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Drug treatment of epilepsy in adults

Article in BMJ (online) · February 2014


DOI: 10.1136/bmj.g254 · Source: PubMed

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S TAT E O F T H E A RT R E V I E W

Drug treatment of epilepsy in adults


Dieter Schmidt,1 Steven C Schachter2
1
Epilepsy Research Group,
Goethestr. 5, 14163 Berlin, A B S T RAC T
Germany
2
Epilepsy is a serious, potentially life shortening brain disorder, the symptoms of which can be
Departments of Neurology, Beth
Israel Deaconess Medical Center, successfully treated in most patients with one or more antiepileptic drug. About two in three adults with
Massachusetts General Hospital new onset epilepsy will achieve lasting seizure remission on or off these drugs, although around half
and Harvard Medical School,
Boston, MA, USA will experience mild to moderately severe adverse effects. Patients with epilepsy, especially the 20-30%
Correspondence to: D Schmidt whose seizures are not fully controlled with available drugs (drug resistant epilepsy), have a significantly
dbschmidt@t-online.de
increased risk of death, as well as psychiatric and somatic comorbidities, and adverse effects from
Cite this as: BMJ 2014;348:g2546
doi: 10.1136/bmj.g254 antiepileptic drugs. Newer drugs have brought more treatment options, and some such as levetiracetam
cause fewer drug interactions and less hypersensitivity than older ones. However, they do not reduce
the prevalence of drug resistant epilepsy or prevent the development of epilepsy in patients at high risk,
such as those with a traumatic brain injury. The development of antiepileptic drugs urgently needs to be
revitalized so that we can discover more effective antiseizure drugs for the treatment of drug resistant
epilepsy, including catastrophic forms. Antiepileptogenic agents to prevent epilepsy before the first
seizure in at risk patients and disease modifying agents to control ongoing severe epilepsy associated
with progressive underlying disease are also needed.

Introduction Treatment is empirical and often based on trial and error.


Epilepsy is a heterogeneous and serious brain disorder Seizures are widely recognized as the clinical hallmark of
with multifactorial origins and manifestations. It com- epilepsy, but epileptogenesis—the disease process by which
prises many seizure types and epilepsy syndromes,1 some epilepsy develops after brain insults or as a result of gene
of which are life shortening.2 Although 70-80% of patients mutations—begins before the first seizure and probably
with new onset epilepsy have complete seizure control continues after the onset of seizures.8  9 Although current
with current antiepileptic drugs,3  4 unmet treatment antiepileptic drugs achieve symptomatic seizure relief,
needs remain. About half of patients report at least one which is why they are more appropriately called antiseizure
adverse effect during treatment with first line antiepilep- drugs, they do not prevent or reverse the pathological pro-
tic drugs.5  6 Drug resistant epilepsy occurs in 20-30% of cess that underlies human epilepsy or other clinical mani-
patients newly diagnosed with epilepsy, depending on the festations of epilepsy, such as the comorbidity of epilepsy.
definition used.7 Long term observations have shown that They therefore do not prevent the development of epilepsy,
14% of patients with new onset childhood epilepsy who even in patients at high risk (for example, after brain injury
remain in remission for many years will develop refractory or craniotomy),10 and nor do they exert disease modifying
epilepsy while still being treated with antiepileptic drugs.4 effects that prevent or reverse drug resistant epilepsy. Also,

S U M M A RY P O I N T S SOURCES AND SELECTION CRITERIA

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

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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.

Epidemiology of epilepsy varies by population. In developed countries,


Worldwide about 65 million people have epilepsy,15 making the annual incidence of epilepsy is nearly 50 per 100 000
it the most common neurological disorder after stroke and a population and prevalence is around 700 per 100 000.18
major burden for public health systems.16  17 The prevalence In low and middle income countries, such estimates are

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

Partial and generalized Focal and generalized seizures


Enzyme inducer, not useful in absence seizures, skin
Phenobarbital convulsive seizures, (intravenous); most cost effective
GABA potentiation hypersensitivity. Less effective than carbamazepine or
(1912) sedation, anxiety disorders, treatment for epilepsy, particularly in low
phenytoin for focal seizures in mostly new onset epilepsy
sleep disorders resource countries

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

Enzyme inducer, not useful in absence seizures, sedative,


Primidone Partial and generalized
GABA potentiation Focal and generalized seizures skin hypersensitivity. Less effective than carbamazepine
(1954) convulsive seizures
or phenytoin for focal seizures in new onset epilepsy

First line antiepileptic drug, no skin


Ethosuximide T-type Ca2+ channel hypersensitivity. Use for absence Gastrointestinal adverse effects, insomnia, psychotic
Absence seizures
(1958) blocker seizures only. As effective as valproate episodes
for new onset absence seizures
*Year in which the drug was first approved or marketed in the US or Europe.
EMA=European Medicines Agency; FDA= US Food and Drug Administration; GABA=γ-aminobutyric acid.

