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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
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[Adverse effects]
Rash, Headache, Fatigue, Nausea, Vomiting, Dizziness, Lightheadedness,
Drowsiness, Insomnia, Blurred or Double Vision, Irritability and Impulsive
Behavior, Ataxia (Loss of Coordination), Anxiety. A minority of patients may experience leukopenia, anemia, thrombocytopenia or tremor.
Fundamental andClinical Research
Historical Evolution
Lamotrigine (LTG) is a broad-spectrum antiseizure medication that was developed
and synthesized in the UK in 1978 and came to market in 1990 for the adjunctive
treatment of intractable epilepsy. In 1994, it was approved for the adjunctive treatment of partial seizures in adults, and in 2003, the FDA approved it for monotherapy
of partial-onset seizures in patients aged 16 and older, as well as for adjunctive
therapy in children aged 2years and older with focal seizures. That same year, it
was also approved for treating acute manic episodes and for the maintenance treatment of bipolar disorder in adults. Its current indications are as monotherapy for
simple and complex partial seizures, primary and secondary generalized tonic–
clonic seizures in children older than 12years and adults, and as adjunctive therapy
for partial seizures and primary generalized tonic–clonic seizures in children older
than 2 years and adults. It is also suitable for treating seizures associated with
Lennox–Gastaut syndrome. Lamotrigine acts mainly as a sodium channel blocker
and has some effect on calcium channels (N, P-type). Clinically, it is also used to
treat generalized absence seizures, infantile spasms, and other seizure types.
Management ofDifferent Seizure Types
The International League Against Epilepsy’s Commission on Epilepsy and Gender
in their latest techniques and guidelines for clinicians states that after careful consideration of the teratogenic effects and impact of sodium valproate on women of
childbearing age during pregnancy, the working group considers lamotrigine and
levetiracetam to be the drugs of choice for primary generalized tonic–clonic seizures and juvenile myoclonic epilepsy in women of childbearing age, with lamotrigine being the preferred medication for juvenile absence epilepsy. Another guideline
focused on the relationship between patient compliance and antiseizure medication
(ASM) intake, seizure control, and potential toxicity. Long half-life immediaterelease (IR) medications and extended-release (ER) formulations (such as lamotrigine [IR, ER]) that allow for once-daily dosing have many advantages over short
half-life drugs that require multiple daily doses. These advantages include simplied dosing regimens, reduced medication burden, and less uctuation in serum concentrations, which may decrease the risk of adverse reactions and seizures.
A recent randomized, open-label, controlled trial compared the effectiveness of
levetiracetam and zonisamide with that of lamotrigine as a rst-line treatment for
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newly diagnosed focal epilepsy patients. The initial recommended maintenance
doses for participants aged 12 and above were 50mg (morning) and 100mg (evening) of lamotrigine, 500mg of levetiracetam twice daily, and 100mg of zonisamide
twice daily. For children aged 5–12years, the recommended initial daily maintenance dose was 1.5mg/kg lamotrigine twice daily, 20mg/kg levetiracetam twice
daily, and 2.5mg/kg zonisamide twice daily. A total of 990 participants were
recruited over 4years and were followed up for another 2years. Patients were randomly assigned to receive lamotrigine (n = 330), levetiracetam (n = 332), or
zonisamide (n=328). The results suggest that lamotrigine is more cost-effective
and has greater net health benets. It should remain a rst-line treatment for patients
with focal epilepsy and should be the standard treatment in future trials [319].
Lamotrigine is widely used to treat epilepsy. Chinese scholars [147] assessed the
national trend of ASM prescriptions for adult epilepsy outpatients in China over
6years from 2013 to 2018. Among 225,767 prescriptions available for analysis, the
three most common combination therapy schemes observed were lamotrigine/valproate, levetiracetam/oxcarbazepine, and valproate/levetiracetam.
