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Roughly 70-80% of adults with new onset epilepsy will References for this review were identified through searches
become seizure free with current antiepileptic drugs, of publications listed by PubMed and ScienceDirect from
although around half will experience adverse effects 1 January 1980 to 1 September 2013. We used the search
About 20-30% continue to have drug resistant epilepsy terms “epilepsy”, “treatment”, “antiepileptic drugs”,
with seizures, adverse effects, increased mortality, and “efficacy”, “effectiveness”, “antiepileptogenesis”,
substantial psychiatric and somatic comorbidities “antiepileptogenic drugs”, “disease modification”,
“adverse effects”, “antiepileptic drugs discovery”,
Newer antiepileptic drugs have brought more treatment
“antiepileptic drugs preclinical development”,
options and increased ease of use but do not reduce the
“antiepileptic drugs clinical development”, and “humans”.
frequency of drug resistant epilepsy or prevent epilepsy
References were also identified from relevant review
in those at risk
articles and through searches of the authors’ files. Only
There is an urgent need to revitalize the development of articles published in English were reviewed. We excluded
antiepileptic drugs to discover more effective drugs for articles published in non-peer reviewed journals. The final
the treatment of drug resistant epilepsy reference list was based on relevance to the topics covered
Antiepileptogenic compounds that prevent epilepsy in the review. We included publications published between
before the first seizure in at risk patients are needed, 1983 and 2013, including meta-analyses. Publications of
as well as disease modifying drugs to control ongoing evidence classes I-IV were included because of the limited
severe epilepsy and its comorbidities evidence base on the drug treatment of epilepsy.19
they do not prevent or eliminate the substantial behavioral, Table 1 | Prognostic index from the Multicentre Study of Early
cognitive, and somatic comorbidities seen in many patients Epilepsy and Single Seizures trial* 20
with epilepsy.11 Prognostic index Summary score†
These life limiting currently unmet needs provide a Single seizure before presentation 0
roadmap for the development of more effective antiseizure Two or three seizures before presentation 1
drugs, as well as for disease modifying and antiepileptogenic Four or more seizures before presentation 2
drugs.9 12 13 In this review, we critically assess the current Add if present:
drug treatment of epilepsy in adults and briefly examine Neurologic disorder or deficit 1
prospects for tackling current unmet needs. Drug treatment Abnormal electroencephalogram 1
*Reproduced, with permission, from Lancet Neurology.20
in children with epilepsy is covered elsewhere.14 Non-drug †Low risk of recurrence=0; medium risk=1; high risk=2-4. Antiepileptic drugs
based treatments for epilepsy, such as epilepsy surgery, diets, should generally be considered for patients in the medium or high recurrence
and brain stimulation, are beyond the scope of this review. risk groups.
Presumed main
Drug* Approved use (FDA, EMA) Main uses Main limitations
mechanism of action
Potassium Generalized tonic-clonic Currently for adjunctive use only, not in wide use
GABA potentiation? Focal and generalized seizures
bromide (1857) seizures, myoclonic seizures anymore, sedative
First line drug (intravenous) for focal and Enzyme inducer, non-linear pharmacokinetics.
Phenytoin Partial and generalized
Na+ channel blocker generalized seizures with focal onset; Not useful for absence or myoclonic seizures; skin
(1938) convulsive seizures
similar efficacy to carbamazepine42 hypersensitivity
Fig 1 | Characteristics of widely used first generation antiepileptic drugs for the treatment of epilepsy9 27‑ 29
Presumed main
Drug* Approved use (FDA, EMA) Main uses Main limitations
mechanism of action
Convulsive disorders, status Intravenous use, no clinical hepatotoxicity, Currently for adjunctive use and
Diazepam (1963) GABA potentiation epilepticus, anxiety, alcohol no skin hypersensitivity, use for focal and emergency use only, sedative,
withdrawal generalized seizures substantial tolerance (loss of efficacy)
Multiple (for example, GABA First line drug (used intravenously) for
Partial and generalized
potentiation, glutamate focal and generalized seizures; none of the
convulsive seizures, absence Enzyme inhibitor, substantial
Valproate (1967) (NMDA) inhibition, sodium newer drugs has cuurently been shown to
seizures, migraine prophylaxis, teratogenicity, weight gain
channel and T-type calcium be more efficacious than valproate; no skin
bipolar disorder
channel blockade) hypersensitivity
Fig 2 | Characteristics of widely used second generation antiepileptic drugs for the treatment of epilepsy9 27‑ 29
generally higher. For example, in Ethiopia, a developing recurrence. It is justifiable to recommend treatment after the
country, the prevalence of epilepsy is as high as 29.5/1000 first seizure in patients at higher risk of recurrence because
(95% confidence interval 20.5/1000 to 40.9).15 17 such patients have a slightly better long term outcome with
early versus delayed treatment (table 2). Accordingly, the
When to start treatment new practical clinical definition of epilepsy proposed by the
The Multicentre Study of Early Epilepsy and Single Sei- International League Against Epilepsy (ILAE) includes cer-
zures trial shows that starting antiepileptic drugs after a tain patients after their first seizure. Such patients are those
first seizure reduces the risk of a second seizure compared with a probability of further seizures “similar to the gen-
with no treatment or delayed treatment.20 Immediate treat- eral recurrence risk (≥60%) after two unprovoked seizures,
ment increased the time to second seizure (hazard ratio 1.3, occurring over the next 10 years,” or, as in the previous
95% confidence interval 1.1 to 1.6) and first occurrence of definition, those patients who have had two unprovoked
a tonic-clonic seizure (1.5, 1.2 to 1.8). It also reduced the seizures more than 24 hours apart.21 One important con-
time to achieve two year remission of seizures (P=0.023).20 sequence of the revised definition of epilepsy is that all
Table 1 details factors that place patients at high risk for clinicians who encounter patients after a first seizure need
Presumed main
Drug* Approved use (FDA, EMA) Main uses Main limitations
mechanism of action
Multiple (GABA
Cognitive side effects, kidney stones,
potentiation, glutamate Partial and generalized convulsive
Topiramate First line drug for focal and generalized speech problems, weight loss. Not as
(AMPA) inhibition, sodium seizures, Lennox-Gastaut syndrome,
(1995) seizures. No clinical hepatotoxicity effective as carbamazepine for new
and calcium channel migraine prophylaxis
onset focal seizures
blockade)
Eslicarbazepine Use for focal and generalized seizures with Currently for adjunctive use only,
Na+ channel blocker Partial seizures
acetate (2009) focal onset enzyme inducer, hyponatremia
Perampanel Glutamate (AMPA) Use for focal and generalized seizures with Currently for adjunctive use only. Not
Partial seizures
(2012) antagonist focal onset useful for absence or myoclonic seizures
*Year in which the drug was first approved or marketed in the US or Europe.
AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptors; EMA=European Medicines Agency; FDA=US Food and Drug Administration;
GABA=γ-aminobutyric acid; GTCS=generalized tonic clonic seizures on awakening; SV2A=synaptic vesicle protein.
Fig 3 | Characteristics of widely used third generation antiepileptic drugs for the treatment of epilepsy9 27‑ 29
Phenytoin
Carbamazepine
Voltage gated Na+ channel Oxcarbazepine
Eslicarbazepine acetate
Lamotrigine
Lacosamide
Na+
K+ Zonisamide
Depolarization
KCNQ K+ channel
Retigabine
SV2A Levetiracetam
Vesicular release
Gabapentin a2δ-subunit of Ca2+ channel Ca2+
Pregabalin
Retigabine
Benzodiazepines
Ethosuximide Ethosuximide
Barbiturates
Fig 4 | Mechanisms of action of antiepileptic drugs, which act by diverse mechanisms, mainly involving modulation of voltage activated ion channels, potentiation of
GABA, and inhibition of glutamate.27 30 Approved antiepileptic drugs have effects on inhibitory (left hand side) and excitatory (right hand side) nerve terminals. The
antiepileptic efficacy in trials of most of these drugs as initial add-on does not differ greatly, indicating that seemingly similar antiseizure activity can be obtained by
mechanisms aimed at diverse targets. However, putative mechanisms of action were determined only after discovering the antiseizure effects; mechanism driven
drug discovery has been largely ignored.9 Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; GAT-1, sodium
dependent and chloride dependent GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A. Modified, with permission, from Nature Reviews Neurology.28
Class I evidence for the comparative efficacy and effec- withdrawal was 1.02 (0.74 to 1.41) for levetiracetam versus
tiveness of drugs for new onset epilepsy is limited.19 The extended release valproic acid and 0.84 (0.66 to 1.07) for
SANAD trial, a large randomized unblinded pragmatic levetiracetam versus controlled release carbamazepine.45
study of antiepileptic drug monotherapy in new onset For treatment of refractory partial epilepsy, taking into
epilepsy, showed similar efficacy of carbamazepine, account baseline risk, random effects meta-analysis was
lamotrigine, and oxcarbazepine, but a lower comparative used to derive pooled estimates of odds ratios and number
efficacy of gabapentin and topiramate, for treating focal needed to treat or number needed to harm (NNT/NNH).46
seizures.44 Time to 12 month remission was the primary Sixty two placebo controlled trials (12 902 patients) and
efficacy parameter. Compared with carbamazepine, the eight head to head randomized controlled trials (1370
hazard ratios (95% confidence interval) were 0.72 (0.58 to patients) were included. Pooled odds ratios for responder
0.89; P<0.05) for gabapentin, 0.81 (0.66 to 1.00; P<0.05) and withdrawal rates (versus placebo) were 3.00 (95%
for topiramate, 1.01 (0.83 to 1.22; P>0.05) for lamotrigine, confidence interval 2.63 to 3.41) and 1.48 (1.30 to 1.68),
and 0.92 (0.73 to 1.18; P>0.05) for oxcarbazepine. A hazard respectively. Indirect comparisons of responder rate based
ratio greater than one indicates that 12 month remission on relative measurements of treatment effect favored topira-
occurs more rapidly on that drug than with carbamaz- mate (1.52, 1.06 to 2.20) over all other antiepileptic drugs,
epine.44 whereas gabapentin (0.67, 0.46 to 0.97) and lacosamide
In another unblinded randomized study, levetiracetam (0.66, 0.48 to 0.92) were less efficacious, without signifi-
monotherapy was as effective as controlled release carba- cant heterogeneity. When analyses were based on absolute
mazepine for focal seizures or extended release valproic estimates (NNTs), topiramate and levetiracetam were more
acid/valproate for generalized seizures in patients with efficacious, with gabapentin and tiagabine being less effica-
new onset epilepsy.45 The hazard ratio for time to treatment cious. Withdrawal rates were higher with oxcarbazepine
(1.60, 1.12 to 2.29) and topiramate (1.68, 1.07 to 2.63), individual drugs given as monotherapy is limited to short term
and lower with gabapentin (0.65, 0.42 to 1.00) and lev- randomized controlled trials, which typically show a similar
etiracetam (0.62, 0.43 to 0.89). However, differences were proportion of patients with adverse effects when comparing
too small to make any conclusions about which new drugs newer drugs such as levetiracetam and zonisamide with car-
had superior effectiveness. The choice of drug for refractory bamazepine.33 48 In the SANAD trial, about 50% of patients
partial epilepsy should therefore be guided more by other reported at least one adverse effect from carbamazepine or
aspects, such as patient characteristics and pharmacoeco- valproic acid/valproate as well as from newer drugs, such as
nomics, than only by evidence from randomized trials.46 lamotrigine, gabapentin, oxcarbazepine, and topiramate.5 6
Figure 5 lists dosages and effective plasma concentra- There is thus no compelling evidence that these recently
tions of antiepileptic drugs for the treatment of epilepsy approved drugs are better tolerated than older ones.5 6 49 50
in adults. The incidence of many adverse events can be With regard to safety, valproic acid/valproate seems to be the
reduced by slow titration and avoiding high dosages. most teratogenic antiepileptic drug on the market,51 52 and
newer drugs, such as gabapentin and levetiracetam, cause
Tolerability and safety of drugs in new onset epilepsy fewer or no dermatological hypersensitivity reactions and do
Given the similar efficacy of many first line antiepileptic not induce or inhibit hepatic enzyme function.