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)

First line drug for focal and generalized seizures


Partial and generalized Enzyme inducer, not useful for
Carbamazepine with focal onset; none of the newer drugs has
Na+ channel blockade convulsive seizures, trigeminal absence or myoclonic seizures, skin
(1964) currently been shown to be more efficacious
pain, bipolar disorder hypersensitivity
than carbamazepine

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

Lennox-Gastaut syndrome, Currently for adjunctive use only,


Clonazepam No clinical hepatotoxicity, use for focal and
GABA potentiation myoclonic seizures, panic sedative, substantial tolerance (loss of
(1968) generalized seizures
disorders efficacy)

Currently for adjunctive use only,


Lennox-Gastaut syndrome, No clinical hepatotoxicity. Use for focal and
Clobazam (1975) GABA potentiation sedative, substantial tolerance (loss of
anxiety disorders generalized seizures
efficacy)
*Year in which the drug was first approved or marketed in the US or Europe.
EMA=European Medicines Agency; FDA=US Food and Drug Administration; GABA=γ-aminobutyric acid; NMDA=N-methyl-D-aspartate subtype of glutamate receptors.

Fig 2 | Characteristics of widely used second generation antiepileptic drugs for the treatment of epilepsy9  27‑ 29

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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

Not useful for absence or myoclonic


Infantile spasms, complex partial No clinical hepatotoxicity. Use for infantile
Vigabatrin seizures. Causes a visual field defect
GABA potentiation seizures (currently for adjunctive spasms, focal and generalized seizures with
(1989) and weight gain. Not as efficacious as
use only) focal onset
carbamazepine for focal seizures

Partial and generalized convulsive Enzyme inducer, skin hypersensitivity.


Lamotrigine First line drug for focal and generalized
Na+ channel blocker seizures, Lennox-Gastaut syndrome, Not as effective as valproate for new
(1990) seizures
bipolar disorder onset absence seizures

Enzyme inducer, hyponatremia, skin


Oxcarbazepine First line drug for focal and generalized
Na+ channel blocker Partial seizures hypersensitivity. Not useful for absence
(1990) seizures with focal onset
or myoclonic seizures

Currently for adjunctive use only. Not


Partial and generalized convulsive useful for absence or myoclonic seizures
Gabapentin Ca2+ blocker (α2δ No clinical hepatotoxicity. Use for focal and
seizures, postherpetic and diabetic and can cause weight gain. Not as
(1993) subunit) generalized seizures with focal onset
neuralgia, restless leg syndrome effective as carbamazepine for new
onset focal seizures

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)

First line drug (intravenous) for focal


Partial and generalized convulsive and generalized seizures with focal
Levetiracetam Not useful for absence or myoclonic
SV2A modulation seizures, partial seizures, GTCS, onset and myoclonic seizures. No
(2000) seizures. Psychiatric side effects
juvenile myoclonic epilepsy clinical hepatotoxicity. As efficacious as
carbamazepine for new onset focal seizures

First line drug for focal and generalized


Zonisamide seizures. No clinical hepatotoxicity. Non- Cognitive side effects, kidney stones,
Na+ channel blocker Partial seizures
(2000) inferior to carbamazepine for new onset sedative, weight loss
focal seizures

Stiripentol GABA potentiation, Na+ Use for seizures in Dravet syndrome. No


Dravet syndrome Currently for adjunctive use only
(2002) channel blocker clinical hepatotoxicity

Partial seizures, neuropathic pain, Currently for adjunctive use only,


Pregabalin Ca2+ blocker (α2δ Use for focal and generalized seizures with
generalized anxiety disorder, not useful for absence or myoclonic
(2004) subunit) focal onset. No clinical hepatotoxicity
fibromyalgia seizures, weight gain

Rufinamide Use for seizures in Lennox-Gastaut


Na+ channel blockade Lennox-Gastaut syndrome Currently for adjunctive use only
(2004) syndrome. No clinical hepatotoxicity