Medication inSpecial Populations
Clavenna A. and colleagues [148] described the prescription patterns of ASMs
among pregnant women and women of childbearing age in the Lombardy region of
Italy from 2010 to 2019. The results showed that the proportion of women of childbearing age taking valproic acid (VPA) decreased from 30.2% in 2010 to 20.0% in
2019; over the decade, the proportion of pregnant women using VPA also decreased
from 24.9% to 14.1%. Starting in 2017, lamotrigine and levetiracetam became the
most frequently used drugs among pregnant women.
Spoendlin J. and others [186] studied the usage of ASMs in Switzerland during
pregnancy and among women of childbearing age from 2014 to 2018 and found
lamotrigine to be the most commonly used ASM during pregnancy, followed by
levetiracetam and pregabalin. Another study aimed at assessing pregnant women
receiving polytherapy, particularly prenatal exposure to different combinations of
ASMs, suggested that the combination of lamotrigine and levetiracetam could control seizures well without increasing the risk of fetal malformations [320].
Cohen JM etal. [321] also suggested that lamotrigine use does not increase the
risk of major congenital malformations (MCMs), and Pekoz MT etal. [322] reached
similar conclusions; meanwhile, Bromley R. and colleagues [103] speculated that
lamotrigine might slightly increase the aforementioned risk.
Many scholars have focused on the uctuations in the serum concentrations of
lamotrigine during pregnancy and the exposure of newborns to lamotrigine during
breastfeeding. Barry JM and others [323] assessed the potential impact of specic
dosing regimens of lamotrigine on the increased risk of epilepsy or toxicity.
Simulation studies revealed that metabolic changes in pregnant women could lead
to blood concentrations that are either too low or too high, potentially increasing the
risk of seizures or toxicity; hence, there is a need for individualized monitoring and
management of lamotrigine dosing during pregnancy.
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Freund B and associates [324] reported that the dose-normalized concentration
(DNC) of lamotrigine signicantly decreased during the rst half of early pregnancy. However, the timing and frequency of drug serum concentration monitoring
during pregnancy may not have a signicant overall effect on seizure control, with
preventive dose adjustments showing similar seizure control outcomes to those
based on clinical or laboratory results.
Kacirova I et al. [325] analyzed the exposure of breastfeeding newborns to
lamotrigine and reported relatively low drug concentrations in breast milk. However,
the concentrations of lamotrigine in maternal serum and breast milk signicantly
increased after delivery, which could lead to newborn serum concentrations
approaching general therapeutic levels for epilepsy, suggesting the need to monitor
newborn serum levels for potential adverse events.
Pedersen S and collaborators [326] investigated changes in the serum concentrations of ASMs in children with drug-resistant epilepsy receiving ketogenic diet
therapy. The results indicated that after 12weeks of ketogenic diet therapy, the
serum concentration of lamotrigine signicantly decreased, potentially increasing
the risk of seizures.
Another study focused on the impact of ASM use on bone metabolism in children with self-limited epilepsy with centrotemporal spikes (SeLECTS). Lamotrigine
use improved the levels of several bone metabolism indicators in epilepsy patients
[327]. In elderly patients, Assis T. and others [328] examined medication usage
among hospitalized elderly epilepsy patients between 2009 and 2010 and between
2015 and 2019, during which lamotrigine prescriptions increased from 5.5%
to 33.6%.
A randomized double-blinded trial in newly diagnosed epilepsy patients aged
≥65years showed that lamotrigine was as effective as CBZ (with more than 60% of
patients in both groups achieving seizure freedom), but lamotrigine was better tolerated [329].
Lamotrigine forTreating Symptomatic Epilepsy andEpilepsy Syndromes
Lamotrigine plays an important role in treating symptomatic epilepsy and various
epilepsy syndromes. However, in comparative studies of juvenile myoclonic epilepsy (JME), sodium valproate and levetiracetam showed comparable effectiveness.
