Curr Neurol Neurosci Rep (2016) 16:39
DOI 10.1007/s11910-016-0640-y
EPILEPSY (C. W. BAZIL, SECTION EDITOR)
Practice Update: Review of Anticonvulsant Therapy
Derek J. Chong 1 & Andrew M. Lerman 1
# Springer Science+Business Media New York 2016
Abstract Since 2010, the Food and Drug Administration has
approved the use of four new anti-epilepsy drugs (AEDs) for
the treatment of epilepsy in the USA: clobazam (Onfi),
ezogabine (Potiga), p erampanel (Fycompa), and
eslicarbazepine (Aptiom) as well as two extended release for-
mulations, topiramate ER (Qudexy XR and Trokendi) and
oxcarbazepine ER (Oxtellar). This not only provides practi-
tioners ample choice to match medication profiles to their
patients’ preferences and co-morbidities better, but also chal-
lenges us to be proficient in the use of all. In addition to
providing a brief overview of these new medications and of
the current medical management of epilepsy, this review dis-
cusses new data regarding vitamin D and AED-related osteo-
porosis, pregnancy registries, suicidality, marijuana-related
compounds for epilepsy, and the recently published guidelines
on the approach and management of a first unprovoked sei-
zure in adults and guidelines for when to stop AEDs.
Keywords Antiepileptic agents . Seizures . Drug therapy .
Adverse effects . Disease management . Selection
Introduction
The goal of epilepsy treatment remains: Bno seizures, no side-
effects.^ We aim for reduction or elimination of seizures and
This article is part of the Topical Collection on Epilepsy
* Derek J. Chong
dchong2@northwell.edu
1
Department of Neurology, Comprehensive Epilepsy Center, New
York University, 223 E 34th Street, New York, NY 10016, USA
also the acute and chronic side effects of treatment. Anti-con-
vulsants, often termed anti-epilepsy drugs (AEDs) remain the
mainstay of treatment; however, not all medications work for
all types of epilepsy or for every individual. Knowledge of the
properties and profile of each medication allows for earlier
successful pairing of AED to each patient, leading to happier
patients sooner. The choice of when to start an AED has been
made simpler with a new guideline for new onset seizures;
estimate recurrence risks of stopping AEDs once seizures
are controlled for a period of time are available as well.
Since the last update on AEDs [1], there have been four new
medications and two new formulations of older molecules.
Novel agents are helpful because about a third of patients con-
tinue to be pharmaco-resistant. The cause of intractability is still
unknown, though multi-drug resistance proteins are still poten-
tially a factor. These efflux proteins were initially implicated in
chemo-resistant tumors, but any cell-upregulating proteins such
as P-glycoprotein (P-gp) may pump out AEDs that are
substrates. P-gp upregulation is seen in resected epileptic tissue,
and patients with the best post-resection outcomes had both
evidence of high pre-surgical and low post-surgical P-gp activ-
ity on PET [2]. Despite this, only one open-label clinical trial
has been attempted per clinicaltrials.gov (#NCT00524134) and
there is debate as to whether these proteins are a consequence
rather than the cause of intractibility.
While the causes of intractability continue to be investigat-
ed, newer AEDs and different combinations need to be used.
In a population with at least monthly seizures, 5 % per year
achieved a 12-month seizure-remission with a 6-year follow-
up, meaning the goal was reached in about 30 % [3•].
However, 71 % relapsed in the following 6 years, meaning
patients must still remain vigilant and compliant. Rational
polytherapy—harmonizing mechanisms of action when
attempting to choose multiple AEDs—may relate to
adverse-effect (AE) profiles. This was seen in a post hoc
39 Page 2 of 14
analysis of clinical trials of lacosamide (LCM) when uptitrated
with traditional sodium-channel Bblockers^ at fixed dose [4],
whereas cross-titration resulted in better tolerability when
attempting to reach a high 300-mg bid dose of LCM [5].
The four recent additions to the US market all differ in their
mechanisms of action, two of which are first-in-class. The
dramatic increase in available agents over the past decade,
many with improved day-to-day tolerability profiles, makes
seizure freedom without AEs a potential reality for greater
numbers of patients.
Other topics that have continued to develop include bone
health, congenital malformations, and neurodevelopment re-
lated to in utero AED exposure, suicidality, and the potential
of marijuana and its cannabinoids to treat the various epilepsy
syndromes.
General Principles
When to Start?
Approximately 150,000 adults have a first unprovoked seizure
yearly, with recurrence risks greatest within the first 2 years
(21–45 %) [6]. A prior brain insult, an EEG with epileptiform
abnormalities, a significant brain-imaging abnormality, and a
nocturnal seizure are factors that impart a twofold increase in
recurrence risk [7••]. Immediate AED initiation, as compared
with awaiting a second seizure, reduces risk of recurrence
within the subsequent 2 years by roughly 35 %, yet is unlikely
to prevent longer-term seizure remission. Among those re-
ceiving treatment, adverse events may range from 7 to 31 %,
predominantly mild and reversible. These should be weighed
against potential physical harms and psychosocial impact of
seizure recurrence, particularly in those with higher risks, to
make individualized treatment decisions.
When to Stop?
Evidence supports waiting 2+ years of seizure-freedom in
children prior to discontinuation of AEDs [8]. Evidence for
adults is less definitive, though guidelines have suggested 2–
5 years of seizure freedom [9]. The Medical Research Council
studied adults after 2-year seizure freedom, and randomized
them to stay on AEDs or have medications decreased every
4 weeks, with a goal of complete withdrawal over 6 months
[10•]. The immediate risk of recurrence was 30 % (95 %
confidence interval (CI) 25–35 %), but subjects that
remained seizure-free for 3 months after AED withdrawal,
had a 15 % (95 % CI 10–19 %) risk for recurrence within
their next 12 months, which dropped to 9 % at 6 months.
Driving was advised to be restricted for at least 3 months
after AED withdrawal.
