Seminar

Adult epilepsy
Ali A Asadi-Pooya, Francesco Brigo, Simona Lattanzi, Ingmar Blumcke

Lancet 2023; 402: 412–24 Epilepsy is a common medical condition that affects people of all ages, races, social classes, and geographical regions.
Published Online Diagnosis of epilepsy remains clinical, and ancillary investigations (electroencephalography, imaging, etc) are of aid
July 14, 2023 to determine the type, cause, and prognosis. Antiseizure medications represent the mainstay of epilepsy treatment:
https://doi.org/10.1016/
they aim to suppress seizures without adverse events, but they do not affect the underlying predisposition to generate
S0140-6736(23)01048-6
seizures. Currently available antiseizure medications are effective in around two-thirds of patients with epilepsy.
Epilepsy Research Center,
Shiraz University of Medical Neurosurgical resection is an effective strategy to reach seizure control in selected individuals with drug-resistant
Sciences, Shiraz, Iran focal epilepsy. Non-pharmacological treatments such as palliative surgery (eg, corpus callosotomy), neuromodulation
(Prof A A Asadi-Pooya MD); techniques (eg, vagus nerve stimulation), and dietary interventions represent therapeutic options for patients with
Jefferson Comprehensive
drug-resistant epilepsy who are not suitable for resective brain surgery.
Epilepsy Center, Department of
Neurology, Thomas Jefferson
University, Philadelphia, PA, Introduction and lifestyle considerations for patients with epilepsy. We
USA (Prof A A Asadi-Pooya); Epilepsy is a common chronic brain disorder that affects discuss what epilepsy is and whom it affects, why it is
Department of Neurology,
people of all ages and has no geographical, social, or important, novel achievements in the research and
Hospital of Merano (SABES-
ASDAA), Merano, Italy racial boundaries. Conceptually, epilepsy is a disease of clinical fields, and what developments are yet to come.
(F Brigo MD); Lehrkrankenhaus the brain that is characterised by a long lasting
der Paracelsus Medizinischen predisposition to recurrently generate epileptic seizures.1,2 Classification of epilepsies
Privatuniversität, Salzburg,
An epileptic seizure is defined as a “transient occurrence As epilepsy is not a single disease entity the diagnosis
Austria (F Brigo); Neurological
Clinic, Department of of signs and/or symptoms due to abnormal excessive or should be as specific as possible.8 The International
Experimental and Clinical synchronous neuronal activity in the brain”.2 This League Against Epilepsy (ILAE) has provided a
Medicine, Marche Polytechnic presentation differs from acute symptomatic seizures, classification system at three different levels: seizure type
University, Ancona, Italy
(S Lattanzi MD); Institute of
which occur in close temporal relationship with an acute (classified into focal onset, generalised onset, or
Neuropathology, University brain insult.3 In acute symptomatic seizures, a CNS unknown onset), epilepsy type (classified as generalised
Hospitals Erlangen, Erlangen, insult (eg, toxins) transiently lowers the seizure epilepsy, focal epilepsy, combined generalised and focal
Germany (Prof I Blumcke MD); threshold; therefore, seizures are not expected to recur epilepsy, or unknown), and epilepsy syndrome (figure 1).9
Charles Shor Epilepsy Center,
Neurological Institute,
once the precipitating factor or condition has been An epilepsy syndrome refers to a collection of specific
Cleveland Clinic, Cleveland, OH, removed or reversed.3 Epilepsy has neurobiological, clinical characteristics that can include seizure types,
USA (Prof I Blumcke) cognitive, psychological, and social consequences. electroencephalogram (EEG) findings, brain imaging
Correspondence to: Premature mortality remains a major problem in results, and other features (eg, age at seizure onset,
Prof Ali A Asadi-Pooya, Epilepsy patients with epilepsy globally. This chronic neurological comorbidities, seizure triggers, aetiology, and prognosis),
Research Center, Shiraz
University of Medical Sciences,
condition poses a substantial burden for health systems, which often occur together.9 It is ideal to make a syndromic
Shiraz 71437, Iran individuals, and their families.4–7 Therefore, it is diagnosis in a patient who has epileptic seizures (eg,
[email protected] important for all health-care professionals to be familiar juvenile myoclonic epilepsy, focal epilepsy syndromes
with this condition. In this Seminar, we have provided with genetic, structural, or genetic-structural aetiologies
the most up-to-date information on classification, [eg, sleep-related hyper­motor epilepsy, mesial temporal
epidemiology, pathophysiology, diagnosis, treatment, lobe epilepsy with hippocampal sclerosis], etc). Recently,
the ILAE has provided detailed classification systems for
various epilepsy syndromes.10,11 However, the epilepsy type
Search strategy and selection criteria
could be the final level of diagnosis that is achievable; the
We searched PubMed for articles from Jan 1, 2018 to clinician might not have sufficient information to make a
Dec 31, 2022, with the search terms “epilepsy”, “EEG”, “MRI”, syndromic diagnosis.9 Under normal circumstances, and
“seizure”, “epidemiology”, “mortality”, “antiepileptic drug”, when the resources to collect enough information to make
“antiseizure”, “surgery”, “mechanisms”, “autoimmune”, a syndromic diagnosis (such as EEG, MRI) are available, if
“complementary and alternative medicine”, “exercise”, a clinician is not able to make a syndromic diagnosis of
“sleep”, and “diet”. Articles written in English were included. the condition they should at least be able to classify the
We largely selected publications in the past 5 years, but did epilepsy type (panel 1). The diagnostic level establishes the
not exclude commonly referenced and highly regarded older foundation for the treating health-care provider to
publications. We also searched the reference lists of articles contemplate an appropriate management strategy for the
identified by this search strategy and selected those we condition.12 In some instances of resource-limited settings,
judged to be relevant. Review articles and book chapters are classification according to seizure type might be the only
cited to provide readers with more details and more reachable diagnosis due to an inability to access EEG or
references than this Seminar has room for. Our reference list imaging studies, as these diagnostic measures might be
was modified on the basis of comments from peer reviewers. necessary to differentiate focal from generalised epilepsy
types.9 In such circumstances, a detailed clinical history of

