Review

Drug resistance in epilepsy

Emilio Perucca, Piero Perucca, H Steve White, Elaine C Wirrell

Drug resistance is estimated to affect about a third of individuals with epilepsy, but its prevalence differs in relation to Lancet Neurol 2023
the epilepsy syndrome, the cause of epilepsy, and other factors such as age of seizure onset and presence of associated Published Online
neurological deficits. Although drug-resistant epilepsy is not synonymous with unresponsiveness to any drug June 20, 2023
https://doi.org/10.1016/
treatment, the probability of achieving seizure freedom on a newly tried medication decreases with increasing
S1474-4422(23)00151-5
number of previously failed treatments. After two appropriately used antiseizure medications have failed to control
Department of Medicine,
seizures, individuals should be referred whenever possible to a comprehensive epilepsy centre for diagnostic re- Austin Health, University of
evaluation and targeted management. The feasibility of epilepsy surgery and other treatments, including those Melbourne, Melbourne, VIC,
targeting the cause of epilepsy, should be considered early after diagnosis. Substantial evidence indicates that a delay Australia (Prof E Perucca MD,
P Perucca MD); Department of
in identifying an effective treatment can adversely affect ultimate outcome and carry an increased risk of cognitive
Neuroscience, Central Clinical
disability, other comorbidities, and premature mortality. Research on mechanisms of drug resistance and novel School, Monash University,
therapeutics is progressing rapidly, and potentially improved treatments, including those targeting disease Melbourne, VIC, Australia
modification, are on the horizon. (Prof E Perucca, P Perucca);
Bladin-Berkovic
Comprehensive Epilepsy
Introduction Epilepsy (ILAE) in 2010 proposed a definition of drug- Program, Department of
Despite the availability of more than 30 antiseizure resistant epilepsy as “failure of adequate trials of Neurology, Austin Health,
medications, a third of people with epilepsy do not two tolerated, appropriately chosen and used antiepileptic Melbourne, VIC, Australia
(P Perucca); Department of
achieve seizure freedom with pharmacological therapy.1 drug schedules (whether as monotherapies or in
Neurology, Royal Melbourne
Although an appreciable proportion of these individuals combination) to achieve sustained seizure freedom”.7 Hospital, Melbourne, VIC,
can be rendered seizure-free by epilepsy surgery or, less The rationale for this definition is that after failing Australia (P Perucca);
frequently, by other non-pharmacological treatments two appropriately chosen and used antiseizure medi­ Department of Neurology,
Alfred Health, Melbourne, VIC,
such as dietary therapies and neuromodulation, a large cations, the probability of achieving seizure freedom Australia (P Perucca);
majority suffer from uncontrollable disabling seizures with subsequent manipulations of drug treatment is Department of Pharmacy,
for many years, often for a lifetime.2 Drug-resistant relatively low. School of Pharmacy, University
epilepsy is associated with poor quality of life due to Since 2010, the ILAE definition has been widely of Washington, Seattle, WA,
USA (Prof H S White PhD);
many factors, including the direct physical and adopted and tested in different settings. It should be Divisions of Child and
psychosocial effects of seizures, the burden of psychiatric, emphasised that persistence of seizures despite anti­ Adolescent Neurology and
cognitive, and somatic comorbidities, and adverse effects seizure medication therapy is not synonymous with Epilepsy, Department of
of treatment.3 People with uncontrolled seizures are also drug-resistant epilepsy as defined by the ILAE. In a Neurology, Mayo Clinic,
Rochester, MN, USA
at increased risk of premature mortality resulting from cohort of 194 adults with chronic uncontrolled epilepsy (Prof E C Wirrell MD)
seizure-related accidents, status epilepticus, and sudden from Hong Kong, 115 (59%) met ILAE criteria for drug- Correspondence to:
unexpected death in epilepsy.3 Furthermore, drug- resistant epilepsy. The remainder of the cohort had Prof Emilio Perucca, Melbourne
resistant epilepsy places a substantial economic burden undefined responsiveness for a variety of reasons, Brain Centre, University of
on individuals and their families, health-care systems, including inadequate use of antiseizure medications Melbourne, Melbourne,
VIC 3084, Australia
and society.4 (35 [18%]), lack of information on treatment response emilio.perucca@unimelb.edu.
Not surprisingly, major research efforts focus on (18 [9%]), and failure of only one adequately used anti­ au
improving our understanding of drug-resistant epilepsy seizure medication (11 [6%]).8 In another cohort from
and its mechanisms and developing strategies by which Scotland, comprising 311 adults with persisting seizures
drug-resistant epilepsy can be predicted, prevented, and despite antiseizure medication therapy, the proportion
overcome. These efforts are complicated by the with drug-resistant epilepsy was even lower (44%).8
heterogeneous causes, pathogenic mechanisms, clinical Application of ILAE criteria for drug-resistant epilepsy
manifestations, and prognostic features of different requires determining whether a previously used anti­
epilepsy syndromes and related conditions.5 The purpose seizure medication was tolerated, appropriately chosen,
of this Review is to provide an overview of progress that and used, which can be a matter of subjective judgment.
has been made, particularly in the past 5 years, in Inter-rater agreement in categorising treatment out­comes
defining drug-resistant epilepsy and understanding its was evaluated in an Italian multicentre study,9 in which
prevalence, underlying mechanisms, and ways by which 1053 consecutive adults with focal epilepsy were enrolled,
it can be managed, predicted, and prevented. who were diagnosed by local neurologists (investigators)
as having drug-resistant epilepsy by ILAE criteria.
Definition Treatment outcomes for each patient were reassessed in
Although the concept of drug-resistant epilepsy is rotation by two members of a 16-member expert panel,
somewhat intuitive, operational definitions of the who had access to individual patient data. Agreement in
condition have historically varied widely.6 To establish a categorising outcomes was almost perfect between expert
common terminology, the International League Against panel member pairs (92%, Cohen’s k=0·83) and

www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5 1

 Review
moderate between the expert panel and investigators
(68%, k=0·50). About a fifth (19%) of individuals
classified initially as having drug-resistant epilepsy were
considered by the expert panel to have undefined
responsiveness to the antiseizure medications tried,
mostly due to inadequate dosing. The inter-rater
variability in applying ILAE criteria was comparable with
that reported in an earlier Canadian study of 97 patients
with different epilepsy syndromes.10 The Canadian
researchers also found that the reliability and validity of
ILAE criteria for diagnosing drug-resistant epilepsy
compared favourably with previous definitions of drug-
resistant epilepsy.
The Italian investigators also prospectively evaluated
seizure outcomes after a treatment change in
850 individuals whose diagnosis of drug-resistant
epilepsy by ILAE criteria had been validated by the expert
panel.11 Within this population, seizure freedom rates
after introduction of a newly administered antiseizure
medication ranged from 12% in those who had previously
not responded to two antiseizure medications to less
than 3% in those who had failed five or more antiseizure
medications (figure 1). These findings confirm that drug-
resistant epilepsy is not synonymous with unres­
ponsiveness to any drug treatment, even though the
probability of becoming seizure-free on a newly tried
antiseizure medication decreases with increasing
number of previously failed medications.12 By showing
that the probability of achieving seizure freedom with
drug therapy after non-response to two antiseizure
medications is relatively small, these data support the
16
Patients achieving seizure freedom (%)
11·8%
12
8·0%
8 103 studies published between 1970 and 2020 that
4·6%
4 incidence of drug-resistant epilepsy across 24 relevant
2·5% 2·6%
0
2 (n=313) 3 (n=212) 4 (n=130) 5 (n=80) 6 (n=39)
Previously failed antiseizure medications (number of patients)
Figure 1: Seizure freedom rates after a newly added antiseizure medication, by number of previously tried
antiseizure medications
Data are derived from a study by Mula and collagues11 that included 850 individuals with focal epilepsy who met
ILAE criteria for drug resistance, as confirmed by an expert panel. Study participants were followed up
prospectively over 18 months (for a maximum of 34 months, if needed) after the introduction of another
antiseizure medication into their regimen. Seizure freedom was defined by ILAE criteria as the absence of seizures
for a period of at least 12 months or three times the longest pre-intervention interseizure interval, whichever was
longer. Among individuals not attaining seizure freedom after a newly added antiseizure medication, outcome
was classified as either treatment failure or undetermined, as per ILAE criteria. ILAE=the International League
Against Epilepsy.
2 www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5
ILAE criteria defining drug-resistant epilepsy. Yet, it has
been suggested that the number of previous antiseizure
medications not responded to required to define drug-
resistant epilepsy should be re-evaluated as it might vary
across epilepsy types.13 The type of antiseizure medi­
cations that elicited no response also affects the prob­
ability of achieving seizure freedom with subsequent
drug trials. In particular, evidence suggests that the most
important predictor of drug resistance in individuals
with genetic generalised epilepsies is non-response to
valproic acid.14
Epidemiology
When interpreting incidence and prevalence estimates of
drug-resistant epilepsy, it is important to consider that
drug responsiveness is a dynamic rather than a fixed
state.15 In a retrospective study of 1006 children and
adults followed up for 10–57 years after a diagnosis of
epilepsy, 923 (92%) became seizure-free for at least 1 year
during follow-up.16 Most individuals (52%), however,
displayed a relapsing–remitting course, with periods of
seizure freedom alternating with periods of seizure
recurrence. About a third achieved either early (24%) or
late (7%) seizure freedom, persisting until the end of
follow-up. The remaining individuals (17%) were split
evenly between those who never achieved remission and
those who, after being seizure-free for at least 1 year,
relapsed without subsequent remission. Another factor
relevant to the epidemiology of drug-resistant epilepsy is
that seizure outcome assessment typically relies on
reports by patients or their caregivers, who on average
document 50% or less of actual seizures.17 Undocumented
seizures also occur among reportedly seizure-free
individuals.18 Although conscious concealment might
contribute to under-reporting of seizures, the main
explanation is that individuals are often unaware of their
seizures. Seizures with subtle features can also elude
recognition by observers.
A systematic review and meta-analysis identified
examined incidence, prevalence, or factors associated
with drug-resistant epilepsy.19 The pooled cumulative
2·6%
studies (9059 individuals) was 20% (95% CI 14–25). The
pooled prevalence of drug-resistant epilepsy across
59 studies (1 479 385 individuals) was 32% (95% CI
≥7 (n=76)
28–37). Incidence and prevalence estimates varied
greatly between studies. Incidence estimates tended to
be higher in children (25%, 95% CI 17–34) than in adult
or mixed-age populations (15%, 95% CI 9–22), which
might reflect different causes as well as the fact that
paediatric studies often excluded individuals with less
severe epilepsy syndromes (eg, self-limited epilepsy with
centrotemporal spikes or childhood absence epilepsy).
Clinic-based studies (vs population or community-based
studies) and focal epilepsy (vs any type or generalised
epilepsy) were associated with a 22% and 20% relative
 Review