Lamotrigine was associated with a greater failure rate in terms of epilepsy control,
myoclonic seizures, and adverse drug reactions, suggesting that it is not a suitable
sole treatment option for JME patients [330].
Larsson D. etal. [331] noted a lack of evidence guiding antiseizure medication
selection for poststroke epilepsy patients. By analyzing Swedish registry data of acute
adult stroke patients from July 2005 to December 2010 and individual data on seizures before 2015, they found that compared to CBZ, lamotrigine had the lowest risk
for all-cause mortality (risk ratio 0.72, 95% CI 0.60–0.86) and cardiovascular mortality (risk ratio 0.76, 95% CI 0.61–0.95) among drugs such as LEV, VPA, PHT, and
OXC.Another study showed that more than 60% of poststroke epilepsy patients were
treated with levetiracetam, followed by CBZ, lamotrigine and sodium valproate [332].
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Van Opijnen MP etal. [333] studied lamotrigine, a non-enzyme-inducing sodium
channel blocker, assessing its effectiveness compared to that of lacosamide as a
second-line treatment for epilepsy in patients with diffuse glioma. After a 1-year
follow-up of 139 patients, no signicant difference in the cumulative incidence of
treatment failure or adjusted risk ratios was found between lamotrigine and lacosamide, indicating similar efcacy.
Mahamud Z. etal. [334] analyzed the treatment of 129 patients with multiple
sclerosis who developed symptomatic epilepsy. Among drugs such as CBZ, LTG,
LEV, VPA, and PHT, lamotrigine had the highest 1-year and 5-year retention rates
and was the only antiseizure medication (ASM) showing a lower risk of discontinuation (HR 0.41, 95% CI 0.17, 0.99). Le Roux M. etal. [335] described 18 patients
with new or hereditary CACNA1A mutations who presented with seizures, commonly induced by fever or manifesting as absence/motion arrest. ASMs, including
lamotrigine, can halt seizures. Nevertheless, lamotrigine is not always the rst
choice for syndrome treatment. Milano C. etal. [336] examined 28 patients with
juvenile myoclonic epilepsy (JME) who switched from VPA to LTG or LEV due to
potential teratogenicity or adverse reactions and reported that LEV was signicantly
more effective than LTG for both myoclonic and generalized tonic–clonic seizures,
with similar tolerabilities for both drugs.
Adverse Effects
Adverse reactions to aromatic ASMs have always been a focal point for physicians,
especially since the early detection and of life-threatening serious adverse effects
and intervention can greatly improve patient outcomes.
Chinese scholar Zhang N and others [337] compared two different titration
schedules for lamotrigine (LTG)—once daily versus twice daily—in newly diagnosed epilepsy patients. They found no signicant difference between the two
groups in terms of the efcacy and safety of LTG.However, the retention rate of
patients in the once-daily dosing group was signicantly greater than that in the
twice-daily dosing group.
Cutaneous Adverse Effects
Korean scholar Chung SJ etal. [338] used a nationwide health claims database to
assess the incidence of serious cutaneous adverse reactions (SCARs) caused by
seven commonly used antiseizure drugs and found that lamotrigine had an incidence rate of 3860/100,000 person-years. Fukasawa T. etal. [339] reported the rst
study in Japan to document the different risks of Stevens-Johnson syndrome (SJS)/
toxic epidermal necrolysis (TEN) caused by ASMs in an observational setting, with
the risk of SJS/TEN signicantly increased in patients newly using CBZ (OR 68.00)
and lamotrigine (OR 36.00). For the Asian population, several genetic loci associated with cutaneous adverse drug reactions (cADRs) have been thoroughly studied,
including signicant associations between HLA-A*24:02 and HLA-A*30:01in the
southern Han Chinese population and aromatic antiseizure drug-induced cADRs
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[340]. HLAB*15:02, which increases susceptibility to SJS induced by lamotrigine
and CBZ, has been found in Chinese and other Southeast Asian populations, and
HLAB*31:01in Japanese patients and HLA-B*44:03in Koreans increases the risk
of SJS when taking the aforementioned drugs [341]. Mortazavi H. et al. [342]
reported that HLA-B*38 and HLA-DRB1*13 are signicantly associated with
lamotrigine-induced SJS/TEN in Iranian intensive care patients.
