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4 Clinical Application ofAnti-seizure Medication asDrug Therapy
401
the ASM is adequately dosed; fourth, how well the patient adheres to the medication
and whether the medications are being taken as prescribed; and fth, whether the
patient has a poor lifestyle (substance abuse, addiction to sensory stimuli such as
games) that can easily induce seizures [50–56].
4.2.3.2 Objectives ofTreatment
Studies have shown that patients with DRE have signicant neuropsychological,
psychiatric, and social impairments, and they are also affected in terms of their
employment, decreased marriage rates, increased divorce rates, and decreased quality of life [57]. The primary goal pursued by domestic and international epileptologists is to completely control seizures, improve the quality of life of patients, and
enable them to return to normal life. However, drug-refractory epilepsy has a complex mechanism and etiology, and it is often difcult to achieve complete seizure
control; therefore, the goal is to minimize seizures and to improve quality of life so
that patients can adapt to a normal social life [58].
4.2.3.3 Principles andMethods ofTreatment
The current principles for the selection of ASMs are based on the type of seizure
and epileptic syndrome, as well as the etiologic prole; the efcacy, tolerability,
half-life, and potential drug–drug interactions, as well as the individual-specic
adverse effects of the ASMs; and the impact on comorbidities and the pharmacoeconomic cost of the medication. Issues to consider when replacing or combining drugs
with a second drug when the rst drug is poorly controlled or when intolerable side
effects occur include proper drug selection, failure to titrate the drug to the individual’s optimal dose, poor timing of dosing, too rapid a dose increase, and poor
control of the cause of the seizure. If seizure control is not achieved with an adequate dose of the second ASM, a combination of drugs should be considered [59].
The most famous study on how patients respond to combination medication was
published by Brodie MJ etal. [60] in 2012, patients who were newly diagnosed with
epilepsy and prescribed their rst ASM between July 1, 1982 and April 1, 2006,
were followed up with gradual adjustments of the ASM regimen as seizures progressed, up to March 31, 2008. This study had a total enrollment of 1098 patients,
and at the time of the last outpatient visit, 749 (68%) patients were seizure-free. The
maximum number of drugs used was nine. In terms of progressively added ASMs
versus seizure-free status, the use of two ASMs resulted in a seizure-free rate in the
cohort of up to 62.8%, whereas the cohort was only 5.5% seizure-free when the total
number of additional medications was increased from 3 to 9 (Table4.3) [60].
The pharmacological treatment of DRE is mainly a combination therapy, and
many epileptologists have different opinions about combination therapy. However,
the most important point is that a combination of ASMs based on different mechanisms of action is more effective and has fewer side effects than a combination of
402
L. Zhou and Z. Chen
Table 4.3
Seizure-free rates with continuous use of anti-seizure medications
Order of addition
of drugs
First drug 1098 49.5 49.5
Second drug 398 13.3 36.7
Third drug 168 3.7 24.4
Fourth drug 68 1.0 16.2
Fifth drug 32 0.4 12.5
Sixth drug 16 0.2 12.5
Seventh drug 9 0.2 22.2
Eighth drug 3 0.0 0.0
Ninth drug 2 0.0 0.0
Number of
patients
Seizure-free rate of the
cohort (%)
Seizure-free rate (%) of the
additive drug order present
drugs with the same mechanism; this is understood by most people [61]. The mechanisms of common ASMs are summarized in Table4.4 [62]. The metabolic effects