Curr Neurol Neurosci Rep (2016) 16:39
Selection
Levetiracetam (LEV), lamotrigine (LTG), zonisamide (ZNS),
topiramate (TPM), clonazepam (CLN), phenobarbital (PB),
rufinamide (RFN), valproic acid (VPA), and now clobazam
(CLB) and perampanel (PER) are considered Bbroad spec-
trum,^ as they can be used to treat any seizure type. VPA is
avoided in women of childbearing age, due to higher risks of
teratogenesis and neurobehavioral deficits following fetal ex-
posure [11], but it is still considered the gold standard in terms
of efficacy in the treatment of idiopathic (primary) generalized
epilepsies [12, 13]. Case reports for lacosamide (LCM) effec-
tiveness in juvenile myoclonic [14] and symptomatic general-
ized epilepsies [15] should encourage larger studies. Other
AEDs are considered narrow-spectrum, as they treat only fo-
cal seizures (simple or complex) and both secondarily and
primary generalized tonic-clonic seizures, but some worsen
absence or myoclonic seizures. Individual drugs appear suited
to specific seizures. Ethosuximide (ETH) is effective only
against absence seizures, and CLN and LEV have been useful
for myoclonic seizures [16, 17]. Selection by seizure type is
summarized in Fig. 1.
Specific AEDs may have more data to support monother-
apy use [18–20] although most have been used successfully in
practice regardless of labeled indication (notably levetirace-
tam does not have a monotherapy indication despite wide-
spread use as such). Newer studies are studying monotherapy
efficacy and safety, such as ZNS non-inferiority to CBZ [21,
22] and though pregabalin (PGN) was inferior to LTG [23], it
was non-inferior to LEV [24]. Efficacy in a specific individual
cannot be predicted, thus the positive and negative secondary
properties (see Table 1) of AEDs should be considered to
maximize tolerability and compliance.
About half of patients achieve seizure freedom with the
first agent attempted, but the chance decreases precipitously
with subsequent trials [25]. Some advocate using polytherapy
only after three monotherapy trials have failed [26] while
others advocate add-on combination therapy earlier [27] as
delays to seizure-freedom risk irreversible psychosocial con-
sequences. The decision, much like the choice of AED, can be
tailored for that individual.
AED costs are important for some, and brand name medi-
cations are often not initially covered by insurance companies.
The AAN remains against automatic substitution of generics
for brand versions without the consent of the ordering physi-
cian [28] though breakthrough seizures due to generic ver-
sions have not been easily proven [29] (also EQUIGEN,
clinicaltrials.gov #NCT01713777, #NCT01733394). The re-
cent FDA report that two approved generic extended-release
mechanisms of Concerta are not bioequivalent to the brand
name version (http://www.fda.gov/Drugs/DrugSafety/
ucm422568.htm), in addition to reports of intermittent
quality, control issues at certain factories continue to fuel
Curr Neurol Neurosci Rep (2016) 16:39
Fig. 1 An algorithm outlining steps in the choice of an AED for a patient
diagnosed with epilepsy. The first step is to assess whether seizures
originate focally, or from both hemispheres essentially simultaneously.
When unknown, broad-spectrum agents are best. There are many
concerns (http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm382736.htm).
Plasma AED levels are helpful for establishing a baseline
once seizure-free, for suspected toxicity, suspected non-
compliance or medico-legal verification of treatment, loss of
therapeutic effect, alteration in absorption or metabolism by
age, gastrointestinal or other disease, changed physiological
state (e.g., pregnancy), change of manufacturer, or drug-drug
interaction [30].
Gliomas
Treatment of seizures with VPA was shown to increase sur-
vival in glioblastomas and is preferred by many [31••]. LEV
has been shown in multiple studies to be effective in different
grades of gliomas, and is currently the treatment of choice
when efficacy is the primary concern. LEV-VPA
Page 3 of 14 39
choices for each seizure-type, which narrowed based on the potential
for intolerable side-effects, of which psycho-behavioral and weight are
among the most concerning for patients
combinations are often used [31••]. PGN was considered
non-inferior to LEV and is another option [24], and other
suggestions include LCM, LTG, and ZNS.
Adverse Event Update
Hypersensitivity
Severe reactions to medications include mucocutaneous blis-
tering diseases such as Stevens-Johnson Syndrome (SJS) and
toxic-epidermal necrolysis (TEN) with mortality of 10–50 %,
and Drug Reactions with Eosinophilia and Systemic
S ym pt om s ( D R E SS ) , w i t h m or t al i t y n ea r 10 % .
Pharmacogenomics and ethnicity are established factors, as
CBZ-SJS is highly associated with HLA-B*15:02, but specif-
ic to people of Han Chinese decent [32]. This association is
39 Page 4 of 14
Table 1 AED summary
Drug Mechanism of Action
Carbamazepine Voltage-gated Na+ channel blockade Inexpensive
(Tegretol, Tegretol XR, Mood stabilizer
Carbatrol) Treats some neuropathic pain
Known average rate of teratogenesis
Clobazam (Onfi) Prolongs GABA-A Cl− opening
Clonazepam (Klonopin) Prolongs GABA-A Cl− opening
Eslicarbazepine (Aptiom) Voltage-gated Na+channel blockade
Ethosuximide (Zarontin) T-type (low-voltage activated) Ca2+
channel blockade
Ezogabine (Potiga) Potassium channel Bopener^
Felbamate (Felbatol) GABA-A enhancement NMDA
blockade
Gabapentin (Neurontin, Binds α2−δ subunit of L-type
Horizant) voltage-regulated Ca2+ channels
(high-voltage activated class)
Lacosamide (Vimpat) Enhances slow inactivation of
voltage-gated Na+ channels
reduces of CRMP-2 activity
Lamotrigine (Lamictal, Presynaptic inhibition of
Lamictal XR) neurotransmission (e.g., GLU,
ASP)
Voltage-sensitive Na+ channel
blockade
Inhibits high-voltage activated Ca2+
currents
Levetiracetam (Keppra, Binds to synaptic vesicle protein 2A
Keppra XR) (SV2A)
Oxcarbazepine (Trileptal, Voltage-sensitive Na+ channel
Oxtellar) blockade
Perampanel (Fycompa) AMPA-receptor non-competitive