increase, respectively, in prevalence of drug-resistant drug-resistant epilepsy during follow-up.23 However, a

epilepsy. Other sources of heterogeneity included
variations across studies in follow-up duration and in the
definition of drug-resistant epilepsy that was used.20
However, incidence and prevalence estimates were not
affected by whether the ILAE definition of drug-resistant
epilepsy was used or not, consistent with a previous
meta-analysis that also highlighted how information
required to categorise antiseizure medication response
by ILAE criteria was absent in many studies.21 Factors
most commonly associated with drug-resistant epilepsy
across 83 studies included young age of onset, focal or
multiple seizure types, high baseline seizure frequency,
abnormal diagnostics (neurological examination, EEG,
or neuroimaging), symptomatic epilepsy, and psychiatric
comorbidity (figure 2).
Age at seizure onset as a predictor of drug-resistant
epilepsy deserves further discussion. People in whom
epilepsy presents very early in life are at high risk of
drug resistance. A Scottish prospective study found that
139 (36%) of 390 children whose epilepsy started in the
first 3 years of life met ILAE criteria for drug-resistant
epilepsy by 24 months after seizure onset.22 Seizure pro­
g­­nosis is more favourable in adolescent-onset epilepsy
syndromes. Among 332 adolescents (age 13–19 years)
who began antiseizure medications after a new diagnosis
of epilepsy and who were followed up for 2–30 years at a
single centre, only 31 (9%) met ILAE criteria for
third experienced relapses after attaining seizure
freedom, often due to poor antiseizure medication
adherence, sleep deprivation or other seizure precipitants
(comorbidities or stress), or attempts to withdraw
treatment. Epilepsy with onset in old age also generally
carries a good seizure prognosis. Of 201 individuals
treated at age 65 years or older for new-onset epilepsy
and followed up for at least 2 years (median 7·5 years),
158 (79%) were seizure-free for at least 1 year at last
follow-up.24 All but nine of these individuals were seizure-
free on one antiseizure medication, generally at a low
dose, and about three-quarters were so on their very first
drug.
The increase in number of available antiseizure
medications has not substantially improved the
probability of drug treatment leading to seizure freedom.
In a Scottish single-centre study of 1795 individuals
started on treatment between 1982 and 2012 and followed
up for at least 2 years (median 11 years) up to 2014,
1144 (64%) were seizure-free for at least 1 year at last
assessment.12 Seizure freedom rates were similar irres­
pective of the decade in which antiseizure medication
was started (1982–91, 1992–2001, and 2002–12), despite
much greater use of new antiseizure drugs in the later
cohorts. The study could not meaningfully assess
outcomes for the most recently developed antiseizure
medications (eg, perampanel, brivaracetam, everolimus,

Younger age at onset*

Neurological deficit
Symptomatic epilepsy†
Abnormal EEG
High baseline seizure frequency
Multiple seizure types
Cryptogenic epilepsy†
Psychiatric comorbidity (in particular depression)
No response to first antiseizure medication
ABCB1 gene
Neuroimaging abnormality
Seizure type (in particular focal)
Status epilepticus
Developmental delay
Febrile seizures
Hippocampal sclerosis
Female sex
Inborn errors of metabolism
0 4 8 12 16 20
Number of studies where factor was significantly associated with drug-resistant epilepsy

Figure 2: Most common predictors and correlates of drug-resistant epilepsy

Data are derived from Sultana and colleagues,19 who identified factors reported to be significantly associated with drug-resistant epilepsy among 83 relevant studies.
Shown in this figure are predictors and correlates of drug-resistant epilepsy reported in three or more studies as being statistically significant. *Infantile epilepsy onset
carries the highest risk of drug-resistant epilepsy. †Symptomatic and cryptogenic epilepsy are old terms no longer used in the current ILAE classification of epilepsy
syndromes. Broadly, symptomatic epilepsy refers to epilepsy due to an identifiable genetic or acquired cause, often associated with structural brain abnormalities
indicating an underlying disease or condition. Cryptogenic epilepsy refers to an epilepsy presumed to be symptomatic, but in which the cause has not been identified.
ILAE=the International League Against Epilepsy.

www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5 3

 Review

cannabidiol, cenobamate, fenfluramine, and ganaxolone),
the indications for which signal a gradual shift from
targeting of common epilepsy types to targeting of
specific causes or syndromes, including highly drug-
resistant syndromes. To evaluate the effect of the most
recently developed antiseizure medications, we did a
systematic search of randomised placebo-controlled
adjunctive-therapy trials with these medications, and
tabulated the proportion of individuals (as a percentage
of those randomly assigned) who completed the trial and
were seizure-free throughout a maintenance phase of at
See Online for appendix least 12 weeks. As shown in the appendix (pp 1–6), only a
few (≤5%) individuals achieved seizure freedom on the
newest antiseizure medications, in keeping with
estimates from trials of second-generation antiseizure
medications introduced before 2012.25 A notable
exception is cenobamate, which in a single trial was
associated with relatively high seizure-free rates (up to
14% at the highest dose tested).26 Despite their modest
effect on the prevalence of drug-resistant epilepsy,
second-generation antiseizure medications still provide a
valuable addition to the pharmacological armamen­
tarium, by permitting clinically relevant reductions in
seizure frequency or burden of adverse effects, at least in
some individuals. However, the extent by which quality
of life has been improved overall by second-generation
antiseizure medications remains unknown.
Mechanisms of drug resistance
Studies on the underpinnings of drug-resistant epilepsy
have identified several testable hypotheses (table 1),
many of which are substantiated by both human and
animal data.3,27–31 Each hypothesis can account for why an
individual might be resistant to a particular antiseizure
medication, but none explains why some individuals are
resistant to multiple antiseizure medications. For
example, the transporter hypothesis is based on the
finding that, in animal models, chronic seizures and
chronic use of some antiseizure medications can
increase the expression of the drug efflux transporters
such as P-glycoprotein, multidrug resistance proteins
and, possibly, breast cancer resistance protein at the