drugs in new onset epilepsy, comparative tolerability and Pharmacogenomics may be helpful in selecting specific
safety become important considerations when selecting antiepileptic drugs.53 People of Asian descent who take
treatment. carbamazepine, lamotrigine, or phenytoin and carry the
Figure 6 provides an overview of the main tolerability and HLA-B*15:02 allele have a significantly increased risk of
safety considerations for currently available antiepileptic developing Stevens-Johnson syndrome or toxic epidermal
drugs. The evidence base for the comparative tolerability of necrolysis.54 In drug specific analysis, the carrier rate of
Oxcarbazepine 150 mg every 3-7 days 800-1800 bid, tid 7.5-20 (MHD)
Topiramate 25 mg for 1-2 weeks; beyond 100 mg, 25-50 mg/week 100-400 bid, tid NA
Valproate 500 mg every 3-7 days 600-1500 bid slow release 40-120
MHD=monohydroxy metabolite; NA=not applicable; PHB=phenobarbital; qd=once a day; bid=twice a day; tid=three times a day.
Fig 5 | Dosages and effective plasma concentrations of antiepileptic drugs for the treatment of epilepsy in adults26 47
Adverse effect CBZ CLB ESL ETS FBM GBP LCM LEV LTG OXC PGN PER PHB PHT TGB RTG TPM VPA VGB ZNS
Somnolence – – – – – –
Dizziness – – – – – – – –
Seizure aggravation – – – – – – – – – – –
Gastrointestinal – – – – – – – – – – – –
Hypersensitivity (SJS/
– – – – – – – – – –
TEN)
Rash – – – – – – – – – – – – – – – –
Encephalopathy
Depression
Behavioral problems
Psychotic episodes
Leukopenia
Aplastic anemia
Thrombocytopenia
Megaloblastic anemia
Pancreatitis
Liver failure
Nephrolithiasis
Osteoporosis
Hyponatremia
Weight gain
Weight loss
Cognition impaired
Teratogenicity
Retinal dysfunction
Fig 6 | Overview of adverse effects of individual antiepileptic drugs.9 26 29
HLA-B*15:02 was significantly higher in patients with car- as gabapentin, lamotrigine, and levetiracetam (fig 7).
bamazepine related Stevens-Johnson syndrome or toxic epi- The evidence on the potential adverse effects of long term
dermal necrolysis than in carbamazepine tolerant controls enzyme induction with antiepileptic drugs has been recently
(92.3% v 11.9%, P<0.005; odds ratio 89.2, 19.2 to 413.8). reviewed.60 Clinical problems can occur as a result of phar-
This was also true in patients with phenytoin related Ste- macokinetic interactions altering the serum concentration
vens-Johnson syndrome or toxic epidermal necrolysis com- and, possibly, the efficacy or the adverse effects of concur-
pared with phenytoin tolerant controls (46.7% v 20.0%, rently taken antiepileptic drugs and other drugs when the
P=0.045; 3.50, 1.10 to 11.18.55 Screening is therefore rec- inducer is introduced or withdrawn.60 Enzyme induction will
ommended before starting these drugs in patients with Han continue for as long as the patient takes the inducer and will
Chinese and South East Asian ancestry.56 affect future drugs that are prescribed. The enzyme inducing
With older antiepileptic drugs, drug interactions can effects of antiepileptic drugs therefore have implications for
greatly lower the efficacy of other drugs, including other the general health of people with epilepsy.