antagonist
Phenobarbital Prolongs GABA-A activation
(Phenobarb)
Curr Neurol Neurosci Rep (2016) 16:39
Advantages Disadvantages
Drug interactions (incl OC) enzyme
induction
Hypersensitivity reactions possible
bone density loss hyponatremia
Leukopenia (us. asymptomatic) rare
aplastic anemia
Long-acting/QD dosing Severe withdrawal side effects Cannot
Few drug interactions be stopped suddenly Increased
Broad spectrum incidence of pneumonia or
Some anxiolytic effects respiratory illness
Cognitive and sedation effects
Broad spectrum useful for myoclonus Tachyphylaxis
Useful for anxiety Physical addiction and dependence
Can be used as abortive/rescue therapy
Dissolving tablet available
QD dosing Interferes with OC
Primarily renally excreted
Not a scheduled medication
Relatively lower incidence of hyponatremia
Oral solution available Narrow spectrum, only for absence
seizures
Irritability
GI side-effects
Does not affect the metabolism of other Discoloration of the skin
AEDs Retinal abnormalities
Rare urinary retention
Psychiatric symptoms
QT prolongation
Oral solution available Serious potential side-effects,
including liver failure and aplastic
anemia
TID dosing
No drug interactions Dose-dependent absorption
Rapid titration
Useful in neuropathic pain and spasticity
and restless legs
QD dosing available
No drug interactions Sedation
Broad spectrum Hypersensitivity
Few drug interactions Slow titration
BID or QD with XR Useful in bipolar Levels affected by OC
disease
No drug interactions Possible neurobehavioral side-effects
Rapid titration
BID or QD with XR
Few drug interactions Medium enzyme induction
Rapid titration Interferes with OC
BID or QD with XR Hypersensitivity
Hyponatremia
Long-acting/QD dosing Behavioral side effects (aggression)
Little blood monitoring required Low titration
Inexpensive Sedation
QD dosing Withdrawal
IV available Drug interactions (including OC)
Possible bone density loss
Curr Neurol Neurosci Rep (2016) 16:39 Page 5 of 14 39

Table 1 (continued)

Drug Mechanism of Action Advantages Disadvantages

Phenytoin (Dilantin) Voltage-gated Na+ channel blockade Inexpensive
QD dosing
IV available
IM available as fosphenytoin
Pregabalin (lyrica) Binds alpha2delta subunit of L-type
voltage-gated Ca2+ channels
Rufinamide (banzel) Prolongation of inactive state of
sodium channel
Tiagabine (Gabatril) inhibitor of GABA uptake
Topiramate (Topamax, Voltage-gated Na+channel
Qudexy, Trokendi) Voltage-gated Ca2+ channel
Enhances GABA-A activity
Inhibition of AMPA activity
Carbonic anhydrase inhibitor
Valproic acid and Increased GABA-ergic transmission
derivatives (Depakene, Reduced release and/or effects of
Depakote ER, excitatory amino acids (NMDA?)
Depakote DR) Voltage-gated Na+ channel blockade
Modulation of dopaminergic and
serotoninergic transmission
Vigabatrin (Sabril) Irreversible GABA-transaminase
inhibitor
Zonisamide (Zonegran) Fast inactivation of voltage-
dependent sodium channel
T-type calcium channel inhibitor
Carbonic anhydrase inhibitor
Complicated pharmacokinetics drug
interactions (including OC)
Highly protein bound
Hypersensitivity
Bone density loss
Sedation
Cosmetic effects
No drug interactions Weight gain
Rapid titration
Useful in neuropathic pain and spasticity
Some anxiolytic effects
Specifically tested in LGS GI side-effects
few drug interactions Highly protein bound slow titration
cognitive, GI effects
Broad spectrum Slow titration
Few drug interactions Cognitive effects
BID or QD with XR Interferes with OC
Useful in migraine Potential for weight loss
Potential for weight loss Renal stones (rare)
Broad spectrum Drug interactions
Useful in migraine and bipolar disease High protein binding
IV, sprinkles, and QD forms available Dose-dependent hematological toxicity
(including thrombocytopenia and
acquired von Willebrand disease)
Tremor and Parkinsonism
Weight gain
Teratogenic and in utero
Neurodevelopmental risks
Rare sedation
Hepatic toxicity especially in pediatrics
<2 years old
Proven efficacy in infantile spasms Risk for loss of visual field—
mandatory in depth
Ophthalmological assessments
Potential for psychiatric side-effects
Weight gain
Broad spectrum Hypersensitivity
Few drug interactions Potential for weight loss
Potential for weight loss Possible mood worsening
Mild antiparkinsonian agent Rare renal stones
Some headache prophylaxis
QD dosing

QD once daily, BID twice daily, TID three times daily, QID four times daily, IV intravenous, OC oral contraceptives

strong (odds ratio (OR) 89.25; 95 % CI 19.25–413.83) but not
absolute, as HLA-B*15:02 was seen in 11.9 % of CBZ-
tolerant cases [33]. Since then, phenytoin (PHT)-related SJS/
TEN was found to have a moderate association with HLA-
B*15:02 (OR 4.25; 95 % CI 1.93–9.39) [33]. PHT-SJS/TEN
is actually more closely linked to CYP2C single-nucleotide
polymorphisms at 10q23.33, including CYP2C9*3 (OR 12;
95 % CI 6.6–20), known to cause reduced clearance of PHT
by 93–95 %[34]. This implicates CYP2C9 enzymatic dys-
function and delayed PHT clearance in hypersensitivity.
Non-genetic causes of high PHT levels can also contribute
to hypersensitivity, and must be considered when loading
PHT in those with poor clearance for any reason.
Suicidality
Risks of completed suicide increase within the first 6 months
of epilepsy diagnosis, during 72 h following a focal-onset
seizure, and within the first 3 months after surgery and it
may be that incomplete treatment of seizures may worsen
suicidal ideation [35]. The World Psychiatry Association dis-
agrees with the FDA’s determination that suicidality is a Bclass
39 Page 6 of 14
effect^ of all AEDs [36•], highlighting protective effects of
CBZ and VPA versus concerns about LTG, LEV, and TPM.
Discussing and documenting a patient’s past and current his-
tory of mood disorders and suicidality, in addition to the fam-
ily history of psychiatric disorders may help define higher-risk
populations. The Neurological Disorders Depression
Inventory for Epilepsy (NDDI-E) is a self-report 6-item scale
that can quickly provide objective information [37]. Total
scores ≥15 should lead to urgent psychiatric assessment.