Enhanced slow Use (intravenous) for focal and generalized


Lacosamide
inactivation of voltage Partial seizures seizures with focal onset. No clinical Currently for adjunctive use only
(2008)
gated Na+ channels hepatotoxicity

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

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to be familiar with the varied clinical presentations of sei-


Box 1 | Disease burden and treatment gap
zures, especially those that are non-convulsive, as well as
The global burden from epilepsy as measured by disability adjusted life years increased by
the appropriate investigations to determine the underlying
30% between 1990 and 2010.35 In 2010, the disease burden from epilepsy was higher than
that for Alzheimer’s disease and other dementias, multiple sclerosis, and Parkinson’s disease cause.22
combined.35 For patients diagnosed as having epilepsy,22 treatment
The often substantial comorbidity of epilepsy includes injury and drowning, depression and with an antiepileptic drug is usually recommended, espe-
anxiety associated with high suicide rates, and mortality three times the rate expected in the cially if further seizures might cause serious morbidity or
general population, including sudden unexplained death in epilepsy (SUDEP).36 Estimates mortality. Underlying this standard recommendation is a
indicate that most people with epilepsy in developing countries live in rural and remote areas 73% risk of seizure recurrence (95% confidence interval
and have no easy access to skilled medical care.37  38 The difference between the number of
59% to 87%) within four years of two unprovoked sei-
people with active epilepsy and the number who are being appropriately treated in a given
zures.23 The risk of a third seizure is nearly twice as high
population at a given point in time is known as the treatment gap.37
Epilepsy imposes a large economic burden on patients and their families, particularly in rural in patients whose seizures have a known cause as in those
and remote regions and the developing world.37 Throughout the world, epilepsy imposes an with idiopathic or cryptogenic seizures,23 as defined by
additional hidden burden associated with stigmatization and discrimination against patients the ILAE.24 Nevertheless, no randomized controlled trials
and their families in the community, workplace, school, and home. Social isolation, emotional have been performed in unselected patients who have had
distress, dependence on family, poor employment opportunities, and personal injury add two or more seizures, and the size of the treatment effect of
to the suffering of people with epilepsy.38 Because of the seriousness of the disorder and antiepileptic drugs is currently unknown.25 If the diagnosis
its psychosocial dimensions, it is worrying that epilepsy is often suboptimally diagnosed
of epilepsy is uncertain, it may be best not to start antiepi-
and managed, even in developed countries, and especially among certain socioeconomic
groups.11  39 leptic drugs but to undertake further evaluations, such as
electroencephalography monitoring, or adopt a watch and
How to close the treatment gap
The Global Campaign Against Epilepsy, which is jointly sponsored by the World Health
wait approach.26
Organization, ILAE, and International Bureau for Epilepsy, advocates using phenobarbital to
close the high treatment gap in low income countries.40 The suggested first step is for all patients Selecting the first antiepileptic drug
with epilepsy to be given phenobarbital, which will control seizures in most of them. In resource Ideally, antiepileptic drugs should fully control seizures,
poor countries, phenobarbital can cost as little as $5 (£3; €3.7) to $10 a year. Phenobarbital be well tolerated with no long term safety problems (such
has an extremely low potential for misuse.41 Its use in developed countries has been limited as teratogenicity, hypersensitivity reactions, or organ tox-
by a comparative trial that showed that phenobarbital and primidone (which is metabolized icity), and be easy for clinicians to prescribe and patients
to phenobarbital) were less well tolerated than phenytoin or carbamazepine.42 This finding is
to take (once or twice daily, no drug interactions, and no
less relevant for resource poor countries when the only choice is between phenobarbital or no
treatment at all. The side effects of phenobarbital—mainly sedation, possible mild cognitive need for serum monitoring).26 The introduction of more
impairment, and depression—can be minimized by using the lowest possible effective dose.41 than 15 antiepileptic drugs since the 1980s has provided
Thus, phenobarbital is the current drug of choice for large scale, community based programs, more choice but has made it more difficult, even for epi-
particularly in rural and remote areas of developing countries.41 Despite the availability of lepsy specialists, to select the optimum drug for individual
phenobarbital for more than 90 years and its modest cost, the treatment gap for epilepsy still patients because each drug has its advantages and limita-
exceeds 90% in many developing countries.41 tions (figs 1-4).

