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Chapter 4
Clinical Application ofAnti-seizure
Medication asDrug Therapy
LieminZhou andZiyiChen
4.1 Pharmacological Treatment ofDifferent Types
ofEpileptic Seizures
4.1.1 Classication ofEpileptic Seizures
The International League Against Epilepsy (ILAE) established its classication system for epileptic seizures, which is currently the most widely used classication
system worldwide, in 1981 [1]. In 2017, the ILAE introduced the latest version of
the classication system based on accumulating clinical evidence over the past
30years, in an effort to revise and supplement the types of seizures and terms used
[2]. This chapter discusses the selection of anti-seizure medications (ASMs) according to the latest classications of seizures, with some evidence-based medical references comparing the two sets of classications from 1981 and 2017.
Seizures are classied based on initial clinical manifestations and electroencephalogram (EEG) changes. In addition to symptomatic descriptions, the use of seizure
recordings is encouraged. The latest classication emphasizes the practicality of
clinical use and allows for specic renement of classication based on clinical needs.
L. Zhou (*)
Department of Neurology, The Seven Afliated Hospital of Sun Yat-sen University,
Shenzhen, China
Z. Chen
Department of Neurology, The Seven Afliated Hospital of Sun Yat-sen University,
Shenzhen, China
Ltd. 2025
X. Wang, L. Zhou (eds.), Pharmacological Treatment of Epileptic Seizures,
https://doi.org/10.1007/978-981-96-8520-2_4
391© The Author(s), under exclusive license to Springer Nature Singapore Pte
392
L. Zhou and Z. Chen
4.1.1.1 Focal Onset Seizures
Seizures consistently originate from a localized or more widely distributed epileptogenic network within one cerebral hemisphere, with predominant conduction
pathways of discharge, and can subsequently involve the opposite cerebral hemisphere. Focal-onset seizures may originate from subcortical gray matter structures.
Some patients may have multiple epileptogenic networks and various types of seizures, but the initiating brain region for each seizure type is consistent. The EEG
manifestations of various focal seizures during the seizure period show evolving
features of epileptic activity, with specic manifestations varying due to differences
in the starting site, propagation speed, and range of discharge. Focal-onset seizures
are classied into three levels. The rst level is based on whether the patient perceives themselves and the environment throughout the entire seizure process; seizures are thus classied into preserved awareness and impaired awareness. The
second level is based on the initial symptoms, including motor symptom onset, such
as automatisms, atonia, clonic, tonic, hyperkinetic, myoclonic, and tonic–clonic seizures; and nonmotor symptom onset, such as autonomic, behavioral arrest, and cognitive, emotional, and sensory symptoms. The third level includes progression to
bilateral tonic–clonic seizures.
4.1.1.2 Generalized-Onset Seizures
Seizures originate from a point in the epileptogenic network formed by the bilateral
cerebral cortex and subcortical structures and rapidly spread throughout the entire
network. The origin point of each seizure varies within the network. Generalizedonset seizures may not necessarily involve all cortices and can be asymmetric.
Generalized onset seizures include tonic–clonic seizures, tonic seizures, clonic seizures, myoclonic seizures, myoclonic-tonic–clonic seizures, atonic seizures,
myoclonic- atonic seizures, epileptic spasms, typical absence seizures, atypical
absence seizures, myoclonic absence seizures, and eyelid myoclonic absence
seizures.
4.1.1.3 Seizures ofUnknown Onset
Patients with insufcient information about seizure onset may be temporarily classied into this category until further information is available to determine focal or
generalized onset.
4.1.1.4 Unclassiable Seizures
Patients with insufcient information about seizures may be temporarily classied
into this category until further information is available for seizure type diagnosis.
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
393
4.1.2 Principles ofSelecting Anti-seizure Medications
Selecting medications based on seizure types and syndromes is the fundamental
principle of epilepsy treatment, and takes into consideration the patient’s age, sex,
adverse drug reactions, comorbidities, concomitant medications, and patient or
caregiver preferences.
