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improvement after primidone treatment, 58% saw no change in symptoms. Overall,
this case series suggests that primidone therapy effectively manages idiopathic
acoustic tremors in a subset of patients, offering an alternative to Botox neurotoxin
therapy [139]. Hitomi etal. investigated the impact of ASMs, including primidone
and valproic acid, on the accumulation of free cholesterol (C) in NPC1-empty CHO
cells and NPC1* broblasts derived from individuals with NPC1 mutations. Like
treatment with valproic acid, primidone treatment led to decreased free cholesterol
levels in lysosomes/endosomes in NPC1-null/mutant cells. Furthermore, primidone
partially restored cholesterol ester levels in NPC1-null cells and upregulated the
mRNA expression levels of HMG-CoA reductase and low-density lipoprotein
receptor in NPC1* cells. This nding suggested that primidone facilitates the transport of free cholesterol from lysosomes/endosomes to the endoplasmic reticulum in
NPC1-null/mutant cells. In NPC1-decient mice, oral administration of primidone
(100mg/kg/day) extended the lifespan by approximately 5days, although initial
treatment had no effect on ataxia, a classic symptom of neuromotor dysfunction.
These ndings underscore the therapeutic potential of primidone in the management of nasopharyngeal carcinoma [140].
2.1.1.6 Valproic Acid
Drug Characteristics
[Chemical name] 2-Propylvaleric acid; 2-n-propyl n-valeric acid; 2,2-di-n-propyl
acetic acid; A-propylvaleric acid; α-propylvaleric acid
[Chemical structure]
[Molecular formula] C8H16O2
[Molecular weight] 144.21100
[Indications] Valproic acid is suitable for treatment in adults and children over
3years old. It can be used as a single-drug treatment or as an add-on treatment. It
can be used to treat generalized epilepsy: nonmotor seizures (absence), myoclonic
seizures, tonic–clonic seizures, atonic seizures, and some types of epilepsy syndromes (West, Lennox–Gastaut syndrome), etc.; it can also be used for the treatment of focal epileptic seizures that progress from focal to generalized seizures.
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[Specications]
Regular tablets: Sodium valproate tablets 0.1g 0.2g
Magnesium valproate tablets 0.2g
Sustained-release
tablets:
Oral liquid: Sodium valproate oral solution 300mL: 12g
Injection: Sodium valproate for injection 0.4g
Sodium valproate extended release tablets
0.2g; 0.5g (each tablet contains 0.333g sodium valproate and 0.145
valproic acid, equivalent to 0.5g sodium valproate)
Magnesium valproate extended release tablets
0.25g
Sodium valproate syrup 100mL: 5g
[Dosage]
Syrup and tablets are started at a dose of 5–10mg/kg, and the dosage is gradually
increased. The maintenance dose is 0.6–1.2g/day for adults, taken orally two to
three times, with a maximum dose of 1.8–2.4g.
Sustained-release tablets: The starting dose for newly diagnosed epilepsy is
usually 10–15 mg/kg/day, one to two times a day, and the dose is gradually
increased, with an interval of 2–3days between each dose increase. The maintenance dose is 20–30mg/kg. This product can be broken in half and taken but cannot be ground or chewed. If the daily dosage exceeds 50mg/kg, the patient must
be closely monitored.
Oral solution: generally starting from 0.6g/day and taken two times, the usual
dosage range is 1–2g/day, up to 2.5g/day.
When elderly patients take this product, the dosage should be determined based
on seizure control.
For patients whose condition is well-controlled with regular sodium valproate
formulations, it is recommended that the current daily dose be maintained when
using extended-release tablets as an alternative.
[FDA Black Box Warning]
• Hepatotoxicity: In the general population, frequent serum liver metabolite tests
are imperative, especially before and after treatment initiation, particularly
within the rst 6months, to monitor for fatal liver failure. Children under 2years
old, especially those taking multiple antiseizure medications, who are aficted
with congenital errors of metabolism, severe epilepsy accompanied by intellec-
tual disability, or organic encephalopathy, face signicantly heightened risks of
fatal hepatotoxicity. Patients with mitochondrial diseases characterized by muta-
tions in mitochondrial DNA and those with hereditary neurometabolic syn-
dromes such as Alpers-Huttenlocher syndrome caused by POLG gene mutations
are particularly prone to valproate-induced acute liver failure and mortality.
