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4 Clinical Application ofAnti-seizure Medication asDrug Therapy
471
failure, nor was it due to donor liver rejection as a result of ineffective immunosuppressive drugs [452].
Known major side effects of levetiracetam, such as somnolence, weakness,
infection, and dizziness, are commonly observed. Behavioral abnormalities, including irritability, personality changes, psychotic-like episodes, and mild leukopenia,
are relatively infrequent. In addition to levetiracetam, lacosamide is also considered
an alternative drug, and it may be benecial for patients with drug-resistant posttransplant epilepsy. The recommended initial dose is typically 50mg twice daily,
with an incremental increase of 100mg per week to reach a therapeutic dose range
of 200–400mg/day. No dose adjustment is required for patients with mild to moderate renal impairment. However, a 25% reduction in the maximum dose is recommended for patients with mild or moderate hepatic impairment. Dose adjustments
in patients with hepatic impairment should be approached with caution, and lacosamide is not recommended for use in patients with severe hepatic impairment.
Common adverse reactions include dizziness, headache, nausea, and diplopia,
which are typically mild to moderate in severity. Some reactions are dose-related
and can be resolved by dose reduction. Other side effects may include immune system abnormalities and psychiatric abnormalities. Notably, no clinically relevant
drug–drug interactions are currently known.
The selection of anti-seizure medications can vary based on the type of organ
transplantation. For patients after liver transplantation, careful consideration should
be given to avoiding the use of anti-seizure medications metabolized by the liver.
The new generation of anti-seizure medications, which undergo minimal or no liver
metabolism, exhibit limited drug–drug interactions and have low protein-binding
capacity, making them a preferred choice. Benzodiazepines are typically used as
rst-line therapeutic agents for status epilepticus. However, in the management of
acute seizures after liver transplantation, benzodiazepines, such as diazepam, lorazepam, and midazolam, which are primarily metabolized by the liver, are not utilized
as rst-line agents. Levetiracetam is the preferred option, and lorazepam metabolism is minimally affected by liver disease, reducing the likelihood of drug–drug
interactions [453, 454]. While a broader range of choices is available for the treatment of seizures after renal transplantation, given that most anti-seizure medications are metabolized by the liver, attention must be given to the interaction of these
medications with immunosuppressants to avoid potential drug interactions. In addition to levetiracetam, lamotrigine and the combination of clonazepam and levetiracetam appear to be viable options [423]. The selection of drugs for treating
seizures after heart transplantation must be individualized and take into consideration the overall health of the patient, as most patients typically do not exhibit
abnormalities in liver and kidney function. The primary concern in this context is
often focused on potential drug–drug interactions. Currently, there is no consensus
on the standardized choice of anti-seizure medications after heart transplantation. In
a study by Ocal etal., levetiracetam demonstrated efcacy in controlling 80% of
seizures in pediatric patients and some seizures in adult patients. Additionally, the
combination of levetiracetam with phenytoin sodium was effective in controlling
persistent status epilepticus [426]. Other studies have indicated that gabapentin and
472
valproic acid can also be effective in managing seizures after heart transplantation
[455]. Some studies recommend benzodiazepines, such as valium or midazolam, as
rst-line anti-seizure medications for patients with seizures after hematopoietic
stem cell transplantation [456]. Levetiracetam, commonly recommended for solid
organ transplantation, is not recommended in this context. A study described
instances of secondary graft failure after levetiracetam use, suggesting a potential
association with levetiracetam-induced myelodysplastic syndrome [457].
In summary, the treatment approach for epilepsy after organ transplantation
aligns with conventional epilepsy management. The primary goal is to control seizures and prevent their recurrence, with drug therapy being the initial choice.
However, a key difference lies in the need to be vigilant about potential adverse
effects on the transplanted organ resulting from anti-seizure medication use, as well
as interactions with immunosuppressants, hormones, and other medications.
When selecting anti-seizure medications after organ transplantation, levetiracetam is the preferred treatment option. Its safety and efcacy have been conrmed in
various studies. Other anti-seizure medications, including lacosamide and lamotrigine, should be chosen based on the specic characteristics of the organ transplantation and individual patient considerations. Careful consideration of potential
interactions with immunosuppressants, hormones, and other drugs is essential during the selection process.