The occurrence of cADRs also involves cross-reactivity and many variations. A
history of adverse skin reactions may affect the use of antiseizure drugs, with crossreactivity being more common in severe cases, and most patients being affected by
mild, self-limiting rashes [135]. Packard E. etal. [343] described a case of drug
reaction with eosinophilia and systemic symptoms (DRESS) caused by crossreactivity between lamotrigine and lacosamide. Considering age differences in
patient populations, Shirzadi M. etal. [344] assessed 236 adults and 167 children
during their rst exposure to LTG, with seven children (4.2%) judged to have “skin
reactions less likely caused by LTG hypersensitivity mechanisms” compared to
0.8% (two cases) in adults. Early rashes during LTG treatment are not always drug
allergies, and other potential causes, especially in children, should be considered.
Alfares I. etal. [345] conducted a systematic review and reported that females are
more likely to develop cADRs due to ASM use (odds ratio (OR) 1.76, 95% condence interval (CI) 1.55–1.99), with the largest difference occurring in those treated
with lamotrigine (OR 2.17, 95% CI 1.53–3.08), and the pathophysiological mechanisms underlying this difference remain unclear.
Hematological Adverse Effects
Zhu X. and colleagues [346] described the case of a 15-year-old female epilepsy
patient who developed asymptomatic leukopenia after combined treatment with
lamotrigine (LTG) and valproic acid (VPA). In this patient, leukopenia was clearly
related to increased LTG serum levels and was reversed after the discontinuation of
VPA, highlighting the importance of therapeutic drug monitoring (TDM) because
of the interaction between these two drugs. Wang C. and others [347] reviewed the
occurrence of hemophagocytic lymphohistiocytosis (HLH) in patients using
lamotrigine, with the main clinical features including fever, cytopenia, rash, and
hyperferritinemia, and bone marrow showing increased numbers of hemophagocytes. Of the 17 patients, two died from severe adverse reactions.
Cardiovascular Adverse Effects
Lamotrigine has a potential risk of causing arrhythmias in patients with heart disease. In 2020, the FDA issued a warning about the risk of this medication prolonging the QRS interval, thereby increasing the risk of arrhythmias and sudden death in
high-risk populations. European researchers used the novel PHARMACOM-EPI
framework to evaluate the relationship between plasma concentrations of lamotrigine in elderly patients and the risk of death. The results showed that in patients with
plasma concentrations within the toxic range, there was a signicant increase in the
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risk of all-cause mortality and cardiovascular-related deaths [348]. However,
Christensen J and others [349] conducted a 2-year study of patients newly treated
with lamotrigine and reported that the use of lamotrigine did not increase the risk of
heart conduction disorders or all-cause mortality in patients with conduction disorders and preexisting heart disease compared to patients with no prior history of
heart disease. To date, there is no support from human or animal studies or postmarketing data for this conclusion [350, 351].
A study by Aboukaoud M and others [352] compared the risk of arrhythmias
caused by lamotrigine in patients with epilepsy to that caused by other antiseizure
drugs. The results indicated that lamotrigine use did not signicantly increase the
risk of cardiac arrest in patients with epilepsy compared to that of other drugs; however, in patients with psychiatric disorders, the use of lamotrigine might be associated with cardiac arrest, potentially related to the combined use of other medications,
overdose, and suicide attempts.