Bone Metabolism
Bone health involves vitamin D metabolism, which is either
synthesized cutaneously through UVB exposure, or absorbed
in the intestines, though oily fish are the few foods with sig-
nificant levels of vitamin D [38]. The metabolite 25(OH)-vi-
tamin D is inactive but the best indicator of total levels. In
sunny Atlanta, levels from 596 adults with epilepsy were an-
alyzed. Deficiency (<20 ng/mL) was seen in 54 % of 196
patients on enzyme-inducing AEDs (EIAEDs: CBZ, PB,
PHT, primidone (PRM)); 50 % of 115 taking weak EIAEDs
(oxcarbazepine (OXC) and TPM); and 37 % of 285 on non-
EIAEDs (gabapentin (GBP), LTG, LEV) (p = 0.002) [39].
Levels were lower in Blacks versus Caucasians. Women,
obese patients, and those not taking vitamin D supplements
also had lower levels (p = 0.01, p = 0.000, p = 0.000, respec-
tively). The pediatric population appears also to be at risk of
vitamin D deficits. An Australian study found 22 % of 111
deficient (<20 ng/mL) and 41 % insufficient (20–29 ng/mL)
[40]. Deficiency was associated with use of >2 AEDs and
genetic disorders.
During a retrospective cohort study comparing veterans on
AEDs, fracture rates did not differ whether prescribed calcium
and vitamin D supplementation or not, though doses and
levels were not evaluated [41]. A subsequent 2-year longitu-
dinal, double blind placebo-controlled study evaluated 80
male veterans with epilepsy, normal calcium levels, and vita-
min D levels >20 ng/mL taking PHT, CBZ, PB, or VPA and
randomized them to a bisphosphonate (risedronate) versus
placebo [42•]. All participants received calcium (1000–
1500 mg) and vitamin D (500–750 IU) supplementation.
Bone mineral density (BMD) significantly improved in about
70 % of participants in both groups, but greater BMD im-
provement in the lumbar spine occurred with risedronate
(p = 0.0066), and new fractures only occurred in the placebo
group (six vertebral, one non-vertebral). DEXA scans in at-
risk patients were recommended every 1–2 years.
Baseline 25(OH) vitamin D levels should be tested in all
individuals with epilepsy, regardless of their age and which
anticonvulsants they are taking. Current guidelines from the
Endocrine Society suggest deficiency (<20 ng/mL) be supple-
mented by 50,000 IU of D2 or D3 once weekly for 8 weeks
(equivalent of 6000 IU/day for 67 days) [38]. In epilepsy
Curr Neurol Neurosci Rep (2016) 16:39
specifically, those with low levels may require continued sup-
plementation of 4000 IU in adults and 2000 IU in the pediatric
age group [43] along with 1000–1200 mg/day of calcium.
Endocrine consultation may help investigate other causes of
deficiency, including defective absorption (celiac disease, cys-
tic fibrosis) and optimizing treatment. A baseline DEXA is
also reasonable, as half a pediatric population had low
BMD, though particularly prevalent in those with cerebral
palsy, severe mental retardation or lacking autonomous
gait [44].
Pregnancy
There are potential physiological and traumatic effects from
seizures to both the fetus and pregnant mother [45]. Exposure
to more intrauterine GTCs increases risk (OR 1.34) of new-
borns being small for gestational age [46], and with five or
more, an association with lowered IQ at the age of 6 [47].
There is a suggestion that AED discontinuation is a factor in
the 10 times higher mortality rate in pregnancy for women
with epilepsy (WWE) [47]. However, there are also significant
risks to AED exposure.
The Cochrane Collaboration consolidated the major find-
ings of neurodevelopmental outcomes to children exposed to
AEDs up to 2013 [48••] and reported that IQ was reduced in
those VPA-exposed, in a dose-dependent manner, and that
results for CBZ, PHT, and LTG varied between studies and
were not significant overall. Since then, further results have
become available from the Neurodevelopmental Effects of
Antiepileptic Drugs (NEAD) Study, a prospective observa-
tional study performed in 25 centers in the UK and USA.
This study investigated fetal exposure to monotherapy of only
CBZ, LTG, PHT, or VPA. The outcome data at 6 years of age
were published. The VPA-group showed continued deficits in
not only IQ, but also in adaptive functioning and had an ele-
vated risk for ADHD from both parent and teacher surveys,
though only those in the PHT-group were negative on both
surveys [49]. A separate study found IQ to be 8–15 points
lower only on VPA >800 mg/day, whereas ≤800 mg/day IQ
was no different than the unexposed [47]. Small for gestation
age (SGA) occurred more frequently in the VPA- and CBZ-
groups [50]. Microcephaly was also common, but normalized
by 24 months of age.
Major congenital malformation (MCM) rates are higher in
WWE (7.08 %) than in those without (2.28 %) [45], were
particularly elevated with VPA monotherapy use (10.73 %),
and as high as 16.78 % with polytherapy that included PHT,
PB, or VPA. MCM most significantly higher in WWE were
hernia, ear/neck/face, cleft lip, and spina bifida. The EURAP
epilepsy and pregnancy registry further defined risks with
doses on 4540 outcomes from WWE with 47 % focal, 39 %
generalized, and 14 % other types of epilepsy. Pregnancies
involved monotherapy of CBZ (1402), LTG (1280), VPA
Curr Neurol Neurosci Rep (2016) 16:39
(1010), and PB (217). Similar to prior results, MCM were
seen in 6 % of pregnancies. All were discovered in utero or
within the first 2 months post partum. The higher the dose
(documented at conception) within each monotherapy group,
the higher the malformation rate. The worst rate was VPA at
≥1500 mg/day (24.2 %), but doses <700 mg/day had a rate of
only 5.6 %. CBZ MCM rates were 3.4, 5.3, and 8.7 % for
<400, ≥400 to <1000, and ≥1000 mg/day, respectively. LTG
MCM rates were 2 and 4.5 % for <300 and >300 mg/day. In
comparison to LTG at <300 mg/day (the lowest rate of mal-
formation), CBZ ≥ 1000 (p < 0.0001), PB ≥150 mg/day
(p < 0.0001), and all VPA doses were worse. Seizure freedom
was similar (62–71 %) within each dose of each medication.
