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4 Clinical Application ofAnti-seizure Medication asDrug Therapy
tumor grade, location, and type of treatment). Molecular pathologic features with an
IDH 1/2 gene negative for mutations may predict a good prognosis in patients with
grade 2 or 3 glioma, who generally have stable brain tumor disease and can achieve
long-term seizure-free status. However, phasing out ASM use has to be considered
for patients who develop serious side effects (which cannot be resolved by changing
medication), or in patients who still have a clear will even after a detailed understanding of the risk of recurrent seizures and the impact on daily life (e.g., whether
they are t to drive).
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4.3.4 Pharmacologic Treatment ofFocal Cortical
Dysplasia-Associated Epilepsy
Focal cortical dysplasia (FCD) is a common cause of focal epilepsy, and it occurs in
a majority of patients with drug-resistant epilepsy. Despite the increasing predominance of surgery, medication use remains fundamental for treating FCD.This section focuses on the pharmacologic treatment of FCD-related epilepsy.
4.3.4.1 Denition
Focal cortical dysplasia refers to alterations in cortical cells and lamina structures
resulting from abnormal cell proliferation, differentiation, migration, synaptogenesis, and reorganization during brain development [224]. Focal cortical dysplasia
occurs mainly during in utero brain development and is also associated with perinatal and early postnatal injuries. It is a subtype of malformation of cortical development (MCD) and can be categorized into different pathological subtypes based on
different pathological, imaging, and electrophysiological features [225].
4.3.4.2 Pathologic Typing
Historical Evolution
In 1957, Crome [226] rst identied and described giant, morphologically abnormal neurons in brain specimens from three patients with drug-refractory epilepsy
(DRE). In 1971, Taylor etal. [227] rst coined the term “focal cortical dysplasia,”
based on irregular dysmorphic neurons and enlarged, ballooned cells in the cortex
outside of the rst layer, by analyzing the histopathology of surgical specimens
from 10 patients with DRE who underwent surgery. In 2004, Palmini etal. [228]
categorized FCDs into two types based on the presence (FCD type II) or absence
(FCD type I) of dysmorphic neurons. In 2011, the ILAE proposed a more detailed
classication system [229], namely, FCD type I (including Ia [abnormal radial
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lamination], Ib [abnormal tangential lamination] and Ic [abnormal radial and tangential lamination]), FCD type II (including IIa [dyslamination with dysmorphic
neurons] and IIb [dyslamination with dysmorphic neurons and balloon cells]), and
FCD type III (including IIIa [cortical lamination abnormalities in the temporal lobe
associated with hippocampal sclerosis], IIIb [cortical lamination abnormalities
adjacent to a glial or glioneuronal tumor], IIIc [cortical lamination abnormalities
adjacent to vascular malformation], and IIId [cortical lamination abnormalities
adjacent to any other lesion acquired during early life, e.g., trauma, ischemic injury,
encephalitis]). In 2018, Najm IM etal. [230] introduced the challenges in distinguishing FCD I and FCD III and discussed the possibility of classifying FCDs in the
context of molecular/genetic mechanisms and clinical practice. In 2021, Blümcke
etal. [231] proposed the use of genetic analysis of somatic brain mutations in neurosurgically resected brain specimens to better categorize FCDs.
Updated Classication forFocal Cortical Dysplasia
In 2022, the ILAE developed an updated histopathology-based FCD classication
for FCD [232]:
(1) FCD type I: FCD type Ia (abundant microcolumns); FCD type Ib (abnormal
layering); and FCD type Ic (vertical and horizontal abnormalities).
(2) FCD type II: FCD IIa (dysmorphic neurons); FCDIIb (dysmorphic neurons and
balloon cells).
(3) FCD type III: FCD IIIa (cortical dyslamination associated with hippocampal
sclerosis); FCD IIIb (cortical dyslamination adjacent to brain tumor); FCD IIIc
(cortical dyslamination adjacent to vascular malformation); FCD IIId (cortical
dyslamination adjacent to lesion acquired during early life, e.g., stroke).
(4) White matter: mild malformations of cortical development (mMCD) with
excessive heterotopic neurons; mMCD with oligodendroglial hyperplasia in
epilepsy (MOGHE).
(5) No denite FCD on histopathology: abnormalities in cortical organization
remain ambiguous, and histopathological ndings are not compatible with FCD
I, II, or III.