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Seizure type Epilepsy type Epilepsy syndrome

(basic level in diagnosis) (mandatory where resources to diagnose (ideal diagnosis)
are available)
Examples for appropriate first drug options:
Focal: start treatment with carbamazepine, Focal 1) Juvenile absence epilepsy: lamotrigine in
lamotrigine, or levetiracetam women and valproate in men
2) Juvenile myoclonic epilepsy: levetiracetam
Generalised in women and valproate in men
Generalised: start treatment with valproate, 3) Focal epilepsy: carbamazepine, lamotrigine,
lamotrigine, or levetiracetam or levetiracetam
Combined focal and generalised 4) Lennox-Gastaut syndrome: valproate
5) GLUT1 deficiency syndrome: ketogenic diet
Unknown: start treatment with a
broad-spectrum drug (see table 1) Unknown

Figure 1: Framework for classification of seizures and epilepsies and its practical implications
The suggested treatment options could differ considering other variables (eg, sex, age, comedications, comorbidities, availability, cost).

Panel 1: Key points in the diagnosis of epilepsy type in adult patients with epilepsy
Generalised epilepsy • Postictal state: common after all seizure types (except focal
• Age at seizure onset: usually in childhood, adolescence, or aware seizures)
young adulthood (<25 years) • Family history: rarely positive for epilepsy (might be positive
• Aura: not common; if present, is often non-specific in familial cases)
(eg, dizziness) • Epilepsy risk factors (traumatic brain injury, CNS infections,
• Ictal events: absence, myoclonic, tonic-clonic, and rarely etc): might be present
atonic and tonic seizures • EEG: might show focal epileptiform discharges
• Postictal state: common after generalised tonic-clonic seizures • MRI: might show structural brain abnormality (dedicated
(not present after absence and myoclonic seizures) epilepsy protocol)
• Family history: might be positive for epilepsy
Combined generalised and focal epilepsy
• Epilepsy risk factors (traumatic brain injury, CNS infections,
• Age at seizure onset: often in childhood
etc): absent
• Has different seizure types with features from both categories.
• EEG: might show generalised spike-waves or polyspikes
For example, some patients with Lennox-Gastaut syndrome
• MRI: MRI is not needed if a syndromic diagnosis of an
might have tonic seizures, myoclonic seizures, tonic-clonic
idiopathic generalised epilepsy (based on history and EEG) is
seizures, and focal impaired awareness seizures.
made; if performed, it is normal or might show incidental
findings (not related to epilepsy) Unknown
• Age at seizure onset: at any age
Focal epilepsy
• Aura: none or non-specific (eg, dizziness)
• Age at seizure onset: at any age
• Ictal events: tonic-clonic seizures
• Aura: common, might be location specific (eg, focal sensory
• Postictal state: non-specific (eg, sleepiness, fatigue,
aura)
confusion)
• Ictal events: focal aware seizures (motor or non-motor), focal
• EEG: normal
impaired awareness seizures (motor or non-motor), and focal
• MRI: normal
to bilateral tonic-clonic seizures

the patient is often revealing. If a patient presents with per 100 000 people.14 The prevalence and incidence rates
tonic-clonic convulsions without enough clinical evidence of epilepsy are higher in low-income and middle-income
to ascertain either a focal or a generalised onset, their countries compared with those in high-income nations.13
seizures can be classified as unknown onset tonic-clonic We estimate the point prevalence of active epilepsy in the
seizures.9 world (as of Feb 24, 2023) to be about 51 million people.15
Similarly, our estimates suggest that every year about
Epidemiology 4·9 million people in the world develop new-onset
In a systematic review and meta-analysis of international epilepsy, based on the world population and the incidence
studies, the point prevalence of active epilepsy was 6·4 rate of epilepsy. High-quality studies on the epidemiology
per 1000 individuals (95% CI 5·6–7·3) and its incidence of epilepsy types or syndromes are scarce, but it seems
was 61·4 per 100 000 person-years (50·8–74·4).13 A that about two-thirds of all epilepsies are focal onset in
previous systematic review found the median crude nature, about a-fifth of all epilepsies are idiopathic
incidence rate of cerebrovascular disease to be 149·5 cases generalised epilepsies, and the rest are other epilepsy