4.1.2.1 Medication Selection forFocal-Onset Seizures
Carbamazepine, lamotrigine, and levetiracetam are rst-line drugs for patients with
newly diagnosed focal-onset seizures [3, 4]. The Standard and New Antiepileptic
Drugs (SANAD) study compared the effects of extended-release carbamazepine
tablets with those of lamotrigine and gabapentin, while the SANADII study compared the effects of lamotrigine with levetiracetam and zonisamide. Both studies
showed that lamotrigine had better efcacy and safety, and recommended it as the
rst choice for focal-onset seizures [3, 4]. A meta-analysis of monotherapy for focal
epilepsy included ten ASMs—carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, valproic acid, zonisamide, topiramate, phenytoin, phenobarbital, and
gabapentin—with the highest retention rates observed for lamotrigine and levetiracetam [5]. Oxcarbazepine is the rst-line treatment for newly diagnosed focalonset seizures in children. If carbamazepine, oxcarbazepine, or lamotrigine is not
suitable or is not tolerated, valproic acid, primidone, or lacosamide may be considered. If the rst-selected drug among these seven ASMs is ineffective, another drug
can be selected from them. If a second ASM agent with good tolerability is ineffective, combination therapy may be considered [5].
When rst-line treatment is ineffective or intolerable, carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, valproic acid, topiramate, clobazam, gabapentin, zonisamide, primidone, pregabalin, and lacosamide can be added for focal-onset
seizures. If additional treatment is ineffective or intolerable, other ASMs to consider
include phenobarbital and phenytoin. The difference in the efcacy of these drugs
for focal-onset seizures is not signicant, and the choice should take into consideration the patient’s age, comorbidities, accompanying diseases, potential adverse
reactions, economic burden, drug accessibility, and expectations for quality of life.
There is a lack of evidence-based medicine for drug selection in focal-onset
myoclonic seizures and atonic seizures. Focal-onset myoclonic and atonic seizures
often present with drug resistance and have poorer drug responsiveness than focalonset tonic–clonic seizures or sensory seizures. Currently preferred drug spectra for
focal-onset seizures and for worsening of generalized-onset myoclonic or atonic
seizures are exactly the same. Therefore, broad-spectrum ASMs such as valproic
acid, levetiracetam, and clonazepam are often used in clinical practice [6].
Occasional reports of the effectiveness of carbamazepine and phenobarbital, as well
as reports of worsening seizures, have emerged [7].
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L. Zhou and Z. Chen
4.1.2.2 Medication Selection forGeneralized Onset Seizures
Tonic–Clonic Seizures andMyoclonic-Tonic–Clonic Seizures
Valproic acid has been a rst-line drug for newly diagnosed generalized-onset
tonic–clonic seizures for nearly half a century [5, 8, 9]. If valproic acid is not suitable, lamotrigine or levetiracetam may be used [9]. Carbamazepine and oxcarbazepine can be used only for patients with generalized tonic–clonic seizures. When the
rst-line drug therapy is ineffective or intolerable, lamotrigine, clobazam, levetiracetam, valproic acid, topiramate, perampanel, and lacosamide can be added as
adjunctive therapies [10]. If patients with generalized-onset tonic–clonic seizures
also have absences or myoclonic seizures, carbamazepine, oxcarbazepine, gabapentin, phenytoin, pregabalin, tiagabine, and vigabatrin cannot be used [11]. In patients
who have myoclonic seizures or suspected juvenile myoclonic epilepsy, lamotrigine
may exacerbate myoclonic seizures. There are no targeted clinical trials for
myoclonic- tonic–clonic seizures, and drug selection is generally based on principles for tonic–clonic seizures.
Generalized-Onset Tonic, Clonic, or Atonic Seizures
Valproic acid is the rst-line drug treatment for patients with generalized-onset
tonic, clonic, or atonic seizures. If valproic acid is ineffective or not tolerated,
lamotrigine or runamide may be added. If adjunctive therapy is still ineffective or
intolerable, topiramate may be considered. Carbamazepine, oxcarbazepine, gabapentin, pregabalin, vigabatrin, and tiagabine are not recommended [11].
