion T2-­FLAIR 3D 1 × 1 × 1 mm, no interslice gap Allows for reformatting to different
recovery (FLAIR) angulations and view planes, fluid
attenuation enhances visibility of
lesions such as FCD, hippocampal
sclerosis, and tubers
Coronal spin echo (acquisition T2 2D 0.4 × 0.4 × 2 mm High in-­plane resolution and coronal
plane perpendicular to long view plane provides optimal
axis of the hippocampus) visualization of hippocampal
internal structure
Optional sequences
Gadolinium-­enhanced MRI T1 3D Contrast agent improves assessment of
tumors, vascular malformations, or
infectious processes
Susceptibility-­weighted imaging T2*/SWI 3D Sensitive to iron deposits, blood
products and calcifications, e.g., for
assessment of cavernomas
NASCIMENTO et al.    | 9

other clinical information.12 Experience of the examiner is distribution of functional cortex (e.g., motor and sensory
also fundamental, and an MRI reported as normal might cortex) as well as language-­related areas.60,61 The aim of
really harbor a subtle structural abnormality not initially epilepsy surgery is to ultimately achieve improvement in
identified by the interpreter,52 in particular FCDs.53 one's quality of life. Consequently, permanent functional
The visual inspection of digitally stored 3D MRIs deterioration from the effect of recurrent seizures must
(usually in DICOM format), acquired with the smaller be avoided. However, individual functional anatomy is
isotropic voxel size as possible,11 should be done using a variable and epileptogenic lesions may lead to consider-
platform that allows multiplanar reformatting. There are able reorganization, especially when they occur early in
several options of user-­friendly DICOM viewers that run life. Functional imaging thus contributes to evaluating
on most desktop computers and can be incorporated into the viability of surgical therapy and aids planning of re-
the routine of epileptologists. section extents. Additional information from functional
multimodal imaging improves MRI detection of subtle
lesions.44
6.4 | MRI post-­processing

In patients with subtle lesions, visual analysis of MRI may 7 | DIAGNOSTIC WORKUP
not be sufficient. Post-­processing techniques may offer so- OF FOCAL EPILEPSIES,
lutions by computationally analyzing morphological MRI NEUROPHYSIOLOGY
features, such as sulcal depth, contrast of the gray-­white
matter junction, volumes, and cortical thickness, among 7.1 | Confirmation of focal epilepsy
others. A comparison to healthy controls then provides
objective metrics of structural alterations potentially pro- Once a diagnosis of focal epilepsy is considered, EEG can
viding evidence for a subtle lesion.54 The use of artificial be used to confirm or refute clinical suspicions, and in
intelligence approaches in parallel to the visual analyses some cases establish an electroclinical diagnosis: a clini-
may enhance further the detection of very subtle FCDs in cal diagnosis supported by EEG. Several factors, however,
previously negative MRIs.55 limit the use of EEG as an auxiliary test in the diagnosis
of focal epilepsy.