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types.16,17 Despite the global nature of the prevalence of contemporary recognition of neuro­stimulation
epilepsy, there is a considerable epilepsy treatment gap techniques in the current treatment portfolio for drug-
defined as the proportion of people living with active resistant epilepsy. Modern multiomics approaches have
epilepsy who do not receive appropriate treatment of the identified, however, an increasing number of candidate
total number of people living with active epilepsy in a genes for epilepsy across many epilepsy syndromes.
population.18 Common risk factors and causes of epilepsy Published studies highlighted genetic alterations in ion
vary by age group. Cerebrovascular and neurodegenerative channels and synaptic transmission (including SCN1A
diseases are common risk factors in older people, whereas and GRIN1 genes, and many more) in generalised
epilepsy associated with traumatic brain injury, infections, epilepsies.25,26 These alterations differ from structural
and tumours might occur at any age. Geographical focal epilepsies in which, for example, mosaic alterations
location is also an important factor. For example, parasitic of the mammalin target of rapamycin (mTOR) or
conditions such as malaria (in sub-Saharan Africa) and mitogen-activated protein kinase signal transduction
neurocysticercosis (in Asia, sub-Saharan Africa, and Latin represent pathogenic key events.27 Single-cell genomics
America) are among the most common preventable further exposed the susbtantial burden of brain somatic
aetiologies of epilepsy in some low-income and middle- gene variants in our trillions of neurons evolving from
income countries, whereas traumatic brain injuries are the approximately 30 mitotic cycles of neuronal divisions
particularly common in war-torn regions and nations in to build the human neocortex.28 Each patient’s individual
the world.8,19 Although patients with epilepsy are subject brain mosaicism is likely to contribute to or modify the
to similar causes of death as those without epilepsy, seizure threshold and also change with age.29
mortality in patients with epilepsy is greater than that in Any change to the human neocortex with its excitable
the general population. Sudden unexpected death in neuronal network structure can cause seizures and
epilepsy (SUDEP), status epilepticus, drowning, injuries, eventually progress into a hyperexcitable epileptogenic
and directly related causes (eg, brain tumour) are epilepsy- disease condition. This knowledge reflects well on the
related threats.4,20 The standardised mortality rate of recognised spectrum of focal brain lesions associated
patients with epilepsy in low-income and middle-income with focal epilepsies. In the temporal lobe, the site of the
countries (3·7) is higher than that in high-income most common epilepsies in adults, epileptiform activity
countries (2·3); the reason for this higher mortality rate is eventually imprints the epigenetic coding machinery of
not known, but could be due to methodological neurons in support of epileptogenesis—an epilepsy diary
differences across studies.21 The incidence rate of SUDEP in support of epigenetic memory by DNA methylation.28
is 23 times the incidence rate of sudden death in the age- Whether this holds true also for neocortical
matched general population.22 For SUDEP, young epileptogenesis remains yet to be shown.30 Indeed,
adulthood and the presence of tonic-clonic seizures surgically amenable focal epilepsy encompasses a well-
appear to be the most consistent risk factors in published recognised spectrum of structural lesions that are
studies. Other important risk factors include nocturnal histopathologically detectable in human brain samples.
seizures, sleep (particularly in the prone position), high The most common lesions in patients amenable to
seizure frequency, intellectual disability, inadequate epilepsy surgery include hippocampal sclerosis, low-
treatment, and male sex.4 grade developmental brain tumours, and malformations
of cortical development (eg, focal cortical dysplasia).31
Pathophysiology However, not all of these lesions can always be considered
Focal epilepsy can be defined by a seizure onset localised amenable to surgical resection.
to one or multiple circumscript brain regions as indicated
by seizure semiology or neurophysiological recordings. Diagnosis
A generalised epileptic seizure occurs due to hyper­ Epilepsy is a clinical diagnosis. Unless one happens to
synchronised electrophysiological bursts simultaneously witness a seizure, the diagnosis of epilepsy relies on the
in both hemispheres. Pathophysiological concepts in discernment of the physician on the basis of the history
epileptology have changed considerably over the past provided by the patient and their caregivers. When
decades.8,23 The primarily neurophysiology-driven cellular evaluating a patient with a seizure, the physician should
approach argued for an imbalance between excitation determine whether an epileptic seizure has occurred or
versus inhibition through aberrantly assembled ion whether a condition exists that mimics epilepsy (eg,
channels or neurotransmitter receptor subunits as a syncope, functional (psychogenic) seizures, panic
fundamental basis. This hypothesis has been reproduced attacks, sleep disorders, and movement disorders).
in animal models, but seems oversimplified based on Signs and symptoms that precede the attack or occur
advancements in the understanding of epilepsy. when it begins, as well as signs and symptoms during
Technical advancements in human intracerebral and immediately after the ictus offer clues as to the type
recordings then evolved into concepts of larger, aberrantly of the attack and therefore the correct diagnosis.32
oscillating cortical networks that might also engage Syncope is often initiated with fading vision into black,
subcortical regions.24 This notion facilitated the often accompanied by dizziness, followed by a loss of

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consciousness. Syncope can be associated with one or

Date: Name: Gender:
more irregular jerks or even convulsive activity, leading Age: Age at seizure onset:
to ambiguity in diagnosis, and often lasts for less than
30 sec with a quick postictal recovery.32,33 Functional Seizure history (course of illness):
seizures are characterised by paroxysmal movements,
Seizure type 1.
sensations, or behaviours that might look like epileptic
a. Seizure description:
seizures, but are not associated with ictal epileptic b. Seizure frequency:
discharges on the EEG. When interpreting the ictal c. Classification:
signs and symptoms, it is necessary to understand that Seizure type 2.
no single sign or symptom is pathognomonic for a. Seizure description:
functional seizures. However, some signs and b. Seizure frequency:
symptoms are strongly associated with functional c. Classification:
seizures and are infrequently seen in epileptic Other seizure types:
seizures.34 Preictal headache, eye closure during
the seizure, wax and wane motor activity, side-to-side Epilepsy risk factors:

