Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
160
W. Jing et al.
performed in 114 patients receiving up to three ASMs treatments. The primary efcacy analysis was based on the proportion of patients with ≥50% reduction in the
mean number of focal attacks per week over the 16-week treatment period. The
results showed that levetiracetam was signicantly more efcacious than placebo.
Levetiracetam has been shown to be effective and safe in children and adults with
refractory focal epilepsy [377].
Alejandro Ballve [378] observed 26 women of childbearing age (16–45years)
with idiopathic generalized epilepsy (IGE) including four cases of juvenile myoclonic epilepsy, eight cases of tonic–clonic seizures and four cases of adolescent
absence epilepsy. The patients were rst treated with levetiracetam as monotherapy
and were followed for more than 24months. Ultimately, the one-year retention rate
was 78.1%, and the 5-year retention rate was 51%, suggesting that LEV is effective
in treating idiopathic generalized epilepsy and can be used as a rst-line treatment
for IGE in women of childbearing age.
Regarding the treatment of epilepsy associated with brain tumors, a European
study of neurooncologist medication questionnaires found that ASMs were most
commonly used to treat glioma patients with epilepsy, followed by patients with
brain metastases and meningiomas. 86% of the respondents started antiseizure medications in brain tumor patients at the rst seizure, and levetiracetam was the most
effective drug to reduce the frequency of seizures (72%) and showed fewer adverse
effects than other ASMs. Meanwhile, the effective rates of other ASMs selected for
the rst time were lacosamide (33%), lamotrigine (22%), and valproic acid (21%)
[379]. In a study comparing the effects of levetiracetam with those of enzymeinduced anticonvulsants in the treatment of glioma patients with epilepsy [380] that
included 808 patients, LEV was signicantly more effective than enzyme-induced
anticonvulsants with fewer treatment failures due to any cause or adverse effects.
A meta-analysis [291] evaluated the effectiveness of ASM therapy in preventing
seizures in patients with brain injury. A total of seven randomized controlled trials
and 18 nonrandomized controlled trials were included. The results showed that both
LEV and phenytoin sodium (PHT) prevented early and late posttraumatic seizures
(PTS), and PHT also reduced the mortality of patients with traumatic brain injury
(TBI). The treatment-related adverse effects of LEV and PHT were higher than
those of placebo. However, LEV carries a slightly lower incidence of treatmentrelated adverse effects than PHT. Compared with PHT, LEV did not reduce the
length of hospital stay, but it did shorten the length of ICU stay. Based on the results
of the meta-analysis, it is speculated that LEV is the best treatment option for
patients with TBI.However, further high-quality randomized controlled trials are
required to conrm these ndings. Regarding LEV dose, studies suggest that LEV
(>1000mg/day) may reduce the incidence of clinical and electroencephalitic seizures in patients with TBI [381].
Another randomized, double-blinded, placebo-controlled phase 3 clinical trial
[382] investigating the safety and efcacy of levetiracetam in preventing seizures
during acute cerebral hemorrhage showed that clinical or electrical seizures were
observed in 3 of 19 patients (16%) in the levetiracetam group within the rst 72h.
This was compared to an incidence of 10 of 23 patients (43%) in the placebo group.
2 Antiseizure Medications
161
It is suggested that levetiracetam is effective in preventing acute seizure caused by
cerebral hemorrhage.
Application ofLevetiracetam inRefractory Epilepsy andEpileptic Syndrome
LEV can be used to treat Dravet syndrome, epilepsy, and eyelid myoclonus. Expert
consensus supports LEV as a common drug used in the treatment of Angelman
syndrome [73]. An observational study randomly divided 102 patients with juvenile
myoclonic epilepsy into a valproic acid group, a levetiracetam group and a lamotrigine group. The results indicated that levetiracetam had the same efcacy as valproate sodium, and was signicantly more effective than lamotrigine in the control of
seizures and myoclonic jerks, and had fewer adverse effects than valproic acid and
lamotrigine. It is suggested that levetiracetam is a good substitute for valproate in
JME patients, especially in women of childbearing age [330].