L. Zhou and Z. Chen
4.4 Seizures inNeurodegenerative Diseases
4.4.1 Seizures inMultiple Sclerosis
Many neurodegenerative diseases can involve seizures. Since the courses of these
degenerative diseases and epilepsy are relatively long, it is not clear whether the
relationship between degenerative diseases and epilepsy is causal or only a comorbidity. In 2024, Ouyang J [458
nucleotide polymorphisms in patients with a variety of neurodegenerative diseases
based on genome-wide association studies and found that only MS and epilepsy had
a causal relationship. The causal relationships between Alzheimer’s disease (AD),
Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and epilepsy were
not supported, suggesting that the causal relationship between MS and epilepsy is
supported by genetic prediction.
4.4.1.1 Historical Evolution
The literature described the occurrence of epileptic seizures in multiple sclerosis
patients in the 1930s. In 1947, BRONISCH FW [459] studied the possible mechanism of epileptic seizures in multiple sclerosis; in 1955, HAMLIN PG [460]
] used Mendelian randomization to analyze single-
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
473
reported that status epileptic persists in multiple sclerosis patients. In 1962,
Rafalowska J [461] described the epidemiological data of epileptic seizures in
patients with multiple sclerosis; in 1965, Boudin G [462] described two anatomic
clinical cases of multiple sclerosis with epileptic seizures; and in 2023, Van Klink N
[463] described cases in which surgery did not induce multiple sclerosis in patients
with epilepsy. In recent years, researchers have begun to study the novel mechanism
of epilepsy in multiple sclerosis, and representative research results on the relationships among brain networks, epilepsy, and multiple sclerosis have been described
by Ciolac D etal. [464]. In 2023, Drulovic J etal. [465] reported that epileptic seizures had a signicant impact on multiple sclerosis patients, and these ndings contributed to a deeper understanding of epileptic seizures in multiple sclerosis patients.
4.4.1.2 Epidemiology
The prevalence of epilepsy in multiple sclerosis patients varies widely. Drulovic J
[465] studied 326 patients with multiple sclerosis and reported that 127 of them
(38.0%) had seizures. Among the 361 patients with multiple sclerosis described by
Nurre ER [466], 74 (20.4%) had seizures. Sanchez M [467] reported that only
1.95% of patients with multiple sclerosis had epilepsy. A Ghezzi [468] described
2353 patients with multiple sclerosis, 40 of whom had seizures. The overall prevalence of epilepsy in multiple sclerosis patients is approximately 1.7% to 20%.
4.4.1.3 Relationship Between Multiple Sclerosis andEpilepsy
The prevalence of epilepsy in people with multiple sclerosis is 3–6 times greater
than that in the general population, but the relationship between the two is unclear.
To understand whether there is a causal relationship between multiple sclerosis and
epilepsy, Zuo H and Peng [469] used Mendelian randomization analysis and inverse
variance weighting as the main methods to study the relationship between multiple
sclerosis and epilepsy and found that there was an obvious causal relationship
between the two, which is consistent with the results of Ouyang J etal. [458] supporting a causal relationship between multiple sclerosis and epilepsy.
4.4.1.4 Clinical Features ofEpilepsy inMultiple Sclerosis Patients
Seizures inMultiple Sclerosis
The main characteristics of multiple sclerosis are the presence of multiple lesions in
the brain and the remission of recurrent disease, which are often accompanied by
paroxysmal symptoms, such as trigeminal neuralgia, paroxysmal dysarthria, and
seizures. To understand the characteristics of epilepsy in patients with multiple
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sclerosis, Nurre ER [466] described the results of a single-center retrospective
study, which revealed a high incidence of epilepsy in patients with multiple sclerosis. At the time of the seizure, most imaging studies can nd multiple focal points,
and EEG data also show that the patient has cortical dysfunction, mainly in the
temporal lobe. The authors suggested that the timing of seizures in multiple sclerosis varies according to the type of multiple sclerosis, and epilepsy is more likely to
occur in patients with progressive multiple sclerosis. Sanchez M [467] also conducted an observational retrospective study of multiple sclerosis patients and found
that 25 patients (18 women) had epilepsy, and most of these patients had brain
atrophy and cortical or paracortical lesions. There were no signicant differences in
disease activity, level of disability, or response to disease treatment between MS
patients with epilepsy and those without epilepsy, suggesting that the epilepsy
course in MS patients is benign.