First, EEG is a low-­amplitude, continuous and dynamic
6.5 | PET and SPECT biosignal that requires considerable expertise for interpre-
tation. The EEG signal recorded at the scalp reflects the
Positron emission tomography (PET) and single photon summed potentials generated in a relatively large area (≥6–­
emission computed tomography (SPECT), imaging meth- 10 cm2) of the cortex at the cerebral convexity and, there-
ods that are mainly used in the presurgical evaluation fore, represents only a small portion of brain activity of
context, provide additional localizing information espe- clinical interest. Multiple non-­brain sources further lower
cially in selected (e.g., non-­lesional) cases.56–­59 Interictal the signal to noise ratio (SNR). This low SNR is partly re-
PET, currently largely fluorodeoxyglucose (FDG)-­ PET, sponsible for high inter-­observer variability. Furthermore,
can reveal decreased glucose metabolism, which may be there is a risk of over-­or under-­reading EEG findings. The
observed in the seizure onset zone. SPECT evaluates re- former constitutes misinterpreting normal variants, arti-
gional cerebral blood flow, which is increased during a facts, or other clinically irrelevant transients as epilepti-
seizure. If the radioactive SPECT tracer is injected at sei- form. The latter constitutes dismissing a subtle but true
zure onset or shortly thereafter, an ictal SPECT may local- epileptiform abnormality. Even experienced EEG readers
ize the seizure onset zone. Subtraction of ictal-­interictal may still have a practice style of interpreting with “high
SPECT co-­ registered with MRI (SISCOM) has shown sensitivity” or with “high specificity.”62,63 “Conservative”
increased specificity58 relative to interictal SPECT alone EEG reading has been recommended to achieve high
and is less informative especially in extratemporal lobe specificity and avoid over-­reading with resultant epilepsy
epilepsy.59 misdiagnosis.64
Second, epileptiform abnormalities can occur in the
EEG of up to 4% of school-­aged children in the absence of
6.6 | Functional imaging epilepsy, that is, on average 1 child in every classroom of
30 children if everyone were to undergo an EEG without
Functional imaging with fMRI or magnetoencephalogra- indication. This fraction increases in children with comor-
phy (MEG), also primarily used in the presurgical evalu- bid learning disabilities, attention deficit hyperactivity
ation context, provides information about the spatial disorder, and autism spectrum disorder.65,66
10 |    NASCIMENTO et al.

In clinical practice, therefore, the diagnostic yield in a dedicated epilepsy monitoring unit is the gold-­standard
of an EEG depends on the prior (or pre-­test) probability. to diagnose, classify, quantify, and characterize patients re-
According to Bayes' theorem for calculating conditional ferred for uncontrolled seizures when the event of interest
probabilities, a clinician should update prior information is captured. Prolonged high-­ quality assessment of both
(e.g., is focal epilepsy present in this patient?) whenever background and interictal patterns provide supportive in-
new and relevant information is provided (e.g., the EEG is formation in conjunction with ictal EEG.
abnormal and contains temporal epileptiform discharges).67 Interictal EEG also has an important role in the diagno-
In clinical practice, evidence and information are presented sis of epilepsy.71 When seizures are highly suspicious from a
sequentially, not all at once. For example, a neurologically clinical standpoint, the diagnosis of epilepsy is a clinical one
healthy toddler with a spell of brief unresponsiveness and that can be made irrespective of the presence or absence of an
an EEG with one focal epileptiform discharge may still not epileptiform EEG. In these cases, however, EEG can be help-
have epilepsy. The same EEG, however, could be support- ful in classifying epilepsy—­focal, generalized, or combined
ive of an epilepsy diagnosis when the pre-­test probability generalized and focal, or unknown—­with respective treat-
is higher: a new event occurs, or a more detailed history is ment implications. If spells are of moderate clinical suspicion
provided by an eyewitness in the same patient. The EEG has for epileptic seizures, the presence of interictal epileptiform
important limitations, and the results should be interpreted abnormalities on EEG establishes the diagnosis of epilepsy.71
within the appropriate clinical context of the patient.68 The absence of interictal epileptiform abnormalities on EEG
The diagnostic yield of EEG can be improved in various though does not rule out the diagnosis of epilepsy. When
ways. If the first routine EEG is normal, consider obtain- spells are of low clinical suspicion, the presence of interictal
ing a repeat routine EEG that captures sleep and, ideally, epileptiform abnormalities on EEG may increase the likeli-
is recorded following sleep deprivation.69 Ambulatory EEG hood of epilepsy. A proposed algorithm is shown on Figure 1.