Bunschoten JW and others [353] conducted a systematic review including 26
studies, nearly half of which concluded that there was no obvious increase in the
risk of sudden unexpected death in epilepsy (SUDEP), and an additional four reports
on sudden death also did not conrm an increased risk of death with lamotrigine
use. Researchers speculate that mild prolongation of the PR interval and QT interval
is more likely related to cardiac structure rather than to medication. Another study
compared patients taking lamotrigine and other sodium channel-modulating antiseizure medications with a control group, showing that the use of lamotrigine or other
NaM-ASMs was not signicantly associated with an increased risk of SUDEP over
a period of up to 16years after hospital admission [354].
Miscellaneous
Kamitaki BK and others [182] analyzed 2.6million adverse event reports submitted to the FDA’s Adverse Event Reporting System (FAERS) database from July
2018 to March 2020 for drug-induced liver injury (DILI). A total of 2175 DILI
cases were attributed to antiseizure medications (ASMs), with the reported odds
ratio (ROR) for each individual ASM compared to all non-ASM reports calculated for DILI.Lamotrigine had an ROR of 2.06, higher than that of diazepam,
levetiracetam, and clobazam. Scholars have also focused on the data on ocularrelated adverse reactions to new antiseizure drugs in the FAERS database [355].
Oxcarbazepine use is mainly associated with several cornea-related side effects,
levetiracetam tends to cause adverse reactions related to neuromuscular diseases,
and lacosamide rarely causes any serious ocular adverse reactions. In contrast,
topiramate and lamotrigine are more likely to cause serious ocular-related adverse
reactions.
A study assessing gingival overgrowth in patients with epilepsy revealed that, in
addition to that of phenytoin sodium, lamotrigine, oxcarbazepine, and phenobarbital use were also associated with an increased incidence of gingival overgrowth. The
incidence rate of this effect following lamotrigine use is between that of oxcarbazepine and that of phenobarbital [265].
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Chen Y and others [356] reported that in patients treated with LTG, blood ammonia levels were elevated and positively correlated with plasma LTG concentrations.
This abnormal laboratory indicator may be related to factors such as concurrent use
of sodium valproate, epileptic seizures, and increased neutrophil counts. Tran DH
and others [357] described the case of a 27-year-old woman who developed a range
of symptoms, including fever, rash, meningitis, and joint pain, after using lamotrigine. Laboratory tests revealed an immune system abnormality, and the patient was
ultimately diagnosed with hemophagocytic lymphohistiocytosis (HLH). A 32-yearold African American male patient developed rapidly progressing drug-induced
pneumonia during treatment for depression after taking 25 mg of lamotrigine.
Despite the absence of other potential etiological signs, the onset of pneumonia had
a clear temporal association with lamotrigine [358]. In addition to common adverse
reactions, Ge J and others [359] described a rare side effect in which lamotrigine
caused persistent erections in an 11-year-old boy. Previous studies have suggested
that lamotrigine may improve sexual function in adult male patients.
Fundamental Research
Huang J. etal. [360] used cryogenic electron microscopy to reveal the structure of
lamotrigine (LTG) in complex with a human Nav1.7 channel and showed that LTG
blocks Nav channels through a dual-pocket mechanism, thereby providing a signicant molecular basis for understanding the pharmacological mechanism of lamotrigine. Chmielewska N and others [361] investigated whether reduced responsiveness
to lamotrigine is associated with the expression of sodium channel subunits and
miRNAs. The results showed that in drug-resistant rats, miR-9a-5p was the only
miRNA with its expression signicantly downregulated, and bioinformatics analysis revealed that miR-9a-5p targets expressed in the hippocampus were most signicantly associated with epilepsy and were involved in regulating pathways related to
neurotrophic factors, inammatory responses, cell proliferation, and apoptosis.
Faustmann, T.J. and colleagues [362] studied the effects of LTG on the pathophysiological processes of astrocyte and microglial inammatory responses and
showed that LTG reduces the viability of glial cells in a concentration-dependent
manner but does not cause signicant changes in microglial phenotype. Although
LTG may convey neuroglial toxicity, it can reduce inammatory activity and may
have a positive effect on neuroinammatory changes underlying the pathogenesis of
epilepsy.