Characteristics ofSeizures
① The time of seizure: Sokic DV [469] described 20 patients with multiple sclerosis
who had seizures. Among these patients, 4 had seizures 1–5years before the diagnosis of multiple sclerosis, 8 had seizures during the relapse period of multiple
sclerosis, 2 of whom had seizures as the only manifestation of recurrence, and 12
had seizures throughout the whole process. Among the 40 patients described by A
Ghezzi [468], 13 had epilepsy occurring before MS, 4 had both diseases occurring
simultaneously, and 23 had epilepsy occurring after MS onset. P Striano [471]
reported that 4.8% of 270 patients diagnosed with MS had seizures, 4 of whom had
seizures 1–2years after the MS diagnosis and 6 of whom had seizures 8–23years
after the MS diagnosis. Gurtubay [472] analyzed the clinical, EEG and neuroimaging results of epileptic seizures in 7 patients with multiple sclerosis and found that
epilepsy was the rst symptom in 2 patients. ② Seizure type: Among the 74 patients
described by Nurre ER [466], 12% had general tonic–clonic seizures, 68% had
focal seizures, and 13% had unclassied epileptic seizures. Most of the cases
described by Sokic DV [470] involved focal secondary generalized seizures, and 5
patients had status epilepticus. Striano [471] reported that most of the patients had
focal or focal secondary generalized seizures. Among the 7 patients described by G
Gurtubay [472], 2 had general seizures, 3 had partial sensory and/or motor seizures
and secondary general seizures, 1 had simple partial motor seizures, 2 had partially
complex seizures, and 1 had multiple seizure types. ③ EEG and magnetic resonance
ndings: Among the patients described by Sokic DV [470], 11 had abnormal EEG;
among the patients described by A Ghezzi [468], 11 had episodic discharge on
EEG, 15 showed theta and/or delta activity on EEG, and 14 had normal
EEG.Magnetic resonance imaging (MRI) was performed for 12 patients: 3 patients
had lesions adjacent to the cerebral cortex.
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
475
4.4.1.5 Treatment
In addition to the treatment of the primary disease, antiepileptic drugs should be
used in patients with seizures to control the seizures. Nurre ER etal. [466] suggest
that early use of antiepileptic drugs is benecial to patients, the specic drug selection is no different from general seizures, and that ASM selection can be determined
based on other symptomatic epilepsies.
4.4.1.6 Prognosis
Recent research indicates that seizures do not affect the prognoses of MS patients.
4.4.2 Seizures inAlzheimer’s Disease
Alzheimer’s disease and epilepsy are common neurological disorders in elderly
people. Neurodegenerative diseases, mostly Alzheimer’s disease, account for
approximately 10% of late-onset epilepsy patients over the age of 65. There is a
bidirectional association between Alzheimer’s disease and epilepsy. Epilepsy is a
risk factor for Alzheimer’s disease, and Alzheimer’s disease is also an independent
risk factor for epilepsy in elderly people [473].
4.4.2.1 Historical Evolution
AD was described very early. However, the relationship between AD and epilepsy
was described later. NAVILLE [474] rst noted the relationship between epileptic
seizures and AD in 1946. Dascalov D etal. [475] described epileptiform discharge
on the EEG of AD patients in 1969. In 1986, Gimenez-Roldan S [476] reported that
patients with AD had myoclonic and photosensitive seizures, suggesting that epilepsy might be an early manifestation of AD.Later, Paul LA [477] reported that AD
and epilepsy might share a common brain structure. In 1994, Mendez MF [478]
described a clinicopathological study of epileptic seizures in AD patients. In 2019,
Paudel YN [479] reported that the Tau protein may represent a common pathway
connecting AD and epilepsy. In 2023, Hautecloque-Raysz G [480] reported that
anti-seizure drugs may improve cognitive function in AD patients. Tombini M etal.
[481] reported that there may be a bidirectional relationship between epilepsy and
AD.Patients with AD are more likely to suffer from epilepsy, and patients with lateonset epilepsy also have a signicantly increased risk of suffering from AD, further
revealing the relationship between the two.
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4.4.2.2 Epidemiological Investigation
To understand the prevalence of epilepsy in AD patients, Xu Y etal. [482] conducted a study of 380,777AD patients and 727,446 epilepsy patients and reported
that the seizure rate in AD patients was 4.2–31.5 times/1000 people/year and that
the prevalence of epilepsy in clinically diagnosed AD patients was 1.5–12.7%. The
prevalence of epilepsy in pathologically conrmed AD patients was 16%, and the
younger the age of the patient, the greater the risk of seizures. Haoudy S etal. [483]
conducted a study on patients diagnosed with AD whose cerebrospinal uid examination showed positive AD markers and found that 40% of the patients had seizures.