Effectiveness in new onset epilepsy


Box 2 | Preferred first line antiepileptic drugs for new onset and refractory epilepsy in
adults26 43 Most patients with newly diagnosed epilepsy have a con-
All drugs that are regarded as first line for new onset cases are also considered for patients
stant course that can be predicted early on.31  32 About 50%
with refractory epilepsy because they differ from one another in their pharmacological profile. of patients with new onset focal or generalized seizures,
as internationally defined,24 become seizure free while
New onset partial epilepsies
Carbamazepine taking the first appropriately selected and dosed first line
Gabapentin antiepileptic drug (assuming that patients have access to
Lamotrigine healthcare resources; box 1).4  7  33  34
Levetiracetam The current evidence base of comparative efficacy among
Oxcarbazepine first line antiepileptic drugs is limited to a surprisingly few
Topiramate class I trials (box 2).
Valproate
New onset idiopathic generalized epilepsies Table 2 | Estimates of seizure recurrence risk from the
Lamotrigine Multicentre Study of Early Epilepsy and Single Seizures trial*
Topiramate 1 year probability 3 year probability 5 year probability
Treatment of recurrence (%) of recurrence (%) of recurrence (%)
Valproate
Low risk:
Refractory partial epilepsy Early start 26 35 39
Lacosamide Delayed start 19 28 30
Pregabalin Medium risk:
Zonisamide Early start 24 35 39
Perampanel Delayed start 35 50 56
Clobazam High risk:
Refractory idiopathic generalized epilepsies Early start 36 46 50
Clobazam Delayed start 59 67 73
Levetiracetam *Modified, with permission, from Lancet Neurology.20
All results were significantly different

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RESPONSE TO ANTIEPILEPTIC DRUGS

Propagated action potential

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

Inhibits also glial GAT-1


Tiagabine GAT-1
Glutamate
GABA

Retigabine

Benzodiazepines
Ethosuximide Ethosuximide
Barbiturates

Postsynaptic neuron GABA A receptor AMPA KCNQ T-type Ca2+ channel


CI- receptor K+ channel
NA+ Ca2+

Inhibitory synapse Excitatory synapse

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

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(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

Suggested range of average target dose Target plasma


Drug Suggested titration of daily dose
(total mg/day; frequency of dosing) concentration (mg/L)

Carbamazepine 200-400 mg every 7 days 600-1200 bid or tid 3-12

Clobazam 10 mg/day 10-60 mg bid or qd NA

Eslicarbazepine 400 mg every 3-7 days 800-1200 qd NA

Felbamate 300 mg every 7 days 2400-3600 bid, tid 20-45

Gabapentin 300 mg every 1-3 days 900-3600 bid, tid NA

Lacosamide 100 mg every 3-7 days 400-600 bid NA

Monotherapy: 25 mg for 2 weeks, 50 mg for the next 2 weeks, then increases of


50-100 mg/week; add-on in the presence of valproate: 25 mg every other day for
Lamotrigine 2 weeks, 25 mg/day for the next 2 weeks, then increases of 25-50 mg/week; add- 100-400 qd, bid 2-15
on in the presence of enzyme inducing drugs: 50 mg for 2 weeks, 100 mg for the
next 2 weeks, then increases of 50-100 mg/week

Levetiracetam 500 mg every 1-3 days 1000-3000 bid NA

Oxcarbazepine 150 mg every 3-7 days 800-1800 bid, tid 7.5-20 (MHD)

Phenobarbital 50 mg every 7 days 50-200 qd, bid 10-40

200-300 bid, tid, qd for extended release


Phenytoin 50-100 mg every 3-5 days; beyond 200 mg in 25-30 mg steps 5-25
availability

Perampanel 2 mg every 3-7 days 8-12 qd NA

Pregabalin 75-150 mg every 3-7 days 150-600 bid, tid NA

Primidone 62.5-250 mg every 7 days 500-750 bid, tid 10-40 (PHB)

Retigabine 100 mg/day increased by 150 mg/day 900-1200 bid, tid NA

Tiagabine 6 mg every 5-7 days 36-60 bid, tid NA

Topiramate 25 mg for 1-2 weeks; beyond 100 mg, 25-50 mg/week 100-400 bid, tid NA

Vigabatrin 500 mg every 7 days 500-3000 bid NA

Valproate 500 mg every 3-7 days 600-1500 bid slow release 40-120

Zonisamide 100 mg every 3-7 days 200-600 bid, tid NA

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

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Adverse effect CBZ CLB ESL ETS FBM GBP LCM LEV LTG OXC PGN PER PHB PHT TGB RTG TPM VPA VGB ZNS