Molecular Pathological Characterization
The presence of cells expressing immature markers such as microtubule-associated
protein 1B (MAP 1B), neuronal nuclei (NeuN), vimentin, nestin, and α-internexin
is a marked characteristic of FCD type II, in contrast to FCD type I, in which cells
hardly express progenitor proteins [233, 234]. In addition, balloon cells in FCD type
II also express stem cell markers such as Sox2, Oct4, c-Myc, and Klf4, a feature that
has been associated with enhancement of the mammalian target of rapamycin
(mTOR) signaling pathway [233].
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
433
4.3.4.3 Clinical Features andEpidemiology
Seizures are the predominant clinical manifestation in patients with FCD.Nathan T
Cohen et al. [235] investigated the prevalence of seizures in 143 patients with
3 T-MRI-conrmed FCD from the Children’s Hospital of George Washington
University and found that 124 (87%) of them had recurrent noninduced seizures
(i.e., epilepsy), 12 (8.5%) had only one seizure or multiple induced seizures, and
only 7 (4.9%) had no seizures. Moreover, FCD accounts for approximately 25% of
patients with focal epilepsy [236]. In patients who have undergone epilepsy surgery,
approximately 40–50% of children and 20% of adults experience FCD [237]. FCD
type I is most often located in the temporal lobe and is usually negative for, or has
only slight, gray–white matter border blurring on brain MRI [238, 239]. FCD type
II occurs predominantly outside the temporal lobe, especially in the frontal lobe,
and MRI frequently reveals abnormal changes, such as focal thickened cortex, blurring of gray–white matter boundaries, and the “transmantle sign” (i.e., a funnelshaped high signal from the gyrus pointing to the ventricles on the T2/T2-Flair
sequence of MRI; in other words, a “penetration sign,” which is a characteristic sign
of FCD type IIb) [240, 241].
4.3.4.4 Pathogenic Mechanisms
The mechanisms of epileptogenicity in FCD have been extensively studied over the
past two decades. There may be three main mechanisms involved: altered synaptic
function, glial cell dysfunction, and dysregulation of extrasynaptic regulation [225].
Alterations inSynaptic Function
Some researchers have compared the pathological alterations between FCD type I/
II and non-FCD patients and discovered that in FCD type I patients, the postsynaptic function of GABAA receptors remains unchanged or mildly decreased, in contrast to that in FCD type II patients [242]. Moreover, in FCD type II patients, the
most pronounced postsynaptic changes were observed in the areas with the greatest
morphological abnormalities, which were characterized by loss of inhibitory neurons and reorganization of GABAergic and glutamatergic neurons. The most predominant synaptic changes were GABAergic rather than glutamatergic and were
accompanied by an increase in the function of pre- and postsynaptic GABA.It is
unclear whether the increase in GABA synaptic activity is a compensatory mechanism to control hyperexcitability or is a component of epileptic triggering.
In specimens of FCD from patients with drug-resistant epilepsy, the expression
of α4-containing GABAA receptors was greater than that of α1-containing GABAA
receptors. The expression of the α4 and γ2 subunits of the GABAA receptor is
increased in patients with FCD type I and FCD type II compared to controls, while
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L. Zhou and Z. Chen
the alterations are more severe in patients with FCD type II [243]. Patients not taking benzodiazepines also showed increased expression of α4-containing GABAA
receptors, suggesting that altered GABAA receptor expression may be responsible
for resistance to benzodiazepines.
The effects of GABAA receptor activators are dependent on the intra- and
extracellular concentration differences of Cl- ions. In healthy human neonatal cortical neurons, the efux of Cl- ions via KCC2 is more potent than the uptake of Cl
ions by NKCC1, and GABAergic signaling triggers an inward ow of Cl ions,
resulting in the emergence of a postsynaptic hyperpolarizing current. However,
under conditions of neuronal injury, NKCC1 expression is functionally upregulated more than that of KCC2, and GABAergic signaling triggers a reversal of the
Cl ion current, leading to depolarization of the GABA response. Under these conditions, the administration of GABAA receptor activators (phenobarbital or benzodiazepines) may lead to depolarization of the Cl ion current and exacerbate
seizures [244].