Pathogenic variants in the gene encoding the proline-rich transmembrane protein
2 (PRRT2) have been identied as the primary cause of self-limiting sporadic and
familial infantile epilepsy. A multicenter, retrospective, cross-sectional cohort study
[383] included 52 patients with infantile convulsions with a genetic diagnosis of a
probable/pathogenic PRRT2 variant. Observation showed that in PRRT2-related
infant epilepsy, sodium channel blockers CBZ and oxcarbazepine are associated
with reduced seizure frequency, while levetiracetam has poor efcacy and low
retention rate, and LEV is not recommended for this type of patient.
Familial adult myoclonic epilepsy (FAME) is a genetic disorder characterized by
cortical tremors, myoclonus, and epilepsy. The current clinical treatment is mainly
symptomatic treatment and is based on ASM use. LEV is the drug of choice, and
other drugs used include valproate, benzodiazepines and perampanel; sodium channel blockers are prohibited [384].
In addition to treatment for refractory focal seizures in children, a systematic
review and network meta-analysis [385] showed that lamotrigine and levetiracetam
were more effective than other ASMs (gabapentin, Topamax, lacosamide, perampanel, oxcarbazepine, and eslicarbazepine). Levetiracetam is more likely to allow
patients to be seizure-free.
However, during LEV treatment, there may be an increase in the frequency of
seizures, an increase in the severity of seizures, or incidence of a new type of seizures, which is called an anomalous effect. Especially in patients with drug-resistant
focal epilepsy, rhythmic epileptiform discharges upon electroencephalogram is an
independent inuencing factor for abnormal effects of LEV [386].
Wolf-Hirschhorn syndrome (WHS) is caused by the deletion of a region at the
end of the short arm of chromosome 4 and is often associated with refractory epilepsy. The most effective ASM for WHS treatment is levetiracetam [387].
Syntaxin binding protein 1 (STXBP1) is located on chromosome 9q34.11 and
encodes STXBP1. STXBP1-associated encephalopathy is a type of brain dysfunction caused by STXBP1 variants, which play an important role in the release of
synaptic vesicles. Qiu-Hong Wang etal. [388] studied 40 patients with multicenter
pathogenic STXBP1 mutation, whose clinical manifestations were Otahara
162
W. Jing et al.
syndrome, West syndrome, early-onset epileptic encephalopathies (EOEE), and
epilepsy of infancy with migrating focal seizures (EIMF). The group systematically
analyzed medical histories, video EEGs, imaging data, and antiseizure medication
histories. After 6months of LEV treatment (39.6 mg/kg/day), seizure frequency
was reduced by 50% in 88.5% of patients, and seizure freedom was achieved in
53.8% of patients.
Application ofLevetiracetam intheTreatment ofStatus Epilepticus
Phenytoin (PHT), phenobarbital (PB), and valproic acid are the second-line treatments for status epilepticus (SE) after rst-line treatment with benzodiazepines
fails. In recent years, more and more evidence has shown that the efcacy of levetiracetam as a second-line treatment for SE is comparable to that of classic drugs.
After LEV (2500mg) was injected intravenously in 20 patients with early SE,
LEV blood concentrations were 81.6μg/mL at 15min, and the median valley concentrations after 12, 48, and 96h were 28.8, 10.5, and 9.1 μg/mL, respectively.
About 95% of patients had valley concentrations higher than the lower limit of
therapeutic plasma concentration (>12μg/mL) after 12h, and seizures were suppressed in 83% of patients and 92% of nonintubated patients at 15min to 48h,
respectively. The elevated levels of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) returned to normal in two patients without treatment, without
affecting vital signs [389].