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 7.2 | Utility in classification and guiding
time which can prevent assessment of interictal findings. (workup and) therapy
Children, uncooperative patients, and prolonged record-
ings may be susceptible to artifact obscuring meaningful In addition to confirming the diagnosis of focal epilepsy,
interpretation. Inpatient long-­term video-­EEG monitoring 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.    | 11

understanding prognosis, and guiding further evaluation. a patient is identified as drug-­resistant is associated with
Self-­limited focal epilepsies of childhood, which account higher rates of seizure freedom and improved quality of
for approximately 25% of pediatric epilepsies72 often have life compared to continued medical therapy.75 Therefore,
characteristic EEG features that, in the correct clinical it is in the best interest of patients and health systems to
context, can indicate benign course. Typically, children determine best candidates for early epilepsy surgery be-
with characteristic clinical and EEG features do not fore they accumulate the negative medical and social
need neuroimaging, which is important and relevant for outcomes associated with intractability. Patients with uni-
resource-­limited settings.7 lateral temporal lobe discharges on EEG and a concordant
Self-­
limited epilepsy with centrotemporal spikes MRI lesion have some of the best changes for postopera-
(SeLECTS) features, on EEG, high-­amplitude (≥200 μV), tive seizure freedom and would benefit most from early
bi/triphasic spike/sharp-­slow wave discharges with max- surgical referrals.76,77
imal negativity in the centrotemporal region and frontal Another proposed role for EEG in the management
positivity that are activated in drowsiness.7,73 Discharges of patients with focal epilepsy is to identify patients who
are typically bilateral and independent but a single rou- can be withdrawn from antiseizure medication(s) after
tine EEG may only identify discharges on one side. The prolonged seizure freedom. There is some controversy
presence of interictal focal slowing, solely unilateral as to whether an abnormal EEG, including epileptiform
discharges on multiple EEGs, and exclusively diurnal discharges, indicates risk of relapse in weaning antisei-
discharges are atypical for self-­limited epilepsy with cen- zure medication(s).78 A meta-­analysis of available studies
trotemporal spikes and should prompt consideration of an on antiseizure medication withdrawal in seizure-­free pa-
alternative diagnosis, including an underlying structural tients suggests that the contribution of an abnormal EEG
brain abnormality.7 to relapse risk is modest at best and the presence of ep-
Self-­
limited epilepsy with autonomic seizures ileptiform abnormalities in the absence of other clinical
(SeLEAS) features, on EEG, multifocal, high-­amplitude risk factors for relapse like a structural lesion or develop-
epileptiform discharges that are sleep-­activated. At ini- mental delay.79 However, patients with focal seizures, in
tial presentation, discharges are most common in the the absence of a self-­limiting syndrome as above, are at a
posterior head regions but can be seen throughout the higher risk for recurrence.
scalp in older ages.7
Childhood-­ onset visual epilepsy typically occurs in
children aged 8 to 9 years (range 1–­19 years) with brief 8 | DIAGNOSTIC WORKUP
focal aware visual seizures and postictal headache.74 The OF FOCAL EPILEPSIES,
EEG is characterized by sleep-­predominant occipital dis- NEUROPATHOLOGY
charges but centrotemporal spikes can also be seen. Focal
slowing and unifocal discharges should prompt consider- The best outcome of histopathology examination of epi-
ation of an alternative diagnosis in both childhood-­onset lepsy surgery brain tissue samples can be achieved in a
visual epilepsy and self-­limited epilepsy with autonomic setting of collaborative interaction between epileptolo-
seizures (SeLEAS).7 gists, neurosurgeons, and neuropathologists.80 The neu-
Lastly, developmental and epileptic encephalopa- ropathology laboratory should be responsible, however,
thies (DEE) or epileptic encephalopathies (EE) with for the standardized brain tissue procurement from any
spike-­and-­wave activation in sleep (EE-­SWAS and DEE-­ neurosurgical intervention. Standardized operational pro-
SWAS, respectively) may derive from focal epilepsy syn- cedures (SOP) for the neuropathology workup, including
dromes such as SeLECTS, SeLEAS, or other structural inspection, distribution, and processing of epileptogenic
focal epilepsies. Clinically, (D)EE-­ SWAS consist of a brain tissue, have been developed by the ILAE, as it will
group of conditions characterized by a combination reduce sampling errors in any pathology laboratory, en-
of cognitive, language, behavioral, and motor regres- sure the best possible histological assessment, and support
sion.7 Electroencephalographically, (D)EE-­SWAS feature research activities and brain banking initiatives.80
marked activation of epileptiform abnormalities during Long-­term tissue storage and archiving will become
sleep with nearly continuous spike-­and-­wave complexes. more important in modern diagnosis as new molecular
These cases are an example wherein EEG may be valuable tests are increasingly available (e.g., BRAF V600E and
to guide treatment and monitor for therapy response. IDH1 variant in the differential diagnosis of low-­grade
Interictal EEG may also be an important tool to stratify epilepsy-­
associated tumors (LEAT) and mTOR signal-
candidates for early epilepsy surgery (including neuro- ing pathway genes or SLC35A2 variants in FCD).53,81
stimulation). Studies have shown that, at least in temporal Clinicians may increasingly start requesting retrospec-
lobe epilepsy, surgery early in the course of epilepsy once tive investigations or additional review of stored tissue
12 |    NASCIMENTO et al.