Regarding the interaction between lamotrigine and other drugs, Filiz AK etal.
[363] proposed that a combination of lamotrigine with vitamin B12 could prevent
behavioral decits, hippocampal damage, and oxidative and proinammatory states
during the development of epilepsy. Their study revealed that this combination
could reduce the total oxidative status (TOS), oxidative stress index (OSI), and
IL-1β and TNF-α levels and increase the total antioxidant status (TAS) in the hippocampus and cerebral cortex of a PTZ-induced epilepsy model.
Another study evaluating the effects of anakinra, lamotrigine, and their combination on the mechanisms of temporal lobe epilepsy showed that the severity of
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seizures was signicantly reduced, which may be related to a reduction in neuronal
loss in the hippocampal CA1 area caused by these two drugs [364].
Łuszczki JJ and others [365] attempted to nd effective drug combinations in a
study of intractable epilepsy; they used a maximal electroshock-induced seizure
(MES) model to validate the combination of three antiseizure drugs. The combination of “lamotrigine+phenobarbital+oxcarbazepine” had an additive anticonvulsant effect, which could be benecial for further translation into clinical trials for
patients with intractable epilepsy.
To explore the role of lamotrigine in status epilepticus (SE), Onishi K etal. [366]
conducted experiments using a mouse model and found that lamotrigine could
extend the latency period of SE, reduce mortality, decrease nitric oxide and malondialdehyde levels, and increase glutathione concentrations. The study also revealed
that the antioxidant action of lamotrigine may not entirely depend on the NMDArelated pathway.
With increasing attention being given to prehospital emergency care and nonintravenous routes of administration, Abdelmonem R. etal. [367] aimed to use Spanlastics
nanovesicular carriers as a drug carrier to deliver lamotrigine through the intranasal
route for brain targeting to improve its solubility and therapeutic effect. This method
revealed a high efcacy of brain targeting in a rat model and is promising as a prospective brain-targeted treatment for epilepsy. Mohsen AM and others [368] prepared
a cubosomal dispersion of LTG and loaded it into a thermosensitive intranasal gel to
enhance intranasal absorption and efcacy. This novel formulation increased the antiseizure effects of LTG through pathways such as those related to increasing GABA
release and inhibiting calcium ions and GFAP activity.
Lamotrigine inPsychiatric Disorders
Lamotrigine is also a standard medication for the treatment of bipolar disorder and
is often used as a mood stabilizer in psychiatric diseases [369]. Research by Vieta
E. etal. [370] revealed that in women of childbearing age with type I bipolar disorder, lamotrigine delayed the onset of mood episodes and particularly delayed the
intervention time for depressive episodes. Although it had no signicant effect on
manic episodes, lamotrigine showed good tolerance in this population. The longterm response to lithium is reduced in patients with bipolar disorder combined with
epilepsy, emphasizing a preference for valproate salts and lamotrigine as rst-line
treatments [198]. Thompson SI etal. [371] described two veterans with war-related
posttraumatic stress disorder (PTSD) who exhibited signicant anger, aggression,
and excitement; these symptoms were not controlled by selective serotonin reuptake
inhibitors (SSRIs) but were eventually successfully managed with lamotrigine.
Cuomo A and others [372] summarized the literature and concluded that
lamotrigine shows signicant efcacy in preventing or delaying depressive episodes
of bipolar disorder, with a standard dose of 200mg/day and slow titration to ensure
good tolerance and a lower risk of side effects. After the risk-benet ratio is assessed,
LTG can be used in patients who are pregnant or lactating or who have liver or kidney disease.
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2.1.2.2 Levetiracetam
Drug Characteristics
[Chemical name] (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide
[Chemical structure formula]
[Molecular formula] C8H14N2O2
[Molecular weight] 170.21
[Indications] For the treatment of partial seizures in adults and children over
4years old.