The NMDA receptor 1 subunit (NR1) protein and NMDA receptor 2B (NR2B)
mRNA/protein subunits are selectively expressed on dysplastic neurons in
resected tissues of FCD patients [245]. Changes in the expression of AMPA
receptors have also been observed. Immunocytochemical assays have revealed
signicantly increased expression of GluR2/3 subunits in dysplastic and giant
neurons [246].
Glial Cell Dysfunction
Impaired glial buffering mechanisms to glutamate and potassium have been identied in animal models of tuberous sclerosis complex (TSC) and human tissues and
may increase neuronal excitability in TSC and thus cause seizures. A large number
of balloon cells express glial biomarkers. A recent study revealed differential
expression of the glial glutamate transporter (GLT1) and glutamine synthase (GS)
in balloon cells but not in aberrant or normal neurons. This differential expression
of GLT1 and GS may be responsible for the hyperexcitability observed in balloon
cells [247].
Extrasynaptic Mechanisms
Recent studies of a large number of FCD type I and type II samples have shown
increased astrocyte proliferation and diffusion disorders in abnormally hyperplastic
tissues. In addition, the same studies have shown increased extracellular space in
FCD type II lesions (but not FCD type I lesions). These observations suggest altered
diffusion of neuroactive substances through the extracellular space, but the exact
signicance is unclear [225].
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
435
4.3.4.5 Treatment
Risk ofDrug Resistance inFocal Cortical Dysplasia
The study by Nathan T Cohen etal. [235] reported that up to 74% of patients with
FCD-related epilepsy were medically refractory, and failure of the rst ASM was
strongly associated with early development of medically refractory epilepsy (OR
346; 95% CI 19.6–6100). Cox regression analysis suggested that the location or
pathologic subtype of FCD and age at onset of epilepsy were not risk factors.
Another study showed that up to 94.2% of patients with FCD-related epilepsy were
drug resistant, while 59.8% of those who received surgery were seizure free for at
least 1year after surgery [248]. This study also revealed that concordance between
the location of the FCD on MRI and ictal EEG and an older age of seizure onset
were two factors associated with a favorable surgical outcome after 1year. In addition, a meta-analysis showed that the shorter the interval between surgical treatment
and the onset of epilepsy was, the greater the proportion of patients who were seizure free after surgery [249].
Mechanisms ofDrug Resistance
The mechanisms of drug resistance in FCD are still unclear. Apart from its epileptogenic nature, another mechanism that explains the drug resistance of FCD may be
the overexpression of multidrug resistance gene-1 p-glycoprotein (MDR1) and multidrug resistance-associated protein-1 (MRP1) [250] which can remove ASMs from
the nervous system, thereby reducing the concentration of effective drugs in the
brain. However, whether the overexpression of these transporters in epileptogenic
tissues is the cause of drug resistance or is secondary to chronic seizures as well as
the use of ASMs is unclear. Moreover, whether it can be used as a therapeutic target
has not been determined.
Selection ofAnti-seizure Medications
None of the ASMs have been shown to be more effective than others in patients with
FCD. The selection of ASMs depends on the type of seizure (focal seizures or
spasms) and the age of the patient. In the majority of patients, there is a trend toward
drug resistance, with only approximately 17% of patients treated with ASMs maintaining a brief seizure-free period of at least 1year [224].
In a recent retrospective study [251], the authors analyzed the efcacy of ASMs
in 164 patients with epilepsy due to MCD, 87 of whom had FCD or giant gyrus. In
the initial regimen during which most patients received monotherapy, the therapeutic response rate (reduction in seizure frequency≥50%) was 50% for lamotrigine,
31.6% for carbamazepine, 30% for oxcarbazepine, 20.5% for valproic acid, and
only 4.5% for levetiracetam. The difference in drug responsiveness between
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L. Zhou and Z. Chen
levetiracetam and sodium channel blockers (carbamazepine, oxcarbazepine, and
lamotrigine) was statistically signicant.