samples for patients who underwent epilepsy surgery in Surgery is a well-­accepted treatment for patients with
the past.82,83 Advanced frozen storage facilities, adequate drug-­resistant epilepsy yet delays of up to 20 years may
record keeping, and protocols for microscopic review of occur.88 Three prospective longitudinal cohort studies
snap frozen samples will facilitate this process and im- involving adults and children demonstrate high-­ level
prove diagnostic accuracy. All histopathology reports evidence for the efficacy of epilepsy surgery (including
should refer to anatomical landmarks and orientation and neurostimulation) in patients with drug-­ resistant focal
clearly state a histopathological diagnosis according to epilepsy.75,89,90 Nevertheless, only a small minority of pa-
current classification systems. tients are evaluated for surgery.
The concept of an integrated multi-­layer diagnostic The goal of a presurgical evaluation is to identify the
scheme has already been acknowledged in the 1st up- location and extent of the epileptogenic zone approximat-
date of the international FCD consensus classification.53 ing the minimum amount of brain required for seizure
Herein, the histopathology diagnosis builds one layer freedom. Detailed interview of the patient and a witness
only and is amended by additional diagnostic findings of their seizures lies at the cornerstone of a comprehen-
(i.e., MRI and genetics) to comprehensively describe the sive evaluation. Basic modalities include long-­term video-­
genotype–­phenotype correlation of a given FCD subtype. EEG, high-­resolution brain MRI, and neuropsychological
This will turn out to be more important in the near fu- assessment. As complexity increases functional neuroim-
ture, when neurosurgical resections become less available aging, electric/magnetic source imaging, functional MRI,
due to thermo-­coagulation or laser ablation procedures, advanced MRI post-­ processing, and intracranial EEG
when a genetic mosaicism becomes a therapeutic target in monitoring may further resolve discordant non-­invasive
patients not being seizure-­free following surgery, or when evaluations.91 Each result has limitations. None should be
the available histopathology report is not concordant with used in isolation. With multimodal concordance using a
the clinical findings, for example, due to sampling errors multidisciplinary approach success is readily obtainable.
or unavailable accessory histochemical and/or immuno-
histochemical stainings. The integrated diagnosis should
then be assembled during a postsurgical patient manage- 10 | CONCLUSION
ment conference led by the epileptologist in charge of the
patient following a comprehensive multidisciplinary re- Being able to correctly diagnose and classify focal epilep-
view of all available diagnostic reports.53 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-
9 | RO L E O F PR E SU RG ICAL lepsies. We hope that this article contributes to the ILAE's
E VA LUAT I O N IN DRU G -­R E SISTANT mission to ensure that worldwide healthcare profession-
FO C A L E P I LE PSIE S als, patients, and caregivers continue to have high-­quality
resources that are crucial in understanding, diagnosing,
For patients with epilepsy, lifelong seizure freedom with- and treating epilepsy.
out adverse effects is the desired outcome of any interven-
tion.84 The ILAE defines drug resistance as failure of two CONFLICT OF INTEREST STATEMENT
adequate trials of tolerated and appropriately used antisei- F. Nascimento is Associate Editor of Epileptic Disorders.
zure medications to achieve sustained seizure freedom.85 S. Beniczky is Editor-­ in-­
Chief of Epileptic Disorders.