Guiding concept
Transporter Seizure-induced or genetically determined
increase or modification of efflux
transporters at the blood–brain barrier
leads to reduced antiseizure medication
concentrations at their site of action
Target Acquired or genetic modifications in
antiseizure medication target proteins
contribute to a reduction in drug response reduced phenobarbital efficacy at GABAA
Intrinsic Epilepsy-related and seizure-related
severity modification of neuronal milieu and
seizure network contribute to progressive
seizure worsening and poor antiseizure
medication efficacy
Gene Variation in selected epilepsy genes and
variant genes encoding antiseizure medication
transporters can contribute to drug
resistance
Neural Seizure-induced neuronal degeneration,
network axonal sprouting, gliosis, aberrant
neurogenesis, and remodelling lead to
abnormal neural networks that can
suppress the brain’s seizure control
system and can reduce antiseizure
medication action at intended targets
Supporting clinical evidence
Expression of P-glycoprotein and other
transporters is increased in seizure networks
of individuals with drug-resistant epilepsy;
multiple antiseizure medications are
substrates for P-glycoprotein or other
transporters; some studies found an
association of drug-resistant epilepsy with
polymorphisms of ABCB1 gene, which
encodes P-glycoprotein, and ABCC2 gene,
encoding multidrug resistance protein 2
Reduced carbamazepine efficacy at VGSC in
individuals with drug-resistant epilepsy;
receptors in individuals with drug-resistant
epilepsy; modified GABAA receptors in
human temporal lobe epilepsy
High seizure frequency and extensive
epileptogenic lesions are associated with
poor antiseizure medication response
Rare variants in genes associated with severe
drug-resistant epilepsy syndromes
(eg, SCN1A, SCN2A) and polymorphisms in
multidrug resistance genes, comprising ABC
subfamily B member 1 (P-glycoprotein or
multidrug resistance gene 1) and ABC
subfamily C member 2 (multidrug resistance
protein 2)
Common abnormalities associated with
drug-resistant epilepsy and several
neuropsychiatric comorbidities include
hippocampal mossy fibre sprouting, cortical
malformations, and network dysfunctions
Supporting preclinical evidence
Increased expression of P-glycoprotein and
other transporters in rodent models;
increased expression of P-glycoprotein is
associated with phenytoin and
phenobarbital resistance in rat models of
epilepsy and inhibition of P-glycoprotein
restores pharmacosensitivity
Reduced carbamazepine efficacy at VGSC in Overlaps with gene variant hypothesis
the rat model of temporal lobe epilepsy
after pilocarpine-induced-status epilepticus;
modified GABAA receptor responsiveness in
epileptic rats
High seizure frequency and seizure burden
in rodent models of chronic epilepsy is
associated with poor antiseizure medication
efficacy and antiseizure medication
resistance
Experimental models of severe monogenic Overlap with the target, transporter,
epilepsies have been developed that show
resistance to several antiseizure medications
Mossy fibre sprouting, hippocampal
sclerosis, and cellular reorganisation are
often found in animal models of epilepsy
Relation to other hypotheses
Overlaps with gene variant and intrinsic
severity hypotheses (high seizure
frequency leads to greater expression of
P-glycoprotein and multidrug
resistance proteins and increased
probability of drug-resistant epilepsy)
Overlaps with the gene variant, neural
network, and transporter hypotheses—
ie, poor seizure control is associated
with increased expression of efflux
transporters and network
reorganisation
and intrinsic severity hypotheses
Overlaps with intrinsic severity
hypothesis

ABC=ATP-binding cassette. GABAA=GABA type A. VGSC=voltage-gated sodium channel. For a source of references, refer to recent reviews.3,27–31

Table 1: Summary of major hypotheses of drug-resistant epilepsy and examples of supporting clinical and preclinical evidence

4 www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5


blood–brain barrier. Increased expression of transporters
can lead to a decrease in antiseizure medication
concentration in epileptogenic brain tissue, which can be
reversed by pharmacological inhibition of the relevant
transporter.3 Many antiseizure medications have been
shown to be substrates for P-glycoprotein, whereas only a
few appear to be substrates of multidrug resistance
proteins or breast cancer resistance protein.3 Although
there is evidence supporting the transporter hypothesis
for phenytoin and phenobarbital, evidence is insufficient
to suggest that the same hypothesis accounts for
resistance to other antiseizure medications. For example,
knockout of P-glycoprotein in the mouse kainic acid
model of mesial temporal lobe epilepsy does not reverse
resistance to several antiseizure medications that are
P-glycoprotein substrates.32
The target hypothesis posits that a particular molecular
target can be rendered less sensitive to antiseizure
medications acting on that target.31 The best evidence for
this hypothesis is provided by the reduced ability of
carbamazepine to inhibit voltage-dependent sodium
channels in a very limited set of experiments on epileptic
tissue resected from the brain of individuals with drug-
resistant epilepsy, and in more extensive studies in
epileptic brain tissue of post-status epilepticus rats that
display resistance to carbamazepine.33 However, the
target hypothesis does not account for why patients with
drug-resistant epilepsy are resistant to multiple
antiseizure medications acting through diverse mole­
cular targets. It is highly unlikely that chronic seizures or
antiseizure medication use affect multiple targets in
such a way to produce resistance to all antiseizure
medications, irrespective of their molecular action.
The intrinsic severity hypothesis builds on preclinical
and clinical data suggesting that drug resistance is an
“inherent property…related to disease severity,”3 implying
that underlying molecular mechanisms are too intense
or widespread to be fully controlled by antiseizure
medications. Seizure frequency, or the extent of structural
epileptogenic lesions (eg, hippocampal sclerosis or focal
cortical dysplasia), are often regarded as biomarkers of
disease severity.3 However, it is unclear what happens at a
molecular level to render the epileptic network resistant
to multiple antiseizure medications.
The hypotheses of drug-resistant epilepsy summarised
in table 1 are not mutually exclusive, and they can be
linked to one another. For example, overexpression of
drug transporters can lead to a reduction in brain
antiseizure medication concentrations, which can
result in worsened seizure control and subsequent
neuro­chemical and neurophysiological changes at the
network and target level. Moreover, one or more
mechanisms could apply to any individual with drug-
resistant epilepsy. In fact, multiple factors beyond
seizure frequency and antiseizure medication
pharmacology can contribute to drug-resistant epilepsy.
Servilha-Menezes and Garcia-Cairasco28 rightfully
www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5 5
Review
suggest a holistic approach that considers the effect of
comorbid anxiety, depression, and sleep disorders,
because each of these factors can alter seizure threshold
and contribute to poor seizure control.
Neuro­inflammation has emerged as a potential com­
mon mechanism underlying different hypotheses of
drug-resistant epilepsy,27 including refractory status
epilepticus.34 For example, seizures release inflammatory
proteins that can contribute to hyperexcitability, gliosis,
activation of microglia, disruption or dysfunction of the
blood–brain barrier, neural network reorganisation, and
increased P-glycoprotein expression. These findings
justify the interest in targeting neuroinflammation as a
strategy to treat or prevent drug-resistant epilepsy.35
However, clinical data supporting the broad involvement
of neuroinflammation in drug-resistant epilepsy is
scarce, and it would be oversimplistic to expect that drug
resistance could be counteracted in all individuals by
blocking neuroinflammatory processes. In a placebo-
controlled trial that tested the value of targeting brain
inflammation, the anti-α4-integrin agent natalizumab
did not reduce seizure frequency significantly in indivi­
duals with drug-resistant focal epilepsy,36 even though a
modest effect could not be excluded due to the limited
power of the study. Moreover, there could be mechanisms
of neuroinflammation not targeted by natalizumab, and
inflammation might not contribute to drug resistance in
all individuals with focal epilepsy. In syndromes for
which inflammation has a well documented pathogenic
role, such as new-onset refractory status epilepticus and
febrile infection-related epilepsy syndrome, some
individuals have been reported to benefit from the
interleukin-1 receptor antagonist anakinra37–39 or the
inter­leukin-6 receptor antagonist tocilizumab.40,41
Prediction and prevention
Among several factors that have been found to be
predictive of drug-resistant epilepsy, those most relevant
are the epilepsy syndrome and the underlying cause.42,43
An epilepsy syndrome is defined as a characteristic cluster
of clinical and EEG features, often supported by specific
aetiological findings, and often with age-dependent
presentations and a range of specific comor­ bidities.
Epilepsy syndromes frequently carry therapeutic
implications, because any specific syndrome might
respond preferentially to certain treatments or contra­
indicate use of some medications that could have an
aggravating effect on that syndrome. Syndromes are much
more commonly identified in early life, being present in
54% of individuals with epilepsy beginning before the age
of 3 years.22 Developmental and epileptic encephalopathies
and syndromes with progressive neurological deterioration
are typically associated with drug resistance from epilepsy
onset (appendix p 9).5 Some focal epilepsy syndromes,
including mesial temporal lobe epilepsy with hippocampal
sclerosis, are often drug-resistant but might respond to
antiseizure medications transiently.44 By contrast, drug
 Review