Unlike other studies, the North American AED Pregnancy
Registry’s most recent report (Fall, 2014) includes outcomes
from 11 AEDs [51••]. It also showed the highest MCM rate
with VPA. ZNS was most intriguing with 0 MCM with 119
exposures (95 % CI 0–3.3) and OXC at 1.9 (95 % CI 0.5–4.8)
with 211 exposures, but more numbers will be required to
differentiate these from CBZ (3.1 %, 95 % CI 2.1–4.3).
LEV has continued to show low rates of MCM (2.2 %,
95 % CI 1.2–3.6 %) [51••], or as low as 2 of 304 (0.7 %) in
monotherapy and 19 of 367 (6.47 %) in polytherapy [52].
Children with fetal exposure to LEV (n = 53, mean dose
2070 mg/day) at 36–54 months of age were superior in gross
motor skills, comprehension and expression language abili-
ties, as compared to VPA exposure (n = 44, mean dose
980 mg/day), and no different than controls (n = 131) [53].
No dose effect was noted for either AED in this study.
The NEAD study confirmed folic acid’s benefit for IQ [54],
and it is used for the theoretical benefit against MCM and
neural tube defects. Some advocate 4 mg/day for those imme-
diately planning a pregnancy and 1 mg/day for all WWE of
childbearing age.
About one third of WWE experience increased seizures
during pregnancy which may be due to AED levels, which
decline especially in the second half of pregnancy. Levels
should be monitored and doses often doubled to compensate.
Hemorrhage is a perinatal risk that led to recommendations
for WWE on EIAEDs to receive oral vitamin K1 20 mg daily
for a minimum of 2 weeks before expected delivery [55]. Due
to potential MCM and other potential obstetrical risks [56],
high-risk obstetrics should be involved. Encouraging patients
to enroll into the Pregnancy Registry (http://www.
aedpregnancyregistry.org) will help collect data for the ever-
growing list of AEDs.
Breastfeeding
Two studies recommend continuing breastfeeding in mothers
using AEDs. The Norwegian Mother and Child Cohort study
(MoBa) included 223 children with in utero exposure to an
AED, predominantly in monotherapy (n = 182), and most
Page 7 of 14 39
commonly LTG (n = 71), CBZ (n = 48), and VPA (n = 27)
[57]. Children continuously breastfed ≥6 versus <6 months,
had less impairment at 6 and 18 months of age, including
autistic traits and both fine and gross motor skills. These
trends continued at 36 months of age. It raised the hypothesis
that the risk of deficits from fetal AED exposure could be
reduced with continuous breastfeeding ≥6 months. The
NEAD study found the adjusted IQ was 4 points higher in
children who were breastfed [58]. Mean duration was
7.2 months.
Breastfeeding was less common in women taking
AEDs [57], but this should not be due to fear of AEDs.
Breastfeeding with the AEDs studied is not associated
with worse outcomes, and instead looks to exert positive
influences when continued ≥6 months [59]. Clinically in-
significant amounts of PHT, CBZ, PB, and VPA cross into
the breast milk, while GPN, LTG, and TPM may reach
potentially clinically relevant levels [60].
Characteristics of the Newest Antiepileptic Drugs
Perampanel (Fycompa)
Perampanel (PER) is a first-in-class orally active, selective,
non-competitive alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptor antagonist [61]. It
received FDA approval in October 2012 for adjunctive treat-
ment of focal seizures in patients ages 12 years and older, then
in June 2015, for primary generalized tonic-clonic seizures.
There were three phase-III clinical trials that supported doses
of 4–12 mg/day [62–64] and one supporting use in refractory
primary generalized epilepsy [65].
PER has a long half-life of 70–120 h, and administered
once nightly. It is rapidly and completely absorbed following
oral administration [66]. Steady state plasma concentrations
are achieved within 14 days and protein binding is 95 % [61].
Significant metabolism is via the p450 system and will be
cleared faster with EIAEDs but PER does not affect concen-
trations of other AEDs [66]. PER at 12 mg/day, but not 8 mg
or less/day significantly increased clearance of the progester-
one component of oral contraceptives, potentially rendering it
ineffective [67].
Dizziness and somnolence were AEs prompting drug
discontinuation or dose reduction [62, 63], and other com-
mon AEs were ataxia, headache, and irritability. Insomnia,
anxiety, aggression, hostility, confusional state, and anger,
were uncommon but important [66]. The potential for ter-
atogenic effects in humans is unknown, but neither a sig-
nificant impact on fertility nor teratogenic effects were
seen in animal models [64].
The starting dose is 2 mg daily, but 4 mg daily with con-
comitant EIAEDs, then increased by 2 mg weekly, depending
on tolerability and seizure control, to a maximal dose of 12 mg
39 Page 8 of 14
daily [68]. Titration should be slowed in patients who are
elderly or have mild to moderate hepatic impairment and is
not recommended for patients with severe renal or hepatic
failure.
Ezogabine (Potiga)
Ezogabine (EZG) is the first neuronal potassium channel ac-
tivator for epilepsy [69] and was FDA approved in 2011 as an
add-on therapy for focal seizures in adults with daily dosages
of 600 to 1200 mg/day [70]. It may stabilize neuronal potas-
sium channels in an Bopen^ position, and suppress of repeti-
tive firing [69]. EZG is rapidly absorbed following oral ad-
ministration and metabolized through glucuronidation.
Kinetics are linear without clinically significant food effect,
and metabolites are eliminated primarily by renal excretion,
with a half-life of 6–10 h [71]. EZG is not metabolized by
CYP isozymes and does not induce or inhibit them at clinical-
ly relevant concentrations. There was no effect on trough con-
centrations with concomitant use of most anticonvulsants, in-
cluding CBZ, GBP, LEV, OXC, PB, PHT, TPM, VPA, and
ZNS. EZG was associated with a 20 % decrease in trough
LTG concentration [72].