head movements, and pelvic thrusting are symptoms or Pregnancy complications: History of CNS infection:
Development: History of significant head trauma:
signs that are strongly suggestive of functional seizures.
Febrile convulsion: Family history of epilepsy:
A functional seizure often lasts for more than 3 min
and the postictal recovery is usually slow.33,35,36 It is Past medical history:
noteworthy to remember that a patient might have Drug allergies:
comorbid conditions such as epilepsy and functional Medical comorbidities:
seizures, making the diagnosis of either condition Psychiatric problems:
more challenging.37 Social history:
When a diagnosis of epilepsy is made, a detailed clinical Educational level: Driving: Employment:
history will be key to further classify an epilepsy type or Marital status: Tobacco: Alcohol: Illicit drugs:
syndrome (figure 2). It is important to ask the patient and Family history:
their caregivers about the age at seizure onset and the Physical examination:
course of the illness (eg, if there was a preceding febrile
Record review:
illness), aura type and description (ask the patient), ictal
EEG:
events (ask the patient and their caregivers), and postictal
MRI:
events (ask the patient and their caregivers). Epileptic Labs:
seizures often last for less than 2 min. Many patients have
more than one seizure type and this should be inquired Diagnosis:
Plan and recommendations:
about carefully. It is necessary to consider that home videos
of the seizures might be more helpful in picking up Figure 2: An example of a predesigned template for data collection during the first visit of a patient with
semiological signs and classifying epilepsy types than the seizures
history provided by the patient and their caregivers.38 It is
important to instruct the caregivers to record a seizure make a correct diagnosis in patients with a suspicion of
with their mobile phone camera, if they can. It is also seizures.39,40
important to inquire about the sleep cycle of the individual
with epilepsy (eg, seizures only during sleep suggest focal Electroencephalography
epilepsy), the temporal pattern of the seizures (eg, the EEG is one of the most important and helpful ancillary
association of seizures with the menstrual cycle), past tests in diagnosing epilepsy, and should be ordered in all
medical history of the patient, and their family history, patients with a suspicion of seizures. The EEG may provide
psychiatric history, and social history. Finally, it is also information on the presence of abnormal brain electrical
important to know the risk factors for epileptic seizures.2 activity, as well as information that helps in the classification
Although a comprehensive physical examination is of epilepsy type or syndrome. For example, a focal interictal
mandatory, most patients with epilepsy have a normal spike (figure 3) suggests focal epilepsy (such as temporal
physical examination. However, it is particularly lobe epilepsy), whereas a generalised spike-wave complex
important to evaluate for skin lesions and other congenital (see figure 3) suggests a generalised epilepsy syndrome
abnormalities; for example, adenoma sebaceum is (such as idiopathic generalised epilepsy).41,42 A normal EEG
associated with tuberous sclerosis, a rare genetic disorder does not exclude the clinical diagnosis of epilepsy; in about
that is often associated with epilepsy. Other important half of patients with epilepsy, a single routine EEG will be
findings during a physical examination may include focal normal.32 If the suspicion of epilepsy is high, additional
neurological deficits.32,33 In areas with scarce resources EEG recordings after sleep deprivation or protracted EEG
(such as areas with no neurologists with expertise in monitoring might improve the opportunity of observing
epilepsy), the use of validated digital apps could help waveforms associated with epilepsy.32

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A B

Cz-C4 FP2-A2
C4-T4 F8-A2
T4-T2 T4-A2
T2-T1 T6-A2
T1-T3 FP1-A1
T3-C3 F7-A1
C3-Cz T3-A1
ekg1-ekg2 T5-A1
Fp2-F8 F4-A2
F8-T4 C4-A2
T4-T6 P4-A2
T6-O2 O2-A2
Fp1-F7 F3-A1
F7-T3 C3-A1
T3-T5 P3-A1
T5-O1 O1-A1

Figure 3: EEG patterns

(A) T2 (right anterior temporal) sharp waves in a 26-year-old woman with temporal lobe epilepsy. (B) Generalised spike-wave complexes in a 16-year-old girl with
idiopathic generalised epilepsy.

review by an epilepsy expert alongside voxel-based post-

processing techniques could improve the yield to detect a
focal lesion.45 Emergency neuroimaging (which is often a
CT scan) should be performed in all patients with a head
injury (eg, as a result of a seizure), a postictal focal deficit,
or change in mental status that does not quickly resolve.32

Autoimmune investigations
Seizures due to immunological causes represent a major
challenge in neurology clinics; such seizures are
increasingly encountered in clinical practice and their
recognition depends on the index of suspicion. It is crucial
to identify immune-related causes of seizures early in their
course since they could be responsive to immunotherapy,
but are usually resistant to conventional antiseizure
Figure 4: Brain MRI
medications.46,47 The term autoimmune-associated epilepsy
Right hippocampal sclerosis in a 32-year-old man with mesial temporal lobe
epilepsy. is often used to describe a condition with a long-lasting
predisposition to unprovoked seizures with evidence of an
immunological aetiology, such as Rasmussen’s
Neuroimaging encephalitis. The term seizures secondary to autoimmune
An MRI scan of the brain is an important diagnostic tool encephalitis is often used for seizures that occur as a
in many patients with epilepsy. It is appropriate to obtain symptom of active autoimmune encephalitis, such as anti-
an MRI scan to investigate for a structural lesion if n-methyl-d-aspartate receptor encephalitis. In any patient
epilepsy is not believed to be idiopathic, such as juvenile with a cluster of symptoms including frequent focal
myoclonic epilepsy in an adult patient. An MRI is seizures or status epilepticus, cognitive and memory
preferable to a CT scan because it has much greater impairments, personality and psychiatric changes, and
sensitivity. MRI for the evaluation of patients with movement disorders, one should seriously consider and
epilepsy should be done using a dedicated epilepsy investigate the possibility of seizures secondary to
protocol,43 and should be read by physicians who have autoimmune encephalitis.46
experience with epilepsy.44 An MRI might detect brain
structural lesions such as tumours, cortical dysplasia, Other investigations
encephalomalacia, and mesial temporal sclerosis Electrolytes, chemistry panels, and toxicology screening
(figure 4). In a patient with uncontrolled focal seizures might be considered if a patient receives medical
and a non-conclusive brain MRI by visual inspection, attention soon after a seizure. Lumbar puncture is