Generalized-Onset Myoclonic Seizures
Valproic acid is the rst-line treatment for newly diagnosed myoclonic seizures. If
valproic acid is not suitable or tolerable, use of levetiracetam [12] or topiramate [13]
may be considered; however, compared to levetiracetam and valproic acid, topiramate has more side effects. When the rst-line treatment is ineffective or intolerable, levetiracetam, valproic acid, or topiramate may be added for patients with
myoclonic seizures. If adjunctive therapy is ineffective or intolerable, options may
include clonazepam, clorazepate, lorazepam, or zonisamide. Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, vigabatrin, and tiagabine cannot be
used [11].
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
395
Myoclonic-Atonic Seizures
This seizure type is common in Doose syndrome patients. The rst-line drugs for
treating seizures are valproic acid, levetiracetam, and zonisamide. If drug tolerance
is needed, a ketogenic diet may be considered [14].
Epileptic Spasms
The UKISS and PERC studies recommend the use of ACTH and aminohexenoic
acid for the treatment of epileptic spasms [15–18]. The International Collaborative
Infantile Spasms Study (ICISS) further recommends early combination therapy
with ACTH and vigabatrin [19].
Absence Seizures
① Typical absence seizures and myoclonic absence seizures: Ethosuximide or val-
proic acid is the rst-line drug for treating typical absence seizures [20]. If there
is a high risk of generalized tonic–clonic seizures, valproic acid should be con-
sidered rst if there are no contraindications [21]. When ethosuximide and val-
proic acid are not suitable, ineffective, or not tolerated, lamotrigine use may be
considered [22]. If two rst-line anti-seizure medications are ineffective, a com-
bination of ethosuximide, valproic acid, and lamotrigine may be considered. If
combination therapy is ineffective or not tolerated, clinical data should be
reviewed to re-evaluate the diagnosis, and if accurate, clorazepate, clonazepam,
levetiracetam, topiramate, lorazepam, or zonisamide use may be considered.
Carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, vigabatrin,
and aminohexenoic acid cannot be used. The treatment of myoclonic absence
seizures requires robust evidence-based medicine, and currently, clinical practice
remains consistent with the principles of treating typical absence seizures.
Atypical Absence Seizures: Broad-spectrum anti-seizure medications such as val-
②
proic acid, levetiracetam, topiramate, clonazepam, and clobazam are routinely
used for atypical absence seizures. Stiripentol can also be used for monotherapy
in refractory patients [23].
③ Eyelid Myoclonic Absence Seizures: Traditional anti-seizure medications for
treating eyelid myoclonic absence seizures include ethosuximide, valproic acid,
benzodiazepines, and phenobarbital. Levetiracetam has been shown to be effec-
tive for treating this seizure type in multicenter placebo-controlled studies [24].
In clinical practice, lamotrigine is as effective as the aforementioned drugs
[25, 26].
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L. Zhou and Z. Chen
4.1.2.3 Medication Selection forUnclassiable Seizures
For unclassiable seizures, it is recommended in clinical practice to collect as much
data as possible and to improve seizure classication. This may include telephone
inquiries with witnesses who were not present at the outpatient clinic, asking family
members to search for surveillance footage around the time of the seizure, or exporting data from motion bracelets or watches worn by the patient at the time of the
seizure. If these methods do not provide sufcient information, long-term video
electroencephalographic monitoring should be conducted to capture clinical seizures and obtain more accurate clinical-electrophysiological evidence for newly
diagnosed epilepsy patients.
There is limited evidence-based treatment for unclassiable seizures. The
SANAD study suggested the use of phenytoin as a preferred option due to its low
rate of adverse reactions and high retention rate, with lamotrigine and topiramate as
alternative options for patients of childbearing age or those with contraindications
to valproic acid [8]. The SANADII study compared the effects of valproic acid with
those of levetiracetam and found no signicant advantage of the latter; thus, levetiracetam is recommended as an alternative when valproic acid cannot be used.