Main mechanism of action Epilepsy indication under investigation (trial registration Development
number) phase
GABA GABA-receptor agonist Epilepsy associated with attention-deficit hyperactivity Phase 2/3
disorder (NCT04144439)
Basimglurant Metabotropic glutamate receptor 5 antagonist  Seizures associated with tuberous sclerosis complex Phase 2
(NCT05059327)
Carisbamate (YKP509, Blockade of Na+ channels Seizures associated with Lennox-Gastaut syndrome Phase 3
RWJ-333369) (NCT05219617)
Darigabat (CVL 856) Subtype-selective GABAA receptor positive allosteric modulator Focal seizures (NCT04244175) Phase 2
2-deoxy-glucose Glycolytic inhibitor Epilepsy, not otherwise specified (NCT05605301) Phase 2
ENX-101 Subtype-selective GABAA receptor positive allosteric modulator Focal seizures (NCT05481905) Phase 2
ES-481 Not reported Drug-resistant epilepsy (NCT04714996) Phase 2
ETX-101 Non-replicating, recombinant adeno-associated viral vector Seizures associated with Dravet syndrome (NCT05419492) Phase 1/2
comprising a GABAergic regulatory element and an engineered
transcription factor that increases transcription of the SCN1A gene
ETX-155* Neurosteroid GABAA receptor positive allosteric modulator Focal epilepsy Phase 1
Fecal microbiota suspension Modulation of gut microbiota Epilepsy, not otherwise specified (NCT02889627) Phase 2/3
JNJ-40411813 Positive allosteric modulator of the mGlu2 glutamate receptor Focal seizures with suboptimal response to levetiracetam or Phase 2
brivaracetam (NCT04836559)
Lactobacillus probiotic Modulation of gut microbiota Drug-resistant epilepsy in children (NCT05539287) Phase 2
Lentiviral gene therapy Delivery of an engineered potassium channel Drug-resistant focal epilepsy (NCT04601974) Phase 1
LP352 5-HT2C receptor superagonist Dravet syndrome, Lennox-Gastaut syndrome, and other Phase 2
developmental and epileptic encephalopathies (NCT05626634
and NCT05364021)
NBI921352 (XEN901) Selective Nav1.6 sodium channel inhibitor Focal seizures, adults (NCT05159908); and SCN8A- Phase 2
developmental and epileptic encephalopathy, children
and adults (NCT04873869 and NCT05226780)
NPT-2042 Sodium-potassium-chloride cotransporter inhibitor Intractable epilepsy (NCT05503511) Phase 1
NRP2945* Activation of chemokine receptor with CXC motif 4 leading to Lennox-Gastaut syndrome, drug-resistant temporal lobe Phase 2
increased expression of GABAA receptor α and β subunits and epilepsy
upregulation of GABA signalling
NRTX-1001 (NTX101) Regenerative GABA-releasing neural cell therapy Drug-resistant unilateral mesial temporal lobe epilepsy with Phase 1/2
hippocampal sclerosis (NCT05135091)
PRAX-562* Preferential inhibitor of persistent sodium current SCN2A-related and SCN8A-related developmental and Phase 2
epileptic encephalopathies
Radiprodil* Negative allosteric modulator at NR2B subunits of NMDA Epilepsies caused by pathogenic GRIN2B gain-of-function Phase 2
receptors  variants
Rozanolixizumab Human neonatal Fc receptor antagonist Seizures associated with leucine-rich glioma-inactivated 1 Phase 2
autoimmune encephalitis (NCT04875975)
Soticlestat Selective inhibitor of cholesterol 24-hydroxylase Seizures associated with Dravet syndrome and Lennox-Gastaut Phase 3
syndrome (NCT04940624, NCT05163314, NCT04938427, and
NCT03635073)
Sodium selenate* Activation of protein phosphatase 2A leading to reduced Drug-resistant temporal lobe epilepsy (disease modification Phase 2
hyperphosphorylated tau in the brain trial [ACTRN12623000446662p])†
STK-001 Antisense oligonucleotide aimed at increasing productive SCN1A Seizures associated with Dravet syndrome (NCT04740476 and Phase 1/2
mRNA NCT04442295)
Tricaprilin Ketogenic C8 medium chain triglyceride Infantile spasms (NCT04727970) Phase 1
Vatiquinone (PTC-743, EPI-743) Inhibitor of 15-lipoxygenase Motor seizures in drug-resistant epilepsy associated with Phase 2/3
mitochondrial disease (NCT04378075 and NCT05218655)
XEN1101 Selective Kv7.2 and Kv7.3 potassium channel opener Focal seizures or generalised tonic-clonic seizures Phase 3
(NCT05718817, NCT03796962, NCT05716100,
NCT05614063, and NCT05667142)
The list includes both recruiting and non-recruiting clinical trials listed in ClinicalTrials.gov (searched on Jan 4, 2023, using search terms “seizures” or “epilepsy”). GABAA=GABA type A. *Denotes compounds
known to be in clinical development but with trials not yet listed on ClinicalTrials.gov. †Denotes registration number in the Australian New Zealand Clinical Trials Registry.

Table 2: Potential therapeutic agents currently under clinical investigation for the treatment of seizures or epilepsy

resistance is less common among individuals with self- of cortical development, and severe traumatic brain
limited focal epilepsies of infancy and childhood,45 and injury—also are highly correlated with drug resistance.
idiopathic generalised epilepsies.46 Some causes of In the past 10 years, interest has been increasing in
epilepsy—such as hippocampal sclerosis, malformations potential molecular markers of drug-resistant epilepsy,

6 www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5


including markers of neuroinflammation as well as
genetic and epigenetic biomarkers.47 Among those, high-
mobility group box 1 (known as HMBG1)—a mediator of
inflammatory and immune reactions in the brain—has
been proposed as a possible pathogenic factor as well as a
mechanistic biomarker of severe epilepsy.48–51 To date,
however, no one biomarker has been established as
having sufficient power to guide clinical management.
At present, the likelihood of an individual’s epilepsy
being drug-resistant is best assessed by considering
multiple factors. Multivariate prediction models incor­
porating a wide range of risk factors for drug resistance
have been developed for application to individuals with
epilepsy at large52,53 or specific conditions such as MRI-
negative epilepsy,54 generalised epilepsies,55 and juvenile
myoclonic epilepsy.56 One large study used machine
learning to predict drug-resistant epilepsy based on
pharmacy, medical, and insurance claim data from
175 735 individuals with epilepsy.52 One of the models
tested was able to identify probable drug resistance
approximately 2 years before failure of the second
antiseizure medication. A 2021 review of evidence on the
value of machine learning concluded that this approach
has prognostic potential, but data thus far are scarce,
with most studies coming from single centres, involving
few patients, and often without external validation.57
Another area of great interest relates to prevention of
drug-resistant epilepsy. Primary prevention—defined as
preventing exposure to epileptogenic insults—could
alleviate approximately a quarter of cases of epilepsy.58
These measures include improved prenatal care,
immunisations, healthier lifestyles, and safety measures
to prevent traumatic brain injury. Secondary prevention—
defined as halting or ameliorating the course of the
pathogenic process once epileptogenesis has started—is
much more challenging for two reasons. First, sensitive
and specific biomarkers of epileptogenesis must be
identified, and these will probably vary depending on the
underlying cause. Second, antiepileptogenic and disease-
modifying therapies must be developed, such that
epilepsy will either be prevented or converted from drug-
resistant to drug-responsive. Moreover, prevention would
be most applicable to individuals at high risk of epilepsy
after insults such as traumatic brain injury, or with
known pathogenic gene variants, for whom treatment
could be given early in the epileptogenic process.59
For most individuals at risk of developing epilepsy, no
effective antiepileptogenic therapies are currently avail­
able. However, progress is being made for individuals
with specific causes, such as pathogenic gene variants
identifiable early in life. Tuberous sclerosis complex
usually presents with early-life seizures and high rates of
drug resistance. The EPISTOP trial suggested that EEG
biomarkers could identify infants at risk of epileptic
spasms and epilepsy, and that early therapy might
prevent drug resistance.60 This trial included 54 infants
aged 4 months or younger with definite tuberous
www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5 7
Review
sclerosis complex without previous clinical or
electrographic seizures on baseline video-EEG. Infants
were followed-up periodically by video-EEG through
24 months of age after being allocated to treatment with
vigabatrin (100–150 mg/kg per day) started after onset
of clinical or electrographic seizures (conventional
treatment) or after epileptiform EEG activity appeared,
before actual seizure onset (preventive treatment).
Compared with conventional treatment, preventive
treatment reduced the risk of drug-resistant epilepsy
(odds ratio [OR] 0·23, 95% CI 0·06–0·83, p=0·025) and
the occurrence of infantile spasms (OR 0·00, 95% CI
0·00–0·33 p<0·001). Although there was a trend towards
lower rates of neurodevelopmental disability in the
preventive group, no significant between-group
difference in rates of autism were noted. A similar study
(PREVENT, NCT02849457) is investigating whether
preventive treatment with vigabatrin improves develop­
mental outcome at 24 months, with occurrence of
seizures and drug-resistant epilepsy as secondary
outcomes. Results are expected by the end of 2023. Trials
that focus on specific ion channels, gene replacement or
modulation, and targeted augmentation of nuclear gene
output using antisense oligonucleotides are also under­
way or planned (table 2).
Management
The management of drug-resistant epilepsy requires a
multistep approach (figure 3) and should be handled
whenever possible by an epilepsy specialist, preferably at
a comprehensive epilepsy centre. This strategy is
important not only for optimal control of seizures and
comorbidities but also for prevention of premature
mortality.66 Early diagnostic assessment is essential to
exclude a non-epileptic nature of the symptoms or
misclassification of seizure type or syndrome. Potential
causes of poor response to antiseizure medication, which
include incomplete adherence to the dosing regimen,
suboptimal choice of antiseizure medication, inadequate
dosing schedule, or unhealthy lifestyle (eg, exposure to
seizure precipitants such as alcohol abuse or sleep
deprivation), should be investigated and addressed. In
some epilepsy syndromes, use of ineffective or potentially
aggravating antiseizure medications is relatively com­
mon, and failure to take timely corrective action can cause
severe outcomes, including irreversible seizure-related
cognitive disability.67
If a diagnosis of drug-resistant epilepsy is confirmed,
consideration of the underlying causes of epilepsy could
identify an indication for surgery or suggest other therapies
that target the cause of the seizures. Early surgical
evaluation is indicated in most individuals with drug-
resistant epilepsy in whom a focal onset of seizures is
suspected, without restrictions related to age, co­ mor­
bidities, or seizure type.61,62,68 For both adults69 and
children,70 the evidence for superiority of surgery over
medical therapy in the management of drug-resistant
 Review