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performed only if an infection or an autoimmune epilepsy is frequent and sometimes challenging to

problem is suspected.32 recognise accurately due to the wide range of diagnostic
mimics (eg, syncope or transient ischaemic attacks) and
Treatment chameleons (eg, post-ictal Todd’s palsy due to a focal
Antiseizure medications seizure misdiagnosed with acute stroke) that might lead to
Antiseizure medications represent the mainstay for the underdiagnosis or misdiagnosis.55 In this specific
management of epilepsy. These drugs reduce the risk of population it is therefore crucial to start antiseizure
seizure relapse, with little or no effect on the medications only when necessary. Whenever possible, an
epileptogenesis process. Consequently, the use of antiseizure medication with the following properties
antiseizure medications should be restricted to patients should be chosen: linear pharmacokinetics with scarce
with a high risk of long-term seizure relapse (epilepsy). risk of accumulation; an absence of drug-to-drug
However, the decision of starting an antiseizure interactions; elimination through renal excretion and an
medication should be individualised, and can be even absence of hepatic metabolism; and favourable tolerability
deferred in specific situations, for instance, if there are profile (including on memory and cognitive performance).55
only very mild or infrequent seizures, with a low risk of To minimise the adverse effects, it is important to start the
seizure-related injuries. antiseizure medication at a low dose and to slowly increase
Several antiseizure medications are approved for the the dose over time, if required.
treatment of epilepsy and their selection should rely on an
evidence-based framework, integrating the best available Polytherapy
evidence for efficacy and tolerability, risk of drug As a rule, pharamacological treatment should begin with
interactions and teratogenicity, presence of comorbidities, a single antiseizure medication. If the first antiseizure
patient preferences, and costs.48 It is important to consider medication does not control the seizures, considering an
the spectrum of efficacy of various antiseizure medications alternative monotherapy or combining a second
to avoid prescribing drugs that are inappropriate for medication are common therapeutic options. To our
specific epilepsy or seizure types (panel 2). Carbamazepine knowledge, there is no robust evidence supporting the
has been regarded as the first-choice monotherapy for
focal-onset seizures for many years. Over time, randomised
controlled trials have shown that various antiseizure Panel 2: The spectrum of clinical efficacy of some
medications (such as lamotrigine and oxcarbazepine) are antiseizure medications
non-inferior to carbamazepine.49–51 However, the evidence Narrow-spectrum antiseizure medications (drugs
from these trials is partly limited by strict inclusion and effective primarily against focal onset seizures and focal
exclusion criteria with subsequent risk of poor evolving to bilateral tonic-clonic seizures)
generalisability, and by efficacy outcomes measured over • Carbamazepine*
time periods which are too short.49–51 Evidence from • Cenobamate
pragmatic trials comparing the long-term effectiveness of • Eslicarbazepine
antiseizure medications showed that lamotrigine is • Ethosuximide†
clinically more effective than carbamazepine, and that • Gabapentin
levetiracetam and zonisamide do not appear to be cost- • Lacosamide
effective alternatives to carbamazepine.52 Valproic acid is • Oxcarbazepine*
an effective first-line monotherapeutic option for • Phenytoin*
generalised seizures but should be avoided as a first-line
drug in women of childbearing potential due to its serious Broad-spectrum antiseizure medications (drugs effective
teratogenic effects.52 Although probably less effective, against both focal and generalized onset seizures)
lamotrigine and levetiracetam appear reasonable • Clobazam
alternatives to valproic acid (in women) due to their low • Lamotrigine‡
risks of congenital malformations.52,53 • Levetiracetam
In the presence of comorbidities, special attention • Perampanel
should be given to not choosing a drug that might worsen • Topiramate
the comorbid condition.54 The physician should adjust the • Valproate
dose if liver or renal failure affects the efficacy of the • Zonisamide
antiseizure medication, and avoid drugs that could interact Drugs are listed in alphabetical order. The choice of antiseizure medication should not
with other medications; where this is not possible, dose rely solely on their clinical efficacy, but also thier tolerability (including the
teratogenicity in women of childbearing potential), risk of drug interactions,
adjustments should be considered.48 Women of
comorbidities, frequency of administration, patient preferences, and costs.
childbearing age should be warned against the reduced *These drugs might have some efficacy also against generalised onset tonic-clonic
effectiveness of oral contraception by enzyme-inducing seizures, but might aggravate other generalised seizures (particularly absence seizures).
†Ethosuximide is effective only against absence seizures. ‡Lamotrigine might
antiseizure medications. Special attention should also be aggravate myoclonic seizures
given to the older population. This is an age group where

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taking multiple antiseizure medications, one drug