4.2 Pharmacologic Treatment ofRefractory Epilepsy
Epilepsy is a chronic brain disorder caused by a variety of etiologies, characterized
by recurrent, seizure-inducing, and transient central nervous system malfunctions
due to excessive neuronal discharge, affecting more than 70million people worldwide. Despite the continuous introduction of new ASMs, approximately one-third
of patients with epilepsy have seizures for which pharmacological treatment is ineffective. In 2010, the International League Against Epilepsy dened drug-refractory
epilepsy (DRE) as a condition in which a sustained seizure-free status has not been
achieved with the application of two correctly selected and tolerated ASMs (monotherapy or combinations), assessed over a period of time that can be 1year or at
least three times the previous longest seizure-free interval [27]. DRE is associated
with the emergence of multiple comorbidities, mood disorders, and personality
changes, severe psychosocial problems, increased risk of sudden death, increased
mortality, cognitive problems, and decreased quality of life [28–31]. One study
reported that in 2016, epilepsy accounted for the loss of more than 13 million
disease- adjusted life years [32]. Between 30% and 40% of pediatric patients with
epilepsy also suffer from intellectual disability, making it the most burdensome disease across the spectrum of neurological disorders in children and young adults [33,
34]. When assessing direct and indirect costs, the wage-based productivity losses
associated with epilepsy are nearly equal to the combined wage losses due to anxiety, asthma, and depression [35].
Therefore, there is an urgent need to explore and study the treatment of
DRE. Identifying which epilepsies can develop into DRE at an early stage is
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
397
important for determining the prognoses of patients, and understanding the causes
or mechanisms of DRE resistance is crucial for determining the exact treatment
strategy and precise treatment. Current therapeutic strategies for DRE include pharmacologic therapy, epilepsy surgery, neuromodulation, a ketogenic diet, and lifestyle modication [28]. Among these options, anti-seizure medication is still the
main treatment for DRE [36]. This section discusses in detail the strategies used for
the pharmacologic treatment of refractory epilepsy.
4.2.1 Risk Factor Prediction forDrug-Refractory Epilepsy
It is important to assess the timing of treatment for DRE, and if DRE can be identied at an early stage during clinical diagnosis and treatment, early standardized
management can help to improve patient prognosis. At present, an increasing number of scholars have conducted studies on the risk factors or predictors of DRE.Wang
etal. [37] published a meta-analysis on the risk factors for refractory epilepsy in
2019, summarizing the studies that retained patients for the longest follow-up period
or the largest sample size among 8397 studies between 1993 and 2018. Ultimately,
16 studies were included in the nal meta-analysis, including 9 prospective analyses
and 7 retrospective analyses. The prevalence of DRE was approximately 27%,
according to the criteria of DRE dened by the International League Against
Epilepsy in 2010, in which electroencephalogram (EEG) abnormalities (including
slow waves and epileptiform discharges), status epilepticus (SE), symptomatic etiology, febrile convulsions, and multiple seizure types are strong risk factors for
refractory epilepsy, while poor short-term treatment outcomes, neurodevelopmental
delay, and high seizure frequency in the initial stages of epilepsy are not denite risk
factors for DRE; however, the predictive effect of focal seizures is erratic.
In 2022, by summarizing and comparing the results of national and international
studies, Li etal. [38] classied the levels of evidence of association found in the
studies into four levels: (a) very little evidence: ≤1 available study; (b) insufcient
(weak) evidence: two available studies reported signicant associations in the same
direction or three available studies, two of which reported signicant associations in
the same direction, and the third reported no signicant associations; (c) strong
evidence: three available studies reporting signicant associations in the same
direction or ≥4 available studies, of which >66% reported signicant associations
in the same direction and<25% reported opposite associations; and (d) inconsistent
evidence: remaining cases. However, the level of evidence for no association was as
follows: (a) strong evidence: > four available studies, > 85% of which reported no
association; (b) insufcient (weak) evidence: > four available studies, > 75% of
which reported no association. Evidence was obtained on the basis of available
univariate associations or on the basis of multivariate associations when univariate
associations were unavailable. Clinical predictors of participation in the studies
included ① age at onset, ② abnormal EEG (abnormal EEG (not rened), focal slowing, epileptiform discharges, generalized discharges), ③ type of seizure not rened
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L. Zhou and Z. Chen
(focal seizures, generalized seizures, mixed seizures), ④ status epilepticus, ⑤ febrile
convulsions, ⑥ initial frequency of seizures not rened (at any time of the day, >1
seizure per month, >10 seizures prior to treatment), ⑦ symptomatic etiology (cortical dysplasia, asphyxia, perinatal hypoxic ischemic encephalopathy, temporal lobe
medial sclerosis, neoplastic etiology, infectious etiology, vascular etiology, traumatic etiology, history of brain surgery, history of brain injury), ⑧ developmental
delay, ⑨ comorbidities not subdivided (psychiatric disorders, depression, obesity),
⑩ failure to respond or poor response to the rst ASM, ⑪ epileptic duration, ⑫
male sex, ⑬ neonatal epilepsy, ⑭ family history of epilepsy, ⑮ abnormalities in
neuroimaging, and ⑯ abnormal neurological examination (remarks: not rened: a
specic determinant or type not clearly identied in the study; EEG). Results: In the
clinical predictor analysis, mixed seizure types, status epilepticus, no or poor
response to rst ASM, neonatal seizures, abnormal neuroimaging ndings, and
abnormal neurologic examination ndings were strong predictors of DRE, whereas
the grade of unassociated evidence showed that male sex and family history of epilepsy were strongly unassociated with DRE [38].