Therefore, the use of sodium valproate injection is strictly prohibited in children
under 2years old with suspected mitochondrial disease.
• Fetal risk: Valproic acid can cause serious congenital malformations, particularly
neural tube defects such as spina bida. Hence, valproate is contraindicated for
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W. Jing et al.
preventing migraines in pregnant women and those of childbearing age who are
not practicing effective contraception. It should not be utilized to treat epilepsy
during pregnancy or in individuals planning pregnancy, except in cases where
other medications fail to control symptoms or are otherwise unsuitable.
• Pancreatitis: Life-threatening cases of pancreatitis have been reported in children
and adults. Patients and caregivers should be vigilant for symptoms such as
abdominal pain, nausea, vomiting, and anorexia, as these symptoms may indi-
cate pancreatitis and necessitate prompt medical evaluation.
[Adverse reactions]
This product has a range of potential adverse effects, including liver failure, birth defects,
intellectual disability, pancreatitis, hyperammonemic encephalopathy, suicidal behavior, bleeding, and various hematopoietic disorders. Additionally, it may lead to hypothermia and has been associated with drug reactions with eosinophilia and systemic
symptoms (DRESS), as well as multiple organ hypersensitivity drug reactions.
[Contraindications]
People who are allergic to any ingredient in this product.
Patients with acute or chronic hepatitis.
People with a history or family history of severe hepatitis, especially drug-related
hepatitis.
Patients with hepatic porphyria.
Patients with known mitochondrial disease caused by mutations in the mitochon-
drial DNA polymerase gamma gene (see “FDA Black Box Warning”).
Patients with known urea cycle disorders.
[Matters Needing Attention]
• Severe liver injury: Clinical signs are crucial for early diagnosis. This should be
considered, especially in the presence of jaundice in at-risk patients; liver func-
tion tests should be performed before starting treatment (see “Contraindications”)
and regularly during the rst 6months, especially in at-risk patients.
• Pancreatitis: When a patient presents with acute abdominal pain, immediate
medical evaluation should be performed. If pancreatitis has been diagnosed, val-
proic acid treatments should be discontinued.
• Girls, female adolescents, women of childbearing age, and pregnant women (see
the Special Populations section on the next page).
• Suicidal intent and behavior: Patients should be monitored for signs of suicidal
intent and behavior, and appropriate treatment should be considered. Patients
(and patient caregivers) should be advised to seek immediate medical help if they
notice signs of suicidal intent or behavior.
• Carbapenems: Concurrent use is not recommended.
• Patients with known or suspected mitochondrial diseases: POLG gene testing
should be performed according to the clinical diagnostic criteria of the relevant
disease.
• Worsening of convulsions: If worsening of convulsions occurs, the patient should
be advised to seek immediate medical attention.
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103
• Blood tests (blood count, including platelet count, and bleeding time) are recom-
mended before treatment, before surgery, or when spontaneous bruising or
bleeding occurs.
• In patients with systemic lupus erythematosus, the potential benets should be
weighed against the risks.
• Patients with carnitine palmitoyltransferase II deciency should be warned of an
increased risk of rhabdomyolysis when receiving valproic acid treatment.
• Risk of weight gain: Patients should be warned of this risk when initiating treat-
ment, and appropriate measures should be taken to minimize the risk.
• Special groups.
1. For children under 3years old, monotherapy is advised; however, the potential
advantages must be carefully considered in light of the risks of liver injury or
pancreatitis before treatment initiation. Due to the risk of hepatotoxicity, simultaneous administration of salicylates should be avoided in this age group.
2. Renal Impairment: dose adjustment may be warranted. Given that plasma con-
centration monitoring might not accurately reect the situation, dosage adjustments should be guided by clinical monitoring.