Mendez M [484] found that the incidence of epilepsy in dementia patients varied
according to the cause of dementia. In Alzheimer’s disease, approximately 10–22%
of patients have had at least one seizure. In a cohort of 177 newly diagnosed AD
patients, Lozsadi DA [485] reported that 12 (6.8%) had a history of epilepsy and/or
were using antiepileptic drugs at the time of diagnosis. In his study on 937AD
patients, Cheng CH [486] reported that 44 (4.7%) had seizures. Hommet C etal.
[487] conducted a study on hospitalized AD patients and reported for the rst time
that 2.5% of AD patients were admitted to a hospital with epilepsy. Accordingly, the
prevalence of epilepsy in patients with AD ranges from 1.5% to 41.7%.
4.4.2.3 The Tau Hypothesis inAD andEpilepsy
Multiple studies have suggested a bidirectional link between these two common
neurodegenerative diseases. Compared with healthy subjects, patients with either
disease had almost twice the risk of contracting the other, suggesting a common
underlying mechanism between seizures and AD [488]. The bridge between them is
the tau protein. Tau is a microtubule-associated protein that binds and promotes the
assembly of microtubules in neurons under physiological conditions. However,
under pathological conditions, the accumulation of overphosphorylated tau proteins
can produce neurotoxicity, cause neurodegeneration, and lead to the occurrence of
Tau disease [489].
Tau protein is generally present in cells, but there is tau phosphorylation and
hyperphosphorylation in patients with AD. This phosphorylated tau protein is
released from the cell, leading to decreased neuronal stability and the formation of
AD in neurobrillary tangles. However, increased or excessive phosphorylation of
the tau protein can cause neuronal excitatory toxicity and cascade reactions, thus
destroying the balance between neuronal excitation and inhibition and leading to
epilepsy [481, 490]. Zawar I etal. [491] also suggested that gene mutation in AD
patients could increase the accumulation of tau protein, thus increasing the overexcitability of neurons, and that the overexcitability of neurons could increase the
secretion of tau and trigger epileptic seizures, which are speculated to be manifestations of AD.Alves SS [492] used animal experiments to support this view. This
group established an AD model by streptozotocin (STZ) induction and then stimulated it with high-frequency sound, resulting in seizures, and determined that AD
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
477
was the cause of the seizures. However, some people speculate that epilepsy itself is
a type of tau protein disease, and an increase in tau protein levels, especially of
excessive phosphorylation, can cause neuronal excitotoxicity and brain tissue damage through cascade reactions, thus causing the occurrence of AD.It is suggested
that AD is consistent with the cognitive function damage caused by repeated seizures in patients with epilepsy. Inhibition of neuronal excitotoxicity with antiepileptic drugs can improve the cognitive function of AD patients [490], and Rizzello E
[493] conrmed the hypothesis that epilepsy causes AD through animal experiments. They found that repeated seizures can selectively lead to memory decits
and an increase in oligaβ42 expression and bril types, which are important links in
the formation of AD.However, Ouyang J [458] used a Mendelian randomization
method to analyze the single nucleotide polymorphisms of AD and found no causal
relationship between AD and epilepsy, suggesting that epilepsy is more likely to be
a comorbidity of AD.This view is supported by the study of Haoudy S etal. [483],
who suggest that epilepsy is a comorbidity of AD, accounting for 40% of AD
patients. This view is also supported by Cretin B [494], who speculates that epilepsy
is an increasingly recognized comorbidity in AD.These studies support a bidirectional association between AD and epilepsy, as epilepsy is a risk factor for
Alzheimer’s disease, and in turn, Alzheimer’s disease is an independent risk factor
for epilepsy in older adults [494].
4.4.2.4 Clinical Characteristics ofSeizures inAD Patients
Types ofSeizures
Although the study by Haoudy S [483] on patients diagnosed with AD accompanied
by seizures showed that the main seizure types of patients were tonic clonus (25%),
temporal lobe epilepsy (25%), myoclonus (25%), focal extratemporal lobe epilepsy
(8%), and 17% unclassied epilepsy, Andras Horvath [495] monitored 42 patients
with AD accompanied by seizures with 24-h ambulatory EEG and found that most
patients’ seizures manifested as focal seizures without motor symptoms, 24% of
which needed to be conrmed by EEG.Seventy-two percent of patients presented
with focal seizures of unconsciousness disturbance, 55% did not have any motor
activity, and 28% had epileptiform discharges but no clinical seizures. Samudra N
etal. [496] also reported that this “subclinical epileptiform activity” is common in
AD patients, with prevalence estimates ranging from 22% to 54%, and Yang F etal.