A meta-analysis of 11 studies (1933 patients) evaluated the efcacy and safety of
levetiracetam and phenytoin in the treatment of patients with conrmed SE.LEV
was signicantly more effective than PHT in overall seizure cessation and conveyed
fewer severe side effects than PHT, suggesting that LEV could replace phenytoin
sodium as the drug of choice for benzodiazepine-resistant status epilepticus [390].
The efcacy of LEV as a second-line ASM in the treatment of convulsive SE in
children is similar to that of PHT.However, the recurrence rate of seizures and the
proportion of intubation and mechanical ventilation from 1 to 24h in the PHT group
were signicantly higher than those in the LEV group [391].
In a retrospective, observational, cohort study, adult patients received at least one
dose of undiluted LEV intravenously. Three thousand six hundred seventy-four
patients (42.9%) received more than 1000mg LEV and the maximum was 4500mg,
often administered through a peripheral vein (79.1%), and adverse effects were limited to local injection site reactions (such as redness, burning and loss of peripheral
vein lines) [392].
A systematic review [393] that included ve studies comparing intravenous levetiracetam with valproic acid and phenytoin in adult SE patients showed no statistically signicant difference in efcacy or safety outcomes. There were more cases of
hypotension and respiratory failure in phenytoin users and more cases of psychiatric
side effects (such as postictal psychosis) in levetiracetam users.
Mehmet Tolga Kole etal. [394] conducted a retrospective study comparing intravenous LEV and PTH as second-line treatment for children aged 1–18years with
convulsive status epilepticus (CSE) and acute repetitive seizures (ARS). The results
2 Antiseizure Medications
163
suggested that LEV is as effective as intravenous PTH and can be used as secondline treatment for CSE and ARS in children.
Application ofLevetiracetam inSpecial Populations
The teratogenic rate of antiseizure medication therapy in pregnant women has
always been concerning. A retrospective study from India involved the observation
of 103 patients with active epilepsy taking levetiracetam during pregnancy, and the
results showed no signicant increase in the teratogenic rate, suggesting that levetiracetam monotherapy is a better drug for women with epilepsy of childbearing age
than other options [395]. However, due to the decrease in ASM plasma concentration during pregnancy, scMS etal. [396] conducted a retrospective cohort study of
29 pregnant patients treated with LEV.The results showed that decreased LEV concentration was associated with increased seizure frequency in the nonepileptic
remission group. It is recommended that LEV concentration should be controlled at
higher than 65% of prepregnancy concentration for patients who are not in remission. For patients without seizures, LEV concentration is recommended to be controlled at 46% of the prepregnancy concentration.
By establishing a physiological pharmacokinetic (PBPK) model, scholar Jiarui
Chen [397] predicted that the recommended dose of levetiracetam in the rst trimester, second trimester and third trimester was 1.2, 1.6 and 1.5 times of the baseline dose, respectively, and should not exceed 4000mg/day in the third trimester
due to fetal safety considerations. An observational study [320] analyzed the effects
of combined treatment with different antiseizure meidications on pregnancy outcomes in 110 pregnant women with epilepsy. The results showed that a combination
of lamotrigine and levetiracetam helped control seizures and achieve fetal safety.
Phenobarbital has been the preferred treatment for epilepsy following full-term
neonatal asphyxia for decades. A nonblinded, single-center, randomized, controlled
and practical clinical study included 103 neonates with acute seizures, 29 (65.9%)
of whom were in the levetiracetam group and 13 (34.2%) of whom were in the phenobarbital group with clinical seizures controlled. The difference between groups
was statistically signicant. Of the infants in the phenobarbital group who did not
respond to the original drug, 57.8% showed seizure control after the addition of
levetiracetam. It is suggested that levetiracetam may be used as the rst and second
line drug for asphyxiation epilepsy in full-term infants [398]. For acute symptomatic seizures caused by neonatal stroke, a systematic review found that the use of
ASMs acting through the GABAergic mechanism was insufcient to control seizures secondary to stroke in full-term newborns. Lidocaine and levetiracetam appear
to be very effective and have a clear safety prole in both the short and long
term [399].