Basic Research andClinical Applications
History andPrescription Evolution ofValproic Acid
Valproic acid (VPA) stands out as a distinctive drug and ranks among the most commonly prescribed ASMs globally. Originally derived from the low molecular weight
carboxylic acid valeric acid, VPA was rst synthesized by the American chemist
Beverley Burton in 1882 [141]. Initially existing as a clear, colorless to light yellow
liquid, it exhibited slight solubility in water but high solubility in organic solvents.
However, its anticonvulsant properties remained undiscovered until the early 1960s.
VPA debuted in the European market under the brand name Depakine in France in
1967, followed by introduction in the UK in 1973 and in other European countries
in the subsequent decade. Its efcacy in treating epilepsy, particularly in children,
was established in 1975 by S E Barnes [142]. N Bohlen etal. subsequently identied
side effects associated with valproic acid ASMs [143]. After receiving approval from
the U.S.Food and Drug Administration (FDA) in 1978, VPA was introduced to the
United States. Over the years, VPA has gained widespread acceptance and is now
available in more than 100 countries. It is recognized as a primary treatment for both
generalized and partial epilepsy in both adults and children. Its utility has extended
to include the management of bipolar disorder, preventive care for various disorders,
schizophrenia, neuropathic pain, and migraines. Recent research into the effects of
VPA on the human body and its novel mechanisms of action with toxic byproducts
has led to an expansion of its applications. Consequently, VPA is now considered a
crucial component in the treatment of diverse conditions, such as tumors, neurodegenerative diseases (including Huntington’s disease, Parkinson’s disease, Duchenne
progressive muscular dystrophy), and human immunodeciency syndrome [144].
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W. Jing et al.
The European Medicines Agency (EMA) strengthened its recommendations on
the use of VPA in women in 2016 and restricted its use in female patients of childbearing potential. A study using the French National Health Insurance Database
revealed that among pregnant women with epilepsy (n=2607), the proportion of
those exposed to VPA during pregnancy decreased from 26.4% in 2013 to 9.3% in
2016. Similarly, among pregnant women with bipolar disorder (n=4278), the proportion of those exposed to VPA decreased from 3.7% in 2013 to 1.9% in 2016
[145]. In Germany, a longitudinal analysis of the individual prescription patterns of
1642 adult patients with epilepsy from 2008 to 2020 revealed that the prescription
frequency of VPA decreased signicantly (15.4% to 8.7%), and the prescription
frequency of VPA also decreased signicantly among women of childbearing
potential (16.1% to 6.1%) [146]. In China, a survey of the most commonly used
ASMs among adult outpatients with epilepsy from 2013 to 2018 revealed that VPA
and levetiracetam (LEV) were the most frequently prescribed medications. However,
the proportion of VPA usage has declined in recent years, while the proportion of
LEV usage has increased in terms of both the number of prescriptions and expenses
[147]. In Italy, a study analyzing ASM prescription patterns among pregnant women
and women of childbearing age in the Lombardy Region Administrative Health care
Database between 2010 and 2019 revealed that the proportion of VPA prescriptions
among women of childbearing age decreased from 30.2% in 2010 to 20.0% in 2019
[148]. In Japan, a study investigating the prescription data of pregnant patients with
epilepsy aged 16–49years who visited outpatient clinics between 2016 and 2020
revealed that VPA ranked after LEV and lamotrigine (LTG). The proportion of pregnant patients with epilepsy using VPA prescriptions decreased from 12.4% in 2016
to 10.1% in 2020 [149]. There has been a notable decline in the exposure of women
to VPA during and prior to pregnancy. Newer and less-interacting ASMs, such as
LEV, LTG, and lacosamide (LCM), have gradually taken the place of VPA, particularly among women of childbearing age, reecting a shift in prescription patterns
aimed at reducing the teratogenic effects of the drug. Nevertheless, some of the
aforementioned data highlight that despite the decreasing trend in VPA prescriptions, this medication remains one of the most commonly prescribed ASMs for
women of childbearing age. This underscores the importance of educating and raising awareness among health care professionals and the general public, especially
women [149]. Supporting this notion is an online survey carried out in Sweden and
Norway from May to September 2021. Neurologists from both countries were
invited to participate in the survey, which aimed to evaluate their familiarity with
VPA restrictions, knowledge of the Marketing Authorization Holder (MAH), and
utilization of VPA information resources, as well as their experiences in prescribing
VPA to women of childbearing age over the previous 2years. The results revealed
that 51% of the respondents were highly familiar with the EMA restrictions, 49%
were acquainted with the educational materials provided by the MAH, and 88 (44%)
had prescribed VPA to women of childbearing age in the past 2years, with only a
small fraction consistently using the patient information leaet and an even smaller
number utilizing the VPA risk acknowledgment form. These ndings suggest a limited implementation rate of the new EMA restrictions on VPA usage, as well as
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restricted acceptance and utilization of the information materials and risk acknowledgment forms by doctors. This reminds us that we may need to perform more
information campaigns and communicate with those involved in treatment. Doctors
must also collaborate more closely [149].