of combining ASMs should also be taken into account, e.g., sodium valproate is a
selective hepatic enzyme inhibitor that increases the blood levels of other medications; while carbamazepine, phenytoin, phenobarbital, and pramipexole are broadspectrum hepatic enzyme inducers that decrease the blood levels of other medications
metabolized by the liver. The prevalence of comorbidities in patients with epilepsy
is two to eight times greater than that in the general population. Approximately half
of patients with epilepsy have at least one comorbidity, and it is even more common
in patients with DRE [62]. Drug combinations should also focus on comorbidities,
and the selection of ASMs for epilepsy with concomitant comorbidities is summarized as follows: ① Obesity ± diabetes mellitus: choose topiramate (TPM),
zonisamide(ZNS); avoid VPA, pregabalin (PGB), gabapentin (GBP), pirempanel
(PER). ② Migraine: choose TPM, VPA, ZNS, PBG, GBP. ③ Rash: choose levetiracetam (LEV), GBP, PGB, TPM, VPA, PER, lacosamide (LCM), avoid lamotrigine (LTG), oxcarbazepine (OXC), carbamazepine (CBZ), phenytoin (PHT), PB. ④
Neuropathic pain: choose PGB, GBP, CBZ, OXC, PHT. ⑤ Depression ± behavioral/
psychological problems: choose LTG, CBZ, OXC, VPA, PGB; avoid LEV, PB,
pramipexole (PRM), TPM, ZNS. ⑥ Cognitive dysfunction: choose LTG, LEV,
OXC; avoid phenobarbital (PB), TPM, ZNS. ⑦ Concomitant drug use: choose GBP,
LEV, PGB, VPA; avoid enzyme-inducing drugs. ⑧ Restless legs syndrome: choose
GBP, PGB, clonazepam (CZP). ⑨ Kidney stones: avoid TPM, ZNS. ⑩ Glaucoma:
avoid TPM. ⑪ Hematological diseases: avoid CBZ, VPA. ⑫ Hyponatremia: avoid
OXC, escrivastigmine (ESL), CBZ. ⑬: choose new ASMs (nonhepatotoxic, renal
excretion), avoid VPA. ⑭ Kidney disease: choose obsolete ASMs (excretion
through hepatic metabolism). ⑮ Osteoporosis: choose LTG, LEV; avoid enzymeinducing drugs, TPM, VPA, ZNS. ⑯ Gait disorders: avoid CBZ, PHT, PER. ⑰
Tremor: choose TPM, PER; avoid VPA. ⑱ Parkinson’s syndrome: choose ZNS. ⑲
Arrhythmia: avoid CBZ, LTG, LCM, and other sodium channel blockers. ⑳ Cancer:
choose VPA, LEV, PER; avoid enzyme-inducing drugs. 21 Heat stroke: avoid TPM,
ZNS. 22 Atherosclerosis: avoid enzyme-inducing drugs [63]. Lee BI etal. also proposed steps for drug combination therapy (Table4.5) [63].
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
Weak
carbonic
Weak
carbonic
Regulation of
presynaptic
anhydrase
inhibitor
anhydrase
inhibitor
neurotransmitter
release through
SV2A receptor
binding
403
++ ++
+++ +++ +++ ++ + +++ +++ ++ ++ +++
+ + +++ ++ ++ + + ++ ++ ++
+++ +++ + + ++ + +++ ++
Veterinary
drug/machine BZDs PB CBZ PHT V PA ETV FBM GBP LCM LT G LEV OXC PGB RUF TGB TPM ZNS
Sodium
channel
Calcium
channel/
current
GABAergic
Transmission
effects of
Table 4.4 Mechanisms of anti-seizure medications
Glutamate
receptor
(Glu), an
amino acid
Binds to
CRMP-2
receptor
Other
mechanisms
Abbreviations: GABA gamma-aminobutyric acid, ϒ-aminobutyric acid type B, SV2A synaptic vesicle glycoprotein 2A
++ likely target; +++ very likely target
404
L. Zhou and Z. Chen
Table 4.5
selection process, the
therapeutic index was dened
as the ratio of the effective
dose (ED50) to the toxic
dose (TD50)
In the second drug
Comprehensive drug selection
Step 1: Preferred drug candidate
Medications that have not been used before
Previously used drugs have proven at least partially
effective
Drugs with the high therapeutic index or good tolerability
Drugs with no or low risk of pharmacokinetic interactions
with concomitant drugs
Drugs with ideal mechanisms of action
Effective for patients with comorbidities