postponement can lead to impaired cognitive development

Has the occurrence of non-epileptic events Re-assess the diagnosis and adjust (particularly in young children), seizure-related comor­
(eg, psychogenic non-epileptic spells, syncope, No management accordingly
and transient ischemic attacks) been excluded? bidities, excess mortality, and even a reduced probability of
post-surgical seizure freedom.62,72 When epilepsy is caused
by a well defined lesion in the non-eloquent cortex, pre­
Yes surgical evaluation should be considered even before drug-
resistant epilepsy becomes established, including
Has a diagnosis of pseudo-pharmacoresistant Address the cause of poor seizure control by
indi­viduals who become initially seizure-free on one or
epilepsy* been excluded? No providing counselling, or by adjusting two antiseizure medications.73 This strategy is particularly
antiseizure medication justified for lesions likely to lead to drug-resistant
epilepsy—eg, hippocampal sclerosis, cavernous
malformations, glioneuronal tumours, and focal cortical
Yes
dysplasia type II.62,74
Diagnostic investigations can also reveal causes of
Investigate the cause of the seizure disorder. Prescribe targeted therapy as appropriate seizures that can be targeted with specific pharmacological
Are targeted pharmacological or dietary (eg, ketogenic diet for GLUT-1 deficiency or
therapies indicated? immunotherapy for immune- related seizure
or dietary treatments. For autoimmune-related seizure
Yes disorders). Should this approach not work, disorders, a delay in diagnosing the underlying cause can
proceed to the next step in the management lead to drug-resistant epilepsy, which could have been
algorithm.
pre­vented by early implementation of appropriate
immuno­therapy.75 Treatments targeting specific mech­
No anisms have also been proposed for many monogenic
epilepsies (appendix p 7).76–78 Some have not yet been
adequately evaluated or have variable efficacy, but
Is the individual a potential candidate for Refer to presurgical evaluation and epilepsy
epilepsy surgery? surgery if appropriate. Should the surgical
others—such as those addressing remediable metabolic
Yes option prove to be unfeasible or ineffective, defects—are highly effective, and failure to recognise the
proceed to the next step in the management treatment target could have a disastrous effect on a
algorithm.
person’s life.79 Broad access to genetic testing has
facilitated early recognition of epilepsies that can be
No targeted with specific interventions, which might simply
entail removal of contraindicated medications or dietary
constituents that worsen the underlying functional
Consider further trials of antiseizure Schedule regular follow-up and review clinical
medications or other therapeutic options, management as needed
defect.67 As an indication of the value of this approach, a
including dietary therapies and Chinese study of genetic testing in 273 children with
neuromodulation-based therapies. If seizures drug-resistant epilepsy due to no obvious acquired cause
persist after surgery, investigate the cause of
surgical failure and the possibility of repeat identified 34 individuals with gene defects addressable
surgery. Organise a comprehensive plan with corrective therapies, 18 of whom (53%) became
including, as appropriate, management of
adverse drug effects, seizure exacerbation,
seizure free.80 Similarly, an international survey reported
seizure clusters, and risk of seizure-related that a genetic diagnosis led to changes in management
injury or mortality. Avoid overtreatment and in 208 (50%) of 418 individuals.81 Among 167 people with
address comorbidities as needed.
follow-up data after treatment changes, 125 (75%)
reported positive outcomes, most commonly improve­
Figure 3: Approach to the clinical management of individuals with suspected or confirmed drug-resistant
epilepsy ment in seizure control. Another survey from Europe,
*Pseudo-pharmacoresistant epilepsy is defined as persistence of seizures due to suboptimal treatment or however, presented a more sobering scenario on the real-
management.6 Common causes of pseudo-pharmacoresistance include poor adherence, prescription of world effect of targeted therapies driven by genetic
inappropriate antiseizure medications, use of suboptimal antiseizure medication doses or dosing regimens,
testing, with only ten (3%) of 293 individuals with a
and an unhealthy lifestyle leading to exposure to seizure precipitants (eg, sleep deprivation and alcohol abuse).
For information supporting the proposed approach, please refer to recent articles.61–65 molecular genetic diagnosis benefitting from drugs
targeting the known pathophysiological mechanism of
epilepsy is compelling. A Cochrane review and meta- their epilepsy.82
analysis that included 16 855 participants from 182 studies Although the likelihood of achieving seizure freedom
found that 10 696 (64%) of individuals experienced a good with drug therapy decreases with the increasing
post-surgical outcome (defined as seizure control or number of medications tried, a few individuals with
seizure-free status for at least 1 year, or Engel class 1).71 drug-resistant epilepsy will achieve sustained seizure
Although most of the studies were retrospective, reported control on a newly tried antiseizure medication and,
outcomes were far superior to those achieved in drug- therefore, further medication trials are important. In
resistant epilepsy managed with antiseizure medication. an extension trial of cenobamate in people with focal
Epilepsy surgery remains underused in most settings, seizures, 36 (10%) of 354 individuals were seizure-free
despite evidence that, in suitable candidates, its during the last 12 months of the 48-month treatment