Pharmacokinetics ofVPA
VPA is available in various preparations, including oral tablets, sustained-release
tablets, lm-coated tablets, capsules, and intravenous solutions, with bioavailabilities ranging from 96% to 100%. The drug is primarily distributed in the blood, with
rapid exchange with the extracellular uid. However, VPA can also be distributed in
the cerebrospinal uid (CSF) and brain, with CSF concentrations similar to those of
free drugs in plasma. Chronic treatment provides greater bioavailability than does a
single dose, with absorption occurring more quickly after a meal. However, taking
VPA 2–3h after a meal can delay absorption, resulting in slower absorption speeds
in the afternoon than in the morning. VPA has a high protein binding rate (87–95%),
resulting in low clearance rates (6–20mL/h/kg) [150]. However, protein binding
depends on the VPA concentration, and if the serum concentration exceeds the therapeutic range (>600 mol/L, 80 g/mL), protein binding may decrease by 67%.
Hypoproteinemia-associated conditions, such as kidney disease, liver disease, old
age, pregnancy, and the use of other protein binding drugs, may also reduce VPA
protein binding, depending on the afnity of competitors for plasma proteins.
The metabolism of VPA is complex and requires further study. The known metabolic pathways of VPA include glucuronidation, β oxidation, and cytochrome P450
(CYP)-mediated oxidation, with glucuronic acid being the main metabolite in urine
(30–50%). However, some products of VPA metabolism produced by mitochondrial
and nonmitochondrial pathways are hepatotoxic. A key step in VPA metabolism is
the production of 4-ene-VPA, which is toxic to cells and is mediated by CYP2C9,
2A6, and 2B6. The complex metabolism of VPA explains the diversity of active and
inactive metabolites that can have therapeutic or toxic effects [144].
The half-life of VPA is 9–18 h and is typically shorter in children. However,
when enzyme-induced drugs, such as phenytoin (PHT), CBZ, and barbiturates are
used simultaneously, the half-life decreases to 5–12h [151]. In the treatment of
some children with VPA, doses exceeding the therapeutic range (50,100μg/mL) are
sometimes necessary for better epilepsy control. Current guidelines emphasize the
importance of therapeutic drug concentration monitoring (TDM) for VPA as a crucial aspect of its treatment. Young et al. [152] conducted a study comparing the
occurrence of common adverse reactions (thrombocytopenia, hepatotoxicity, and
hyperammonemia) in children across various age groups and various maintenance
doses of VPA.This study included 124 children receiving VPA maintenance treatment from January 2013 to January 2021. Among them, 56 patients had concentrations between 50 and 80μg/mL, 44 patients had concentrations between 80 and
100μg/mL, and 24 patients had concentrations between 100 and 120μg/mL.There
were 41 prepubertal patients, 57 pubertal patients, and 26 postpubertal patients. The
results indicated that the primary endpoint of thrombocytopenia varied across
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W. Jing et al.
different serum concentration ranges (P=0.093) and age groups (P=0.628). No
signicant differences were observed in liver dysfunction (P=0.099) or hyperammonemia (P= 0.548) among the different concentration groups. Similarly, there
were no differences in liver dysfunction (P=0.615) or hyperammonemia (P=0.369)
based on age group analysis. The author speculates that according to this study, the
serum VPA level of pediatric patients can be considered to be >100μg/mL.Due to
the high protein binding of VPA, in certain clinical scenarios, the unbound (free)
portion of VPA might be inaccurately substituted for the total VPA serum level.