The most common adverse reactions were dizziness, fa-
tigue, confusion, vertigo, tremor, problems with coordination,
inattention, memory impairment, weakness, and double vision
[70]. EZG can cause significant urinary retention, generally
within the first 6 months of treatment, although it can also
occur later [73]. In 2013, the FDA reported retinal pigment
abnormalities and/or blue-gray discoloration, most notably on
or near the lips, nail beds, sclera, and conjunctiva with long-
term use [74]. In 2015, skin discoloration was considered
cosmetic and vision changes did not occur with retinal pig-
ment changes, though long-term observational studies would
provide final data (http://www.fda.gov/Drugs/DrugSafety/
ucm451166.htm). The FDA recommends eye exams before
initiating and every 6 months during treatment, and avoiding
EZG if not testable. Confusion, hallucinations, and psychotic
symptoms are rare, and resolve with discontinuation [70].
The initial dose is 100 mg tid, increased gradually at week-
ly intervals by no more than 50 mg tid, up to 600 to 1200 mg/
day, based on response and tolerability [69, 70].
Eslicarbazepine (Aptiom)
In 2013, the FDA approved eslicarbazepine (ESL) for adjunc-
tive treatment of adults with focal seizures [75]. ESL is a third-
generation dibenz [b,f] azepine, following CBZ and OXC.
Similar to OXC, metabolism does not produce the toxic me-
tabolite carbamazepine-10,11 epoxide [76]. When OXC is
metabolized, the parent compound can be found in addition
to its metabolites, the R- and the S-licarbazepine enantiomers,
of which only the latter is biologically active, but ESL is
Curr Neurol Neurosci Rep (2016) 16:39
rapidly and almost completely converted to S-licarbazepine.
Steady state plasma concentration is attained after 4–5 days of
once daily dosing, consistent with an effective half-life in the
order of 20–24 h [77]. Both the lack of plasma variability and
relatively long half-life impart potential ease of administration
and tolerability, which should minimize peak-dose side effects
[75]. Co-administration with CBZ, PHT, and TPM resulted in
reduction in serum ESL level by 21–33 and 7–13 %, ESL also
reduces the serum of level of TPM, CBZ, and LTG, and in-
creases PHT concentrations. ESL increases the metabolism of
ethinyl estradiol and levonorgestrel components of oral con-
traceptives [78••].
The most common treatment-related adverse events were
dose-dependent and included the following: headache, then
dizziness, nausea, double vision, and poor coordination.
Hyponatremia is a relatively frequent laboratory abnormality
with OXC and CBZ. However, in the initial studies just one
patient (1.0 %) in the ELC-treated group showed a decrease in
the sodium levels below 125 mmol/L [75]. Patients should
still be monitored for hyponatremia initially, as well as serious
rash, though the rash rate (1 %) in the clinical trials were less
than for CBZ (7 %) and OXC (6 %).
The recommended titration is 400 mg daily for 1 week,
then increase to 800 mg daily. There are some patients who
may benefit from 1200 mg/day [79].
Clobazam (Onfi)
Clobazam (CLB) was FDA approved in October 2011 as an
orphan drug, for adjunctive treatment for seizures associated
with Lennox-Gastaut Syndrome in adults and children
>2 years of age, but had been approved for use since in
1970 in Australia then Europe and Canada, used as a broad-
spectrum agent. Two multicenter studies demonstrated mean
decreases in total seizure frequency with a dose-response re-
lationship [80]. A meta-analysis also showed improvement
specifically in dystonic and myoclonic seizures [81]. CLB is
metabolized primarily by CYP3A4 to its active metabolite, N-
desmethylclobazam (DMC), which is then metabolized pri-
marily by CYP2C19 [82]. These are both 1,5-benzodiaze-
pines. Similar to 1,4-benzodiazepines (i.e., clonazepam) they
bind to the GABA-A receptor to enhance GABA neurotrans-
mission, but with less affinity for the ω1-receptor, instead
with preference for activating the ω2-binding site. CLB is
completely absorbed and 90 % protein-bound [83]. Half-
lives of CLB and DMC are 36–42 and 71–82 h, respectively.
CYP3A4 inducers will promote metabolism to the DMC me-
tabolite while 2C19 genetic polymorphisms or inhibitors (e.g.,
felbamate (FBM), fluconazole, fluvoxamine, omeprazole)
may cause prolonged clearance of DMC. PB, PHT, and
CBZ did not affect the clearance of CLB but significantly
increased the formation of its active metabolite, DMC, while
FBM decreases CLB levels but will increase DMC fivefold
Curr Neurol Neurosci Rep (2016) 16:39
[78••]. CLB does not interact with oral contraceptive drug
levels [84]. Elevated serum CLB and DMC levels are also
observed with concomitant use of cannabidiol (CBD) [85].
Common side effects occur in a dose-related fashion and
include sedation and somnolence, lethargy, psychomotor
slowing, ataxia, fatigue, sleep disturbances, insomnia, aggres-
sion, irritability, and drooling [86]. Patients with propensity to
upper respiratory illnesses and problems swallowing should
also be monitored closely.
Therapy is initiated to patients ≤30 kg body weight at 5 mg
daily and titrated as tolerated up to 20 mg daily in divided
doses. For patients >30 kg body weight, initiated at 10 mg
daily, and titrate as tolerated up to 40 mg daily in divided doses.
Because of the complex metabolism, AEs of CLB may be
accumulate and rapid titration is not recommended [87].
Topiramate ER (Qudexy and Trokendi)
Trokendi XR was FDA approved for seizure through tests of
bioequivalence with immediate-release TPM. Qudexy is also
an extended-release formulation. It was FDA approved in
March 2014 for initial monotherapy in patients aged 10 years
and older with partial-onset seizures or primary generalized
tonic-clonic seizures based on results from a phase III study
[88]. Qudexy has a linear dose-concentration curve of oral
dosage of 50–1400 mg/day with low interpersonal variability
[89], a half-life of 56 h, and 15–41 % protein binding. It is
primarily eliminated unchanged in urine (70–80 %) when ad-
ministered without enzyme-inducing medications, while the
remaining 20–30 % undergoes hepatic metabolism via
glucuronidation, hydroxylation, and hydrolysis [90].