8 www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5


duration.83 However, inclusion criteria simply required
occurrence of uncontrolled seizures despite treatment
with at least one antiseizure medication,26 and therefore
some of the participants might not have had drug-
resistant epilepsy. Selection of the next antiseizure
medication to try in people with uncontrolled seizures is
mainly a trial-and-error process, which requires consider­
ation of any comorbidities, potential drug interactions,
and adverse reactions to previously used medications.
Although no class 1 evidence is available to show that
combining two or more antiseizure medications offers
superior efficacy to monotherapy, polypharmacy is
commonly used. Scarce data suggest that some drug
combinations, particularly valproic acid with lamotrigine,
might be more advantageous than others, and that
combining antiseizure medications sharing the same
mechanism of action is associated with less favourable
outcomes than combining drugs acting by different
mechanisms.84
The value of the ketogenic diet—or modified forms
including the medium-chain triglyceride diet and the
low-glycaemic index treatment—in the management of
drug-resistant epilepsy is well established, particularly in
paediatric epilepsy syndromes.63,85 In GLUT1 deficiency
syndrome and pyruvate dehydrogenase complex
deficiency, the ketogenic diet is often regarded as the
first-line treatment. When used appropriately, dietary
treatments can achieve seizure freedom rates greater
than those observed with antiseizure medications, which
justifies their early use in appropriately selected children
with drug-resistant epilepsy. Dietary treatments can also
be valuable in adults, although responsiveness of adults
is often hampered by poor adherence.86
Another approach to be considered for drug-resistant
epilepsy is neuromodulation.64 Vagal nerve stimulation,
deep brain stimulation, and responsive neurostimulation
are all effective at improving seizure frequency in variable
proportions of individuals with drug-resistant epilepsy.64,87
In controlled trials, very few individuals achieved short-
term seizure freedom with these treatments, but seizure
freedom rates appear to increase after long-term
follow-up, particularly with deep brain stimulation and
responsive neurostimulation.87
When seizures cannot be controlled, the aim of therapy
shifts to striking the best compromise between reducing
seizure frequency and minimising the adverse effects of
treatment. Efforts should be directed at controlling the
most disabling seizure types, particularly those carrying
a high risk of injury and mortality. Adverse events should
be closely monitored, because it is not uncommon for
people with drug-resistant epilepsy to suffer more from
the adverse effects of antiseizure medications than from
the seizures themselves.88 Overtreatment can also cause a
paradoxical worsening of seizure control, and reduction
of excessive antiseizure medication doses or poly­phar­
macy is an important component of the management of
drug-resistant epilepsy. For individuals susceptible to
www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5 9
Review
prolonged seizures, seizure clusters, and status
epilepticus, a strategy to optimise use of rescue medi­
cations should be in place. Attention should also be given
to the management of comorbidities, particularly
psychiatric disorders, which often affect quality of life
more than the seizures.89 Measures to reduce the risk of
seizure-related injury and mortality, including sudden
unexpected death in epilepsy, such as seizure detection
devices and night-time supervision, should also be
considered.
Conclusion and future directions
Drug-resistant epilepsy remains a key challenge faced by
people with epilepsy.2 Although second-generation anti­
seizure medications have not substantially changed the
burden of drug-resistant epilepsy,1 there is clearly an
opportunity for improved application of existing thera­
peutic tools, and for renewed efforts to develop more
effective therapies.
The ILAE definition of drug-resistant epilepsy has
limitations (eg, dependency on subjective assessment to
determine the adequacy of a medication trial, and failure
to account for the fact that the poor treatment outcome of
highly drug-resistant syndromes can be already predicted
at the time of diagnosis), but the introduction of this
definition has led to wider recognition of the fact that
responsiveness to medical treatment can usually be
ascertained within the first 1–2 years from diagnosis.
Thus, early referral to specialist care should be
encouraged, and early use—whenever appropriate—of
non-pharmacological therapies (eg, epilepsy surgery) is
paramount. Increasing evidence indicates that, in
epilepsies due to certain specific causes, drug-resistant
epilepsy might be prevented by early use of antiseizure
medications that target the mechanism of seizure
generation,60 epilepsy surgery,72 or use of other therapies
targeting the underlying pathophysiological mechanism
(eg, immune therapies in autoimmune-related seizure
disorders).75
For most individuals who are not surgical candidates,
management still relies mostly on use of medications not
previously tried. This trial-and-error approach is both
time consuming and frustrating. The need to improve
the efficiency of this process has stimulated the
development of tools to facilitate early selection of
targeted therapies. One such tool, freely available on the
internet, uses an expert opinion-based algorithm to
suggest preferred antiseizure medication choices based
on the individual’s characteristics,90 but it is only
applicable to individuals whose epilepsy begins at age
10 years or older and has been validated only in newly
diagnosed epilepsy.91,92 Another new approach involves
the use of prediction models for response to individual
antiseizure medications based on machine learning-
assisted big data analysis. Initial efforts in this direction
have been only partly successful,93,94 but prediction
models based on artificial intelligence are likely to be
 Review
Search strategy and selection criteria
We searched PubMed and MEDLINE for human and
preclinical studies published in English since Jan 1, 2017,
until Jan 31, 2023, with the search term groupings: (Antiep*
OR AED*) AND (resistan*); (seizure*) OR (epilep*) AND
(outcome*) AND (adjunc* OR add*); (seizure*) OR (epilep*)
AND model* OR (resistan*); (seizure*) OR (epilep*) AND
(prevent*) OR (disease modif*) OR (antiepileptogenesis);
(seizure*) OR (epilep*) AND (clinical trial) OR (randomized ).
For the systematic review of seizure-freedom outcome in
randomised trials of recently introduced antiseizure
medications, we used the search term “randomized” coupled
with each of the following terms: “perampanel”,
“brivaracetam”, “everolimus”, “cannabidiol”, “cenobamate”,
“fenfluramine”, and “ganaxolone”. We also reviewed
references of retrieved publications and personal files.
increasingly pursued in the future. The ultimate goal is
to reduce the burden of drug-resistant epilepsy by
decreasing the time required to identify an effective
antiseizure medication and facilitate early imple­
mentation of non-pharma­cological treatment options.
Efforts to develop effective therapies continue,95–97 and
strategies being pursued include addressing the putative
processes of drug resistance, which include brain
inflammation and mechanisms of epileptogenesis and
disease progression. These novel approaches will involve
testing of interventions directed at novel targets.98,99
Hopefully, these efforts will lead in the future to the
availability of treatments that prevent epilepsy after
specific brain insults, or modify the course of the disease
by preventing progression to drug-resistant epilepsy. Of
note, early use of therapies that target the underlying
causes of epilepsy could potentially suppress not only
epileptogenesis but also disabling comorbidities.
Medical treatments currently under clinical develop­
ment include not only novel chemical or biological
entities (table 2) but also repurposed medications
(appendix p 8). Some of the treatments under investi­
gation, such as gene therapy (ETX-101) and antisense
oligonucleotides that upregulate healthy allele expression
(STK-001), use entirely novel paradigms. Other research
efforts focus on exploring potential advantages of com­
bining medications with complementary mechanisms of
action,98 an approach applied successfully in oncology
and infectious disease. Strategies to improve the efficacy
or reduce the toxicity of existing antiseizure medications
are not being neglected. One example is a novel formu­
lation of valproic acid infused via an implanted intra­
cerebroventricular delivery system.100 Closed loop drug
systems for local delivery of antiseizure medications as
soon as seizure activity is detected or predicted are also
being investigated, as are ways to improve the identifi­
cation of surgical candidates and the effectiveness of
surgical procedures and neuro­stimulation techniques.
10 www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5
The Intersectoral Global Action Plan on Epilepsy and
Other Neurological Disorders, which was approved by
WHO Member States at the World Health Assembly on
April 27, 2022, calls for improved access to epilepsy care
and more investment into research, and is very timely.101
Because of novel paradigms for treatment development,
and a coordinated effort from stakeholders, outcomes
for people with drug-resistant epilepsy are likely to
improve in the not-too-distant future.
Contributors
All authors contributed equally to the conceptualisation, writing,
reviewing, and editing of this Review and accept responsibility for the
decision to submit for publication.
Declaration of interests
EP received speaker fees or fees from consulting or participation in
Advisory Boards or Data Safety Monitoring Board from Angelini,
Arvelle, Biopas, Eisai, GW Pharma, Janssen, PMI Life Sciences, Sanofi
group of companies, Shackelford Pharma, SKL Life Science, Sun
Pharma, Takeda, UCB Pharma, Xenon Pharma, and Zogenix, and
royalties from Wiley, Elsevier, and Wolters Kluwers, all outside the
submitted work. He was immediate Past-President of the ILAE for the
2017–21 term and an Associate Editor of Epileptic Disorders from 2020
to 2022. PP has received speaker honoraria or consultancy fees to his
institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma,
Supernus, the Limbic, and UCB Pharma, outside the submitted work.
He is an Associate Editor for Epilepsia Open. HSW has received grant
funding from UCB Pharma, Eisai Pharmaceuticals, and Neurelis, and
consultant fees from GW Pharmaceuticals, Neurelis, Takeda
Pharmaceuticals, SK Life Sciences, and JAZZ Pharmaceuticals, and
speaker honoraria from SK Pharmaceuticals, Takeda Pharmaceuticals,
and UCB Pharma. ECW has served as a paid consultant for Encoded
Therapeutics, Amicus, Acadia, Neurocrine, and BioMarin. She is the
Editor-in-Chief of Epilepsy.com.
References
1 WHO. Epilepsy: a public health imperative. 2019. https://www.who.
int/publications/i/item/epilepsy-a-public-health-imperative (accessed
Jan 12, 2023).
2 Perucca E, Brodie MJ, Kwan P, Tomson T. 30 years of second-
generation antiseizure medications: impact and future perspectives.
Lancet Neurol 2020; 19: 544–56.
3 Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in
epilepsy: clinical impact, potential mechanisms, and new innovative
treatment options. Pharmacol Rev 2020; 72: 606–38.
4 Foster E, Chen Z, Zomer E, et al. The costs of epilepsy in Australia:
a productivity-based analysis. Neurology 2020; 95: e3221–31.
5 Wirrell EC, Nabbout R, Scheffer IE, et al. Methodology for
classification and definition of epilepsy syndromes with list of
syndromes: report of the ILAE Task Force on Nosology and
Definitions. Epilepsia 2022; 63: 1333–48.
6 Perucca E. Pharmacoresistance in epilepsy. How should it be
defined? CNS Drugs 1998; 10: 171–79.
7 Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant
epilepsy: consensus proposal by the ad hoc Task Force of the ILAE
Commission on Therapeutic Strategies. Epilepsia 2010; 51: 1069–77.
8 Hao X, Goldberg D, Kelly K, Stephen L, Kwan P, Brodie MJ.
Uncontrolled epilepsy is not necessarily the same as drug-resistant
epilepsy: differences between populations with newly diagnosed
epilepsy and chronic epilepsy. Epilepsy Behav 2013; 29: 4–6.
9 Zaccara G, Mula M, Ferrò B, et al. Do neurologists agree in
diagnosing drug resistance in adults with focal epilepsy? Epilepsia
2019; 60: 175–83.
10 Téllez-Zenteno JF, Hernández-Ronquillo L, Buckley S, Zahagun R,
Rizvi S. A validation of the new definition of drug-resistant epilepsy
by the International League Against Epilepsy. Epilepsia 2014;
55: 829–34.
11 Mula M, Zaccara G, Galimberti CA, et al. Validated outcome of
treatment changes according to International League Against
Epilepsy criteria in adults with drug-resistant focal epilepsy.
Epilepsia 2019; 60: 1114–23.