Levetiracetam (LEV) monotherapy may lead to the exacerbation of seizures in
FCD-related epilepsy patients. In a case report [252], the paradoxical effect of
ASMs was dened as an increase in seizure frequency (by at least 25%) and/or the
development of a more severe degree of seizure shortly after the administration of a
medication considered effective in this type of epilepsy; further, the patient experienced a signicant worsening of the baseline seizures closely related to dose titration after intake of a low-dose LEV, accompanied by a rapid improvement in seizure
frequency shortly after LEV discontinuation. In another study [253], the authors
retrospectively analyzed the data of 139 patients treated with LEV.Seizure exacerbation was dened as a 100% or greater increase in seizure frequency within
1month of drug introduction. Five of these patients met the criteria and were treated
with LEV in addition to the original therapy with sodium channel blockers (carbamazepine, oxcarbazepine or lamotrigine). Low-dose (500–1000mg) LEV administration resulted in seizure exacerbation. In addition to increased frequency and
duration, two patients developed new seizure types. The seizure frequency returned
to baseline after the discontinuation of LEV.Four out of the ve patients were considered to have FCD on MRI.No paradoxical effect of LEV was found in the idiopathic epilepsy group or in the group with symptomatic epilepsy other than FCD.
Potential Therapeutic Roles ofmTOR Inhibitors
Tuberous sclerosis complex (TSC) is a genetic disease involving multiple organ
systems caused by abnormalities in the mTOR signaling pathway and is characterized by cortical malformations and migratory abnormalities in the brain. The histopathological, molecular, and physiologic features of the nodules and radial migration
lines of TSC patients are similar to those of FCD type IIb patients [254]. Chimeric
mutations in various genes, such as TSC1/TSC2, PTEN, STRADα, AMPK, NPRL3,
MTOR, and PIK3CA [255], all of which are associated with the mTOR pathway,
are detected in FCD IIb tissues; therefore, both FCD IIb and TSC are thought to be
mTOR signaling-related diseases caused by a series of pathogenic variants in mTOR
pathway protein-encoding genes leading to differential activation of the mTOR signaling pathway.
In electrophysiological studies performed on brain slices of resected brain tissues from patients with TSC, rapamycin (an inhibitor of the mTOR pathway) was
found to reduce the amplitude and frequency of 4-AP-induced paroxysmal discharges and spontaneous excitatory postsynaptic potentials, as well as the bursts of
discharges induced by blockade of the anti-gamma-aminobutyric acid type A receptor (GABAAR) [85, 256]. In a large, randomized, double-blind, placebo-controlled
clinical trial of adjunctive everolimus for treating TSC, the overall efcacy rate
(more than 50% reduction in seizure frequency) was 40% in the group receiving
adjunctive everolimus (vs. 15.1% in the placebo group) [257]. A post hoc analysis
of this clinical trial revealed an efcacy rate of up to 60% in the subgroup of patients
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
younger than 6years old, compared to 30% in the older subgroup [258]. This suggests that the earlier everolimus is administered, the better the outcome may be.
Jae Seok Lim et al. [259] identied a mutation (p.Leu2427Pro) in a protein
related to the mTOR signaling pathway in surgical specimens of patients with FCD
type II, and focal cortical expression of this mutation by in utero electroporation of
mice disrupted neuronal migration and caused cytomegalic neurons as well as spontaneous seizures. Furthermore, inhibition of mTOR with rapamycin successfully
suppressed the development of cytomegalic neurons and reduced seizure symptoms. Mitsuhiro Kato etal. [260] conducted a single-arm, open-label, multicenter
clinical trial evaluating the efcacy and safety of adjunctive sirolimus administration in patients with FCD type IIwith an observation period of 3months. They
reported a 25% reduction in seizure frequency in the adjunctive sirolimus administration group (vs. 0.5% in the control group). However, because of the inconsistency
of baseline data between the two groups, the statistical requirements for comparison
could not be met.
In conclusion, mTOR could be a therapeutic target for intractable epilepsy associated with FCD, and inhibitors of the mTOR pathway, such as everolimus, sirolimus, or rapamycin, offer new therapeutic options.
Other Medications
437
A meta-analysis showed that intravenous gammaglobulin administration in patients
with FCD-related refractory epilepsy can signicantly reduce seizure frequency
[261]. However, due to the small number of patients receiving gamma globulin, its
effectiveness still needs further validation.
4.3.5 Pharmacological Treatment ofEpileptic Seizures
inAutoimmune Encephalitis
Autoimmune encephalitis (AE) is a rapidly progressing inammatory disease of the
brain characterized by a range of clinical symptoms, such as mental abnormalities,
cognitive impairment, seizures, involuntary movements, language disorders, and
decreased levels of consciousness. AE is categorized into two main types based on
the location of the antibody-binding antigen. One type targets the neuronal cell
membrane or synaptic antigens and is exemplied by anti-N-methyl-D-aspartate
receptor (NMDAR) encephalitis. The other type targets cytoplasmic or cytosolic
antigens and is represented by anti-glutamic acid decarboxylase isotype 65 (GAD65)
encephalitis [262].