antiepileptic drugs when taken in combination; this is not Whether enzyme inducing antiepileptic drugs should still
a problem with newer non-enzyme inducing agents, such be used as first line treatment for newly diagnosed epilepsy
Lowers plasma concentrations of lamotrigine, tiagabine, and valproate; Plasma concentration increased by a variety of drugs, including erythromycin,
Carbamazepine
lowers efficacy of drugs for other disorders* propoxyphene, isoniazid, cimetidine, verapamil, diltiazem, and fluoxetine
Eslicarbazepine Lowers plasma concentrations and lower efficacy of other drugs* Plasma concentration reduced by enzyme inducers
Lamotrigine No relevant change Plasma concentration increased by valproate and reduced by enzyme inducers
Etiology
Epilepsy severity
Psychiatric comorbidities
Worsening epilepsy
patterns
Drug related factors
(For example, tolerance)
mTOR PATHWAY
Binding site Protein NRSF Immune functions
Macrophage Monocyte
NKCC1
Cation chloride co-transporters EPILEPSY TREATMENT
Neutrophil
K+
Na+ 2Cl-
2K+
TGFß
GABAA
receptor
Blood-brain barrier
Na/K
ATPase Tight junction
Pericyte
NKCC1 Mitochondrion Astrocyte
ATP Depolarizing
3Na+ end-foot process
CI- Lumen
Basal membrane
MONOAMINERGIC SYSTEM Endothelial cell
Comorbidities
Norepinephrine Dopamine
Attention Alertness DRUG COCKTAILS
Motivation Energy
Pleasure
System biology (network) approaches
Reward
Mood
when many non-inducing, equally effective, alternatives are tolerability to antiepileptic drugs. This can occur by
available is a point for discussion and further research. Sev- unnecessarily exceeding the recommended dosage for a
eral clinical scenarios require patients to be switched to a particular drug (fig 5) or through pharmacokinetic or phar-
non-enzyme inducing antiepileptic drug. Examples include macodynamic effects of other, including inappropriately
patients who need pharmacotherapy for cancer or those prescribed, drugs.62 Adverse effects and the patient’s per-
with other life threatening diseases treated with drugs that ceived risk of adverse effects or safety risks may compro-
are inducible by concurrent antiepileptic drug treatment. mise adherence to the prescribed dose. Poor adherence, in
People with epilepsy who are established on enzyme turn, may lower treatment efficacy, with potentially fatal
inducing antiepileptic drugs should be screened regularly results,63 and paradoxically cause heightened or prolonged
for associated long term problems, such as osteoporosis adverse effects by not allowing tolerance of adverse effects
and sexual dysfunction. The patient’s other care providers to develop.64
should be advised about the potential for harmful pharma- Target plasma concentrations are available for several
cokinetic interactions. Switching patients to non-enzyme antiepileptic drugs (fig 5) but are less useful for optimiz-
inducing drugs to avoid these interactions should be done ing dosages and dosing schedules than for monitoring
with caution, particularly if seizures are not fully controlled. the patient’s clinical course and adherence to therapy.26
For seizure-free patients, the risks and benefits of switching Except for phenytoin, for which monitoring is strongly rec-
need to be carefully weighed given the paucity of data on ommended, particularly at concentrations above 20 mg/L
comparative likelihood of seizure control. In all such situa- because of the non-linear saturation dose kinetics, moni-
tions, the benefits and risks of both courses of action should toring of plasma concentrations of other drugs is needed
be discussed with patients and their families.60 only to confirm suspected non-adherence or to evaluate
Finally, patients may be using over-the-counter dietary unexplained toxicity or uncontrolled seizures in individual
supplements or herbal preparations, some of which may cases.26 65 Even so, although therapeutic drug monitoring
interact with antiepileptic drugs—for example, Gingko may improve the benefit to risk ratio of treatment, there
biloba or St John’s wort can interact with hepatically metab- are many practical limitations,65 including latency in the
olized antiepileptic drugs.61 occurrence of adverse effects or seizures and constraints
in when the blood can be sampled, owing to travel time to
Optimizing drug regimens phlebotomy services. In addition, further work is needed
Iatrogenic overtreatment is a leading cause of poor to clarify the role of drug monitoring in improving seizure
Drug Dose
Levetiracetam, intravenous bolus Optimal dose not known, most often used: 2000-4000 mg
100-250 mg bolus over 20 s then further 50 mg boluses every 2-3 min until seizures are controlled. Then an
Thiopentone
infusion of 3-5 mg/kg/h to maintain burst suppression on electroencephalography
*May be repeated.
Fig 10 | Doses and routes of administration of drugs used to treat different stages of tonic-clonic status epilepticus. From the consensus document of the workshop
of European epileptologists106
control during pregnancy and identifying serum drug human epileptic foci.78 This is supported by the recent iden-
concentrations that may be considered safe for fetal expo- tification of several promising pathways and potential drug
sure.66 targets, with particularly interesting examples illustrated
in fig 10. More extensive discussion of individual targets is
Drug resistant epilepsy available elsewhere.9
Drug resistant epilepsy is one of the most important unmet No class I evidence has shown superior efficacy for any
needs in the daily management of epilepsy,11 and it provides particular antiepileptic drug with market authorization for
a challenge to our understanding of the mechanisms under- treating drug resistant epilepsy.11 In addition, there is no
lying drug resistance and how it can be overcome or avoided evidence that modern antiepileptic drugs have substan-
(fig 8). tially lowered the proportion of patients with drug resist-
Any patient in whom at least two trials of adequately ance.11 New add-on antiepileptic drugs are only moderately
selected and dosed antiepileptic drugs have not brought more effective than placebo. In a recent meta-analysis of 54
sustained remission fulfils the ILAE criteria for drug resist- randomized controlled add-on trials in 11 106 patients with
ant epilepsy.68 Many other definitions exist for different pur- refractory epilepsy, the benefit in efficacy between adding
poses.7 26 69 Epilepsy may also be considered drug resistant a new antiepileptic drug and adding placebo was only 6%
if treatment does not stop seizures for 12 months, for what- for freedom from seizures and 21% for a 50% reduction in
ever reason. By this wide definition, which is based on an seizure frequency.79 This suggests that better strategies for
influential hospital based observational study,7 and which finding more effective antiseizure drugs are needed for refrac-
is increasingly being used in the US, 36% of newly treated tory epilepsy.