Qudexy was not associated with metabolic acidosis, kidney
stones, and glaucoma and the most common AEs of somno-
lence and dizziness, occurred in less than 15 % of patients [89,
90]. Rapid uptitration may be associated with higher inci-
dences of cognitive-related complaints and individual
neurocognitive and neuropsychiatric adverse events, and the
proportion of patients reporting a new adverse event was
greatest in those concomitantly taking ≥3 AEDs [89]. A re-
view [91••] outlined that TPM may cause VPA levels to drop
by up to 13 %, and can increase PHT levels in some individ-
uals due to minor CYP2C19 inhibition. Estradiol levels were
unaffected by doses up to 200 mg/day, but low-dose estradiol
contraceptives may become ineffective at higher doses [78••].
When used with enzyme inducers, TPM levels can decrease
by up to 50 %.
Therapy starts at 25 to 50 mg once daily then increased by
25 to 50 mg weekly up to 200 to 400 mg once daily [92].
Pediatric guidelines recommend initiation at 5–9 mg/kg once
daily for the first week, increasing at 1- or 2-week intervals by
increments of 1–3 mg/kg as tolerated, to a maximum of
400 mg/day [92].
Page 9 of 14 39
Oxcarbazepine ER (Oxtellar)
Oxtellar uses matrix delivery to slowly release OXC for a 24-h
dosing interval [93] to inhibit voltage-sensitive sodium chan-
nels. Oxtellar received FDA approval in October 2012 as ad-
junctive therapy of partial seizures in ages 6 and above after
demonstrating efficacy, tolerability, and safety of adjunctive
once-daily 1200 and 2400 mg [93]. Peak-trough fluctuations
were significantly reduced, contributing to improved
tolerability.
Dizziness, nausea, somnolence, vomiting, headache, and
diplopia were dose-related AEs. Treatment-limiting AE rates
were 8.3 and 14.8 % in the placebo and 1200 mg groups,
respectively, and 30.1 % in the 2400 mg group [93].
Monitoring for hyponatremia is recommended.
Suggesting dosing begins at 600 mg/day on an empty
stomach for 1 week, increasing by 600 mg/day weekly as
tolerated to 1200 to 2400 mg/day. In patients 6–17 years
of age, initiate at 8–10 mg/kg daily with a maximum of
600 mg/day in the first week, increasing weekly by 8–
10 mg/kg daily as tolerated, up to 1800 mg/day [94].
Conversion from immediate-release OXC may require a
higher oxtellar dose of 10–20 %. Serum levels of OXC
metabolites may be reduced by 25–35 % in those receiv-
ing any or multiple EIAEDs (CBZ, PHT, PB), while VPA
can compete for protein binding sites with OXC [91••].
OXC may enhance clearance of LTG, LEV [78••], and
oral contraceptives containing ethinyl estradiol and levo-
norgestrel [78••], but may increase PHT, PB [91••], and
others metabolized by CYP2C19.
Marijuana/Cannabis
The endogenous cannabinoid system is complicated;
modulation can cause both excitation and inhibition, and
can both promote oscillations and suppress them [95•].
The cannabinoid expected to have significant anti-
seizure properties is cannabidiol (CBD). An open-label
multi-center study using 98 % cannabidiol (Epidiolex®)
in 137 patients showed a 46 % responder rate and a 45 %
overall reduction in seizure frequency. Further studies will
better define CBD-AED interactions, populations that de-
rive benefit and potential risks. Placebo-controlled studies
are underway (clinicaltrials.gov #NCT02091375,
NCT02286986, NCT02224703, NCT02091206,
NCT02318563).
Conclusion
Guidelines were developed to advise when to start an
AED, with nearly 50 % risk of recurrence after a new
onset seizure if EEG, MRI, or the physical exam is
 39

Table 2 Practical aspects of AED use

Distinct Drug Year Dosage Usual adult starting Usual adult Dosing Minimum Usual effective Pediatric Issues to
Molecule/ (FDA) forms dose (mg/day) dose (mg/day) schedule titration plasma maintenance monitor
short form code time (days) concentration dose (mg/kg/day)
(μg/mL)
Page 10 of 14

1 CBZ Carbamazepine (Tegretol) 1974 Tabs 200 800–1600 TID 7–14 8–12 10–30 LFT, Na, CBC
Carbamazepine XR 1996, 1997 Tabs 200 800–1600 BID 7–14 8–12 10–30 LFT, Na, CBC
(Carbatrol, Tegretol XR) Capsules
2 (new) CLB Clobazam (Onfi) 2011 Tabs 10 10–40 QD-BID 7–21 10–80 <30 kg, 5–20 mg/day NE
3 CLN Clonazepam (Klonopin) 1996 Tabs 0.5 0.5–1.5 BID-TID 1–7 0.1–0.2 Dependence
ODT
4 (new) ESL Eslicarbazepine (Aptiom) 2013 Tabs 400 800–1200 QD 4–5 NE NE LFT, Na, CBC
5 ESM Ethosuxamide (Zarontin) 1960 Capsules 250 750–1500 BID 7–14 40–100 15–40 CBC, LFT
Solution
6 (new) EZG Ezogabine (Potiga) 2011 Tabs 300 600–1200 TID 14–21 NE NE EKG, urine
retention, opth
7 FBM Felbamate (Felbatol) 1993 Tabs 600 2400–3600 BID–TID 14–21 20–140a 15–60 CBC, LFT,
Solution reticulo-cytes
8 GBP Gabapentin (Neurontin) 1993 Tabs 1800 1800–3600 TID-QID 1–14 4–16 30–90 Weight gain
Capsules
9 LCM Lacosamide (Vimpat) 2009 Tabs 100 400 BID 14–28 NE NE
IV
10 LTG Lamotrigine (Lamictal-IR) 1994 Tabs 12.5–50b 100–600b QD-BID 28–42 2–16 5–15b Rash
ODT
Chewtab
Lamotrigine XR 2009 Tabs 12.5–50b 100–600b QD-BID 28–42 2–16 5–15b Rash
(Lamictal XR)
a
11 LEV Levetiracetam (Keppra-IR) 1999 Tabs 1000 1000–3000 BID-TID 1 5–45 60 Behavior
Solution
IV
Levetiracetam XR 2008 Tabs 1000 1000–3000 QD-BID 1 5–45 60 Behavior
(Keppra-XR)
12 OXC Oxcarbazepine (Trileptal) 2000 Tabs 300 1200–2400 BID-TID 7–14 10–35 c 20–40 CBC, Na