In the biochemical predictor analysis, the biochemical predictors involved in the
analysis included ① inammation-related predictors: high mobility group protein 1
(HMGB1), soluble vascular cell adhesion molecule 1 (sVCAM-1), activation- regulated chemokine (TARC)/soluble intercellular adhesion molecule 5 (sICAM5), neural cell adhesion molecule 1 (NCAM-1), human chitin 40 (YKL-40), programmed
death receptor 1 (PD-1), zinc transporter 3 (ZnT3) and glial cell protobrillary
acidic protein (GFAP), ② epigenetic predictors (miR-4521, miR-139-5p,
miR- 34c-5p, miR-145-5p, miR-146a and miR-134, miR-146a and miR-134,
miR-142 and miR-223, miR-342-5p, miR-584-5p, miR-150-5p, miR-125b-5p,
miR-199a-3p, miR-199a-5p, miR 194-5p, miR-301a-3p, miR-30b-5p, miR-342-5p,
miR-4446-3p), ③ genetic predictors (ABCB1, ABCC2, SCN1A, CACNA1A,
CCL2), resulting in studies that found strong evidence that the inammation-related
marker HMGB1 and the genetic marker SCN1A are associated with DRE [38].
4.2.2 Mechanisms ofDrug-Resistant Epilepsy
Bazhanova ED etal. [39] reviewed the global literature on the causes and mechanisms of drug resistance in epilepsy in 2021 and proposed eight current hypotheses
regarding the causes of drug resistance in epilepsy (Table4.1): the pharmacokinetic
hypothesis, the transporter protein hypothesis, the neural network hypothesis, the
intrinsic severity hypothesis, the genetic variation hypothesis, the epigenetic hypothesis, the target site hypothesis, and the neuroinammatory hypothesis. The following
describes the specic meanings of the eight hypotheses and the evidence supporting
and not supporting the hypotheses. ① The pharmacokinetic hypothesis refers to the
fact that the overexpression of drug efux carriers in peripheral organs reduces anticonvulsant drug levels and that the overexpression of transporters in the blood–brain
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
399
Table 4.1
of drug-resistant epilepsy
mechanisms
Eight hypotheses
Hypotheses of epilepsy drug resistance
Target hypothesis
Genetic variants hypothesis
Transport hypothesis
Epigenetic hypothesis
Neural network hypothesis
Pharmacokinetic hypothesis
Hypothesis of neuroinammation
Intrinsic severity hypothesis
barrier and neurons does not account for the clinically observed decrease in drug
concentrations [28]. There are also animal studies that do not support the pharmacokinetic hypothesis [40]. ② The transporter protein hypothesis states that the overexpression of drug efux carriers in the blood–brain barrier reduces anticonvulsant
drug levels and that multidrug resistance proteins are overexpressed in cerebral capillary endothelial cells and astrocytes of patients with drug-resistant epilepsy [41].
This hypothesis is supported only by animal studies and not in human tissues [42].