Step 2: Medications that match partner medications
Drugs known to interact synergistically
Drugs showing different side effects
Drugs with no or minimal potential for pharmacokinetic
interactions
Charyyeva G etal. [64] summarized the drug preferences for monotherapy and
combination therapy for different seizure types and syndromes as follows: ① Focal
seizures (structural and metabolic): The preferred single drugs include CBZ, LEV,
PHT, ZNS, VPA, GBP, LTG, OXC, EST, LCM, PB, TPM, and CZP [65]. Preferred
drugs for combination therapy or multidrug therapy include CBZ, LEV, ZNS, TPM,
VPA, LTG, OXC, EST, LCM, BRV, PER, GBP, PGB, PB, CZP, and PHT. ② Isolated
generalized epileptic seizures: The preferred drugs for monotherapy include VPA,
PB, PHT, LEV, LTG, and TPM [66]. The preferred drugs for combination or multiple drugs include LTG, OXC, TPM, VPA, LEV, PER, PB, CZP, and PHT. ③
Myoclonic seizures: monotherapy preferred drugs include VPA, TPM, ZNS, and
LEV; combination or polypharmacy preferred drugs include VPA, TPM, LEV, ZNS,
CZP, PB, ESM [67]. ④ Aphasic seizures (juvenile aphasic epilepsy): single-agent
preferences include valproate; combination or multidrug preferences include LEV,
ZNS, TPM, ESM, or LTG [68]. ⑤ Unspecied seizure type: single-agent preferred
drugs include broad-spectrum ASMs. The World Health Organization has developed initial doses of ASM and maintenance therapy for adults (Table4.6).
4.2.3.4 First-Line Anti-seizure Medications
Currently, old and new ASMs are divided into three generations. Generation I ASMs
include PB, PHT, ESM, CZP, CBZ, and VPA; generation II ASMs include LTG,
GBP, TPM, PGB, OXC, LEV, ZNS, and aminocaproic acid; and generation III
ASMs include LCM, ESM, lufenamide, piracetam, and BRV [66, 69]. The advantages, disadvantages, and major side effects of current rst-line ASMs are summarized in Table4.7 [70].
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
405
Table 4.6
Abbreviations: ITD initial target dose, MD maintenance dose, DDD dened daily mean dose
Initial target dose and maintenance dose of anti-seizure medications in adults
Medications ITD (mg/day) MD (mg/day) DDD(mg)
Carbamazepine 400–600 400–1200 1000
Chlorpazan 10 10–40 8
Eslicarbazepine 800 800–1200 800
Ethosuximide 500 500–1500 1250
Gabapentin 900 900–3600 1800
Lacosamide 200 200–400 300
Lamotrigine 150 (single drug) 200–400 300
Lamotrigine 75 (combined with valproic acid) 75–200
Lamotrigine 300 (coenzyme inducer) 200–500
Levetiracetam 1000 1000-3000 1500
Oxcarbazepine 600 600–2400 1000
Perampanel 4 4–12 8
Phenobarbital 60 60–120 100
Phenytoin sodium (a sedative) 200 200–400 300
Pregabalin 300 300–600 300
Povidone 500 500–1500 1250
Lufenamide 1200 1200–3200 1400
Topiramate 100 100–400 300
Valproic acid 500 500–2000 1500
Chlordiazepoxide 1000 1000–3000 2000
Zonisamide 200 200–600 200
Table 4.7
Advantages and disadvantages of rst-line anti-seizure medications
Name of drug Advantages Disadvantages
Carbamazepine Efcacy in focal
seizures, widespread
use, and clinical
experience, mood
stabilizer, low cost
Ethosuximide Effective in
disorienting seizures;
May not have
enzyme-inducing
properties; low cost
Gabapentin Virtually no drug
interactions;
Better-tolerated and
effective for
neuropathic pain
Enzyme inducer; can
exacerbate catatonic and
myoclonic seizures
No therapeutic effect on
generalized tonic–clonic
seizures, can coexist
with catatonic seizures
in some syndromes
Relatively mild, limited
to focal seizures; may
induce myoclonic
seizures
Important adverse
reactions
Hypersensitivity reactions,
cardiac conduction
abnormalities,
hyponatremia
Allergic reactions,
gastrointestinal side effects
Weight gain
(continued)
406
L. Zhou and Z. Chen