patients have drug resistant seizures.7 However, if the defi-
nition of frequent and severe seizures despite optimal treat- Failure of the first drug to induce sustained seizure
ment is used, with alternative treatments such as surgery remission and drug resistant epilepsy
being included, only 5-10% of newly diagnosed patients There are two options for patients who continue to have
are estimated to have drug resistant seizures.70 A diagnosis seizures despite taking the first antiepileptic drug: an alter-
of absolute drug resistance may require failure of at least six native monotherapy (substitution) or combination therapy
antiepileptic drugs, because about 17% of patients become (add-on), which usually means adding a second drug to
seizure free when additional antiepileptic drugs are given, the current monotherapy.26 80 Randomized trials have not
even when two to five drugs have previously failed to control provided evidence of which strategy is best.81 82 Although
seizures.32 71 72 These data suggest that there is no room for substitution is preferable for patients with serious idiosyn-
complacency among physicians treating patients who have cratic side effects from the first drug, many physicians pre-
had persistent seizures over many years despite taking mul- fer add-on treatment with small increments in dose, mainly
tiple antiepileptic drugs. because it avoids the possibility of breakthrough seizures
The mechanisms underlying drug resistant epilepsy after discontinuation of the baseline drug.26 In addition,
are still not fully understood (fig 9).8 73 74 Current theories add-treatment has become easier to implement and main-
include the transporter hypothesis, the target hypothesis, tain with modern non-enzyme inducing drugs.60
the network hypothesis, the gene variant hypothesis, and For patients whose clinical course meets the study spe-
the intrinsic severity hypothesis.8 75 However, none of these cific definition of drug resistant epilepsy,68 relatively short
hypotheses can convincingly explain how drug resistance term randomized controlled trials show that the chance of
arises in human epilepsy,67 and a new synthesis or break- freedom from seizures declines with successive drug regi-
through in understanding is needed. Interestingly, a history mens, most markedly from the first to the third antiepileptic
of depression and a high frequency of seizures before treat- drug, especially in patients with localization related epilep-
ment onset have been associated with drug resistance.76 77 sies.32 In one representative observational study from an
These and other observations suggest that common neuro- epilepsy clinic, seizure-free rates decreased from 61.8% for
biological factors may underlie disease severity, psychiatric the first antiepileptic drug to 41.7% after one drug proved
comorbidity, and drug resistant epilepsy, although more ineffective.71 In patients who had no response to the first
work is clearly needed.67 drug, the proportion who subsequently became seizure free
Recent progress in our understanding of mechanisms was much smaller (11%) when treatment failed because of
involved in ictogenesis and epileptogenesis now permits lack of efficacy rather than intolerable side effects (41%) or
a shift towards target based validation studies in animal an idiosyncratic reaction (55%).7 Encouragingly, a longitu-
models of refractory epilepsy or epileptogenesis. Systems dinal observational study encompassing almost 40 years
biology approaches are a promising source for targets. Such of follow-up found that nearly four of five patients whose
approaches take advantage of newer high throughput tech- seizures were not initially controlled after two trials of suit-
nologies to profile large numbers and types of molecules by able antiepileptic drugs eventually entered remission for at
using functional genomics, transcriptomics, epigenomics, least one year, and half had at least a five year remission.83
proteomics, and metabolomics, enabling identification of Idiopathic or cryptogenic causes were the only significant
causal pathways from the myriad of competing hypotheses, predictor of entering remission in this study.