EARLY ONSET ADVERSE EVENTS

Somnolence – – – – – –

Dizziness – – – – – – – –

Seizure aggravation – – – – – – – – – – –

Gastrointestinal – – – – – – – – – – – –

Hypersensitivity (SJS/
– – – – – – – – – –
TEN)

Rash – – – – – – – – – – – – – – – –

LATE ONSET ADVERSE EVENTS

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

CLB=clobazam; CBZ=carbamazepine; ESL=eslicarbazepine; ETS=ethosuximide; FBM=felbamate; GBP=gabapentin; LEV=levetiracetam; LCM=lacosamide; LTG=lamotrigine;


OXC=oxcarbazepine; PER=perampanel; PGB=pregabalin; PHB=phenobarbital; PHT=phenytoin; PRM=primidone; RTG=retigabine; ; TPM=topiramate; VPA=valproate; VGB=vigabatrin;
ZNS=zonisamide; SJS/TEN=Stevens-Johnson syndrome or toxic epidermal necrolysis. Key: – no increase, low risk, medium risk, high risk

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

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Clinically relevant interactions when added to other drugs including


Drug Clinically relevant interactions when other drugs are added
antiepileptic drugs

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

Clobazam No relevant change No relevant change

Eslicarbazepine Lowers plasma concentrations and lower efficacy of other drugs* Plasma concentration reduced by enzyme inducers

Ethosuximide Uncertain Plasma concentration reduced by enzyme inducers

Increases plasma concentrations of valproate, phenytoin, phenobarbital,


Felbamate Plasma concentration reduced by enzyme inducers
carbamazepine epoxide

Gabapentin No relevant change No relevant change

Lacosamide No relevant change Plasma concentration reduced by enzyme inducers

Lamotrigine No relevant change Plasma concentration increased by valproate and reduced by enzyme inducers

Levetiracetam No relevant change No relevant change

Lowers plasma concentrations of lamotrigine, phenytoin, tiagabine, and


Oxcarbazepine valproate; lowers efficacy of drugs for other disorders* at doses of >900 mg Plasma concentration reduced by enzyme inducers
oxcarbazepine

Perampanel No relevant change Plasma concentration reduced by enzyme inducers

Lower plasma concentrations of lamotrigine, oxcarbazepine, phenytoin,


Phenobarbital Plasma concentration increased by valproate and felbamate
tiagabine, and valproate; lowers efficacy of drugs for other disorders*

Lower plasma concentrations of lamotrigine, tiagabine, and valproate; lowers


Phenytoin† Valproate competes for protein binding
efficacy of drugs for other disorders*

Pregabalin No relevant change No relevant change

Lower plasma concentrations of lamotrigine, oxcarbazepine, phenytoin,


Primidone Plasma concentration reduced by enzyme inducers
tiagabine, valproate, and others; lowers efficacy of drugs for other disorders*

Retigabine No relevant change No relevant change

Topiramate No relevant change Plasma concentration reduced by enzyme inducers

Higher toxicity of phenytoin, phenobarbital, and primidone (which is mainly


Valproate Plasma concentration reduced by enzyme inducers
metabolized to phenobarbital)

Vigabatrin No relevant change No relevant change

Zonisamide No relevant change Plasma concentration reduced by enzyme inducers

*Inducers of cytochrome P450 system. †Need to monitor serum concentrations.


Fig 7 | Summary of drug interaction properties of common antiepileptic drugs.56‑59 *Inducers of cytochrome P 450 enzyme system. †Need to monitor serum concentrations

Etiology
Epilepsy severity

Psychiatric comorbidities

Worsening epilepsy
patterns
Drug related factors
(For example, tolerance)

Morphological (network) RESPONSE TO ANTIEPILEPTIC DRUGS


alterations Alterations in glial
functions

Drug-target alterations Inflammatory processes

Alterations in drug efflux Genetic factors


transporters

Fig 8 | Possible determinants of antiepileptic drug resistance in human and


experimental epilepsies.67 Modified, with permission, from Nature Reviews9

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Fig 9 | E xamples of novel targets that are particularly interesting