Clinically, seizures are one of the core symptoms of AE and are often the rst
symptom of AE.The 2020 International League Against Epilepsy Working Group
on Autoimmunity and Inammation claried the concept of acute symptomatic
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L. Zhou and Z. Chen
seizures secondary to autoimmune encephalitis (ASSAEs). ASSAEs refer to seizures that occur during the acute phase of AE and are a symptomatic concept [263].
In addition to the manifestation of seizures, the acute phase of AE can also cause
new- onset refractory status epilepticus (NORSE), which is dened as the new onset
of refractory status epilepticus in patients without a history of active epilepsy or
neurologic dysfunction and without obvious acute or active structural, toxic, or
metabolic etiology. Febrile infection-related epilepsy syndrome (FIRES) was
dened as the presence of antecedent febrile symptoms during the 2-week-to-24-h
period prior to onset [264].
4.3.5.1 Epidemiological Information.
International epidemiological data reveal that the annual incidence of AE is
0.8/100,000, a rate comparable to that of viral encephalitis (0.6/100,000). The incidence of AE is 13.7/100,000, which is slightly greater than that of viral encephalitis
(8.3/100,000) [265]. There is a lack of epidemiologic information on AE in China.
Seizures are a common clinical symptom during the acute phase of AE, with
79.5% of patients experiencing seizures during this period. Of these, 73.5% originate in the temporal lobe, and the most common type of seizure is focal progression
to bilateral tonic–clonic seizures. Additionally, 28.9% of cases may manifest as status epilepticus [266]. A multicenter study conducted abroad revealed that 37% of
patients with NORSE had AE as the underlying etiology [267].
4.3.5.2 Pathogenesis
The current understanding suggests that persistent neuroinammatory responses
and altered neuronal excitability caused by antibodies acting on synaptic receptors
are responsible for seizures secondary to AE [268]. The binding of NMDAR antibodies to the GluN1 subunit of NMDARs on the postsynaptic membrane of neurons
leads to the internalization of the receptor, thereby affecting the normal electrical
activity of the neuron and resulting in seizures [269]. The pathogenic mechanism of
intracellular antibodies is not clear, but it may be associated with T lymphocytemediated immune responses. In summary, disruption of the neuronal excitatory/
inhibitory balance invivo, due to antibody-mediated immune responses, cytokines,
and T lymphocyte-mediated immune responses, is considered the primary cause of
seizures or status epilepticus in patients with AE.
4.3.5.3 Clinical Manifestations
Clinical AE against neuronal surface antigens is the primary cause of ASSAEs and
NORSE.The most common AE is anti-N-methyl-D-aspartate receptor (NMDAR)
encephalitis, followed by anti-gamma-aminobutyric acid type B receptor
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
439
(GABABR) encephalitis, anti-leucine-rich glioma-inactivated protein-1 (LGI-1)
encephalitis, and anti-contactin-associated protein-like 2 (CASPR2) encephalitis.
① Anti-NMDAR encephalitis, which targets neuronal cell membrane surface anti-
gens, is the most prevalent clinical AE, accounting for approximately 80% of
ASSAE cases in the acute phase of encephalitis [270]. The most common seizure
type is focal progression to bilateral tonic–clonic seizures, with approximately
33.1% of patients experiencing persistent status epilepticus in the acute phase.
Aggressive immunotherapy combined with ASMs yields a favorable overall prog-
nosis, and chronic epilepsy is less common. As a result, the majority of patients
do not require long-term ASM treatment [271, 272]. In most cases, ASMs can be
administered during the acute phase of anti-NMDAR encephalitis, and the deci-
sion to taper ASM use over a year depends on the patient’s seizure prole [273].
Anti-GABABR encephalitis is another prevalent clinical AE caused by the
presence of neuronal cell membrane surface antigens. This type of AE is associated with a high likelihood of seizures and persistent epileptic status in the acute
phase, with ASSAEs occurring in up to 90% or more of patients. The common
seizure types include focal seizures and focal progression to bilateral tonic–
clonic seizures [274]. In addition to seizures, patients with anti-GABABR
encephalitis often present with other limbic system symptoms, such as mental
abnormalities and cognitive decline. Due to the high comorbidity rate with small
cell lung cancer, tumor screening and long-term follow-up are recommended.