Therefore, monitoring the serum free VPA concentration may be necessary when
assessing the clinical response to VPA treatment. A systematic review was conducted to establish the therapeutic range of free VPA serum levels, investigate the
relationship between free VPA serum levels and clinical toxicity and efcacy, and
explore factors contributing to discrepancies between free and total VPA levels.
This review identied 27 relevant studies from 189 sources, including 14 observational studies, 2 case series, and 11 case reports. Three studies dened the therapeutic range of free VPA levels between 20 and 410μmol/L.Two studies indicated that
hyperammonemia and thrombocytopenia could occur when free VPA levels
exceeded 60μmol/L and 103.3μmol/L, respectively. Two other studies suggested
that the upper limits of neurotoxicity for free VPA were 70 and 207.9μmol/L, with
hypoalbuminemia identied as a predictor of inconsistent results. Consequently,
there is a lack of data supporting the clinical efcacy of free VPA at the serum level,
necessitating further high-quality studies to conrm the optimal therapeutic range
for free VPA [153].
Advances in science and technology have facilitated the translation of personalized drug concepts from theory to clinical practice, leading to the emergence of
novel technologies in the TMD eld of VPA.Traditional monitoring methods such
as chromatography or immunoassays are not suitable for real-time or on-site analysis due to their high cost and extended turnaround time. Some researchers have
discovered that ATR-FTMIR combined with nonlinear support vector regression is
more effective in real-time TMD monitoring of VPA in clinical settings [154].
Namera etal. [155] also developed a simple and cost-effective method for determining VPA concentrations in human whole blood and urine using gas chromatography–mass spectrometry.
Mechanism ofVPA
Various mechanisms have been described to explain the antiepileptic effects of
VPA, including increasing GABA synthesis, decreasing GABA turnover, and inhibiting GABA degradation to enhance GABA transmission. Additionally, it reduces
the release of excitatory amino acids (such as β-hydroxybutyric acid), inhibits excitatory transmission mediated by the N-methyl-D-aspartic acid (NMDA) receptor,
and blocks voltage-gated ion channels (such as sodium, potassium, and calcium
channels). VPA also regulates 5-hydroxytryptamine and dopaminergic neurotransmission and inhibits histone deacetylase (HDAC) activity. These mechanisms can
explain the broad-spectrum antiepileptic effects of the drug, which are effective for
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all types of seizures and epilepsy syndromes in children and adults. VPA has been
shown to be effective in treating global (tonic–clonic, absence, and myoclonic) and
local epileptic seizures, as well as in treating Lennox–Gastaut, West, and Dravet
syndromes. It is the rst choice for treating coexisting absence seizures and tonic–
clonic seizures [75]. Intravenous VPA treatment has also been recognized for its
efcacy, safety, and tolerability in treating generalized convulsive status epilepticus
(GCSE). Moreover, VPA has strong analgesic and anti- inammatory effects at low
doses, stemming from the inhibition of TNF-α-related pathways, making it useful
for preventing migraines and treating bipolar and emotional disorders. In the past
few decades, the neuroprotective effects of VPA have been described in various
models of acute central nervous system injury, including stroke, hypoxia, traumatic
brain injury, and spinal cord injury. Its potential use in new indications, such as
cancer treatment and prevention, is also being studied. However, the exact mechanisms underlying the specic clinical effects of VPA are still poorly understood, and
many of its functions may also explain its extensive adverse effects [156].