and thus assisting in defining candidate targets.78 Molecular
profiling of epileptic brain tissues from animal models and Treatment of special patient groups
humans also holds promise to identify new ictogenic and epi- One of the standards of good clinical care is to tailor the
leptogenic drug targets, and it might be possible to discover treatment of epilepsy on the basis of the patient’s individual
a final common pathway of genes consistently induced at needs.26
Women spina bifida, 12.7 (7.7 to 20.7); atrial septal defect, 2.5 (1.4
People with epilepsy, and particularly women, have a to 4.4); cleft palate, 5.2 (2.8 to 9.9); hypospadias, 4.8 (2.9
higher risk of bone fracture than the general population.84 to 8.1); polydactyly, 2.2 (1.0 to 4.5); and craniosynostosis,
This increased risk is secondary to epilepsy (that is, break- 6.8 (1.8 to 18.8).92 93
ing a bone during a seizure) and use of antiepileptic drugs, A recent guideline for treatment of women with epilepsy
especially enzyme inducing ones.60 85 These drugs indepen- also suggested that intrauterine exposure to valproate mono-
dently increased the risk of fracture in the Women’s Health therapy reduces cognitive outcomes for offspring, as has also
Initiative study,86 as well as in a Danish population based been suggested for phenytoin and phenobarbital.94 If clini-
case-control study and a Korean study.85 87 The Women’s cally possible, antiepileptic drugs known to be associated
Health Initiative determined the associations between the with congenital malformations, including valproate, as well
use of antiepileptic drugs and falls, fractures, and bone as combinations of antiepileptic drugs, should be avoided
mineral density over an average of 7.7 years of follow-up in during pregnancy, especially during the first trimester. Simi-
women aged 50-79 years in a longitudinal cohort analysis. larly, valproate, phenytoin, phenobarbital, and antiepileptic
After adjustment for covariates, use of antiepileptic drugs drug polytherapy should be avoided throughout pregnancy
was positively associated with total fractures (hazard ratio if clinically possible to prevent unfavorable cognitive out-
1.44, 1.30 to 1.61), all site specific fractures including the comes in offspring.94
hip (1.51, 1.05 to 2.17), clinical vertebral fractures (1.60, The risk of major congenital malformations seems to be
1.20 to 2.12), lower arm or wrist fractures (1.40, 1.11 to influenced not only by the specific antiepileptic drug but also
1.76), other clinical fractures (1.46, 1.29 to 1.65), and two by dose and other variables.95 96 The lowest malformation rate
or more falls (1.62, 1.50 to 1.74), and was not associated was seen in the International Registry of Antiepileptic Drugs
with baseline bone mineral density or changes in bone min- and Pregnancy (EURAP) with less than 300 mg per day of
eral density (P≥0.064 for all sites). Use of more than one lamotrigine and less than 400 mg per day of carbamazepine
antiepileptic drug and use of enzyme inducing antiepilep- compared with valproic acid and phenobarbital at all studied
tic drugs were significantly associated with total fractures doses, and with carbamazepine at doses greater than 400 mg
(1.55, 1.15 to 2.09 and 1.36, 1.09 to 1.69, respectively). per day.95 Folate supplementation (≥0.4 mg folic acid/day) is
The Women’s Health Initiative concluded that in clinical recommended during pregnancy because this lowers the risk
practice, postmenopausal women who use antiepileptic of cognitive teratogenicity in babies born to women with epi-
drugs should be considered at increased risk for fracture lepsy.96 Primidone and levetiracetam pass into breast milk in
and attention to fall prevention may be particularly impor- amounts that may be clinically important, unlike valproate,
tant in these women. Antiepileptic drugs, especially enzyme phenobarbital, phenytoin, and carbamazepine.96
inducing ones, have been shown to decrease bone mineral
density and alter bone metabolism. Induction of cytochrome Older people
P can accelerate the metabolism of vitamin D to polar inac- The change in pharmacokinetics and higher sensitivity to
tive metabolites.60 The use of risedronate plus calcium and adverse events of many antiepileptic drugs associated with
vitamin D has been shown to prevent the occurrence of new aging usually require more cautious selection of drugs and
fractures in male patients with a high risk of fractures.88 Fur- dosing in older people. Lower glomerular filtration rates
ther studies are needed to clarify the mechanisms by which should prompt reduced doses of renally excreted drugs.
enzyme inducing antiepileptic drugs have these effects on Changes in body fat, albumin, and cytochrome P450 also
bone and whether newer non-enzyme inducing drugs have occur, and oxcarbazepine related hyponatremia may be
advantages over enzyme inducing ones. more common.26 97 In addition, concomitant diseases,
such as hypertension, are common in this age group and
Pregnant women and neonates often require medication, increasing the possibility of drug
Although two of three women with epilepsy who become interactions with antiepileptic drugs. Therefore, mono-
pregnant remain seizure free throughout pregnancy, antie- therapy with a well tolerated antiepileptic drug that is not
pileptic drug dosages may need to be adjusted, particularly associated with drug interactions, such as gabapentin and
when seizures occur in the first trimester. Women prescribed lamotrigine,98 low dose topiramate,99 and levetiracetam (no
lamotrigine and possibly levetiracetam, topiramate, and class I evidence available), is preferable. Providers should
oxcarbazepine may also need dose adjustment to compen- be aware that adherence to antiepileptic drug regimens may
sate for the increased clearance of these drugs during preg- be more difficult in older people with cognitive decline.
nancy and to reduce the risk of breakthrough seizures.89‑91
Offspring of women with epilepsy who took an antiepi- Patients with comorbidities
leptic drug during pregnancy seem to have an increased risk Many disorders are more common in people with epilepsy
of being small for gestational age and having a one minute than in the general population, including cardiac, gastro-
Apgar score of less than 7.91 Many antiepileptic drugs are intestinal, and respiratory disorders; stroke; dementia; and
associated with major congenital malformations, and pre- migraine.100 Alzheimer’s disease and migraine are not only
scribers should routinely consult an updated package insert more common in patients with epilepsy but are also risk fac-
or patient information leaflet for the latest recommendations tors for the development of seizures, suggesting a bidirec-
of regulatory agencies. For example, the use of valproic acid tional association and shared disease mechanisms.100
monotherapy in the first trimester is associated with signifi- The lifetime community based prevalence of depression,
cantly increased risks for six of the 14 malformations under suicidal ideation, and generalized anxiety disorder is twice
consideration. The adjusted odds ratios were as follows: as high in patients with epilepsy than in the general popula-
tion.101 Depression and anxiety substantially affect quality of line reuptake inhibitors (SNRIs) have been assessed in
life and are associated with an increased suicide rate.102 The patients with intractable epilepsy in open label trials, and
psychiatric comorbidities of epilepsy may also manifest as fewer seizures were seen during treatment with the SSRIs
psychogenic non-epileptic seizures or panic attacks.103 Psy- fluoxetine or citalopram.103 The only exception among
chiatric comorbidities are associated with a worse response antidepressant drugs was bupropion, which caused more
to the treatment of the epilepsy, whether by drugs or surgery. seizures in patients with epilepsy.103 Taken together, these
Comorbid mood and anxiety disorders have also been asso- studies suggest that SSRIs and SNRIs may reduce seizures
ciated with more adverse effects when taking antiepileptic and depressive symptoms in patients with epilepsy and
drugs.77 depression, although further controlled trials are needed.