Solution
(new) Oxcarbazepine ER 2012 Tablets 600 1200 mg to 2,400 QD 7–14 10–35 900–1200 mg/day CBC, Na
(Oxtellar XR)
13 (new) PER Perampanel (Fycompa) 2012 Tabs 2 6–12b QD 7–14 30–60 12 and older 4–12 mg/day LFT, CBC,
behavior
14 PB Phenobarbital 1912 Tabs 90 90–180 QD 1 15–40 3–5 LFT
IV
15 PHT Phenytoin (Dilantin, Phenytek) 1938 Capsule 300 300–400 QD 1 10–20 4–8 LFT
Suspension
Curr Neurol Neurosci Rep (2016) 16:39

Chewtab
IV
Fos-phenytoin (Cerebryx) 1996 IV 10–20 PE/kg 4–6 PE/kg/day QD 1 10–20 EKG
IM
16 PGN Pregabalin (Lyrica) 2004 Capsules 150 150–600 BID/TID 7 NE NE Weight gain
Table 2 (continued)

Distinct Drug Year Dosage Usual adult starting Usual adult Dosing Minimum Usual effective Pediatric Issues to
Molecule/ (FDA) forms dose (mg/day) dose (mg/day) schedule titration plasma maintenance monitor
short form code time (days) concentration dose (mg/kg/day)
(μg/mL)

17 PRM Primidone (Mysoline) 1952 Tabs 100–125 750–1500 TID 10 5–12 μg 10–25 LFT
18 RFN Rufinamide (Banzel) 2009 Tabs 800 3200 BID 14 NE 45, up to 3200 mg/day EKG
19 TGB Tiagabine (Gabitril) 1997 Tabs 4 32–56b BID–QID 14–28 NE Up to 32 mg/day
20 TPM Topiramate (Topamax) 1996 Tabs 25 200–600 BID 14–28 4–10 5–9
(new) Topiramate 2014 Capsules 25–50 200–400 QD 14–28 4–10 5–9
Curr Neurol Neurosci Rep (2016) 16:39

(Qudexy XR, Trokendi)

21 VPA Valproic Acid (Depakene) 1978 Capsule 500 1000–3000 TID 7–14 50–120 15–60 LFT, NH4, plt
IV
Sprinkles
Solution
Divalproate (Depakote DR) 1996 Tabs 500 1000–3000 BID 7–14 50–120 15–60 LFT, NH4, plt
Divalproate ER 2000 Tabs 500 1000–3500 QD-BID 7–28 50–120 15–70 LFT, NH4, plt
(Depakote ER)
22 VGB Vigabatrin (Sabril) 2009 Tabs 1000 3000 BID 29 NE 150 Ophth
Solution
23 ZNS Zonisamide (Zonegran) 2000 Capsules 100 100–600 QD–BID 1 10–40a 4–8

In general, older patients (over 65) may require lower doses of all drugs due to reduced renal clearance and/or hepatic function. Labs should be monitored, in general, at initiation of treatment, once on
maintenance dose, then at most every 6 months or (usually) as needed to monitor adverse effects. The exception is felbamate, where labs should be monitored every 2–4 weeks during the first year of
treatment, then at least every 3 months thereafter
NE not established, NA not available, PE phenytoin equivalents (75 mg fosphenytoin is equivalent to 50 mg phenytoin), Ophth mandatory quarterly ophthalmological assessments
a
Not established; represents usual concentration in patients receiving therapeutic dose
b
Varies with concomitant AED (lower with enzyme inducers; higher with enzyme inhibitors)
c
of MHD, active metabolite
Page 11 of 14 39
39 Page 12 of 14
significantly abnormal. For many, this risk favors AED
initiation, but others may wish to wait. The choice of
when to use an AED should be tailored, much like the
choice of which AED to use. There have also been studies
that help define risk of recurrence following slow cessa-
tion of AEDs, which is 2 years of seizure-freedom in
children and may end up being similar in adults. Driving
issues need to be discussed with AED initiation and
discontinuation.
The number of AEDs has reached 23 (practical aspects
compared in Table 2). PAR and EZG add new mecha-
nisms of action. PER and CLB add to the list of broad-
spectrum agents, and both have long effective half-lives
and tend to promote sleep and somnolence. ESL is a third
generation of the CBZ line, and along with new once
daily formulations of OXC and TPM are all aimed at
reducing peak dose effects and toxicity, and improving
compliance.
Despite nomenclature changes, the concept of seizure
management remains the same. Any AED, with the ex-
ception of ETH, may be considered to treat focal seizures.
Only broad-spectrum agents would be expected to treat all
the seizure types seen in generalized epilepsies, and not
exacerbate some of them. Seizure-freedom and long-term
retention of AEDs rely on tolerability, with a goal for
AEDs to be completely unnoticed by the patient. Mood
and weight change may occur with some medications
even within low therapeutic doses. Tolerability screening
must include osteopenia, suicidality, and avoiding
EIAEDs in those with vascular disease and sexual dys-
function [96]. Expert clinicians match the Bpersonality^
of the medication to the personality of the patient in ad-
dition to considering raw efficacy, and in the case of glio-
blastomas, survival appears to be improved with VPA.
Teratogenicity and neurodevelopmental side-effects are
highest risk with fetal exposure to VPA, and MCM rate is
dose dependent, for instance VPA <700 mg monotherapy
rate being closer to AED-exposed average, and doses
<800 mg/day, the IQ being no different than no AED-
exposure. VPA is unavoidable in some WWE, but limit-
ing the dose at conception limits poorer outcomes. IQ and
developmental AEs appear to be ameliorated with pre-
conception folic acid and post-natal breast-feeding for
6+ months.
Compliance with Ethical Standards
Conflict of Interest Andrew M. Lerman declares that he has no conflict
of interest. Derek J Chong has received royalties from Oxford University
Press.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Curr Neurol Neurosci Rep (2016) 16:39
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