In recent years, increasing evidence has shown the potential inuence of microora on the pathogenesis and course of epilepsy. However, the effects of VPA on the
intestinal microora have not been studied in humans. Gong etal. [157] recruited
ten patients who were newly diagnosed with cryptogenic epilepsy and treated with
VPA (1000mg/day) for the rst time. Sequencing of 16S rDNA was used to evaluate the microbial community composition after baseline and after 3months of VPA
treatment. The results showed that the intestinal ora characteristics changed in
patients treated with VPA and that the intestinal ora were related to weight gain
and clinical biochemical indices. These ndings suggest that the composition of the
intestinal ora may be involved in the mechanism of VPA-induced metabolic
disorders.
Basic Research onVPA fortheTreatment ofEpilepsy
Many experimental studies on comprehensive and local seizures in various epileptic
models have conrmed the antiepileptic effect of VPA.In acute seizure models such
as the pentylenetetrazol (PTZ) epilepsy model, intraperitoneal VPA administration
signicantly increases the seizure threshold, and prolonged treatment intensies its
anticonvulsant effects [158]. Another model, the maximal electroshock (MES)
model, mimics full-scale tonic–clonic seizures in humans and has shown that VPA
reduces seizure frequency in a dose-dependent manner [159].
As a chronic epilepsy model, an amygdala-kindling model simulating local epilepsy was also used. VPA increased the after-discharge (AD) required to induce
epileptic seizures in a dose-dependent manner, reduced the duration of AD, effectively prevented epileptic seizures, adjusted membrane permeability, blocked
voltage- dependent sodium channels and T-type voltage-activated calcium channels,
and enhanced GABA-mediated inhibition. In the kindling model, VPA exhibited
neuroprotective effects by safeguarding hippocampal neurons from damage caused
by prolonged epileptic seizures, promoting neuroprotection, and preventing behavioral disorders. Data from drug-resistant epilepsy models indicate that VPA can
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impede both the progression of kindled seizures and their complete manifestation,
serving as both a symptomatic control agent and a disease-modifying agent
[150, 160].
The critical management of epileptogenesis, particularly in status epilepticus
(SE), which can result in neuronal damage and subsequent recurring seizures, relies
on the precise adjustment of glutamatergic and GABAergic pathways along with
the neuroprotective effects of VPA.By employing neuroprotective mechanisms to
curb neuronal harm, VPA represents a promising strategy for preventing epileptogenesis. In the SE kainate model, administering high doses of VPA 40days post-SE
induction not only suppressed spontaneous activity but also safeguarded hippocampal neurons from seizure-induced damage. Furthermore, VPA exposure demonstrated protective effects against seizure-induced cognitive impairments,
emphasizing the importance of neuroprotection in both processes. Further experimental evidence supporting the antiepileptic effects of VPA arises from diverse SE
models in which VPA displays a preference for AMPA receptor subtypes, preventing neuronal apoptosis in an SE model induced by prolonged electrical stimulation
of the basolateral amygdala. Specically, continuous infusion of VPA 24h after the
end of electrical stimulation conferred signicant neuroprotective effects on hippocampal neurons that were comparable to those of antiexcitotoxic and glutamatedepleting agents such as NS1209 [161]. In a genetic epilepsy model derived from a
Bsn gene-manipulated mouse epilepsy model characterized by frequent seizures but
prolonged survival, VPA signicantly decreased both seizure frequency and mortality rates [162]. VPA is a broad-spectrum ASMs with antiabsence effects. Kantarci
etal. [163] studied the effect of in utero exposure to VPA on absence epileptic seizures in rats with Strasbourg hereditary absence epilepsy (GAERS). The electroencephalogram of this model displayed bilateral, symmetrical, and synchronized
spike-wave discharges (SWDs). However, the study results indicated that VPA did
not notably affect the average accumulation time of EEG signals or the average
number of SWDs. The authors suggested that the lack of signicant differences in
SWD parameters might imply that the antiseizure mechanisms of VPA may not be
fully operational during the prenatal period. Recently, a study using a rat model
investigated the impact of VPA on disrupted sleep patterns in epilepsy patients. In
addition to its antiseizure properties, VPA also has hypnotic effects, potentially
through leveraging GABAergic mechanisms to mitigate convulsive seizures and
promote sleep [164].