Before starting antidepressants in patients with epilepsy, it Work is also needed to evaluate anecdotal observations that
is important to look for possible iatrogenic causes of depres- SSRIs and SNRIs increase the number of seizures in patients
sion. Antiepileptic drugs such as phenobarbital, vigabatrin, with slow hepatic metabolism or when taken in overdose.103
topiramate, tiagabine, levetiracetam, and clobazam can Until then, SSRIs with minor pharmacokinetic interactions,
induce depressive symptoms in patients with epilepsy. Sev- such as escitalopram and citalopram, should be considered
eral second generation (carbamazepine and valproate) and as first line drugs, followed by sertraline. Fluoxetine and
third generation (lamotrigine and pregabalin) drugs are asso- paroxetine interfere with cytochrome P450, so their use
ciated with mood stabilizing properties, so discontinuation of may require antiepileptic drug dosages to be adjusted.10
one of these could precipitate depression.77 103 Patients with
both epileptic seizures and psychogenic non-epileptic sei- Patients with status epilepticus and prolonged acute
zures may benefit from reducing high doses of antiepileptic convulsive seizures
drugs or the number of drugs given, if possible.103 Tonic-clonic status epilepticus is associated with serious
Treatments for psychiatric disorders in patients with epi- morbidity and mortality, and treatment depends on seizure
lepsy are severely lacking. Current clinical experience sug- stage (fig 10).106 Unfortunately, this is a therapeutic area in
gests that carbamazepine, valproate, and lamotrigine cannot which there are few randomized trials, and their absence
counteract established depression in patients with epilepsy. has impeded definitive assessment of alternative therapeu-
Although pregabalin is approved for both epilepsy and gen- tic options, particularly in treatment of stage 2 and stage 3
eralized anxiety disorder, it is has not been comprehensively seizures. The regulatory agencies have not licensed drugs for
studied as treatment for patients with epilepsy and comorbid status epilepticus because of the lack of randomized stud-
psychiatric disorders. ies.106
The ability of antidepressants to counteract depression in In the first stage (early status epilepticus), buccal mida-
patients with epilepsy has not been properly studied.77 103 zolam has become an important out-of-hospital treatment
Only two double blind controlled trials have been reported. option. A randomized controlled trial showed that buccal
One small study showed that high dose amitriptyline was midazolam achieved seizure cessation in 8 min compared
superior to placebo against major depressive episodes.104 with 15 min for rectal diazepam (P<0.01). The rate of res-
Reassuringly, the other trial found that sertraline did not piratory depression did not differ between groups.107 In
increase seizure frequency or severity.105 Selective seroto- UK community practice, rectal diazepam and unlicensed
nin reuptake inhibitors (SSRIs) and selective noradrena- buccal midazolam are the two treatment options used for
acute epileptic seizures. In practice, outside the US rectal
Box 3 | Stopping antiepileptic drugs in patients in diazepam is rarely used, with unlicensed buccal midazolam
remission being widely recommended and prescribed by physicians.
High risk profile for seizure recurrence off antiepileptic More recently a licensed preparation of buccal midazolam
drugs106 has become available.108 In a double blind study of children
Being 16 years or older and adults with convulsions that had lasted for more than
Taking more than one antiepileptic drug five minutes, and who were still seizing when paramedics
Having seizures after starting drug treatment arrived, midazolam given by intramuscular autoinjector
History of generalized tonic-clonic seizures had equal efficacy to intravenous lorazepam, with com-
History of myoclonic seizures parable safety. The primary efficacy outcome in this study
Having an abnormal electroencephalogram in previous was absence of seizures on arrival at the emergency depart-
year ment, without emergency medical system rescue therapy.
When it may be safe to discontinue114 115 109
Patients treated with intramuscular midazolam were
Freedom from seizures for more than two years implies a more likely to have stopped seizing on arrival at the emer-
60% chance of persistent remission in certain epilepsy gency department and were less likely to be admitted to the
syndromes hospital or an intensive care unit.109
Favorable factors: In the second stage (established status epilepticus), pre-
––Control easily achieved on a low dose of one drug ferred treatment choices include intravenous valproate, lev-
––No previous unsuccessful attempts at withdrawal etiracetam, and lacosamide among the newer antiepileptic
––Normal neurological examination and drugs, as well as the older agents fosphenytoin, phenytoin,
electroencephalogram and phenobarbital (fig 8). In the third stage (refractory sta-
––Primary generalized epilepsy except juvenile myoclonic tus epilepticus), midazolam, thiopentone, and propofol are
epilepsy
available choices (fig 10). Further treatments such as vari-
––Benign syndromes
ous anesthetics and non-pharmacological treatments may
presumed cause of epilepsy? One possible explanation is cial for overall health or quality of life of patients,132 and
that most epilepsies do not develop from alterations in a nor does it satisfy the requirements for a driver’s license.133
single localized target; rather, they arise from complex alter- This policy has led to the approval of several new antiepi-
ations that result in a wide epileptic network in the brains leptic drugs without demonstrated superiority over older
of individual patients.125 Variability of network properties ones, and which have entered the market at higher prices.