Inflammatory pathways
Free pathogen for development of antiseizure or antiepileptogenic drugs.
clearence by Modified, with permission, from Nature Reviews.9 GABA A=γ-
specific antibody
aminobutyric acid type A; NKCC1=bumetanide sensitive
sodium-(potassium)-chloride cotransporter 1; MHC=major
Antibody Cytokines histocompatibility complex; NRF2=nuclear factor erythroid
Whole 2 related factor 2; NRSF=neurone restrictive silencer factor;
antigen TGFβ=transforming growth factor β; VLA4=very late antigen 4
(α4β1 integrin)
CD4
helper
T cell CD8
B cell
cytotoxic Infected cells display foreign
T cell epitope on their surface
CD4 T cell
helper
Cell death
T cell Mechanisms of drug resistance
Foreign/ Antigen specific T cell receptor
self antigen Efflux
MHC-antigen complex
Antigen GABAA receptor
presenting
cell

INTERLEUKIN-1ß TOLL-LIKE RECEPTOR 4 VLA4 (α4ß1 INTEGRIN)


ATP
ATP
CI-
Transcription factors Drug

Transcription factor NRF2


Regulation AED TARGETS, TRANSPORTERS, AND OTHERS
Gene
ACAGTGA

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

Anxiety Modeling and computation


Network biology
Serotonin Predictive models
Obsessions Data mining
and compulsions Graph theory
Simulation
Biological applications
Intercellular signaling
Experimental approaches Cell cycle
DNA microarrays Brain slices
Proteomics Epilepsy models
Real-time mass spectrometry
Microfluidics

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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

FIRST STAGE: EARLY STATUS EPILEPTICUS

Diazepam, intravenous bolus (not exceeding 2-5 mg/min) 10-20 mg

Diazepam, rectal administration 10-30 mg

Clonazepam, intravenous bolus (not exceeding 2 mg/min) 1-2 mg at 2 mg/min*

Lorazepam, intravenous bolus 0.007 mg/kg (usually 4 mg)*

Midazolam, buccal or intranasal 5-10 mg* intravenous

SECOND STAGE: ESTABLISHED STATUS EPILEPTICUS

Fosphenytoin, intravenous bolus (not exceeding 100 mg phenytoin


Loading dose: 15-20 mg phenytoin equivalents/kg, no faster than 100-150 mg phenytoin equivalents/min
equivalents/min)

Levetiracetam, intravenous bolus Optimal dose not known, most often used: 2000-4000 mg

Phenytoin, intravenous bolus/infusion (not exceeding 50 mg/min) 15-20 mg/kg at 25 mg/min

Phenobarbital, intravenous bolus (not exceeding 100 mg/min) 10-20 mg/kg

Valproate, intravenous bolus 15-30 mg/kg

THIRD STAGE: REFRACTORY STATUS EPILEPTICUS

Midazolam 0.1-0.3 mg/kg at 4 mg/min bolus followed by infusion of 0.05-0.4 mg/kg/h

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

2 mg/kg bolus followed by an infusion of 5–10 mg/kg/h to maintain burst suppression on


Propofol
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

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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

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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-

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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

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cure.119 It has long been recommended that antiepileptic