Clinical Study oftheEffects ofVPA onEpileptic Seizures
There are three classic studies on the clinical application of VPA in the Chinese
population. The rst study included 532 individuals with convulsive epilepsy residing in rural China. VPA monotherapy was administered in primary care facilities,
with adults starting at a dose of 600mg and children starting at a dose of 20mg/kg.
The typical daily maintenance dose ranged from 600 to 1200mg for adults and
20–30mg/kg for children, taken thrice daily and monitored for 12 months. The
results revealed that 84% of patients experienced at least a 50% reduction in seizure
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frequency, and 42.6% of patients were seizure-free after 1year of treatment. The
1-year retention rate for VPA therapy was 96.2%, with 9% of patients reporting mild
adverse events. After 1year of VPA treatment, patients exhibited weight gain, with
most adverse events being mild, transient, and not necessitating VPA discontinuation [165]. The second study, conducted in rural Guangxi, China, corroborated the
favorable outcomes of VPA.This investigation involved 302 epilepsy patients with
various seizure types. All participants received VPA treatment, with retention rates
of 100%, 93.56%, 89.05%, and 77.06% at the 6th, 12th, 18th, and 24th months of
treatment, respectively. Throughout the 1-year follow-up period, 30 patients displayed mild symptoms, with no severe or serious adverse reactions reported [166].
The third study in China, a multi-center, observational cohort study, enrolled 1008
epilepsy patients, with 519 receiving VPA treatment and 489 receiving topiramate
treatment. The primary outcome focused on the time to treatment failure, while the
secondary outcomes included the time to rst seizure and the time to remission at
12 and 24months. The ndings indicated superior primary and secondary outcomes
in the VPA group compared to the topiramate group (28.3% vs. 41.5%, HR=0.62,
P<0.0001; 56.1% vs. 69.3%, HR=0.73, P=0.0002). Both groups exhibited no
signicant disparities in remission time between 12 and 24months or in the incidence of treatment failure or intolerable adverse events [167].
VPA is considered the rst-line treatment for patients with newly diagnosed
genetic generalized epilepsy (GGE) or difcult-to-classify epilepsy. In most cases
of GGE, the lowest daily VPA dose capable of controlling seizures in monotherapy
is typically up to 700mg [168]. Although VPA is recognized as the most effective
antiseizure medication (ASM) in studies of GGE, its use in women of childbearing
age is signicantly restricted due to the heightened risk of teratogenicity and
impaired cognitive development following intrauterine exposure. However, there
are situations where the use of VPA is unavoidable. Steinbart etal. [169] conducted
a retrospective study across tertiary epilepsy centers’ outpatient clinics, analyzing
GGE patients who visited between January 2015 and April 2020. They compared
the proportions of women aged 18–49years who were taking VPA with men in the
same age group and women aged more than 49 years. The study included 125
women of childbearing age, with 28 (22%) receiving VPA, in contrast to 28 (50%)
of 56 men aged 49 or younger and 22 (55%) of 40 female patients over 49years of
age. The results indicated that there was no disparity in seizure-free survival between
women of childbearing age receiving lower VPA doses and men. Multivariate analysis of women aged 49 or younger revealed age as the sole variable independently
linked to VPA use, with no associated variables identied in the other two groups.
The authors concluded that despite concerns regarding the teratogenicity and cognitive risks of VPA, the reduction in VPA doses among women of childbearing age
with GGE from 2015 to 2020, where nearly a quarter of such women were treated
with VPA, seemed adequate to achieve favorable seizure-free rates. Additionally,
for GGE, Dibek etal. [170] investigated the rate of reinitiation after discontinuation
of VPA treatment in women with GGE and the reasons for such resumption. Among
the 199 patients studied, 63 (31.7%) needed reintroduction of VPA.The primary
reasons for discontinuing other ASMs were lack of treatment response in 80.0% of