For patients with epilepsy complicated by liver and kidney function impairment,
a study [400] based on a physiologic pharmacokinetic model (PBPK) predicted that
the LEV dose should be reduced to 70%, 60%, and 45% in patients with mild, moderate, and severe kidney impairment, respectively. Drug concentrations of 95%,
80%, and 57% of the adult dose were administered to impaired populations with
164
W. Jing et al.
low, medium, and high cirrhosis mortality scores, respectively. Dose adjustment is
not required for healthy elderly people, but corresponding dose reduction is required
for elderly people with organ dysfunction, to a similar extent as that in adults.
A multicenter retrospective study compared seizure frequency and seizure-free
rate in women with focal and generalized epilepsy treated with CBZ, lamotrigine,
and levetiracetam monotherapy during the rst 3months of pregnancy, the entire
pregnancy, and the postpartum period. A total of 57 patients with epilepsy (45 with
focal epilepsy and 12 with generalized epilepsy) were enrolled on monotherapy (29
with CBZ, 11 with LTG, and 17 with LEV). The frequency of seizures in the rst
trimester of pregnancy was signicantly lower than before pregnancy in all participants, and was more pronounced in patients with generalized epilepsy and in the
LEV group. In patients overall and in the LEV group, there was a signicant increase
in seizure-free rates in the rst trimester compared to the prepregnancy period, and
this continued into the postpartum period. In addition, 88.57% of women without
seizures remained seizure-free during pregnancy and postpartum. There was 1 case
of major heart malformation in an infant of the CBZ group, while no major heart
malformation was found in the LTG and LEV groups, suggesting that levetiracetam
is effective and safe in treating gestational epilepsy [401].
Levetiracetam can also be used as a rst-line treatment for neonatal epilepsy. A
retrospective cohort study comparing the efcacy of levetiracetam to that of phenobarbital in the initial treatment of epileptic seizures showed that initial treatment of
levetiracetam reached a seizure-free status more quickly than phenobarbital in neonatal epilepsy [402].
A randomized, double-blinded trial compared controlled-release CBZ, levetiracetam, and lamotrigine for the initial treatment of new localized epilepsy in
elderly patients ≥60years of age. The efcacy of the three drugs was similar, but the
retention rate of LEV was signicantly higher than that of controlled-release CBZ,
similar to that of LTG [403]. Another randomized trial comparing the efcacy of
LEV and that of controlled-release CBZ in elderly patients with new poststroke
epilepsy showed no difference in the number of seizure-free patients, but a signicant reduction in side effects caused by LEV was observed [404].
Safety andAdverse Effects ofLevetiracetam
The common adverse reactions of levetiracetam are neuropsychiatric symptoms,
hallucinations, delusions, aggressive behavior, and irritability. Some patients also
showed suicidal and self-harming behavior. Other reported side effects include
drowsiness, nausea, weight gain, and rashes. A case–control study [405] observed
120 adolescent epileptic patients treated with levetiracetam to analyze irritability
and its relationship with psychosocial symptoms and quality of life. The results
showed that self-reported and parent-reported levels of irritability were signicantly
higher in the levetiracetam group than in the control group. Irritability was positively correlated with behavior, emotion and attention/hyperactivity problems, and
negatively correlated with psychosocial quality of life. In a large prospective registry study involving 38,661 fetuses of pregnant women with epilepsy, prenatal
2 Antiseizure Medications
165
exposure to levetiracetam was associated with anxiety and attention decit/hyperactivity disorder [406].
Rashes caused by antiseizure medications are another side effect concerning
to clinicians. One study [407] compared the incidence of drug-related rash in
353 patients with glioma and 125 patients with meningioma who received LEV
or lacosamide (LCM) treatment from 2017 to 2019. The results showed that the
incidence of ASM-associated rash was higher in glioma patients (11%) than in
meningioma patients (1.6%). Multifactor regression analysis showed that radiotherapy adjuvant therapy and drug allergy were signicant risk factors for ASMassociated rash. Patients with both of these factors should be carefully checked
for a rash.