Primary aims Surgical candidates Surgical procedures
should be discontinued at a time.59 In the case of seizures
Curative surgery Sustained seizure Patients with drug-resistant Resective surgery, depending recurrence during or after discontinuation, the last
freedom and improved focal epilepsy with a clearly on the pathology and location
quality of life. identified epileptogenic zone* of the epileptogenic zone. For effective withdrawn drug should be reinstated, or its dose
that could be removed without example, anterior temporal increased back to the previous effective one. Temporary
irreversible neurological deficit. resection or selective driving restrictions (eg, up to 6 months after complete
amygdalohippocampectomy in
hippocampal sclerosis.
treatment cessation) could be advisable.59
Palliative surgery Improvement in Patients with drug-resistant Corpus callosotomy
quality of life and focal or generalised epilepsy Drug-resistant epilepsy
decrease in seizure with severe and frequent About a third of patients continue to have seizures
frequency or severity. (disabling) epileptic seizures. despite appropriate medical treatment.49,61 This proportion
Patients in whom seizure
freedom through resective has remained unchanged over the years and the overall
surgery is extremely unlikely. prognosis of epilepsy has not been affected by the
*A visible lesion on neuroimaging is not always necessary: patients with focal seizures of neocortical origin and normal introduction of several new antiseizure medications.62
brain neuroimaging can still undergo successful resective surgery provided that the epileptogenic zone has been Drug-resistant epilepsy is defined by the ILAE as the
accurately identified in the presurgical evaluation. inability to attain sustained seizure freedom after an
Table: Types of surgical approaches to drug-resistant epilepsy informative trial of two antiseizure medications that have
been appropriately chosen for the individual’s specific
epilepsy or seizure type, used at an adequate effective
superiority of one approach over the other. Generally, an dose, and tolerated.63 Before diagnosing drug-resistant
alternative monotherapy appears preferable in patients epilepsy, it is essential to rule out the potential causes of
who did not tolerate the first antiseizure medication, or if pseudo-resistance. These causes include an incorrect
the first antiseizure medication did not have any benefit diagnosis of epilepsy, administration of an inappropriate
in controlling seizures.48 An adjunctive treatment is drug, poor treatment adherence, or an antiseizure
advisable if the first antiseizure medication had some medication dose that is too low to provide adequate
effects in controlling the seizures, but failed to completely antiseizure control.48 Several biological mechanisms have
stop them.48 If a patient continues to have seizures been proposed to explain drug-resistant epilepsy
despite first or alternative monotherapy, adding a second (pharmacokinetics hypothesis, intrinsic severity
antiseizure medication is usually required. Several hypothesis, genetic variation hypothesis, drug transporter
antiseizure medications can be used in clinical practice hypothesis, etc) and inform the development of newer
as an adjunctive treatment for difficult-to-treat epilepsy antiseizure medications.64 However, despite advances in
(panel 2).48 research, the pharmacological management of patients
Ideally, antiseizure medication polytherapy should with drug-resistant epilepsy remains challenging and
maximise efficacy while also minimising the adverse often frustrating, requiring alternative therapeutic
effects (ie, a rational polytherapy).56 Rational polytherapy options, such as surgery.
could involve combining antiseizure medications with
different mechanisms of action that could synergically Surgery
potentiate the antiseizure efficacy of the combined drugs Surgical treatment is the most cost-effective approach for
(eg, lamotrigine and valproate, or cannabidiol and patients with drug-resistant focal epilepsy when patients
clobazam).57 Conversely, it is also important to avoid carry a coherently identified epileptogenic zone that can
combinations of antiseizure medications that might be appropriately resected or disconnected.65–67 A resective
worsen tolerability (eg, lacosamide added to another surgical treatment primarily aims to achieve complete
sodium channel blocker).58 seizure freedom and improve the quality of the patient’s
life. Epilepsy surgery can also be an option to improve
Withdrawing antiseizure medications the quality of life and decrease seizure severity or
In some patients who are seizure-free (usually for more frequency in patients with drug-resistant focal epilepsy
than 2 years), or in the case of age-dependent epilepsy (who are not amenable to resective surgery), and in those
syndromes beyond the expected age of resolution, it is with generalised epilepsy and disabling seizures; in these
possible to consider withdrawing antiseizure medications cases, the surgery is palliative and not aimed to achieve
on the basis of an accurate estimate of seizure recurrence seizure freedom (see table).66
risk and an individualised balance between the Resective epilepsy surgery requires a systematic
anticipated risks and benefits—this includes the possible presurgical evaluation to precisely identify the epileptogenic
negative psychosocial consequences of seizure relapse, zone, defined as the cortical area that generates seizures
such as the loss of one’s driving license.59 To our and whose removal or disconnection is required for
knowledge there is no robust evidence on the safest complete seizure freedom.68 Identification of the
tapering regimen, although benzodiazepines and epileptogenetic zone can be achieved by integrating
barbiturates should be withdrawn slowly.60 In patients information from different non-invasive and invasive