AREAS FOR FUTURE RESEARCH
drugs are continued for at least one or two years after surgery,
To identify: largely on the basis of antiepileptic drug withdrawal policies
Molecular targets that may lead to the discovery of novel in non-surgical cohorts. Furthermore, it was suggested that
drugs to treat drug resistant epilepsy after successful epilepsy surgery, duotherapy is preferable to
The cellular mechanisms that trigger epileptogenesis after monotherapy to maintain seizure control.120 This raises the
brain insults question of whether it is justifiable to discontinue antiepilep-
The cellular mechanisms that lead to seizure remission tic drugs after surgical remission in all patients.
without relapse on or off antiepileptic drugs (cure) After temporal lobe surgery, the average proportion of
The molecular targets that may lead to the discovery of adults who were cured (at least five years seizure free and
novel drugs to prevent epilepsy before the first seizure off drugs) was only 25%.119 A systematic review found that
The molecular targets that may lead to the discovery cure was more common in children (27%) than in adults
of novel drugs to prevent psychiatric and cognitive (19%).121 This was confirmed in a recent Swedish study—
comorbidity twice as many children were seizure free and had stopped
antiepileptic drugs than adults 10 years after surgery.122
be considered as well, including immunotherapy for cryp- Why are postoperative cure rates so much lower than the
togenic refractory status epilepticus.110 None of the drugs overall surgical seizure freedom rates reported in the litera-
for the second or third stage has been studied in sufficiently ture? Firstly, the follow-up periods of observation may have
powered randomized controlled trials, and multicenter ran- been too short. It takes time to achieve complete discon-
domized controlled comparative trials are needed.111 Treat- tinuation of antiepileptic drugs and at least an additional
ment in individual cases should include consideration of five years of remission off these drugs to establish cure.117
any underlying causes of status epilepticus.111 Most published studies had shorter postoperative follow-
up intervals. Secondly, postoperative seizure freedom rates
Stopping antiepileptic drugs are not stable but decline over time,123 and the extent of
Patients who become seizure free and remain so for a pro- this decline probably depends on underlying disease.124
longed time often wish to discontinue treatment. The deci- Median long term (>5 years) seizure freedom rates ranged
sion to discontinue antiepileptic drugs should be based on from only 27% to 66%,121  122 closer to the reported cure
the patient’s risks of seizure recurrence after discontinuation, rates of 19-45% in a recent review.117
which overall is twice as high in the two years after discon- How can seizures relapse after antiepileptic drug with-
tinuing drugs compared with continuing to take them (box drawal in patients who have had complete resection of the
3). Other studies suggest that the risk of seizure recurrence
when patients stop taking antiepileptic drugs is as high as ADDITIONAL EDUCATIONAL RESOURCES—GUIDELINES
34% (27% to 43%), with a wide range of 12-66%.112 Adults American Academy of Neurology and American Epilepsy
seem to have a higher risk of recurrence than children (39% Society. Efficacy and tolerability of the new antiepileptic
v 31%).113 The revised ILAE definition of epilepsy states that drugs I: treatment of new onset epilepsy. 2004. www.
“epilepsy is considered to be resolved for individuals who neurology.org/content/62/8/1252.full.pdf+html
either had an age dependent epilepsy syndrome but are now American Academy of Neurology and American Epilepsy
past the applicable age or those who have remained seizure Society. Efficacy and tolerability of the new antiepileptic
free for the last 10 years and off anti-seizure medicines for at drugs II: treatment of refractory epilepsy. 2004. www.
neurology.org/content/62/8/1261.full.pdf
least the last five years.”21
American Academy of Neurology and American Epilepsy
Considerations for counseling patients include driving,
Society. Management issues for women with epilepsy—
pregnancy, work, and family. Other considerations are that
focus on pregnancy: teratogenesis and perinatal
a recurrent seizure may be embarrassing and stigmatizing outcomes. 2009. www.neurology.org/content/73/2/133.
for the patient. It could also result in loss of a driver’s license full.pdf
or, rarely, accidental or seizure related death. Furthermore, American Academy of Neurology and American Epilepsy
restarting antiepileptic drugs after seizure recurrence does Society. Management issues for women with epilepsy—
not guarantee immediate and sustained resumption of sei- focus on pregnancy: obstetrical complications and
zure control.116 However, the impact of ongoing drug related change in seizure frequency. 2009. www.neurology.org/
side effects and drug interactions may argue in favor of dis- content/73/2/126.full.pdf
continuing treatment. It may be advisable to offer discontinu- National Institute for Health and Care Excellence. The
epilepsies: the diagnosis and management of the
ation using a slow taper schedule in suitable patients after a
epilepsies in adults and children in primary and secondary
thorough and documented discussion of the pros and cons.
care. 2012. http://guidance.nice.org.uk/CG137
This recommendation also applies to stopping antiepi-
Guidelines for Management of Epilepsy in India (GEMIND).
leptic drugs for patients in seizure remission after epilepsy www.epilepsyindia.org/ies/GUIDELINES/Gemind_
surgery.117  118 Epilepsy surgery improves the prognosis of Combine.pdf
surgical candidates, with rates of freedom from seizures of Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A,
50-80%, depending on the cause of epilepsy, type and site Guerreiro C, Kälviäinen R, et al; ILAE Subcommission
of surgery, age group, and duration of follow-up.118 Unfortu- on AED Guidelines. Updated ILAE evidence review of
nately, in many series, outcomes are given without reference antiepileptic drug efficacy and effectiveness as initial
to whether patients are seizure free on or off antiepileptic monotherapy for epileptic seizures and syndromes.
Epilepsia 2013;54:551-63
drugs, the latter often being referred to as an indicator of

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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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