The negative effects of ASMs on bone metabolism are also common side effects.
A cross-sectional study [408] evaluated the effects of monotherapy on bone metabolism by measuring bone mineral density and biochemical markers 5years after LEV
administration. The results showed that no harmful effects on bone metabolism
were observed in long-term LEV treatment, and no signicant difference was
observed between outcomes at 1 and 5years, suggesting that LEV is relatively safe
for patients with osteoporosis.
ASMs have long been studied for their side effects of inducing thyroid dysfunction. A systematic review and meta-analysis of 945 pediatric patients [238] evaluated the prevalence of thyroid disease in children under 16years of age treated with
valproate (VPA), CBZ, and levetiracetam (LEV) monotherapy. The overall prevalence of thyroid abnormalities was higher in children treated with ASM.In subgroup analysis, the prevalence of thyroid biochemical abnormalities with elevated
TSH levels was higher in patients in the VPA and CBZ groups compared with those
of the control group. This study suggests a higher prevalence of thyroid biochemical
abnormalities in children treated with VPA and CBZ monotherapy, while there is no
such evidence for LEV.It is suggested that LEV should be selected for children with
thyroid predisposition if they meet the epileptic seizure type and epilepsy syndrome
medication. In another meta-analysis [409] involving 4135 participants in 35 studies, eight antiseizure medications and thyroid hormone levels were analyzed, and
LEV was associated with subclinical hypothyroidism. In terms of its impact on
children’s growth and development, LEV has the smallest impact on children’s
weight and appetite [80] of ASMs and can reduce children’s blood phosphorus concentration [410].
For patients with poststroke epilepsy, a cohort study from Sweden used association registry data for all acute adult stroke patients in Sweden from 2005 to 2010,
with 2577 patients receiving continuous ASM monotherapy enrolled in the study.
Results showed that compared with CBZ, levetiracetam could reduce the risk of
cardiovascular death in patients with epilepsy after stroke, but there was no signicant difference in overall mortality between the two drugs [331]. A Danish registry
study of 1345 patients aged 65 years and older with epilepsy with heart failure
showed that VPA treatment was associated with higher all-cause mortality and heart
failure mortality compared with LTG and LEV treatment [261]. Therefore, elderly
patients with epilepsy should choose lamotrigine or levetiracetam as ASMs.
166
W. Jing et al.
Neuropsychiatric side effects of levetiracetam should be monitored. Up to 13%
of children taking LEV reported irritability, aggression, personality changes, emotional instability, anxiety, and depression [411]. Adel Mahmoud etal. [412] studied
105 children with epilepsy taking levetiracetam (as monotherapy or adjunctive therapy) who developed behavioral symptoms at the beginning of levetiracetam therapy.
Patients were randomly and blindly treated to determine whether pyridoxine therapy could reverse or ameliorate behavioral side effects of levetiracetam in children
1–17years of age with epilepsy. The results suggested that children who received a
therapeutic dose of pyridoxine had a more signicant improvement in neuropsychiatric symptoms than the control group.
A population-based matched case–control study in Catalonia, Spain, using
data from primary health care electronic records, showed that levetiracetam
monotherapy showed a higher risk of ischemic stroke, and further research is warranted due to the lack of data related to epilepsy diagnosis and severity of epilepsy
in this study [413]. In a retrospective cohort study, LEV was not found to be associated with insufcient anticoagulation due to drug interactions, and no increased
risk of ischemic stroke was found when combined with new oral anticoagulants [414].
In terms of the effects of LEV on the heart, studies [415] have observed the electrocardiogram parameters (PR interval, QTc, QT interval, and QRS duration) of
levetiracetam before treatment and at the sixth month of treatment, and the results
showed no signicant changes, suggesting that levetiracetam had no effect on electrocardiogram parameters.