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investigations, including detailed analysis of seizure could cause less damage to the surrounding areas than
semiology; video-EEG recordings; structural, functional, conventional surgical approaches (eg, anterior temporal
and metabolic neuroimaging (eg, MRI, functional MRI, resection).79 However, not all patients with focal epilepsy
[¹⁸F]fluorodeoxyglucose-PET, and single photon emission are candidates for resective brain surgery (eg, patients
computed tomography); invasive electrical stimulation; with non-lesional extratemporal epilepsy with an ictal-
neuropsychological testing; speech and language testing; onset zone close to an eloquent cortex).
and visual field examinations.69 Not all of these procedures Overall, epilepsy surgery for drug-resistant focal
are required in every patient. Generally, less invasive seizures is associated with low rates of morbidity and
procedures should be preferred over more invasive ones; mortality when performed at specialised centres.66 The
for instance, stereo-EEG should be reserved for cases in likelihood of postsurgical neurological deficits can be
which anatomical, electrical, or clinical correlations based minimised by completing an accurate presurgical
on detailed medical history, structural imaging, and scalp evaluation and selection of candidates.80,81 Unfortunately,
EEG recording are insufficient to accurately and precisely despite its high effectiveness for seizure control and
identify the epileptogenic zone. Similarly, functional and improved quality of life, epilepsy surgery is an
metabolic neuroimaging should be reserved for patients underutilised treatment option. A prompt referral for a
where there are remaining doubts on the exact correlation surgical evaluation has been recommended in all patients
and overlap between the structural lesions, the irritative with drug-resistant epilepsy as soon as drug resistance is
zone (the area of cortex that generates interictal spikes), the ascertained.65 However, too often potential candidates are
ictal-onset zone (the area of the cortex that initiates clinical not referred for a surgical evaluation due to a substantial
seizures), the symptomatogenic zone (the area of the cortex knowledge gap on this therapeutic option.82
that, when activated, produces the initial ictal symptoms),
the functional deficit zone (the area of the cortex that is not Neuromodulation
functioning normally in the interictal period), and the Neuromodulation techniques can be regarded as
eloquent cortex.68 The best surgical candidates are patients therapeutic options for patients with drug-resistant
with focal unilateral brain lesions seen on neuroimaging, epilepsy who are not suitable for resective surgery.83 The
such as mesial temporal sclerosis or tumours that are techniques are aimed mainly at reducing seizure
correlating with the electro­physiological localisation of the frequency and severity, rather than at attaining seizure
seizure onset. The surgical treatment of focal seizures with freedom. As such, neuromodulation techniques should
non-conclusive normal neuroimaging is more challenging, be regarded as palliative treatments. Beyond reducing
due to the difficulties in defining the extent of tissue that seizure frequency, these techniques could also improve
must be removed for complete seizure abolition without the quality of life of the patients and reduce the risk of
causing irreversible post-surgical deficits.66,70 SUDEP.83 The neuromodulation approaches evaluated in
In patients with drug-resistant focal epilepsy, resective double-blind controlled trials and currently approved for
surgery is superior to long-term medical therapy alone,71,72 the treatment of drug-resistant epilepsy are vagus nerve
with survival methods estimating sustained seizure stimulation, deep brain stimulation of the anterior
freedom at 10 years in 47% (95% CI 42–51) of 615 adults nucleus of the thalamus, and closed-loop responsive
in one study.73 In selected cases (eg, patients with focal neurostimulation of the epileptic focus.83–87
unilateral brain lesions seen on neuroimaging, such as
mesial temporal sclerosis or tumours that correlate with Dietary treatments
the electrophysiological localisation of the seizure onset), The ketogenic diet is a high-fat, adequate-protein,
the likelihood of achieving seizure freedom after surgery low-carbohydrate diet that mimics a starvation state. The
ranges from 50–80%.67 In the presence of some highly classic ketogenic is composed of a 4:1 ratio of fat to
epileptogenic lesions associated with drug-resistant carbohydrate and protein combined; different variants
epilepsy, such as focal cortical dysplasia type 2, surgical have been developed to improve palatability and
removal performed in specialised centres can lead to adherence.88
complete seizure freedom in over 80% of patients.74,75 The evidence for the use of the ketogenic diet in adults
Anterior temporal resection with the removal of the with epilepsy is scarce. In a 2015 meta-analysis, the
temporal pole, hippocampus, and mesio-basal part of the pooled efficacy rate of the classic ketogenic diet was 52%
amygdala has also shown to be efficacious in patients (95% CI 40–64), while that of the modified Atkins diet
with unilateral mesial temporal lobe epilepsy.76,77 In was 34% (19–49).89 A prospective randomised controlled
patients with unilateral mesial temporal lobe epilepsy, trial investigated the modified Atkins diet in people with
selective amygdalohippocampectomy, although superior drug-resistant epilepsy aged 10–55 years; seizure
to medical treatment alone in drug-resistant epilepsy, is reduction of greater than 50% was seen in 21 (26·2%) of
not more effective than anterior temporal lobectomy in the 80 participants in the intervention and two (2·5%) of
reducing seizures.78 Other surgical procedures in these the 80 participants in the control group at 6 months
patients are stereotactic radiosurgery, radiofrequency (p<0·0001).90 The most common adverse effects
ablation, and laser interstitial thermal therapy, which associated with ketogenic diets are gastrointestinal

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effects, weight loss, and derangements in lipid profiles.88 health-care practices that are not currently an integral
Multivitamin and mineral supplements are useful to part of conventional medicine.91 Complementary and
reduce the risk of adverse effects secondary to vitamin alternative medicine therapies are often used by patients
and mineral deficiencies.88 with epilepsy despite the scarce and low-quality evidence
to support their use.92,93 A global survey indicated that
Complementary and alternative medicine most physicians worldwide believe that complementary
Complementary and alternative medicine consists of and alternative medicine might be helpful to treat
seizures in patients with epilepsy, but only a few reported
Panel 3: Lifestyle considerations in patients with epilepsy having prescribed complementary and alternative
Drug adherence medicine for their patients.94 Commonly reported reasons
• Seizure recurrence risk in patients with epilepsy is 21% underlying the belief in complementary and alternative
higher among non-adherers than adherers to antiseizure medicine include inadequate seizure control and adverse
medications107 effects of antiseizure medications, the comorbidities
• Assessment of drug adherence should be routinely associated with epilepsy for which antiseizure
performed on every visit of patients with epilepsy108 medications are of little help, the perception of
• Behavioural interventions (eg, intensive reminders) might complementary and alternative medicine as more natural
improve drug adherence in patients with epilepsy109 and safer than antiseizure medications, and the cost of
• Simplified drug regimens might also improve drug antiseizure medications.95 Physicians should provide
adherence in patients with epilepsy110 appropriate information regarding the possible adverse
effects of various complementary and alternative
Sleep treatments, including their intrinsic proconvulsant
• Patients with epilepsy are commonly advised to maintain properties, contamination by heavy metals, and risk of or
consistent sleep routines111 interactions with the antiseizure medication.92,93 High-
• The sleep quality of patients with epilepsy is often quality controlled trials are warranted to provide robust
disturbed due to various factors (eg, interictal epileptiform evidence on the usefulness and safety of complementary
discharges, seizures, and antiseizure medications)112 and alternative medicine options in patients with epilepsy.
• It is important to screen all patients with epilepsy for
sleep disturbances113 Diagnosis and treatment of status epilepticus
Exercise Status epilepticus is a condition defined by an ongoing and
• Exercise has positive effects in improving cognitive abnormally long-lasting epileptic activity, which can have
functions, fitness levels, and quality of life of patients with negative long-term consequences, depending on the type
epilepsy114–­116 and duration of seizures.96 The threshold time limits for
when an epileptic seizure should be considered a status
Seizure precipitants epilepticus vary according to semiology, and correspond to
• Stress, sleep deprivation, and fatigue are among the most 5 min for generalised tonic-clonic seizures, 10 min for
common seizure precipitants reported by patients with focal status epilepticus with impaired awareness, and
epilepsy117,118 10–15 min for absence status epilepticus.96 Status
• Alcohol119,120 and caffeinated energy drinks121 have also epilepticus can be classified according to the presence or
been described as seizure precipitants absence of prominent motor symptoms (the absence of
• Some patients have reflex epilepsy (eg, photosensitive prominent motor symptoms, also termed non-convulsive
epilepsy)122,123 status epilepticus, requires EEG for the diagnosis).96,97
• The treating physician should try to identify potential The treatment of status epilepticus should be initiated
seizure precipitants in patients with epilepsy and help promptly to minimise the risk of negative consequences
them adopt strategies for avoidance of those factors117 and follow a stepwise approach. Benzodiazepines
• Daily drinking of coffee and tea can be part of a healthy represent the first-line treatment, followed by intravenous
diet and their consumption should not be discouraged in antiseizure medications (eg, fosphenytoin, levetiracetam,
patients with epilepsy124 valproic acid, lacosamide, phenobarbital, or
Occupation phenytoin).98,99 If status epilepticus persists, anaesthetics
• Although patients with epilepsy might find most (propofol, pentobarbital, midazolam) are usually
occupations manageable, it is important to follow the required, with intubation and admission to the intensive
local rules and regulations (eg, about driving eligibility care unit for further treatment and diagnostic
and restrictions for people with seizures)125 investigation.98 Status epilepticus that continues or recurs
• The features of seizures (eg, fall, impaired awareness), 24 h or more after starting anaesthetics or on the
as well as seizure frequency, should be considered when reduction or withdrawal of anaesthesia is termed super-
evaluating the risks associated with seizures in the refractory status epilepticus, which carries a high risk of
workplace126 mortality and morbidity. The treatment of super-
refractory status epilepticus often includes the use of