Table 4.7
(continued)
Name of drug Advantages Disadvantages
Lamotrigine Effective in focal and
most generalized
seizure types, lacks
enzyme-inducing
properties, effective in
bipolar depression
Levetiracetam Effects on focal,
myoclonic, and
predominantly
generalized tonic–
clonic seizures; few
drug interactions;
relatively well
tolerated
Oxcarbazepine Similar to
carbamazepine, it has
a lower risk of rash
and lower enzyme
induction potential
Phenobarbital Effective for focal and
most generalized
seizure types,
well-understood and
studied, once-daily
dosing, low cost
Phenytoin Anti-focal seizures,
experienced and cost
effective
Topiramate Treatment of focal and
generalized attacks;
effective in migraine
prevention
Valproic acid Very effective in most
generalized seizure
types; also effective in
focal seizures;
effective in migraine
prevention; mood
stabilizer
Requires slow titration;
is required for
administration of drugs
that interact with
valproate, enzyme
inducers, and estrogens;
can exacerbate infantile
heavy myoclonic
epilepsy
Costs more than most
other anti-seizure
medications
Reduces blood levels of
oral contraceptives; can
exacerbate catatonic and
myoclonic seizures
Enzyme inducer; can
exacerbate catatonic
seizures
Enzyme inducer,
variable and dosedependent kinetics; may
exacerbate catatonic and
myoclonic seizures
Slow titration Adverse effects of
Selective enzyme
inhibitors; caution
should be taken in
women with epilepsy of
childbearing age
Important adverse
reactions
Rash and other severe
allergic reactions
Irritability, mood changes
Rash and other
hypersensitivity reactions;
hyponatremia more
common than
carbamazepine
Adverse cognitive and
behavioral effects
Rash and other allergic
reactions; connective tissue
and surface adverse effects
cognitive decline, weight
loss, sensory
abnormalities, kidney
stones, glaucoma
Weight gain, adverse
endocrine effects, alopecia,
hepatotoxicity, pancreatitis,
greater teratogenic
potential than other
anti-seizure medications,
postnatal cognitive effects
after fetal exposure
(continued)
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
Table 4.7 (continued)
Name of drug Advantages Disadvantages
Aminohexenoic
acid
Zonisamide Effective against focal
Effective in treating
infantile spasms
and probably the other
most prevalent type of
seizures; lacks
enzyme-inducing
properties; once-daily
dose
Unfavorable risk-benet
ratio for external use in
patients with infantile
spasms
Limited experience
outside Japan and some
Pacic Rim countries
Important adverse
reactions
Irreversible visual eld
defects, weight gain
Rash and other allergic
reactions, weight loss,
kidney stones, low
amniotic uid
407
4.2.3.5 Third-Generation Anti-seizure Medications
andNew-Generation ASMs
Due to the difculty of treating DRE, an increasing number of researchers are investigating new ASMs, and the following summarizes the chemical structures, main
mechanisms of action, indications, maintenance doses, precautions, and side effects
of new-generation ASMs used in the clinic since 2006 (Table4.8) [71–81].
4.2.3.6 Assessment andMonitoring ofTreatment Effects
Assessing the efcacy of ASMs and monitoring the side effects are critical components of DRE management and should result in timely adjustments to medication
regimens and the mitigation of adverse factors. Three specic aspects of treatment
outcome are usually assessed. First, seizure frequency and severity: monitoring
changes in seizure frequency and severity are primary indicators of treatment
response. Accurate seizure diaries and detailed descriptions of patients and their
caregivers are valuable sources of information. EEG can also be reviewed regularly.