Preclinical Research
By binding to synaptic vesicles 2A and inhibiting L-type calcium channels, LEV
inhibits neurotransmitter release and reduces neuronal overexcitation. There are
also other molecular targets, including calcium homeostasis, the GABA energy system, and AMPA receptors. Kouji Niidome etal. [416] showed that LEV reduced the
expression of FosL1 and the activity of AP-1in activated microglia, thereby inhibiting neuroinammation.
Acute brain inammation following status epilepticus (SE) is involved in blood–
brain barrier (BBB) dysfunction and brain edema, leading to the occurrence of
symptomatic epilepsy after SE.Levetiracetam (LEV) inhibited the neutrophil and
monocyte inltration into the hippocampus, which may be involved in the suppression of brain inammation and the incidence of spontaneous recurrent seizures
induced by SE [417].
In lipopol ysaccharide-treated rats, levetiracetam increased TGFβ and IL-10 levels, decreased COX-2, NF-κB, TNF-α and IL-6 expression, and decreased BCL2
2 Antiseizure Medications
167
expression and malondialdehyde levels. LEV improved neuroinammation-related
memory impairment by enhancing cholinergic activity while reducing neuroinammation, apoptosis, and oxidative stress [418].
Harun DEMIRC etal. [209] examined whether ASMs can contribute to axonal
healing after traumatic brain injury. Levetiracetam (80mg/kg, intraperitoneal injection) was given to a rat model with biparietal area brain injury, which can increase
the expression of neuron-glial cell antigen 2 (NG2), suggesting that LEV can accelerate axonal healing.
Early administration of levetiracetam after injury in invitro trauma sections and
in invivo controlled cortical impact (CCI) models may prevent or reduce the occurrence of posttraumatic epilepsy and suggest that the therapeutic window for successful preventive intervention may be narrow [419].
Other Effects ofLevetiracetam besides theAntiseizure Effect
Levetiracetam improved cognition in Alzheimer’s disease (AD) patients with epilepsy. KeithVossel etal. [420] conducted a phase 2a randomized double-blinded
placebo-controlled crossover clinical trial on levetiracetam in 34 adults with AD,
and the results showed that levetiracetam could improve spatial memory and executive function in patients with AD and epileptiform activities.
Nalini R etal. [421] showed that long-term treatment with levetiracetam resulted
in a decrease in Aβ42 levels and amyloid plaque burden by normalizing presynaptic
endocytoprotein levels and altering the tendency of amyloid precursor protein
(APP) to cleave. It provides new evidence for the treatment of levetiracetam to alleviate the pathology of AD.
In rat models of AD, levetiracetam alleviates STZ-induced hippocampal cell
death and memory impairment by reducing oxidative damage, inhibiting the expression of proinammatory cytokines, and inhibiting abnormal hyperphosphorylation
of tau [422].
A review evaluating the role of levetiracetam in the prevention of adult migraine
patients showed a signicant reduction in the frequency, severity, and duration of
migraine, suggesting that levetiracetam appears to be effective in the treatment of
migraine with or without aura, with fewer side effects [423].
Stress during adolescence is a major risk factor for schizophrenia. Stress in adolescents produces anxiety-like responses that impair social skills and cognitive
function. Levetiracetam reduces stress-induced behavioral and electrophysiological
changes in adolescents [424].
168
W. Jing et al.
2.1.2.3 Topiramate
Characteristics oftheDrug
[Name of chemical] 2,3,4,5-Dioxygen-(1-methyl-ethyl)-β-D-fructopyranose sulfonate
[Chemical structure formula]
[Molecular formula] C12H21NO8S
[Molecular weight] 339.362
[Indications for use] (1) Monotherapy in patients with newly diagnosed epilepsy
or concomitant medication use switched to monotherapy; (2) Add-on therapy for
partial seizures in adults and children aged 2–16years.