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immunomodulant therapies, particularly if an and programmes including appropriate maternal and child
autoimmune cause is suspected.100 In every stage, parallel health-care plans, immunisations, and brain injury and
to pharmacological treatment, it is mandatory to identify stroke prevention strategies have the potential, therefore, to
the underlying cause and treat it promptly and adequately. reduce the burden of epilepsy around the world.128
Some epilepsy-related deaths are also potentially
Precision medicine in adult epilepsy preventable. For example, attaining seizure freedom
Precision medicine is defined as the tailoring of medical through effective medical or surgical treatment strategies,
treatment to the individual characteristics of each patient.101 nocturnal supervision strategies such as listening
Three main categories of evidence-based strategies exist to devices, and suicide prevention programmes could
select the optimal treatment. Targeted substitutive reduce the risk of a subset of epilepsy-related deaths.4,20
therapies, which consist of supplementation or restriction
of substrates, are used to manage epilepsies related to Future directions
hereditary metabolic disorders, such as epilepsy caused by There have been substantial developments in the
GLUT1 deficiency syndrome (ketogenic diet as the diagnosis and management of epilepsy in the last two
treatment option), vitamin-responsive epilepsies (such as decades. Some of the new diagnostic and treatment
pyridoxine [vitamin B6]-responsive epilepsy), and epilepsy prospects that are under clinical implementation include
caused by CLN2 disease (treated with enzyme replacement the development of wearable devices for automatic
therapy using cerliponase alfa). Therapies modifying cell- seizure detection, less invasive surgical techniques with
signalling pathways are used to treat epilepsies related to selective ablation of the epileptogenic zone like the laser
the mTOR and immune pathways (eg, everolimus in interstitial thermal therapy, and precision medicine
tuberous sclerosis complex). Function-based therapies can based on the genetic cause of epilepsies. The improve­
be used to treat epilepsies caused by pathogenic variants ment in the understanding of the pathophysiological
resulting in a gain or loss of function of ion channels;101,102 mechanisms underpinning epilepsies might prompt the
for example, antiseizure medications that block sodium development of new agents or therapies directed to
channels (eg, phenytoin) might exacerbate seizures in modify, or even cure, the disease as well as control the
patients with Dravet syndrome caused by loss of function symptoms. Gene therapy and other gene-based
variants in SCN1A, however are optimal for treatment of approaches are still experimental. In gene-related
gain of function variants in SCN2A.103,104 Preclinical and epilepsy, the ultimate goal is to correct the pathogenic
clinical studies of antisense oligonucleotides, a treatment genetic variants or modulate the expression of the
capable of altering the expression of mRNA, are underway mutated gene. Basic research is also addressing agents
and other promising gene-based approaches such as gene that are able to interfere with the expression of
editing are on the horizon.105 endogenous molecules and optogenetic tools for
Beyond targeted therapy, personalised medicine should modulating the epileptic networks, among other
consider other information such as pharmacogenomic innovative ways to help patients with epilepsy.
data. For example, the HLA-B*15:02 or HLA-A*31:01 Contributors
alleles, which are common among individuals from South AAA-P was responsible for conceptulising the manuscript. All authors
Asian ethnic groups, increase the risk of developing contributed to the preparation of the manuscript.
carbamazepine-induced hypersensitivity reactions like Declaration of interests
Stevens-Johnson syndrome.106 Also, individuals with AAA-P has received honoraria from Cobel Daruo, royalties from Oxford
University Press, and a grant from the National Institute for Medical
CYP2C9 polymorphisms that reduce the activity of this Research Development. SL has received both speaker’s and consultancy
enzyme can have altered metabolism of phenytoin fees from Angelini Pharma, Eisai, GW Pharmaceuticals, and UCB
resulting in increased serum concentrations and a greater Pharma and has served on advisory boards for Angelini Pharma, Arvelle
risk of adverse effects.106 Therapeutics, BIAL, Eisai, and GW Pharmaceuticals. All other authors
declare no competing interests.

Lifestyle considerations Acknowledgments

We thank Bernhard Schuknecht for providing the MRI scan shown in
After receiving a correct diagnosis and an appropriate figure 4.
treatment plan, patients with epilepsy need to consider
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