[497] supported this view, suggesting that it is challenging to identify seizures in
AD patients. This type of seizure is usually clinically nonmotor and may overlap
with some AD symptoms. In addition to seizures, epileptiform discharges may also
exacerbate cognitive decline in people with AD, highlighting the importance of
early identication and treatment.
In addition, there are several special types of seizures in AD.In 2023, Lee HC
[498] described two cases of seizures in which aphasia status epileptica was the
only manifestation. Both patients had atypical epileptic EEGs, which improved
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after taking antiepileptic drugs. It is suggested that this type of seizure can occur at
any stage of AD, and signicant improvement in clinical symptoms and EEG after
treatment with antiepileptic drugs is the key to diagnosis.
Time ofOnset ofEpileptic Seizures inAD
Romanelli MF etal. [499] suggested that epileptic seizures generally occur in the
late stage of AD.Among the 44AD patients described, 7 had at least one documented seizure, and all 7AD patients had progressed to the severe stage of dementia when the rst seizure occurred. Mendez M etal. [484] also reported that 10–22%
of AD patients experienced seizures, but most of these seizures occurred in the late
stage of the disease, and the average course of epilepsy was 6years. Among the
937AD patients described by Cheng CH [485], 44 had seizures, most of which
occurred in the late stage of the disease. The average time from the diagnosis of AD
to the occurrence of seizures was 3.6years. However, the results of a study by
Lozsadi DA [485] do not support this view. They reported that 12 of the 177 newly
diagnosed AD patients in their cohort developed seizures, six of which occurred at
approximately the same time as cognitive decline, suggesting that while seizures are
more common later in the course of AD, they can also occur along with and are
symptoms of the disease and may reect a common pathogenesis. A study by Cretin
B [494] also revealed that epileptic seizures can occur in the early stage of AD.When
AD patients have only mild or subjective cognitive impairment, they may have generalized or focal epileptic seizures (usually located in the frontal or temporal lobes).
It has also been found that the rst symptom of AD is epilepsy, and these patients
do not develop cognitive dysfunction until many years after the seizure and are
ultimately diagnosed with AD.These studies suggest that seizures in patients with
AD may accompany the full course of AD.
Other Manifestations
Seizures in AD patients may manifest as subclinical electrical activity that may
cause neuronal necrosis and cognitive dysfunction. Hautecloque-Raysz G [480]
compared the cognitive function of AD patients with seizures and AD patients without seizures and found that AD patients with seizures had more obvious cognitive
dysfunction.
4.4.2.5 Diagnosis ofSeizures inAD
AD and epilepsy are common neurological disorders that are linked to and adversely
affect the quality of life of patients, making them serious public health problems.
The diagnosis of epilepsy in AD patients is a major challenge because seizures in
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
479
AD patients can manifest as subclinical electrical activity with no signicant motor
symptoms, and many of the manifestations overlap with the manifestations of AD.
Epileptic seizures in AD patients can manifest as focal seizures with no motor
symptoms or only subclinical electrical activity, so examination via electroencephalography, especially long-range electroencephalogram monitoring, is necessary.
Because seizures in AD patients are sensitive to anti-seizure drugs regardless of
whether they occur early or late in the disease, observing their response to antiseizure drugs can also aid in diagnosis.
4.4.2.6 Treatment
AD is a lifelong disease that cannot presently be treated, but seizure control can
effectively reduce impairment of cognitive function. Therefore, when AD patients
have seizures, the use of antiepileptic drugs is necessary, and antiepileptic drugs
targeting abnormal network overexcitation may also change the natural progression
of AD [488]. However, until now, there have been no guidelines for treating seizures
in people with AD due to a lack of randomized clinical trials sufcient to answer
relevant questions. Eduardo Cumbo etal. [500] conducted a prospective, randomized, three-group parallel case–control study to evaluate the effect of antiepileptic
drugs on epilepsy in AD patients. Among the patients, 38 took levetiracetam, 28
took phenobarbital, and 29 took lamotrigine; the results showed that there was no
signicant difference in the efcacy of the three AEDs. Levetiracetam causes fewer
adverse events than other AEDs and is associated with improved cognitive function,
which can be used to control seizures in patients with AD [501]. Moreover, animal
experiments have revealed that levetiracetam can reduce abnormal cortical discharge and reverse memory decits in Alzheimer’s disease mouse models and
improve memory difculties in patients with mild cognitive impairment; therefore,
levetiracetam is recommended for the rst time [502]. Filippo Sean Giorgi [503]
also suggested that newer antiepileptic drugs such as levetiracetam and lamotrigine
are good choices.
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