③ The neural network hypothesis refers to neuronal degeneration and synaptic network remodeling leading to the inhibition of the brain’s seizure control system and
the limitation of drug access to targets. Cortical dysplasia is often associated with
drug-resistant epilepsy. The basis of pathological neural networks in focal drugresistant epilepsy [43] supports this hypothesis, while some patients with cortical
dysplasia and altered neural networks are not drug resistant. The nding that some
patients do not respond to anti-seizure medications after temporal lobectomy [44]
does not support this hypothesis. ④ The intrinsic severity hypothesis refers to neurobiological factors that inuence both the severity of epilepsy and drug resistance, a
hypothesis supported by clinical reports and transcriptomic analysis of human hippocampal tissue. However, the results of these studies, suggesting that drug resistance does not depend on the number and severity of pretreatment seizures [28], do
not support this hypothesis. ⑤ The genetic variation hypothesis refers to genetic
polymorphisms that are associated with pharmacodynamics, metabolic pathways,
enzymes, ion channels, and neurotransmitter receptors, and the blockage of drug
binding, metabolism, and transport leads to the development of resistance. It has
been found that polymorphisms are associated with various types of epilepsy, and
that genetic changes occur in patients with untreatable epilepsy [45], supporting this
hypothesis. ⑥ The epigenetic hypothesis refers to the idea that changes in the epigenome can play a role in the pattern of drug resistance, and manipulation of microRNAs can inuence the course of seizures and epileptic episodes in experiments using
laboratory animals [40, 43, 46], supporting this hypothesis. However, it is difcult to
separate cause from effect and signicance from collateral phenomena, especially in
humans, where no favorable evidence can be provided. ⑦ The target hypothesis
refers to potentially dependent quantitative and qualitative changes in ion channels
and neurotransmitter receptors leading to a reduction in drug susceptibility and
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L. Zhou and Z. Chen
development of drug resistance, which is supported by studies of Dravet syndrome
and by studies of the effectiveness of carbamazepine and phenytoin [28, 40, 47],
whereas patients with drug- resistant epilepsy are usually unresponsive to different
classes of drugs with different mechanisms of action. ⑧ The neuroinammatory
hypothesis refers to the fact that neuroinammation can induce blood–brain barrier
dysfunction and upregulate Pgp expression in drug-resistant epilepsy, which has
been found experimentally and clinically to increase blood–brain barrier permeability in patients with chronic epileptic foci. Many studies have shown increased cytokine levels in the brains and plasma of patients with drug-resistant epilepsy and in
animal models [48], supporting this hypothesis.
4.2.3 Pharmacologic Strategies forTreating
Drug-Resistant Epilepsy
It is undeniable that drug treatment of DRE still serves as the main strategy, and
many domestic and international scholars are now investing in research on antiseizure medications; almost one drug is developed every year. The three generations
of anti-seizure medications used are listed in Table4.2 [49]. The selection of effective ASMs and the formulation of effective combination drug regimens are crucial
for the treatment of DRE, which will be explained in detail in the following sections.
4.2.3.1 Pretreatment Assessment
Many epileptologists believe that a careful evaluation is needed before proceeding
with medicating DRE patients and that medication decisions are made after the
evaluation has once again claried the circumstances under which DRE was
achieved. The pretreatment assessment includes the following: rst, the diagnosis of
DRE needs to be reviewed for errors based on medical history; second, whether the
clarication of seizure types and syndromes is correct and complete; third, whether
Table 4.2 Three generations of anti-seizure medications
First-generation ASMs
Bromide, Phenobarbital,
Mephobarbital, Phenytoin,
Acetazolamide, Trimethadione,
Mephenytoin, Paramethadione,
Corticosteroids/ACTH,
Phenacemide, Phensuximide,
Primidone, Methsuximide,
Ethotoin, Ethsuximide
Second-generation
ASMs Third-generation ASMs
Chlordiazepoxide,
Sulthiame, Diazepam,
Carbamazepine,
Valproate,
Clonazepam,
Clobazam
Progabide, Vigabatrin, Zonisamide,
Lamotrigine, Oxcarbazepine,
Felbamate, Gabapentin, Topiramate,
Tiagabine, Levetiracetam,
Pregabalin, Stiripentol, Runamide,
Lacosamide, Eslicarbazepine
acetate, Retigabine (ezogabine),
Perampanel, Imepitoin (dogs),
Brivaracetam, Everolimus