and the extent of these networks may explain why even A concern with placebo controlled trials is the increasingly
complete resection does not guarantee cure, because only unpredictable and unexpectedly high placebo response
part of the potentially epileptogenic network may have been rates, which have been held responsible, at least in part,
removed.126 The development of antiepileptogenic drugs in for the failure of new antiepileptic drugs to show efficacy in
the future may improve cure rates for medical treatment, placebo controlled add-on trials.128 134 Another concern is
and the discovery of biomarkers to assess the extent of the that placebo use seems to be associated with an increased
epileptogenic network in an individual patient may offer a rate of sudden unexplained death in clinical trials.125
chance to improve surgical cure rates. Clinical features such as a history of epilepsy surgery or
There is no proof that antiepileptic drug withdrawal itself lifetime exposure to seven or more antiepileptic drugs are
negatively affects long term seizure outcomes in patients associated with a low placebo response,135 136 which may
who have become seizure free under drug treatment or after maximize the treatment effect of the experimental antiepi-
epilepsy surgery. Discontinuation of drugs merely unveils leptic drug versus placebo. However, limiting clinical trials to
the natural course of the epileptic disorder in medically patients with these clinical features may restrict the generaliz-
treated patients and unmasks true postoperative outcome. ability of the findings. If variations of placebo mechanisms
Given the available evidence, the risk of relapse is prob- are left uncontrolled, it will be more difficult to document any
ably determined more by the clinical characteristics of the specific effects of a drug. Novel clinical trial designs for the
epilepsy syndrome or failure of the surgical procedure to development of antiepileptic drugs that de-emphasize the use
eliminate relevant epileptogenic brain networks than by of placebo controls have recently been proposed.9 131 A further
antiepileptic drug withdrawal and its timing. concern is that current trial designs do not take into account
the heterogeneity of the causes and severity of disease in trial
Emerging treatments participants with drug resistant epilepsy. Although clinical
Novel approaches to the development of new drugs are features such as lifetime exposure to an increasing number
emerging.9 These offer hope of finding more effective of antiepileptic drugs seem to be associated with a decreased
antiseizure drugs to treat ongoing drug resistant epilepsy, likelihood of eventual remission in patients with new onset
antiepileptogenic agents to prevent symptomatic or genetic epilepsy,7 32 71 83 current trial designs do not stratify patients
epilepsy before the first seizure, and disease modifying on the basis of the severity of disease as measured by the total
agents to mitigate established epilepsy. Our understanding number of antiepileptic drugs they have taken, for example.
of the mechanisms mediating the development of epilepsy, This needs more attention and, if confirmed, may render a
the causes of drug resistance, and the emerging role of phar- comparison of efficacy results between trials with individual
macogenetics for drug discovery have grown substantially antiepileptic drugs more difficult.
over the past decade.9 127 Finally, new strategies are being
explored, such as joint endeavors between academia and Conclusions
industry, identification and application of tools for new Most patients will achieve lasting remission of seizures on
target driven and systems biology based approaches, and generally well tolerated antiseizure drug treatment, and
comparative preclinical proof-of-concept studies and inno- the availability of many new antiepileptic drugs over the
vative clinical trials designs.9 past three decades has brought more treatment options. Yet
about 20-30% of patients continue to experience seizures
Barriers to the development of new drugs for drug despite all available drug options, and even more are at high
resistant epilepsy risk of neuropsychiatric comorbidities.
Reliance on established animal models that were used New drugs with fewer side effects and better efficacy
to bring previous antiepileptic drugs to the market as the than the currently available ones are urgently needed.
preferred method to test experimental compounds as well Antiepileptogenic and disease modifying agents are also
as clinically inadequate trial designs in humans are road- needed. Because many large drug companies have stopped
blocks in the development of more effective antiepileptic innovating in this therapeutic area, it is becoming increas-
drugs for drug resistant epilepsy.11 Novel preclinical and ingly important for foundations and government agencies
clinical approaches for the discovery and development of to fund the discovery of new antiepileptic drugs, and to do
drugs with more effective antiseizure activity have recently so at a level commensurate with the substantial prevalence
been suggested.9 28 128 Potential targets for future drug dis- and costs of drug resistant epilepsy.
covery and development have been proposed (fig 10). Contributors: DS wrote an early version of most sections of the manuscript and
The currently accepted minimum measure for efficacy revised the manuscript. SCS edited early and revised versions of the manuscript,
in randomized controlled trials is a statistical difference contributed as author to sections of the manuscript, and is guarantor.
between the placebo arm and the treatment arm in the pro- Competing interests: We have read and understood the BMJ Group policy
on declaration of interests and declare the following interests: DS has
portion of patients showing at least a 50% reduction in sei- received hospitality and consulting fees in the past two years from Eisai,
zure frequency versus the baseline period.11 129‑ 131 This bar Sun, UCB, and Viropharma. None of the companies has had any input to the
is disappointingly low from a clinical perspective because manuscript. SCS: none declared.
50% seizure reduction has not been shown to be benefi- Provenance and peer review: Commissioned; externally peer reviewed.
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