Some studies recommend rechecking once every 4–6months [64]. It is now also
possible to accurately assess the frequency and extent of seizures by wearing articial intelligence seizure monitoring equipment. Assessing the impact of treatment
on an individual’s quality of life can provide a comprehensive picture of the overall
benet of treatment in patients with DRE.Validated questionnaires and scales, such
as the Quality of Life in Epilepsy (QOLIE) measure, can be used to assess the subjective experience of treatment outcome. Neuropsychological assessment, cognitive
functioning, behavior, and emotional well-being can be affected by the epilepsy
itself and its treatments; therefore, neuropsychological assessments can help to
identify any cognitive or behavioral changes in the disease itself related to the
intervention.
408
a
Effective daily
maintenance
dose Comments
eslicarbazepine, the
main active metabolite
of oxcarbazepine
800–1200mg/d Precursor drug of
EU approval: adult
focal epilepsy with or
without secondary
generalization
Low drug–drug
interactions; preliminary
data suggest improved
tolerability when
combined with
nonsodium channel
blockers; also available
200–400mg/day
administered
twice daily
EU approval:
adjunctive treatment of
focal seizures with or
without secondary
generalization in
patients aged
>=16years
as a parenteral
formulation
Carbamazepine,
phenytoin, and
4–12mg once
daily
EU approval:
adjunctive treatment of
L. Zhou and Z. Chen
oxcarbazepine reduce
perampanel serum
concentrations two- to
threefold; approved for
once-daily
administration
focal epilepsy with or
without secondary
generalization in
patients aged >12years
sodium channels
Veterinary drug Chemical structure (2D) Main mechanism of action Approved indications
Table 4.8 Main anti-seizure medications since 2006
Eslicarbazepine acetate Blocking voltage-dependent
Enhanced voltage-dependent
slow inactivation of sodium
channels
Lacosamide
Noncompetitive antagonists of
glutamatergic AMPA receptors
Perampanel
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
High rates of
discoloration of ocular
tissues (including the
retina), skin, lips, and
nails in long-term
studies; therefore,
regabine should be
considered an orphan
drug requiring
ophthalmologic
examination prior to and
600–1200mg/
day, three doses
per day
EU approval:
adjunctive therapy for
drug-resistant focal
seizures with or
without secondary
during use
promotion in patients
aged greater than or
equal to 18years when
other appropriate drug
combinations have
proved inadequate or
are not tolerated
Valproic acid increases
serum lufenamide
concentrations,
especially in younger
children; lufenamide is
an inducer of
Depending on
age and age
variations; twice
daily
EU approval: for
age≥4years
Lennox-Gastaut
Adjunctive therapy for
syndrome-associated
seizures
409
(continued)
cytochrome CYP3A4
Kv7 channel-mediated
enhancement of neuronal
M-type potassium currents
Regabine (also known
as egabine)
Blocking voltage-dependent
sodium channels
Lufenamide
410
a
Effective daily
maintenance
dose Comments
Stavudine inhibits the
metabolism of many
coadministered
anti-seizure medications
and requires dose
adjustment when
50mg/day two
or three times
daily
EU approval:
adjunctive therapy,
combined with
clobazam and
valproate, refractory
generalized tonic
coadministered
clonic seizures in
patients with severe
myoclonic epilepsy in
infancy
recommended and the
most common side
effects are drowsiness,
dizziness, headache and
fatigue;
25–400mg/day Slow titration is
Approved by the
U.S.Food and Drug
Administration (FDA):
drugs for the treatment
of partial (localized)
seizures in adults as
L. Zhou and Z. Chen
further combination
therapy for medically
refractory partial
epilepsy in adults
(continued)
Table 4.8
transmission
Stavudine Enhanced GABAergic
Veterinary drug Chemical structure (2D) Main mechanism of action Approved indications
Binding site different from
conventional sodium channel
blockers blocks sodium
channels and enhances
GABAergic transmission
Phenobarbital