After two failed antiseizure medications, a newly admin- D. Friedman receives salary support for consulting and
istered antiseizure medication is expected to result in clinical trial-­related activities performed on behalf of The
seizure-­free outcome in 11.8%, declining to 2.6% for more Epilepsy Study Consortium, a non-­profit organization. D.
than six drug failures.86 Epilepsy has a dynamic course, Friedman receives no personal income for these activities.
and drug resistance applies only at the time of assessment NYU receives a fixed amount from the Epilepsy Study
and does not imply a permanent condition. Consortium toward D. Friedman's salary. Within the past
Pseudo-­drug resistance is created by conditions mim- two years, The Epilepsy Study Consortium received pay-
icking drug failure with proper use. Functional seizures ments for research services performed by D. Friedman
misidentified as epileptic, antiseizure medication non-­ from: BioXcell, Cerevel, Cerebral, Epilex, Equilibre,
adherence, or adverse patient behavior, inadequate dos- Jannsen, Lundbeck, Praxis, Puretech, Neurocrine, SK Life
age, or inappropriate antiseizure medication selection are Science, Supernus, UCB, and Xenon. He has also served
reasons to explain why treatment fails to control seizures.87 as a paid consultant for Neurelis Pharmaceuticals. He has
It is estimated that one in five patients suspected of drug-­ received travel support from the Epilepsy Foundation.
resistant focal epilepsy are pseudo-­drug-­resistant.86 He has received research support from NINDS, CDC,
NASCIMENTO et al.    | 13

10. Wirrell EC, Grossardt BR, So EL, Nickels KC. A population-­

Epitel, and Neuropace unrelated to this study. He holds based study of long-­term outcomes of cryptogenic focal epilepsy
equity interests in Neuroview Technology. He received in childhood: cryptogenic epilepsy is probably not symptomatic
royalty income from Oxford University Press. J. Peters, epilepsy. Epilepsia. 2011;52(4):738–­45.
M. Bensalem-­Owen, F. Cendes, S. Rampp, W. Tatum, 11. Bernasconi A, Cendes F, Theodore WH, Gill RS, Koepp MJ,
E. Wirrell, and I. Blümcke report no disclosures relevant Hogan RE, et al. Recommendations for the use of struc-
to the manuscript. tural magnetic resonance imaging in the care of patients
with epilepsy: a consensus report from the international
league against epilepsy neuroimaging task force. Epilepsia.
ORCID
2019;60(6):1054–­68.
Fábio A. Nascimento https://orcid. 12. Wang I, Bernasconi A, Bernhardt B, Blumenfeld H, Cendes
org/0000-0002-7161-6385 F, Chinvarun Y, et al. MRI essentials in epileptology: a re-
Stefan Rampp https://orcid.org/0000-0002-4826-1520 view from the ILAE imaging taskforce. Epileptic Disord.
Elaine Wirrell https://orcid.org/0000-0003-3015-8282 2020;22(4):421–­37.
Ingmar Blümcke https://orcid. 13. Lamberink HJ, Otte WM, Blumcke I, Braun KPJ, European
org/0000-0001-8676-0788 Epilepsy Brain Bank Writing Group, European Epilepsy Brain
Bank Study Group, et al. Seizure outcome and use of antiepi-
William Tatum https://orcid.org/0000-0002-4536-3791
leptic drugs after epilepsy surgery according to histopathologi-
Sándor Beniczky https://orcid. cal diagnosis: a retrospective multicentre cohort study. Lancet
org/0000-0002-6035-6581 Neurol. 2020;19(9):748–­57.
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SUPPORTING INFORMATION
with drug-­resistant focal epilepsy. Epilepsia. 2019;60(8):e78–­82.
Additional supporting information can be found online
78. Specchio LM, Beghi E. Should antiepileptic drugs be with-
drawn in seizure-­free patients? CNS Drugs. 2004;18(4):201–­12. in the Supporting Information section at the end of this
79. Lamberink HJ, Otte WM, Geerts AT, Pavlovic M, Ramos-­Lizana article.
J, Marson AG, et al. Individualised prediction model of seizure
recurrence and long-­term outcomes after withdrawal of an-
tiepileptic drugs in seizure-­free patients: a systematic review
and individual participant data meta-­analysis. Lancet Neurol. How to cite this article: Nascimento FA,
2017;16(7):523–­31. Friedman D, Peters JM, Bensalem-­Owen M,
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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.