12 Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in
patients with newly diagnosed epilepsy treated with established and
new antiepileptic drugs: a 30-year longitudinal cohort study.
JAMA Neurol 2018; 75: 279–86.
13 Asadi-Pooya AA, Farazdaghi M. Definition of drug-resistant
epilepsy: a reappraisal based on epilepsy types. Acta Neurol Scand
2022; 145: 627–32.
14 Gesche J, Khanevski M, Solberg C, Beier CP. Resistance to valproic
acid as predictor of treatment resistance in genetic generalized
epilepsies. Epilepsia 2017; 58: e64–69.
15 Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of
treatment response in newly diagnosed epilepsy. Neurology 2012;
78: 1548–54.
16 Beghi E, Beretta S, Carone D, et al. Prognostic patterns and
predictors in epilepsy: a multicentre study (PRO-LONG).
J Neurol Neurosurg Psychiatry 2019; 90: 1276–85.
17 Elger CE, Hoppe C. Diagnostic challenges in epilepsy: seizure
under-reporting and seizure detection. Lancet Neurol 2018;
17: 279–88.
18 Fattouch J, Di Bonaventura C, Lapenta L, et al. Epilepsy,
unawareness of seizures and driving license: the potential role of
24-hour ambulatory EEG in defining seizure freedom.
Epilepsy Behav 2012; 25: 32–35.
19 Sultana B, Panzini MA, Veilleux Carpentier A, et al. Incidence and
prevalence of drug-resistant epilepsy: a systematic review and
meta-analysis. Neurology 2021; 96: 805–17.
20 Berg AT, Kelly MM. Defining intractability: comparisons among
published definitions. Epilepsia 2006; 47: 431–36.
21 Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The
epidemiology of drug-resistant epilepsy: a systematic review and
meta-analysis. Epilepsia 2018; 59: 2179–93.
22 Symonds JD, Elliott KS, Shetty J, et al. Early childhood epilepsies:
epidemiology, classification, aetiology, and socio-economic
determinants. Brain 2021; 144: 2879–91.
23 Alsfouk BA, Alsfouk AA, Chen Z, Kwan P, Brodie MJ.
Pharmacological outcomes in teenagers with newly diagnosed
epilepsy: a 30-year cohort study. Epilepsia 2019; 60: 1083–90.
24 Alsfouk BAA, Hakeem H, Chen Z, Walters M, Brodie MJ, Kwan P.
Characteristics and treatment outcomes of newly diagnosed
epilepsy in older people: a 30-year longitudinal cohort study.
Epilepsia 2020; 61: 2720–28.
25 Gazzola DM, Balcer LJ, French JA. Seizure-free outcome in
randomized add-on trials of the new antiepileptic drugs. Epilepsia
2007; 48: 1303–07.
26 Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive
cenobamate (YKP3089) in patients with uncontrolled focal seizures:
a multicentre, double-blind, randomised, placebo-controlled, dose-
response trial. Lancet Neurol 2020; 19: 38–48.
27 Campos-Bedolla P, Feria-Romero I, Orozco-Suárez S. Factors not
considered in the study of drug-resistant epilepsy: drug-resistant
epilepsy: assessment of neuroinflammation. Epilepsia Open 2022;
7 (suppl 1): S68–S80.
28 Servilha-Menezes G, Garcia-Cairasco N. A complex systems view on
the current hypotheses of epilepsy pharmacoresistance.
Epilepsia Open 2022; 7 (suppl 1): S8–S22.
29 Janmohamed M, Brodie MJ, Kwan P. Pharmacoresistance—
epidemiology, mechanisms, and impact on epilepsy treatment.
Neuropharmacology 2020; 168: 107790.
30 Pérez-Pérez D, Frías-Soria CL, Rocha L. Drug-resistant epilepsy:
from multiple hypotheses to an integral explanation using
preclinical resources. Epilepsy Behav 2021; 121: 106430.
31 Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple
hypotheses, few answers. Front Neurol 2017; 8: 301.
32 Bankstahl M, Klein S, Römermann K, Löscher W. Knockout of
P-glycoprotein does not alter antiepileptic drug efficacy in the
intrahippocampal kainate model of mesial temporal lobe epilepsy
in mice. Neuropharmacology 2016; 109: 183–95.
33 Remy S, Gabriel S, Urban BW, et al. A novel mechanism
underlying drug resistance in chronic epilepsy. Ann Neurol 2003;
53: 469–79.
34 Vezzani A, Di Sapia R, Kebede V, Balosso S, Ravizza T.
Neuroimmunology of status epilepticus. Epilepsy Behav 2023;
140: 109095.
www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5 11
Review
35 Costagliola G, Depietri G, Michev A, et al. Targeting inflammatory
mediators in epilepsy: a systematic review of its molecular basis and
clinical applications. Front Neurol 2022; 13: 741244.
36 French JA, Cole AJ, Faught E, et al. Safety and efficacy of
natalizumab as adjunctive therapy for people with drug-resistant
epilepsy: a phase 2 study. Neurology 2021; 97: e1757–67.
37 Clarkson BDS, LaFrance-Corey RG, Kahoud RJ, Farias-Moeller R,
Payne ET, Howe CL. Functional deficiency in endogenous
interleukin-1 receptor antagonist in patients with febrile infection-
related epilepsy syndrome. Ann Neurol 2019; 85: 526–37.
38 Lai YC, Muscal E, Wells E, et al. Anakinra usage in febrile infection
related epilepsy syndrome: an international cohort.
Ann Clin Transl Neurol 2020; 7: 2467–74.
39 Yamanaka G, Ishida Y, Kanou K, et al. Towards a treatment for
neuroinflammation in epilepsy: interleukin-1 receptor antagonist,
anakinra, as a potential treatment in intractable epilepsy.
Int J Mol Sci 2021; 22: 6282.
40 Jun JS, Lee ST, Kim R, Chu K, Lee SK. Tocilizumab treatment
for new onset refractory status epilepticus. Ann Neurol 2018;
84: 940–45.
41 Stredny CM, Case S, Sansevere AJ, Son M, Henderson L,
Gorman MP. Interleukin-6 blockade with tocilizumab in anakinra-
refractory febrile infection-related epilepsy syndrome (FIRES).
Child Neurol Open 2020; 7: 2329048X20979253.
42 Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of
pharmacoresistant epilepsy. Epilepsy Res 2007; 75: 192–96.
43 Wirrell EC. Predicting pharmacoresistance in pediatric epilepsy.
Epilepsia 2013; 54 (suppl 2): 19–22.
44 Dhamija R, Moseley BD, Cascino GD, Wirrell EC. A population-
based study of long-term outcome of epilepsy in childhood with
a focal or hemispheric lesion on neuroimaging. Epilepsia 2011;
52: 1522–26.
45 Specchio N, Wirrell EC, Scheffer IE, et al. International League
Against Epilepsy classification and definition of epilepsy syndromes
with onset in childhood: position paper by the ILAE Task Force on
Nosology and Definitions. Epilepsia 2022; 63: 1398–442.
46 Hirsch E, French J, Scheffer IE, et al. ILAE definition of the
idiopathic generalized epilepsy syndromes: position statement by
the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;
63: 1475–99.
47 Li Z, Cao W, Sun H, et al. Potential clinical and biochemical
markers for the prediction of drug-resistant epilepsy: a literature
review. Neurobiol Dis 2022; 174: 105872.
48 Ravizza T, Terrone G, Salamone A, et al. High mobility group box 1
is a novel pathogenic factor and a mechanistic biomarker for
epilepsy. Brain Behav Immun 2018; 72: 14–21.
49 Kan M, Song L, Zhang X, Zhang J, Fang P. Circulating high
mobility group box-1 and toll-like receptor 4 expressions
increase the risk and severity of epilepsy. Braz J Med Biol Res 2019;
52: e7374.
50 Wang N, Liu H, Ma B, et al. CSF high-mobility group box 1 is
associated with drug-resistance and symptomatic etiology in adult
patients with epilepsy. Epilepsy Res 2021; 177: 106767.
51 Walker LE, Sills GJ, Jorgensen A, et al. High-mobility group box 1
as a predictive biomarker for drug-resistant epilepsy: a proof-of-
concept study. Epilepsia 2022; 63: e1–6.
52 An S, Malhotra K, Dilley C, et al. Predicting drug-resistant
epilepsy—a machine learning approach based on administrative
claims data. Epilepsy Behav 2018; 89: 118–25.
53 Chen X, Ma XB, Zhang Q, Yin Q, Li XH. A scale for predicting the
outcomes of patients with epilepsy: a study of 141 cases.
Int J Gen Med 2021; 14: 1565–74.
54 Yang SJ, He GN, Han X, et al. A scale for prediction of response to
AEDs in patients with MRI-negative epilepsy. Epilepsy Behav 2019;
94: 41–46.
55 Orozco-Hernández JP, Quintero-Moreno JF, Marín-Medina DS,
et al. Multivariable prediction model of drug resistance in adult
patients with generalized epilepsy from Colombia: a case-control
study. Epilepsy Behav 2018; 88: 176–80.
56 Stevelink R, Al-Toma D, Jansen FE, et al. Individualised prediction
of drug resistance and seizure recurrence after medication
withdrawal in people with juvenile myoclonic epilepsy: a systematic
review and individual participant data meta-analysis.
EClinicalMedicine 2022; 53: 101732.
 Review
57 Smolyansky ED, Hakeem H, Ge Z, Chen Z, Kwan P. Machine
learning models for decision support in epilepsy management:
a critical review. Epilepsy Behav 2021; 123: 108273.
58 Thurman DJ, Begley CE, Carpio A, et al. The primary prevention of
epilepsy: a report of the Prevention Task Force of the International
League Against Epilepsy. Epilepsia 2018; 59: 905–14.
59 Galanopoulou AS, Löscher W, Lubbers L, et al. Antiepileptogenesis
and disease modification: progress, challenges, and the path
forward—report of the Preclinical Working Group of the 2018
NINDS-sponsored antiepileptogenesis and disease modification
workshop. Epilepsia Open 2021; 6: 276–96.
60 Kotulska K, Kwiatkowski DJ, Curatolo P, et al. Prevention of epilepsy
in infants with tuberous sclerosis complex in the EPISTOP Trial.
Ann Neurol 2021; 89: 304–14.
61 Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in children and
adults. Lancet Neurol 2014; 13: 1114–26.
62 Jehi L, Jette N, Kwon CS, et al. Timing of referral to evaluate for
epilepsy surgery: expert consensus recommendations from the
Surgical Therapies Commission of the International League Against
Epilepsy. Epilepsia 2022; 63: 2491–506.
63 Kossoff EH, Zupec-Kania BA, Auvin S, et al. Optimal clinical
management of children receiving dietary therapies for epilepsy:
updated recommendations of the International Ketogenic Diet Study
Group. Epilepsia Open 2018; 3: 175–92.
64 Ryvlin P, Rheims S, Hirsch LJ, Sokolov A, Jehi L. Neuromodulation
in epilepsy: state-of-the-art approved therapies. Lancet Neurol 2021;
20: 1038–47.
65 Perucca P, Scheffer IE, Kiley M. The management of epilepsy in
children and adults. The Med J Aust 2018;208: 226–33.
66 Lowerison MW, Josephson CB, Jetté N, et al. Association of levels of
specialized care with risk of premature mortality in patients with
epilepsy. JAMA Neurol 2019; 76: 1352–58.
67 de Lange IM, Gunning B, Sonsma ACM, et al. Influence of
contraindicated medication use on cognitive outcome in
Dravet syndrome and age at first afebrile seizure as a clinical
predictor in SCN1A-related seizure phenotypes. Epilepsia 2018;
59: 1154–65.
68 Jetté N, Sander JW, Keezer MR. Surgical treatment for epilepsy:
the potential gap between evidence and practice. Lancet Neurol 2016;
15: 982–94.
69 Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled
trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001;
345: 311–18.
70 Dwivedi R, Ramanujam B, Chandra PS, et al. Surgery for drug-
resistant epilepsy in children. N Engl J Med 2017; 377: 1639–47.
71 West S, Nevitt SJ, Cotton J, et al. Surgery for epilepsy.
Cochrane Database Syst Rev 2019; 6: CD010541.
72 Bjellvi J, Olsson I, Malmgren K, Wilbe Ramsay K. Epilepsy duration
and seizure outcome in epilepsy surgery: a systematic review and
meta-analysis. Neurology 2019; 93: e159–66.
73 Hale AT, Chari A, Scott RC, et al. Expedited epilepsy surgery prior to
drug resistance in children: a frontier worth crossing? Brain 2022;
145: 3755–62.
74 Pelliccia V, Deleo F, Gozzo F, et al. Early epilepsy surgery for non
drug-resistant patients. Epilepsy Behav Rep 2022; 19: 100542.
75 Guery D, Cousyn L, Navarro V, et al. Long-term evolution and
prognostic factors of epilepsy in limbic encephalitis with LGI1
antibodies. J Neurol 2022; 269: 5061–69.
76 Perucca P, Perucca E. Identifying mutations in epilepsy genes:
impact on treatment selection. Epilepsy Res 2019; 152: 18–30.
77 Guerrini R, Balestrini S, Wirrell EC, Walker MC. Monogenic
epilepsies: disease mechanisms, clinical phenotypes, and targeted
therapies. Neurology 2021; 97: 817–31.
78 Knowles JK, Helbig I, Metcalf CS, et al. Precision medicine for
genetic epilepsy on the horizon: recent advances, present challenges,
and suggestions for continued progress. Epilepsia 2022; 63: 2461–75.
79 Cani I, Pondrelli F, Licchetta L, et al. Epilepsy and inborn errors of
metabolism in adults: the diagnostic odyssey of a young woman with
medium-chain acyl-coenzyme A dehydrogenase deficiency.
Epilepsia Open 2022; 7: 810–16.
80 Peng J, Pang N, Wang Y, et al. Next-generation sequencing improves
treatment efficacy and reduces hospitalization in children with drug-
resistant epilepsy. CNS Neurosci Ther 2019; 25: 14–20.
12 www.thelancet.com/neurology Published online June 20, 2023 https://doi.org/10.1016/S1474-4422(23)00151-5
81 McKnight D, Morales A, Hatchell KE, et al. Genetic Testing to Inform
Epilepsy Treatment Management From an International Study of
Clinical Practice. JAMA Neurol 2022; 79: 1267–76.
82 Balestrini S, Chiarello D, Gogou M, et al. Real-life survey of pitfalls
and successes of precision medicine in genetic epilepsies.
J Neurol Neurosurg Psychiatry 2021; 92: 1044–52.
83 Klein P, Aboumatar S, Brandt C, et al. Long-term efficacy and safety
from an open-label extension of adjunctive cenobamate in patients
with uncontrolled focal seizures. Neurology 2022; 99: e989–98.
84 Guery D, Rheims S. Is the mechanism of action of antiseizure drugs
a key element in the choice of treatment? Fundam Clin Pharmacol
2021; 35: 552–63.
85 Treadwell JR, Kessler SK, Wu M, Abend NS, Massey SL, Tsou AY.
pharmacologic and dietary treatments for epilepsies in children
aged 1–36 months: a systematic review. Neurology 2023; 100: e16–27.
86 Ye F, Li XJ, Jiang WL, Sun HB, Liu J. Efficacy of and patient
compliance with a ketogenic diet in adults with intractable epilepsy:
a meta-analysis. J Clin Neurol 2015; 11: 26–31.
87 Touma L, Dansereau B, Chan AY, et al. Neurostimulation in people
with drug-resistant epilepsy: systematic review and meta-analysis
from the ILAE Surgical Therapies Commission. Epilepsia 2022;
63: 1314–29.
88 Luoni C, Bisulli F, Canevini MP, et al. Determinants of health-related
quality of life in pharmacoresistant epilepsy: results from a large
multicenter study of consecutively enrolled patients using validated
quantitative assessments. Epilepsia 2011; 52: 2181–91.
89 Mula M, Coleman H, Wilson SJ. Neuropsychiatric and cognitive
comorbidities in epilepsy. Continuum (Minneap Minn) 2022;
28: 457–82.
90 Asadi-Pooya AA, Beniczky S, Rubboli G, Sperling MR, Rampp S,
Perucca E. A pragmatic algorithm to select appropriate antiseizure
medications in patients with epilepsy. Epilepsia 2020; 61: 1668–77.
91 Hadady L, Klivényi P, Perucca E, et al. Web-based decision support
system for patient-tailored selection of antiseizure medication in
adolescents and adults: an external validation study. Eur J Neurol
2022; 29: 382–89.
92 Håkansson S, Zelano J. Big data analysis of ASM retention rates and
expert ASM algorithm: a comparative study. Epilepsia 2022;
63: 1553–62.
93 Hakeem H, Feng W, Chen Z, et al. Development and validation of a
deep learning model for predicting treatment response in patients
with newly diagnosed epilepsy. JAMA Neurol 2022; 79: 986–96.
94 de Jong J, Cutcutache I, Page M, et al. Towards realizing the vision of
precision medicine: AI based prediction of clinical drug response.
Brain 2021; 144: 1738–50.
95 Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new
antiepileptic drugs: a summary of the Sixteenth Eilat Conference on
New Antiepileptic Drugs and Devices (EILAT XVI): II. Drugs in more
advanced clinical development. Epilepsia 2022; 63: 2883–910.
96 Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new
antiepileptic drugs: a summary of the Sixteenth Eilat Conference on
New Antiepileptic Drugs And Devices (EILAT XVI): I. Drugs in
preclinical and early clinical development. Epilepsia 2022;
63: 2865–82.
97 Steriade C, French J. Tackling the unmet therapeutic needs in
nonsurgical treatments for epilepsy. JAMA Neurol 2022; 79: 1223–24.
98 Löscher W, Klein P. New approaches for developing multi-targeted
drug combinations for disease modification of complex brain
disorders. Does epilepsy prevention become a realistic goal?
Pharmacol Ther 2022; 229: 107934.
99 Vezzani A, Ravizza T, Bedner P, Aronica E, Steinhäuser C, Boison D.
Astrocytes in the initiation and progression of epilepsy.
Nat Rev Neurol 2022; 18: 707–22.
100 Cook M, Murphy M, Bulluss K, et al. Anti-seizure therapy with a
long-term, implanted intra-cerebroventricular delivery system for
drug-resistant epilepsy: a first-in-man study. EClinicalMedicine 2020;
22: 100326.
101 WHO. Draft intersectoral global action plan on epilepsy and other
neurological disorders 2022–2031. https://apps.who.int/gb/ebwha/
pdf_files/WHA75/A75_10Add4-en.pdf (accessed Feb 7, 2023).
Copyright © 2023 Elsevier Ltd. All rights reserved.