Adequate immunotherapy for encephalitis typically leads to the resolution of
seizures in patients with anti-GABABR encephalitis, and only a small proportion
of patients require long-term administration of ASMs [272].
The most frequent manifestation of ASSAEs in patients with anti-LGI-1
encephalitis is focal seizures, in which rapid cognitive decline and intractable
hyponatremia are the main clinical features. Faciobrachial dystonic seizures
(FBDSs) and hair-raising seizures are characteristic seizure types of anti-LGI-1
encephalitis, and FBDSs are characterized by recurrent, rapid twitching of the
muscles of one side of the upper limb, face, and neck, with multiple frequent
seizures during the day [275]. Immunotherapy is signicantly more effective for
controlling FBDS symptoms than treatment with ASMs alone [276].
Hormone therapy during immunotherapy may also be more effective than
intravenous gamma globulin infusion in controlling FBDS symptoms in patients
with anti-LGI-1 encephalitis [277]. ASSAEs in the acute phase of anti-LGI-1
encephalitis typically resolve after early and adequate immunotherapy. However,
there is a risk of recurrence, reaching up to 35% over the subsequent 8years of
follow- up [278].
② In anti-contactin-associated protein-like 2 (CASPR2) encephalitis, approxi-
mately 38% of patients develop ASSAEs in the acute phase. The most common
type of seizure observed was focal onset seizures with perceptual decits, followed by bilateral tonic–clonic seizures. Seizures in this condition are often
accompanied by cognitive impairment and mood disorders, in addition to epileptic seizures.
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L. Zhou and Z. Chen
Table 4.9
Common secondary epileptic seizures caused by anti-neuronal surface antigens
Neuronal surface
antigen
NMDAR 70–80% <5% 30–40% Teratoma
GABAbR 90–95% 20–30% 50–60% Small-cell lung
LGI-1 80% 15% <5% Thymoma
CASPR2 40–50% <10% <20% Thymoma
Incidence of
seizure
Incidence of
epilepsy
Tumor incidence
rate Main tumor types
carcinoma
After rst- and second-line immunotherapy combined with ASMs, seizures
are controlled in some patients. However, a subset of patients still requires continued treatment with ASMs at 1-year follow-up [279] (Table4.9).
4.3.5.4 Anti-seizure Medications
Immunotherapy is instrumental in controlling ASSAEs. Findings from international
studies indicate that, following treatment with immunization and ASMs, approximately 89% of patients with antineuronal surface antigen AE can achieve seizurefree status [280]. Importantly, individuals who undergo immunotherapy tend to
achieve seizure remission earlier than those treated solely with ASMs. On average,
the time from the initiation of immunotherapy to achieving a seizure-free status is
reported to be 28 days [281]. The RITE (Rapid Intervention and Treatment
Effectiveness) score, specically a score of ≥7, can serve as a clinical predictor for
a favorable outcome in terms of seizure control after individuals receive immunotherapy for AE [282]. In the realm of immunotherapeutic approaches, traditional
rst-line strategies include intravenous glucocorticoids, intravenous gamma globulin, and plasma exchange. In cases where rst-line immunotherapy is ineffective,
second-line interventions, such as rituximab and cyclophosphamide, may be
considered.
For patients with AE-induced NORSE, rst-line immunotherapy should be initi-
ated within 72h of disease onset. Additionally, second-line immunotherapy and a
ketogenic diet should be initiated within 1week in instances of a poor outcome.
Rituximab is the preferred second-line immunotherapy for antibody-positive
AE-induced NORSE, while blockers of the interleukin receptor (e.g., anabolic acid
and tocilizumab) are recommended for the treatment of cryptogenic NORSE [283].
These comprehensive strategies underscore the importance of timely and targeted
immunotherapeutic interventions for managing AEs and associated complications.
Achieving clinical control of ASSAEs with ASMs alone is often challenging,
with a success rate of only 15%. Compared with levetiracetam, sodium channel
blockers, including carbamazepine, oxcarbazepine, and lacosamide, demonstrate
greater efcacy in controlling seizures [284]. Notably, in the case of anti-LGI-1
encephalitis, the use of carbamazepine, an aromatic ASM, is associated with an
elevated risk of skin sensitization, necessitating close monitoring [281, 285].