[Packing specications] Tablets: 250mg, 500mg, 1000mg; oral liquid: 150mL
(15g) per bottle; Injection: 5mL (500mg)
[Usage and dosage]
For adults (>18years) and adolescents (12–17years) weighing ≥50 kg: 500 mg/
dose, twice daily. 500mg/dose can be added every 2–4weeks, twice daily; the
maximum daily dose is 1500mg, twice daily.
Children aged 4–11years and adolescents weighing less than 50kg (12–17years):
The initial therapeutic dose is 10mg/kg twice daily. The dose can be increased by
10mg/kg twice daily every 2weeks. The maximum starting dose is 30mg/kg twice
daily. The maximum daily dose is 1500mg twice daily. Patients with impaired renal
function may adjust the dose according to creatinine clearance.
[Adverse reactions]
The common adverse reactions are drowsiness, fatigue and dizziness, irritability,
emotional instability, hostility, aggressive behavior, dyspepsia, vertigo, double
vision, tremor, etc.
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Clinical Application andPreclinical Research
The Historical Evolution ofLevetiracetam
Levetiracetam (LEV), a piracetam derivative, was originally approved by the FDA
in 1999 for adults with partial seizures, and it was approved in oral tablets and solutions for the adjunctive treatment of partial seizures in children at least 4years of
age in 2005. It was released in China in 2007 (product name: Caplan). As a new
antiseizure medication (ASM), LEV has a unique biochemical structure and a novel
mechanism of action (blocking synaptic vesicles 2A to prevent the presynaptic
release of neurotransmitters), and has a rapid effect, showing good antiseizure efcacy, tolerance and safety. In addition to adjuvant therapy for refractory epilepsy, its
indications have gradually expanded to include monotherapy for newly diagnosed
epilepsy. This product has the characteristics of high bioavailability, linear pharmacokinetics, low protein binding rate, low liver metabolism, rapid acquisition of stable blood drug concentration and few drug interactions, etc., which makes it a
relatively safe drug for clinical application.
Application ofLevetiracetam inDifferent Seizure Subtypes
Levetiracetam (LEV) was rst approved for the additive treatment of focal seizures
in adults and children over 4years old. Studies have shown that it can also be used
in adults with partial seizures and general seizures. It shows efcacy in children
with absence epilepsy, juvenile myoclonic epilepsy (JME), refractory epilepsy, and
status epilepticus (SE). In addition, LEV has the best efcacy across ASMs in
Alzheimer’s disease, Down syndrome, and PCDH19-associated epilepsy, although
it may show a negligible effect in cortical developmental malformation [373].
A systematic review of two randomized controlled trials involving 574 newly
diagnosed focal epilepsy patients treated with levetiracetam or oxcarbazepine
monotherapy showed that the seizure free rate of LEV at week 24 was not lower
than OXC, but the rate of adverse event (AE)-induced drug withdrawal in adults was
also higher than that of OXC [374].
Lucia Gerstl etal. [375] systematically reviewed 19 clinical studies. The objective
was to assess the rate of childhood epilepsy remission in children with benign epilepsy
of childhood with centrotemporal spikes (BECTS) receiving ASMs. The results suggest
that LEV results in a higher remission rate than CBZ, oxcarbazepine and topiramate in
the treatment of BECT, and is recommended as a rst-line treatment for BECT.
A review of the efcacy and tolerability of levetiracetam or valproate alone in 60
children with epilepsy (2–12years old) showed that LEV monotherapy was equally
effective and tolerated as VPA monotherapy for new idiopathic generalized tonic–
clonic seizures in infants and children. Its efcacy was not related to age, EEG
characteristics or epileptic syndrome [376].
A multicenter, randomized, double-blinded, placebo-controlled, phase III trial
was designed to evaluate the efcacy and safety of levetiracetam as an additive
treatment for focal epilepsy in children and adults (4–65 years old). It was