[Specication] 25mg, 100mg
[Dosage] It is recommended that treatment be started at a low dose and gradually
increased to an effective dose. A dose of 25–50mg can be taken orally every night
and increased by 25–50 mg/day at 1- or 2-week intervals. The dose should be
adjusted according to clinical efcacy, usually 200–400mg/day, twice daily.
[Adverse reactions] Ataxia, impaired attention, confusion, dizziness, fatigue, paresthesia, drowsiness, and abnormal thinking.
Clinical Application andBasic Research
Historical Evolution ofTopiramate
Approved in the United States in 1996, topiramate (TPM) is a broad-spectrum antiseizure drug authorized for the single and adjuvant treatment of various types of
epilepsy, including focal epilepsy, generalized tonic–clonic seizures, juvenile myoclonic epilepsy, epileptic encephalopathy (e.g., West syndrome, Dravet syndrome,
and Lennox–Gastaut syndrome), and status epilepticus. In addition, following the
in-depth study of the mechanism of epilepsy, the treatment scope of topiramate has
also expanded to include other types of epileptic encephalopathy, developmental
and epileptic encephalopathy (DEE) and KCNQ2 encephalopathy.
2 Antiseizure Medications
169
TPM exerts antiseizure effects through several mechanisms of action, including
reducing epileptiform discharges through a voltage-dependent Na+ channel block,
enhancement of γ-aminobutyrate activity at some subtypes of γ-aminobutyrate
receptors, and antagonism of non-N-methyl-D-aspartate (NMDA) glutamate receptors [425].
Application ofTopiramate forDifferent Seizure Types
The antiseizure effects of topiramate in multiple epilepsy subtypes have been widely
demonstrated over the past 20years. There is level 1 evidence that topiramate is
effective as an adjunctive treatment for primary generalized tonic–clonic seizures,
with a greater reduction in seizure frequency occurring in the topiramate group
(56.7%) than in the placebo group (9%) in one study [426]. A systematic review and
network meta-analysis of seven randomized controlled trials (1809 patients) comparing the relative efcacy of antiseizure drugs as monotherapy for generalized seizures showed that topiramate had a comparable seizure-free probability (44%) as
valproate (38%) in the treatment of generalized tonic–clonic, tonic, and clonic seizures [427]. A Cochrane review of 12 RCTs (1650 participants) revealed that topiramate was almost three times more effective than placebo, reducing seizure
frequency by more than 50% when used as an add-on treatment for drug-resistant
focal epilepsy [428].
To evaluate the efcacy and tolerability of topiramate in juvenile myoclonic
epilepsy (JME), Liu J etal. [429] reviewed three randomized controlled trials that
investigated the effects of topiramate versus placebo or sodium valproate in
patients with JME, comprising a total of 83 participants. In terms of efcacy, a
greater proportion of participants in the topiramate group had a 50% or greater
reduction in idiopathic generalized tonic–clonic seizures than did those in the
placebo group. There was no signicant difference between topiramate and valproate with regard to a 50% or greater reduction in myoclonic seizures versus
idiopathic generalized tonic–clonic seizures and no seizures, but topiramate was
better tolerated.
In addition, topiramate has good efcacy in treating epileptic encephalopathy. A
systematic review of 14 studies conducted by Song JM to evaluate the efcacy of
topiramate as a rst-line or adjunctive treatment for West syndrome patients revealed
that 17–40% of patients were seizure-free and 45–70% had at least a 50% reduction
in seizure frequency after taking the drug [309]. In a clinical trial conducted by
Knupp KG’s team, topiramate treatment reduced seizure frequency by 50% in
35–78% of patients with Dravet syndrome and achieved short-term seizure freedom
in 10–17% of patients with Dravet syndrome [430]. A network meta-analysis
included a total of eight randomized controlled trials (1171 patients) comparing the
efcacy of six antiseizure drugs in patients with LGS, and the results showed that
topiramate had a relatively high probability of reducing fall attacks [431]. A retrospective study involving 13 patients showed that topiramate was also effective in the
treatment of KCNQ2 encephalopathy [432].